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  • Generation of an induced pluripotent stem cell line (SDQLCHi009-A) from a patient with 47,XXY and Ornithine Transcarbamylase Deficiency carrying a hemizygote mutation in OTC
    Stem Cell Res. (IF 3.929) Pub Date : 2020-01-17
    Xiaomeng Yang; Beibei Yan; Haiyan Zhang; Yanyan Ma; Qi Zhou; Yue Li; Jingyun Guan; Dong Wang; Yi Liu; Zhongtao Gai

    An induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells of a 3-day-old boy with 47,XXY and Ornithine Transcarbamylase Deficiency carrying hemizygote mutation (c.663+2T>G (sliping)) in OTC. The iPSCs had original 47,XXY, and mutation in OTC, expressing pluripotency markers and bearing differentiation potential in vitro.

    更新日期:2020-01-17
  • Generation of a Human iPSC line (SDQLCHi021-A) from a patient with methylmalonic acidemia cblC type carrying compound heterozygous mutations in MMACHC gene
    Stem Cell Res. (IF 3.929) Pub Date : 2020-01-16
    Jingyun Guan; Zilong Li; Haiyan Zhang; Xiaomeng Yang; Yanyan Ma; Yue Li; Rui Dong; Zhongtao Gai; Yi Liu

    Methylmalonic acidemia and homocystinuria, cblC type is a rare autosomal recessive inheritance disease. Its clinical phenotype involves multiple systems with varying degrees of severity. The disease is caused by the mutations in the MMACHC gene located on chromosome 1p34.1. Here we report the generation of an iPSC line from the PBMCs of a patient with compound heterozygous mutations in the MMACHC gene. This new iPSC line will allow a better understanding of the MMA disease.

    更新日期:2020-01-17
  • E3 ubiquitin ligase TRIM7 negatively regulates NF-kappa B signaling pathway by degrading p65 in lung cancer
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-17
    Jiangbo Jin; Zhuo Lu; Xiaomei Wang; Yufeng Liu; Tianyu Han; Yanan Wang; Tao Wang; Mingxi Gan; Caifeng Xie; Jianbin Wang; Bentong Yu

    The gene trim7 encodes at least four isoforms Glycogenin-interacting protein 1 (GNIP1), GNIP2, GNIP3 and Tripartite motif containing 7 (TRIM7). GNIP1, the longest isoform, has been reported acting as an oncogene. However, it is very interesting that TRIM7, the shortest isoform, only 15 amino acids different from GNIP1 in C-terminal, acts in a completely different way from that of GNIP1 in our present study. TRIM7 expression was decreased in tumor compared with adjacent normal tissues, and the level of TRIM7 was negatively correlated with clinical stage of 94 patients with lung cancer. In vitro, TRIM7 dramatically inhibited the proliferation and migration of tumor cells, and promoted cell apoptosis. Further study showed that TRIM7 interacted with p65 via its C-terminal which is different from GNIP1. The interaction between TRIM7 and p65 promoted the ubiquitination of p65 and finally accelerated the degradation of p65 via 26S proteasome. In vivo, the tumor volume and weight were decreased by TRIM7 stable expression. Meanwhile, Ki67 was down-regulated, thyroid transcription factor 1 (TTF-1) and Caspase 3 were up-regulated in TRIM7 overexpression group in xenograft model. It is very impressive that TRIM7t (a truncated TRIM7 without C-terminal sequence that different with GNIP1) had little effect on the tumor growth in vivo. These findings highlight a curious mechanism for negative regulation of NF-kappa B signaling pathway by TRIM7 and demonstrate that TRIM7 would be a potential therapeutic target for lung cancer.

    更新日期:2020-01-17
  • Role of oxygen and the HIF-pathway
    Cell. Signal. (IF 3.388) Pub Date : 2020-01-02
    Bjoern Buchholz; Kai-Uwe Eckardt

    Kidney cyst growth in ADPKD is associated with regional hypoxia, presumably due to a mismatch between enlarged cysts and the peritubular capillary blood supply and compression of peritubular capillaries in cyst walls. Regional hypoxia leads to activation of hypoxia-inducible transcription factors, with the two main HIF isoforms, HIF-1 and HIF-2 expressed in cyst epithelia and pericystic interstitial cells, respectively. While HIF-2 activation is linked to EPO production, mitigating the anemia that normally accompanies chronic kidney disease, HIF-1 promotes cyst growth. HIF-dependent cyst growth is primarily due to an increase in chloride-dependent fluid secretion into the cyst lumen. However, given the broad spectrum of HIF-target genes, additional HIF-mediated pathways may also contribute to cyst progression. Furthermore, hypoxia can influence cyst growth through the generation of reactive oxygen species. Since cyst expansion aggravates regional hypoxia, a feedforward loop is established that accelerates cyst expansion and disease progression. Inhibiting the HIF pathway and/or HIF target genes that are of particular relevance for HIF-dependent cyst fluid secretion may therefore represent novel therapeutic approaches to retard the progression of APDKD.

    更新日期:2020-01-17
  • Regulation of succinate dehydrogenase and role of succinate in cancer
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-01
    Elisa Dalla Pozza; Ilaria Dando; Raffaella Pacchiana; Elio Liboi; Maria Teresa Scupoli; Massimo Donadelli; Marta Palmieri

    Succinate dehydrogenase (SDH) has been classically considered a mitochondrial enzyme with the unique property to participate in both the citric acid cycle and the electron transport chain. However, in recent years, several studies have highlighted the role of the SDH substrate, i.e. succinate, in biological processes other than metabolism, tumorigenesis being the most remarkable. For this reason, SDH has now been defined a tumor suppressor and succinate an oncometabolite. In this review, we discuss recent findings regarding alterations in SDH activity leading to succinate accumulation, which include SDH mutations, regulation of mRNA expression, post-translational modifications and endogenous SDH inhibitors. Further, we report an extensive examination of the role of succinate in cancer development through the induction of epigenetic and metabolic alterations and the effects on epithelial to mesenchymal transition, cell migration and invasion, and angiogenesis. Finally, we have focused on succinate and SDH as diagnostic markers for cancers having altered SDH expression/activity.

    更新日期:2020-01-17
  • Fumarate hydratase in cancer: A multifaceted tumour suppressor
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    Christina Schmidt; Marco Sciacovelli; Christian Frezza

    Cancer is now considered a multifactorial disorder with different aetiologies and outcomes. Yet, all cancers share some common molecular features. Among these, the reprogramming of cellular metabolism has emerged as a key player in tumour initiation and progression. The finding that metabolic enzymes such as fumarate hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause cancer suggested that metabolic dysregulation is not only a consequence of oncogenic transformation but that it can act as cancer driver. However, the mechanisms underpinning the link between metabolic dysregulation and cancer remain only partially understood. In this review we discuss the role of FH loss in tumorigenesis, focusing on the role of fumarate as a key activator of a variety of oncogenic cascades. We also discuss how these alterations are integrated and converge towards common biological processes. This review highlights the complexity of the signals elicited by FH loss, describes that fumarate can act as a bona fide oncogenic event, and provides a compelling hypothesis of the stepwise neoplastic progression after FH loss.

    更新日期:2020-01-17
  • Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    José M. Matés; Floriana J. Di Paola; José A. Campos-Sandoval; Sybille Mazurek; Javier Márquez

    Metabolic reprogramming in cancer targets glutamine metabolism as a key mechanism to provide energy, biosynthetic precursors and redox requirements to allow the massive proliferation of tumor cells. Glutamine is also a signaling molecule involved in essential pathways regulated by oncogenes and tumor suppressor factors. Glutaminase isoenzymes are critical proteins to control glutaminolysis, a key metabolic pathway for cell proliferation and survival that directs neoplasms’ fate. Adaptive glutamine metabolism can be altered by different metabolic therapies, including the use of specific allosteric inhibitors of glutaminase that can evoke synergistic effects for the therapy of cancer patients. We also review other clinical applications of in vivo assessment of glutaminolysis by metabolomic approaches, including diagnosis and monitoring of cancer.

    更新日期:2020-01-17
  • Stromal-induced mitochondrial re-education: Impact on epithelial-to-mesenchymal transition and cancer aggressiveness
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    Marina Bacci; Luigi Ippolito; Lucia Magnelli; Elisa Giannoni; Paola Chiarugi

    Metabolic reprogramming as well as the flexible utilisation of fuel sources by tumour cells has been considered not only intrinsic to malignant cells but also sustained by resident and/or recruited stromal cells. The complexity of tumour-stroma cross-talk is experienced by neoplastic cells through profound changes in the own metabolic machinery. In such context, mitochondria are dynamic organelles that receive, orchestrate and exchange a multiplicity of stromal cues within the tumour cells to finely regulate key metabolic and signalling pathways, allowing malignant cells to adapt and thrive in an ever-changing environment. In this review, we focus on how tumour mitochondria are coached by stromal metabolic supply and how this re-education sustains tumour malignant traits.

    更新日期:2020-01-17
  • Mitochondrial metabolism: Inducer or therapeutic target in tumor immune-resistance?
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-18
    Joanna Kopecka; Elena Gazzano; Barbara Castella; Iris C. Salaroglio; Eleonora Mungo; Massimo Massaia; Chiara Riganti

    Mitochondria have been considered for a long time only as the principal source of building blocks and energy upon aerobic conditions. Recently they emerged as key players in cell proliferation, invasion and resistance to therapy. The most aggressive tumors are able to evade the immune-surveillance. Alterations in the mitochondria metabolism either in cancer cells or in host immune system cells are involved in such tumor-induced immune-suppression. This review will focus on the main mitochondrial dysfunctions in tumor and immune cell populations determining immune-resistance, and on the therapies that may target mitochondrial metabolism and restore a powerful anti-tumor immune-activity.

    更新日期:2020-01-17
  • The multifaceted effects of metformin on tumor microenvironment
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    Ivana Kurelac; Nikkitha Umesh Ganesh; Maria Iorio; Anna Maria Porcelli; Giuseppe Gasparre

    The efficacy of metformin in treating cancer has been extensively investigated since epidemiologic studies associated this anti-diabetic drug with a lower risk of cancer incidence. Since tumors are complex systems, in which cancer cells coexist and interact with several different types of non-malignant cells, it is not surprising that anti-cancer drugs affect not only cancer cells, but also the abundance and functions of cells of the tumor microenvironment. Recent years have seen a wide collection of reports showing how metformin, as well as other complex I inhibitors, may influence cancer progression by modulating the phenotype of non-transformed cells in a tumor. In this review, we particularly focus on the effect of metformin on angiogenesis, cancer-associated fibroblasts, tumor-associated macrophages and cancer immunosuppression.

    更新日期:2020-01-17
  • Wild type- and mutant p53 proteins in mitochondrial dysfunction: emerging insights in cancer disease
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-23
    Giovanni Blandino; Fabio Valenti; Andrea Sacconi; Silvia Di Agostino

    Deregulated cell metabolism is one of the cancer hallmarks. Mitochondrial DNA mutations and enzyme defects, aberrant tumor suppressor or oncogenic activities cause mitochondrial dysfunction leading to deregulated cellular energetics. The tumor suppressor protein, p53 is a tetrameric transcription factor that in response to diverse genotoxic and non-genotoxic insults activates a plethora of target genes to preserve genome integrity. In the last two decades the discovery of cytoplasmic p53 localization focused intense research on its extra-nuclear functions. The ability of p53 to induce apoptosis acting directly at mitochondria and the related mechanisms of p53 localization and translocation in the cytoplasm have been investigated. A role of cytoplasmic p53 in autophagy, pentose phosphate pathway, fatty acid synthesis and oxidation, and drug response has been proposed. TP53 gene is mutated in more than half of human cancers. In parallel to loss of tumor suppressive functions, mutant p53 proteins often gain new tumorigenic activities (GOF, gain of function). It has been recently shown that mutant p53 proteins mediate metabolic changes thereby promoting cancer development and metastases. Here we review the contribution of either wild-type p53 or mutant p53 proteins to the fine-tuning of mitochondrial metabolism of both normal and cancer cells. Greater knowledge at the mechanistic level might provide insights to develop new cancer therapeutic approaches.

    更新日期:2020-01-17
  • Interorganellar calcium signaling in the regulation of cell metabolism: A cancer perspective
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-24
    Alessandro Rimessi; Gaia Pedriali; Bianca Vezzani; Anna Tarocco; Saverio Marchi; Mariusz R. Wieckowski; Carlotta Giorgi; Paolo Pinton

    Organelles were originally considered to be individual cellular compartments with a defined organization and function. However, recent studies revealed that organelles deeply communicate within each other via Ca2+ exchange. This communication, mediated by specialized membrane regions in close apposition between two organelles, regulate cellular functions, including metabolism and cell fate decisions. Advances in microscopy techniques, molecular biology and biochemistry have increased our understanding of these interorganelle platforms. Research findings suggest that interorganellar Ca2+ signaling, which is altered in cancer, influences tumorigenesis and tumor progression by controlling cell death programs and metabolism. Here, we summarize the available data on the existence and composition of interorganelle platforms connecting the endoplasmic reticulum with mitochondria, the plasma membrane, or endolysosomes. Finally, we provide a timely overview of the potential function of interorganellar Ca2+ signaling in maintaining cellular homeostasis.

    更新日期:2020-01-17
  • Reconciling environment-mediated metabolic heterogeneity with the oncogene-driven cancer paradigm in precision oncology
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    Catherine Vander Linden; Cyril Corbet

    Precision oncology is the practice of matching one therapy to one specific patient, based on particular genetic tumor alterations, in order to achieve the best clinical response. Despite an expanding arsenal of targeted therapies, many patients still have a poor outcome because tumor cells show a remarkable capacity to develop drug resistance, thereby leading to tumor relapse. Besides genotype-driven resistance mechanisms, tumor microenvironment (TME) peculiarities strongly contribute to generate an intratumoral phenotypic heterogeneity that affects disease progression and treatment outcome. In this Review, we describe how TME-mediated metabolic heterogeneities actively participate to therapeutic failure. We report how a lactate-based metabolic symbiosis acts as a mechanism of adaptive resistance to targeted therapies and we describe the role of mitochondrial metabolism, in particular oxidative phosphorylation (OXPHOS), to support the growth and survival of therapy-resistant tumor cells in a variety of cancers. Finally, we detail potential metabolism-interfering therapeutic strategies aiming to eradicate OXPHOS-dependent relapse-sustaining malignant cells and we discuss relevant (pre)clinical models that may help integrate TME-driven metabolic heterogeneity in precision oncology.

    更新日期:2020-01-17
  • Targeting metabolic reprogramming in metastatic melanoma: The key role of nicotinamide phosphoribosyltransferase (NAMPT)
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-14
    Valentina Audrito; Antonella Managò; Federica Gaudino; Silvia Deaglio

    Cancer cells rewire their metabolism to support proliferation, growth and survival. In metastatic melanoma the BRAF oncogenic pathway is a master regulator of this process, highlighting the importance of metabolic reprogramming in the pathogenesis of this tumor and offering potential therapeutic approaches. Metabolic adaptation of melanoma cells generally requires increased amounts of NAD+, an essential redox cofactor in cellular metabolism and a signaling molecule. Nicotinamide phosphoribosyltransferase (NAMPT) is the most important NAD+ biosynthetic enzyme in mammalian cells and a direct target of the BRAF oncogenic signaling pathway. These findings suggest that NAMPT is an attractive new therapeutic target, particularly in combination strategies with BRAF or MEK inhibitors. Here we review current knowledge on how oncogenic signaling reprograms metabolism in BRAF-mutated melanoma, and discuss how NAMPT/NAD+ axis contributes to these processes. Lastly, we present evidence supporting a role of NAMPT as a novel therapeutic target in metastatic melanoma.

    更新日期:2020-01-17
  • Synovial fibroblasts and articular tissue remodelling: Role and mechanisms
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2020-01-16
    Thomas Pap; Berno Dankbar; Corinna Wehmeyer; Adelheid Korb-Pap; Joanna Sherwood

    Synovial joints are unique functional elements of the body and provide the ability for locomotion and for physical interaction with the environment. They are composed of different connective tissue structures, of which the synovial membrane is one central component. It shows a number of peculiarities that makes it different from other membranes in our body, while several lines of evidence suggest that synovial fibroblasts, also termed fibroblast-like synoviocytes (FLS) critically contribute to these peculiarities. This becomes evident particularly under disease conditions such as in rheumatoid arthritis and osteoarthritis, where the synovium is a key pathophysiological component. Therefore, an in-depth knowledge of FLS biology is not only important for understanding key features of articular function but also provides explanations for important characteristics of both degenerative and inflammatory joint diseases. This article reviews the structure, biochemical composition and functions of the synovial membrane and by focusing on the role of synovial fibroblasts explains key features of articular tissue remodelling particularly under disease conditions.

    更新日期:2020-01-17
  • Enhancing Hematopoiesis from Murine Embryonic Stem Cells through MLL1-Induced Activation of a Rac/Rho/Integrin Signaling Axis
    Stem. Cell Rep. (IF 5.499) Pub Date : 2020-01-16
    Weiwei Yang; G. Devon Trahan; Elizabeth D. Howell; Nancy A. Speck; Kenneth L. Jones; Austin E. Gillen; Kent Riemondy; Jay Hesselberth; David Bryder; Patricia Ernst
    更新日期:2020-01-17
  • Trophoblast cell differentiation in the bovine placenta: differentially expressed genes between uninucleate trophoblast cells and trophoblast giant cells are involved in the composition and remodeling of the extracellular matrix and O-glycan biosynthesis
    BMC Mol. Cell Biol. (IF 0) Pub Date : 2020-01-17
    Marina Polei; Juliane Günther; Dirk Koczan; Rainer Fürbass

    In the bovine placenta, intimate fetomaternal contacts are restricted to discrete placentomes. Here, widely branched fetal chorionic villi interdigitate with corresponding maternal caruncular crypts. The fetal trophoblast epithelium covering the chorionic villi consists of approximately 80% uninucleate trophoblast cells (UTCs) and 20% binuclear trophoblast giant cells (TGCs). The weakly invasive TGCs migrate toward the caruncle epithelium and eventually fuse with individual epithelial cells to form short-lived fetomaternal hybrid cells. In this way, molecules of fetal origin are transported across the placental barrier and released into the maternal compartment. The UTC/TGC ratio in the trophoblast remains almost constant because approximately as many new TGCs are produced from UTCs as are consumed by the fusions. The process of developing TGCs from UTCs was insufficiently understood. Therefore, we aimed to detect differentially expressed genes (DEGs) between UTCs and TGCs and identify molecular functions and biological processes regulated by DEGs. We analyzed gene expression patterns in virtually pure UTC and TGC isolates using gene arrays and detected 3193 DEGs (p < 0.05; fold change values < − 1.5 or > 1.5). Of these DEGs, 1711 (53.6%) were upregulated in TGCs and 1482 (46.4%) downregulated. Gene Ontology (GO) analyses revealed that molecular functions and biological processes regulated by DEGs are related to the extracellular matrix (ECM) and its interactions with cellular receptors, cell migration and signal transduction. Furthermore, there was some evidence that O-glycan biosynthesis in TGCs may produce sialylated short-chain O-glycans (Tn antigen, core 1 O-glycans), while the synthesis of other O-glycan core structures required for the formation of complex (i.e., branched and long-chain) O-glycans appears to be decreased in TGCs. The differentiation of UTCs into TGCs particularly regulates genes that enable trophoblast cells to interact with their environment. Significant differences between UTCs and TGCs in ECM composition indicate reduced anchoring of TGCs in the surrounding matrix, which might contribute to their migration and their weakly invasive interaction with the maternal endometrium. Furthermore, increased expression of sialylated short chain O-glycans by TGCs could facilitate the modulation of maternal immune tolerance.

    更新日期:2020-01-17
  • Cyclic dinucleotides at the forefront of innate immunity
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2020-01-17
    Shivam A. Zaver; Joshua J. Woodward

    Cyclic dinucleotides (CDNs) have emerged as ubiquitous signaling molecules in all domains of life. In eukaryotes, CDN signaling systems are evolutionarily ancient and have developed to sense and respond to pathogen infection. On the other hand, dysregulation of these pathways has been implicated in the pathogenesis of autoimmune diseases. Thus, CDNs have garnered major interest over recent years for their ability to elicit potent immune responses in the eukaryotic host. Similarly, ancestral CDN-based signaling systems also appear to confer immunological protection against infection in prokaryotes. Therefore, a better understanding of the host processes regulated by CDNs will be of tremendous value in many areas of research. Here, we aim to review the latest discoveries and recent trends in CDN research with a particular focus on the molecular mechanisms by which these small molecules mediate innate immunity.

    更新日期:2020-01-17
  • A Dimeric Structural Scaffold for PRC2-PCL Targeting to CpG Island Chromatin
    Mol. Cell (IF 14.548) Pub Date : 2020-01-17
    Siming Chen; Lianying Jiao; Xiuli Liu; Xin Yang; Xin Liu
    更新日期:2020-01-17
  • Novel signaling aspects of ceramide 1-phosphate
    BBA Mol. Cell Biol. Lipids (IF 4.402) Pub Date : 2020-01-17
    Natalia Presa; Ana Gomez-Larrauri; Asier Dominguez-Herrera; Miguel Trueba; Antonio Gomez-Muñoz

    The bioactive sphingolipid ceramide 1-phosphate (C1P) regulates key physiologic cell functions and is implicated in a number of metabolic alterations and pathological processes. Initial studies using different types of fibroblasts and monocytes/macrophages revealed that C1P was mitogenic and that it promoted cell survival through inhibition of apoptosis. Subsequent studies implicated C1P in inflammatory responses with a specific role as pro-inflammatory agent. Specifically, C1P potently stimulated cytosolic phospholipase A2 (cPLA2) resulting in elevation of arachidonic acid and pro-inflammatory eicosanoid levels. However, increasing experimental evidence suggests that C1P can also exert anti-inflammatory actions in some cell types and tissues. Specifically, it has been demonstrated that C1P inhibits the release of pro-inflammatory cytokines and blocks activation of the pro-inflammatory transcription factor NF-κB in some cell types. Moreover, C1P was shown to increase the release of anti-inflammatory interleukin-10 in macrophages, and to overcome airway inflammation and reduce lung emphysema in vivo. Noteworthy, C1P stimulated cell migration, an action that is associated with diverse physiological cell functions, as well as with inflammatory responses and tumor dissemination. More recently, ceramide kinase (CerK), the enzyme that produces C1P in mammalian cells, has been shown to be upregulated during differentiation of pre-adipocytes into mature adipocytes, and that exogenous C1P, acting through a putative Gi protein-coupled receptor, negatively regulates adipogenesis. Although the latter actions seem to be contradictory, it is plausible that exogenous C1P may balance the adipogenic effects of intracellularly generated (CerK-derived) C1P in adipose tissue. The present review highlights novel signaling aspects of C1P and its impact in the regulation of cell growth and survival, inflammation and tumor dissemination.

    更新日期:2020-01-17
  • circRNA-002178 act as a ceRNA to promote PDL1/PD1 expression in lung adenocarcinoma
    Cell Death Dis. (IF 5.959) Pub Date : 2020-01-16
    JunFeng Wang; XuHai Zhao; YanBo Wang; FengHai Ren; DaWei Sun; YuBo Yan; XiangLong Kong; JianLong Bu; MengFeng Liu; ShiDong Xu
    更新日期:2020-01-17
  • 更新日期:2020-01-17
  • ADT-OH, a hydrogen sulfide-releasing donor, induces apoptosis and inhibits the development of melanoma in vivo by upregulating FADD
    Cell Death Dis. (IF 5.959) Pub Date : 2020-01-16
    Fangfang Cai; Huangru Xu; Nini Cao; Xiangyu Zhang; Jia Liu; Yanyan Lu; Jia Chen; Yunwen Yang; Jian Cheng; Zi-Chun Hua; Hongqin Zhuang
    更新日期:2020-01-17
  • Utility of the immunohistochemical analysis of DNA mismatch-repair proteins in endometrial hyperplasia
    Acta Histochem. (IF 1.719) Pub Date : 2020-01-17
    Nabiha Missaoui; Nesrine Boukhari; Sarra Limam; Sihem Hmissa; Moncef Mokni

    The utility of the expression lack of DNA mismatch-repair (MMR) proteins in the detection of Lynch syndrome in endometrial hyperplasia as precursor lesion of endometrial carcinoma has not been well-established. The study investigated the immunoexpression pattern of MMR proteins in endometrial hyperplasia from Tunisian patients. We carried out a retrospective study of 60 endometrial hyperplasias diagnosed among Tunisian patients. Expression of MLH1, MSH2, MSH6, and PMS2 proteins was performed by immunohistochemistry on whole-slide sections of archival tissues. Analysis of MLH1 promoter methylation and microsatellite alterations was conducted in appropriate cases. Microsatellite instability screening was assessed using the Bethesda panel, including BAT25, BAT26, D17S250, D2S123, and D5S346 markers. Expression of MMR proteins was observed in all hyperplasias without atypia as well as in 27 out of 29 atypical hyperplasias. Only two atypical hyperplasias exhibited expression loss of MMR proteins. A single case revealed MSH6 expression lack. Expression loss of MLH1 and PMS2 was identified in another atypical hyperplasia and was associated with hypermethylation of MLH1 promoter. This patient had no familial history of endometrial cancer at the diagnostic time. The two deficient MMR cases showed microsatellite stable pattern. In conclusion, only two endometrial hyperplasias displayed an altered pattern of MMR expression. Our results suggest the limited utility of the immunohistochemical analysis of MMR protein in the early detection of Lynch syndrome in Tunisian patients diagnosed with endometrial hyperplasias. Multicenter studies with larger sample size are needed to more explore these findings.

    更新日期:2020-01-17
  • Eicosapentaenoic and docosapentaenoic acids lessen the expression of PPARγ/Cidec affecting adipogenesis in cultured 3T3-L1 adipocytes
    Acta Histochem. (IF 1.719) Pub Date : 2020-01-17
    Fabiane Ferreira Martins; Marcia Barbosa Aguila; Carlos Alberto Mandarim-de-Lacerda

    Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have benefits in the metabolism of adipose tissue. However, its contribution to the adipogenesis is not entirely elucidated. The study aimed to evaluate the effects of EPA and DHA on adipogenesis, especially in the PPARγ (peroxisome proliferator-activated receptor-gamma) and Cidec (cell death-inducing DFFA-like effector c) pathway. Twenty-four hours after confluence, 3T3-L1 adipocytes were treated with EPA (100 μM), DHA (50μM) and EPA (100μM) + DHA (50μM) and at the end of differentiation (day 11) the cells were collected for analysis. Cell viability analysis indicated that the concentrations used for EPA and DHA did not cause cytotoxicity in cultured 3T3l1 adipocytes. The treatments have lessened the triacylglycerol accumulation in the adipocyte cytoplasm that, compared to the control group, were EPA-32%, DHA-38%, EPA + DHA −24%. The double-labeling immunofluorescence showed a signal attenuation of protein expressions of PPARγ, CIDEC, and SREBP-1c (sterol regulatory element-binding protein). EPA and DHA had a significant impact on the expression of cleaved CASPASE 3, which increases cell apoptosis and gene expressions of Pparγ and Cidec in the treated groups. Also, there was a reduction of C/ebpα (CCAAT/enhancer-binding protein alpha), Cd36 (cluster differentiation 36), and Foxo1 (forkhead box O). In conclusion, the study determined the ability of both EPA and DHA, alone or combined, in the adipogenesis modulation in cultured 3T3-L1 adipocytes, affecting the cell differentiation, maturation, and consequently, reducing adipogenesis via PPARγ-CIDEC suppression.

    更新日期:2020-01-17
  • Differences in the expression of catecholamine-synthesizing enzymes between vesicular monoamine transporter 1- and 2-immunoreactive glomus cells in the rat carotid body
    Acta Histochem. (IF 1.719) Pub Date : 2020-01-16
    Kouki Kato; Takuya Yokoyama; Tatsumi Kusakabe; Katsuhiko Hata; Seigo Fushuku; Nobuaki Nakamuta; Yoshio Yamamoto

    Vesicular monoamine transporters (VMAT) 1 and 2 are responsible for monoamine transportation into secretary vesicles and are tissue-specifically expressed in central and peripheral monoaminergic tissues, including the carotid body (CB). The aim of the present study was to examine the expression of catecholamine-synthesizing enzymes in VMAT1- and VMAT2-immunoreactive glomus cells in the rat CB using multiple immunolabeling. The expression of VMAT1 and VMAT2 mRNA in the CB was confirmed by RT-PCR. Immunohistochemistry revealed that VMAT1 immunoreactivity was predominant in glomus cells rather than VMAT2 immunoreactivity. Glomus cells with VMAT1 immunoreactivity exhibited weak/negative VMAT2 immunoreactivity, and vice versa. Immunoreactivities for VMAT1 and tyrosine hydroxylase, the rate-limiting enzyme for catecholamine biosynthesis, were co-localized in the same glomus cells and a positive correlation was confirmed between the two immunoreactivities (Spearman’s coefficient = 0.82; p < 0.05). Although some glomus cells showed co-localization of VMAT2 and dopamine β-hydroxylase immunoreactivity, the biosynthetic enzyme for noradrenaline, VMAT2 immunoreactivity appeared to be less associated with both catecholamine-synthesizing enzymes as indicated by a correlation analysis (TH: Spearman’s coefficient = 0.38, DBH: Spearman’s coefficient = 0.26). These results indicate that heterogeneity on functional role would exist among glomus cells in terms of VMAT isoform and catecholamine-synthesizing enzymes expression.

    更新日期:2020-01-17
  • 更新日期:2020-01-17
  • Integrin αvβ5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy
    Cell Rep. (IF 7.815) Pub Date : 2020-01-16
    Shaobo Wang; Qiong Zhang; Shashi Kant Tiwari; Gianluigi Lichinchi; Edwin H. Yau; Hui Hui; Wanyu Li; Frank Furnari; Tariq M. Rana
    更新日期:2020-01-17
  • Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding
    Cell Metab. (IF 22.415) Pub Date : 2020-01-16
    Wenwen Cheng; Ian Gonzalez; Warren Pan; Anthony H. Tsang; Jessica Adams; Ermelinda Ndoka; Desiree Gordian; Basma Khoury; Karen Roelofs; Simon S. Evers; Andrew MacKinnon; Shuangcheng Wu; Henriette Frikke-Schmidt; Jonathan N. Flak; James L. Trevaskis; Christopher J. Rhodes; So-ichiro Fukada; Randy J. Seeley; Martin G. Myers
    更新日期:2020-01-17
  • Tissue-Engineered Vascular Grafts with Advanced Mechanical Strength from Human iPSCs
    Cell Stem Cell (IF 21.464) Pub Date : 2020-01-16
    Jiesi Luo; Lingfeng Qin; Liping Zhao; Liqiong Gui; Matthew W. Ellis; Yan Huang; Mehmet H. Kural; J. Alexander Clark; Shun Ono; Juan Wang; Yifan Yuan; Shang-Min Zhang; Xiaoqiang Cong; Guangxin Li; Muhammad Riaz; Colleen Lopez; Akitsu Hotta; Stuart Campbell; Yibing Qyang
    更新日期:2020-01-17
  • Self-Organizing 3D Human Trunk Neuromuscular Organoids
    Cell Stem Cell (IF 21.464) Pub Date : 2020-01-16
    Jorge-Miguel Faustino Martins; Cornelius Fischer; Alessia Urzi; Ramon Vidal; Severine Kunz; Pierre-Louis Ruffault; Loreen Kabuss; Iris Hube; Elisabeta Gazzerro; Carmen Birchmeier; Simone Spuler; Sascha Sauer; Mina Gouti
    更新日期:2020-01-17
  • Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis
    Cell Stem Cell (IF 21.464) Pub Date : 2020-01-16
    Zhe Zhu; Pinar Mesci; Jean A. Bernatchez; Ryan C. Gimple; Xiuxing Wang; Simon T. Schafer; Hiromi I. Wettersten; Sungjun Beck; Alex E. Clark; Qiulian Wu; Briana C. Prager; Leo J.Y. Kim; Rekha Dhanwani; Sonia Sharma; Alexandra Garancher; Sara M. Weis; Stephen C. Mack; Priscilla D. Negraes; Jeremy N. Rich
    更新日期:2020-01-17
  • Identification of a Master Regulator of Differentiation in Toxoplasma
    Cell (IF 36.216) Pub Date : 2020-01-16
    Benjamin S. Waldman; Dominic Schwarz; Marc H. Wadsworth; Jeroen P. Saeij; Alex K. Shalek; Sebastian Lourido
    更新日期:2020-01-17
  • Evolutionary Persistence of DNA Methylation for Millions of Years after Ancient Loss of a De Novo Methyltransferase
    Cell (IF 36.216) Pub Date : 2020-01-16
    Sandra Catania; Phillip A. Dumesic; Harold Pimentel; Ammar Nasif; Caitlin I. Stoddard; Jordan E. Burke; Jolene K. Diedrich; Sophie Cook; Terrance Shea; Elizabeth Geinger; Robert Lintner; John R. Yates; Petra Hajkova; Geeta J. Narlikar; Christina A. Cuomo; Jonathan K. Pritchard; Hiten D. Madhani
    更新日期:2020-01-17
  • Cell-Surface Proteomic Profiling in the Fly Brain Uncovers Wiring Regulators
    Cell (IF 36.216) Pub Date : 2020-01-16
    Jiefu Li; Shuo Han; Hongjie Li; Namrata D. Udeshi; Tanya Svinkina; D.R. Mani; Chuanyun Xu; Ricardo Guajardo; Qijing Xie; Tongchao Li; David J. Luginbuhl; Bing Wu; Colleen N. McLaughlin; Anthony Xie; Pornchai Kaewsapsak; Stephen R. Quake; Steven A. Carr; Alice Y. Ting; Liqun Luo
    更新日期:2020-01-17
  • Cerebellar Neurodynamics Predict Decision Timing and Outcome on the Single-Trial Level
    Cell (IF 36.216) Pub Date : 2020-01-16
    Qian Lin; Jason Manley; Magdalena Helmreich; Friederike Schlumm; Jennifer M. Li; Drew N. Robson; Florian Engert; Alexander Schier; Tobias Nöbauer; Alipasha Vaziri
    更新日期:2020-01-17
  • Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery
    Cell (IF 36.216) Pub Date : 2020-01-16
    George M. Burslem; Craig M. Crews

    New biological tools provide new techniques to probe fundamental biological processes. Here we describe the burgeoning field of proteolysis-targeting chimeras (PROTACs), which are capable of modulating protein concentrations at a post-translational level by co-opting the ubiquitin-proteasome system. We describe the PROTAC technology and its application to drug discovery and provide examples where PROTACs have enabled novel biological insights. Furthermore, we provide a workflow for PROTAC development and use and discuss the benefits and issues associated with PROTACs. Finally, we compare PROTAC-mediated protein-level modulation with other technologies, such as RNAi and genome editing.

    更新日期:2020-01-17
  • Cryo-EM Reveals Integrin-Mediated TGF-β Activation without Release from Latent TGF-β
    Cell (IF 36.216) Pub Date : 2020-01-16
    Melody G. Campbell; Anthony Cormier; Saburo Ito; Robert I. Seed; Andrew J. Bondesson; Jianlong Lou; James D. Marks; Jody L. Baron; Yifan Cheng; Stephen L. Nishimura
    更新日期:2020-01-17
  • Transferrin: a blood coagulation modifier
    Cell Res. (IF 17.848) Pub Date : 2020-01-17
    Alvin H. Schmaier
    更新日期:2020-01-17
  • New myotonic dystrophy type 1 mouse model
    Cell Res. (IF 17.848) Pub Date : 2020-01-17
    Yunping Lei; Richard H. Finnell
    更新日期:2020-01-17
  • The mRNA-based reprogramming of fibroblasts from a SOD1E101G familial amyotrophic lateral sclerosis patient to induced pluripotent stem cell line UOWi007
    Stem Cell Res. (IF 3.929) Pub Date : 2020-01-16
    Rachelle Balez; Tracey Berg; Monique Bax; Sonia Sanz Muñoz; Mauricio C. Cabral-da-Silva; Martin Engel; Dzung Do-Ha; Claire H. Stevens; Dominic Rowe; Shu Yang; Ian P. Blair; Lezanne Ooi

    Dermal fibroblasts were donated by a 43 year old male patient with clinically diagnosed familial amyotrophic lateral sclerosis (ALS), carrying the SOD1E101G mutation. The induced pluripotent stem cell (iPSC) line UOWi007-A was generated using repeated mRNA transfections for pluripotency transcription factors Oct4, Klf4, Sox2, c-Myc, Lin28 and Nanog. The iPSCs carried the SOD1E101G genotype and had a normal karyotype, expressed expected pluripotency markers and were capable of in vitro differentiation into endodermal, mesodermal and ectodermal lineages. This iPSC line may be useful for investigating familial ALS resulting from a SOD1 E101G mutation.

    更新日期:2020-01-16
  • CD44 variant 6 is associated with prostate cancer growth and chemo-/radiotherapy response in vivo
    Exp. Cell Res. (IF 3.329) Pub Date : 2020-01-16
    Jie Ni; Belamy B. Cheung; Julia Beretov; Wei Duan; Joseph Bucci; David Malouf; Peter Graham; Yong Li

    We have previously demonstrated that CD44 variant 6 (CD44v6) is associated with prostate cancer (CaP) growth and therapeutic resistance in vitro, however, the role of CD44v6 in CaP in vivo is not fully understood. The purpose of this study is to investigate the effect of CD44v6 on CaP growth and chemo−/radiotherapy response in NOD/SCID mouse models in vivo and to validate its role as a therapeutic target for CaP therapy. CD44v6 was knocked down in PC-3M CaP cell line using short hairpin RNA. Subcutaneous (s.c.) and orthotopic CaP mouse xenografts were established. The effect of CD44v6 knockdown (KD) on tumour growth was evaluated on both s.c. and orthotopic models. Chemo−/radiotherapy response was evaluated on the s.c. model. Association of CD44v6 with PI3K/Akt pathway was validated using immunohistochemistry staining. We found that KD of CD44v6 significantly reduced tumour growth in both models, and enhanced the sensitivity of tumours to chemotherapy and radiotherapy in the s.c. model. In addition, we demonstrated that KD of CD44v6 is associated with downregulation of the PI3K/Akt/mTOR pathway. Our data confirm that CaP growth and chemo−/radiosensitivity in vivo is associated with CD44v6, which holds great promises as a therapeutic target in the treatment of CaP.

    更新日期:2020-01-16
  • Dynamics of cardiomyocyte and muscle stem cell proliferation in pig
    Exp. Cell Res. (IF 3.329) Pub Date : 2020-01-16
    Binxu Yin; Hongyan Ren; Hao Cai; Yunqi Jiang; Shuhong Zhao; Heng Wang

    The cardiac and skeletal muscle tissues are both striated and contractile but their intrinsic cellular properties are distinct. The minimal cardiomyocyte proliferation and the lack of cardiac stem cells directly leads to poor heart repair in adult. But in skeletal muscle, the robust proliferation of widespread muscle stem cells support efficient muscle regeneration. The endogenous cardiomyocyte and muscle stem cell proliferation has been analyzed in common laboratory animals but not in large mammals including pigs, which are more comparable to human. In this study, we rigorously examined the cell cycle dynamics of porcine cardiomyocytes and muscle stem cells through different developmental stages. Proliferative cardiomyocytes and muscle stem cells were broadly observed in the embryonic heart and limb muscle respectively. Muscle stem cells continue to proliferate postnatally but cardiomyocyte proliferation was drastically reduced after birth. However, robust cardiac cell cycle activity was detected around postnatal day 20, which could be attributed to the binucleation but not cell division. Increased proliferating cells were detected in maternal heart during early pregnancy but they represent non-cardiomyocyte cell types. The islet1 expressing cells were only identified in the embryonic and new born porcine hearts. Furthermore, the accumulated oxidative DNA damage in the cardiac but not skeletal muscle during development could be responsible for the diminished cardiomyocyte proliferation in adult pig. Similarities and differences in the proliferation of heart and skeletal muscle cells are identified in pigs across different developmental stages. Such cellular proliferative features must be taken into account when using porcine models for cardiovascular and muscular research.

    更新日期:2020-01-16
  • Unveiling the transcriptome alteration of POMC neuron in diet-induced obesity
    Exp. Cell Res. (IF 3.329) Pub Date : 2020-01-16
    Peng Lyu; Zhishun Huang; Qingjun Feng; Yongfu Su; Mengying Zheng; Yannv Hong; Xiang Cai; Zhonglei Lu

    Loss of neuron homeostasis in the arcuate nucleus (ARC) is responsible for diet-induced-obesity (DIO). We previously reported that loss of Rb1 gene compromised the homeostasis of anorexigenic POMC neurons in ARC and induced obesity in mice. To evaluate the development of DIO, we propose to analyze the transcriptomic alteration of POMC neurons in mice following high fat diet (HFD) feeding. We isolated these neurons from established DIO mice and performed transcriptomic profiling using RNA-seq. In total, 1066 genes (628 upregulated and 438 downregulated) were identified as differentially expressed genes (DEGs). Pathway enrichment analysis with these DEGs further revealed that “cell cycle,” “apoptosis,” “chemokine signaling,” and “sphingolipid metabolism” pathways were correlated with DIO development. Moreover, we validated that the pRb protein, a key regulator of “cell cycle pathway,” was inactivated by phosphorylation in POMC neurons by HFD feeding. Importantly, the reversal of deregulated cell cycle by stereotaxic delivering of the unphosphorylated pRbΔP in ARC significantly meliorated the DIO. Collectively, our study provides insights into the mechanisms related to the loss of homeostasis of POMC neurons in DIO, and suggests pRb phosphorylation as a potential intervention target to treat DIO.

    更新日期:2020-01-16
  • Force and Calcium Transients Analysis in Human Engineered Heart Tissues Reveals Positive Force-Frequency Relation at Physiological Frequency
    Stem. Cell Rep. (IF 5.499) Pub Date : 2020-01-16
    Umber Saleem; Ingra Mannhardt; Ingke Braren; Chris Denning; Thomas Eschenhagen; Arne Hansen

    Force measurements in ex vivo and engineered heart tissues are well established. Analysis of calcium transients (CaT) is complementary to force, and the combined analysis is meaningful to the study of cardiomyocyte biology and disease. This article describes a model of human induced pluripotent stem cell cardiomyocyte-derived engineered heart tissues (hiPSC-CM EHTs) transduced with the calcium sensor GCaMP6f followed by sequential analysis of force and CaT. Average peak analysis demonstrated the temporal sequence of the CaT preceding the contraction twitch. The pharmacological relevance of the test system was demonstrated with inotropic indicator compounds. Force-frequency relationship was analyzed in the presence of ivabradine (300 nM), which reduced spontaneous frequency and unmasked a positive correlation of force and CaT at physiological human heart beating frequency with stimulation frequency between 0.75 and 2.5 Hz (force +96%; CaT +102%). This work demonstrates the usefulness of combined force/CaT analysis and demonstrates a positive force-frequency relationship in hiPSC-CM EHTs.

    更新日期:2020-01-16
  • Toward Guidelines for Research on Human Embryo Models Formed from Stem Cells
    Stem. Cell Rep. (IF 5.499) Pub Date : 2020-01-16
    Insoo Hyun; Megan Munsie; Martin F. Pera; Nicolas C. Rivron; Janet Rossant

    Over the past few years, a number of research groups have reported striking progress on the generation of in vitro models from mouse and human stem cells that replicate aspects of early embryonic development. Not only do these models reproduce some key cell fate decisions but, especially in the mouse system, they also mimic the spatiotemporal arrangements of embryonic and extraembryonic tissues that are required for developmental patterning and implantation in the uterus. If such models could be developed for the early human embryo, they would have great potential benefits for understanding early human development, for biomedical science, and for reducing the use of animals and human embryos in research. However, guidelines for the ethical conduct of this line of work are at present not well defined. In this Forum article, we discuss some key aspects of this emerging area of research and provide some recommendations for its ethical oversight.

    更新日期:2020-01-16
  • iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests
    Stem. Cell Rep. (IF 5.499) Pub Date : 2020-01-16
    Maria Themeli; Amiet Chhatta; Hester Boersma; Henk Jan Prins; Martijn Cordes; Edwin de Wilt; Aïda Shahrabi Farahani; Bart Vandekerckhove; Mirjam van der Burg; Rob C. Hoeben; Frank J.T. Staal; Harald M.M. Mikkers
    更新日期:2020-01-16
  • An Evaluation of T‐Cell Functionality After Flow Cytometry Sorting Revealed p38 MAPK Activation
    Cytom. Part A (IF 3.433) Pub Date : 2020-01-16
    Immanuel Andrä; Hanna Ulrich; Susi Dürr; Dominik Soll; Lynette Henkel; Corinne Angerpointner; Julia Ritter; Sabine Przibilla; Herbert Stadler; Manuel Effenberger; Dirk H. Busch; Matthias Schiemann

    Cell alterations during isolation and preparation for flow cytometry cell sorting by antibodies, temperature, homogenization, buffer composition and mitogens are well known. In contrast, little is known about cell alteration caused by the instrument or the sorting process itself. We systematically evaluated cellular responses to different sorter‐induced physical forces. In summary, flow cytometry cell‐sorting induced forces can affect cellular signaling cascades, especially the MAPK p38. Functional assays, related to the p38 MAPK pathway, of human primary T cells after flow cytometry sorting did lead to minor physiological modulation but no functional impairments. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

    更新日期:2020-01-16
  • Yeast Sporulation and [SMAUG+] Prion: Faster Is Not Always Better
    Mol. Cell (IF 14.548) Pub Date : 2020-01-16
    Iuliia Parfenova; Yves Barral

    Chakravarty et al. (2019) and Itakura et al. (2019) report that the yeast RNA-binding protein Vts1 can convert into the [SMAUG+] prion state and delay meiosis commitment in response to starvation. It enables budding yeast to optimize their sporulation efficiency depending on how quickly nutrient availability fluctuates in their environment.

    更新日期:2020-01-16
  • Ant-icipating Change: An Epigenetic Switch in Reprogramming the Social Lives of Ants
    Mol. Cell (IF 14.548) Pub Date : 2020-01-16
    Marilyn G. Pray-Grant; Patrick A. Grant

    Glastad et al. (2019) describe a role for the neuronal CoREST corepressor and changes in juvenile hormone (JH) and ecdysone signaling during the reprogramming of social behavioral phenotypes in ants that are reflective of a natural mechanism differentiating “Major” and “Minor” worker ants.

    更新日期:2020-01-16
  • Put on Your Para-spectacles: The Development of Optimized CRISPR-Cas13-Based Approaches to Image RNA Dynamics in Real Time
    Mol. Cell (IF 14.548) Pub Date : 2020-01-16
    Brandon J. Davis; Mitchell R. O’Connell

    Live-cell RNA imaging is a powerful approach to observe the real-time dynamics of RNA metabolism. Two recent papers describe an optimized fluorescence-based CRISPR-Cas13 approach to image colocalized or repeat-containing RNAs in real time, as well as demonstrate simultaneous RNA-DNA labeling by using Cas13 and Cas9 in tandem.

    更新日期:2020-01-16
  • Prime Editing: Precision Genome Editing by Reverse Transcription
    Mol. Cell (IF 14.548) Pub Date : 2020-01-16
    Jun Yan; Ann Cirincione; Britt Adamson

    Genome editing is a method for making targeted sequence changes to the genomes of living cells. Prime editing, recently reported by Anzalone et al. (2019), is a new technology that uses reverse transcription to “write” programmed sequence changes into genomic DNA and thus promises significant technical advances.

    更新日期:2020-01-16
  • Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1 MET /APR-246
    Cell Death Dis. (IF 5.959) Pub Date : 2020-01-16
    Edith Aberdam; Lauriane N. Roux; Philippe-Henri Secrétan; Franck Boralevi; Joël Schlatter; Fanny Morice-Picard; Stefano Sol; Christine Bodemer; Caterina Missero; Salvatore Cisternino; Daniel Aberdam; Smail Hadj-Rabia
    更新日期:2020-01-16
  • Targeting alkaline ceramidase 3 alleviates the severity of nonalcoholic steatohepatitis by reducing oxidative stress
    Cell Death Dis. (IF 5.959) Pub Date : 2020-01-16
    Kai Wang; Chuanjiang Li; Xinxin Lin; Hang Sun; Ruijuan Xu; Qingping Li; Yiran Wei; Yiyi Li; Jianping Qian; Cuiting Liu; Qifan Zhang; Sheng Yu; Zhonglin Cui; Xixin Huang; Bili Zhu; Jie Zhou; Cungui Mao
    更新日期:2020-01-16
  • Drp1-mediated mitochondrial fission promotes renal fibroblast activation and fibrogenesis
    Cell Death Dis. (IF 5.959) Pub Date : 2020-01-16
    Yating Wang; Miaoqing Lu; Liping Xiong; Jinjin Fan; Yi Zhou; Huiyan Li; Xuan Peng; Zhong Zhong; Yihan Wang; Fengxian Huang; Wei Chen; Xueqing Yu; Haiping Mao
    更新日期:2020-01-16
  • The nuclear translocation of transketolase inhibits the farnesoid receptor expression by promoting the binding of HDAC3 to FXR promoter in hepatocellular carcinoma cell lines
    Cell Death Dis. (IF 5.959) Pub Date : 2020-01-16
    Minle Li; Xuping Zhang; Ying Lu; Sen Meng; Haoyu Quan; Pingfu Hou; Pan Tong; Dafei Chai; Xiaoge Gao; Junnian Zheng; Xuemei Tong; Jin Bai
    更新日期:2020-01-16
  • 更新日期:2020-01-16
  • Cytosolic domain of SIDT2 carries an arginine-rich motif that binds to RNA/DNA and is important for the direct transport of nucleic acids into lysosomes
    Autophagy (IF 11.059) Pub Date : 2020-01-16
    Katsunori Hase; Viorica Raluca Contu; Chihana Kabuta; Ryohei Sakai; Masayuki Takahashi; Naoyuki Kataoka; Fumihiko Hakuno; Shin-Ichiro Takahashi; Yuuki Fujiwara; Keiji Wada; Tomohiro Kabuta

    RNautophagy and DNautophagy (RDA) are unconventional autophagic pathways where nucleic acids are directly transported through the lysosomal membrane, then degraded inside lysosomes. We have previously shown that bitopic protein LAMP2C and putative RNA transporter SIDT2, both lysosomal membrane proteins, mediate the direct transport of nucleic acids into lysosomes and that LAMP2C interacts with the nucleic acids and functions as a receptor during RDA. Because SIDT2-mediated RDA occurs in isolated lysosomes that lack LAMP2C, in this study, we tested the hypothesis that SIDT2 itself could also interact with the nucleic acids. Our results show that SIDT2 directly binds RNA and DNA through an arginine-rich motif (ARM) located within its main cytosolic domain, and disruption of this motif dramatically impairs SIDT2-mediated RNautophagic activity. We also found that SIDT2 interacts with exon 1 of HTT (huntingtin) transcript through the ARM in a CAG-dependent manner. Moreover, overexpression of SIDT2 promoted degradation of HTT mRNA and reduced the levels of polyglutamine-expanded HTT aggregates, hallmarks of Huntington disease. In addition, a comparative analysis of LAMP2C and SIDT2 functions at the cellular level revealed that the two proteins exert a synergistic effect on RNautophagic activity and that the ARMs which mediate the interactions of SIDT2 and LAMP2C with RNA are essential for the synergy. Together, our results point out the importance of nucleic acid-binding capacity of SIDT2 for its function in translocating nucleic acids through the lipid bilayer and suggests a potential application of RNautophagy activation to reduce the expression levels of disease-causing toxic proteins. Abbreviations: ACTB/β-actin: actin beta; ARM: arginine-rich motif; CBB: Coomassie Brilliant Blue; CD: cytosolic domain; COX4I1/COX4: cytochrome c oxidase subunit 4I1; E. coli: Escherichia coli; EGFP: enhanced green fluorescent protein; EtBr: ethidium bromide; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GOLGA2/GM130: golgin A2; GST: glutathione S-transferase; HRP: horseradish peroxidase; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; HTT: huntingtin; HTTex1: exon 1 of the HTT gene; LAMP2: lysosomal associated membrane protein 2; LMNA: lamin A/C; PAGE: polyacrylamide gel electrophoresis; PBS: phosphate-buffered saline; PEI: polyethyleneimine; polyQ: polyglutamine; qPCR: quantitative PCR; RAB5A: RAB5A, member RAS oncogene family; RDA: RNautophagy and DNautophagy; SCARB2/LIMP2: scavenger receptor class B member 2; SDS: sodium dodecyl sulfate; SID-1: systemic RNA interference deficient-1; SIDT2: SID1 transmembrane family member 2; WT: wild type.

    更新日期:2020-01-16
  • Metabolic effects of RUBCN/Rubicon deficiency in kidney proximal tubular epithelial cells
    Autophagy (IF 11.059) Pub Date : 2020-01-16
    Jun Matsuda; Atsushi Takahashi; Yoshitsugu Takabatake; Shinsuke Sakai; Satoshi Minami; Takeshi Yamamoto; Ryuta Fujimura; Tomoko Namba-Hamano; Hiroaki Yonishi; Jun Nakamura; Tomonori Kimura; Jun-Ya Kaimori; Isao Matsui; Masatomo Takahashi; Motonao Nakao; Yoshihiro Izumi; Takeshi Bamba; Taiji Matsusaka; Fumio Niimura; Motoko Yanagita; Tamotsu Yoshimori; Yoshitaka Isaka

    Macroautophagy/autophagy is a lysosomal degradation system which plays a protective role against kidney injury. RUBCN/Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein) inhibits the fusion of autophagosomes and lysosomes. However, its physiological role in kidney proximal tubular epithelial cells (PTECs) remains uncertain. In the current study, we analyzed the phenotype of newly generated PTEC-specific rubcn-deficient (KO) mice. Additionally, we investigated the role of RUBCN in lipid metabolism using isolated rubcn-deficient PTECs. Although KO mice exhibited sustained high autophagic flux in PTECs, they were not protected from acute ischemic kidney injury. Unexpectedly, KO mice exhibited hallmark features of metabolic syndrome accompanied by expanded lysosomes containing multi-layered phospholipids in PTECs. RUBCN deficiency in cultured PTECs promoted the mobilization of phospholipids from cellular membranes to lysosomes via enhanced autophagy. Treatment of KO PTECs with oleic acid accelerated fatty acids transfer to mitochondria. Furthermore, KO PTECs promoted massive triglyceride accumulation in hepatocytes (BNL-CL2 cells) co-cultured in transwell, suggesting accelerated fatty acids efflux from the PTECs contributes to the metabolic syndrome in KO mice. This study shows that sustained high autophagic flux by RUBCN deficiency in PTECs leads to metabolic syndrome concomitantly with an accelerated mobilization of phospholipids from cellular membranes to lysosomes. Abbreviations: ABC: ATP binding cassette; ACADM: acyl-CoA dehydrogenase medium chain; ACTB: actin, beta; ATG: autophagy related; AUC: area under the curve; Baf: bafilomycin A1; BAT: brown adipose tissue; BODIPY: boron-dipyrromethene; BSA: bovine serum albumin; BW: body weight; CAT: chloramphenicol acetyltransferase; CM: complete medium; CPT1A: carnitine palmitoyltransferase 1a, liver; CQ: chloroquine; CTRL: control; EGFP: enhanced green fluorescent protein; CTSD: cathepsin D; EAT: epididymal adipose tissue; EGFR: epidermal growth factor receptor; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FA: fatty acid; FBS: fetal bovine serum; GTT: glucose tolerance test; HE: hematoxylin and eosin; HFD: high-fat diet; I/R: ischemia-reperfusion; ITT: insulin tolerance test; KAP: kidney androgen regulated protein; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LD: lipid droplet; LRP2: low density lipoprotein receptor related protein 2; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MAT: mesenteric adipose tissue; MS: mass spectrometry; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NDRG1: N-myc downstream regulated 1; NDUFB5: NADH:ubiquinone oxidoreductase subunit B5; NEFA: non-esterified fatty acid; OA: oleic acid; OCT: optimal cutting temperature; ORO: Oil Red O; PAS: Periodic-acid Schiff; PFA: paraformaldehyde; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PPARA: peroxisome proliferator activated receptor alpha; PPARGC1A: PPARG coactivator 1 alpha; PTEC: proximal tubular epithelial cell; RAB7A: RAB7A, member RAS oncogene family; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RT: reverse transcription; RUBCN: rubicon autophagy regulator; SAT: subcutaneous adipose tissue; SFC: supercritical fluid chromatography; SQSTM1: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; SV-40: simian virus-40; TFEB: transcription factor EB; TG: triglyceride; TS: tissue specific; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; UN: urea nitrogen; UQCRB: ubiquinol-cytochrome c reductase binding protein; UVRAG: UV radiation resistance associated; VPS: vacuolar protein sorting; WAT: white adipose tissue.

    更新日期:2020-01-16
  • Transgenic expression of GFP-LC3 perturbs autophagy in exocrine pancreas and acute pancreatitis responses in mice
    Autophagy (IF 11.059) Pub Date : 2020-01-16
    Olga A. Mareninova; Wenzhuo Jia; Sophie R. Gretler; Conner L. Holthaus; Diana D. H. Thomas; Michael Pimienta; Dustin L. Dillon; Anna S. Gukovskaya; Ilya Gukovsky; Guy E. Groblewski

    Pancreatitis is a common, sometimes fatal, disease of exocrine pancreas, initiated by damaged acinar cells. Recent studies implicate disordered macroautophagy/autophagy in pancreatitis pathogenesis. ATG8/LC3 protein is critical for autophagosome formation and a widely used marker of autophagic vacuoles. Transgenic GFP-LC3 mice are a valuable tool to investigate autophagy ; however, comparison of homeostatic and disease responses between GFP-LC3 and wild-type (WT) mice has not been done. We examined the effects of GFP-LC3 expression on autophagy, acinar cell function, and experimental pancreatitis. Unexpectedly, GFP-LC3 expression markedly increased endogenous LC3-II level in pancreas, caused by downregulation of ATG4B, the protease that deconjugates/delipidates LC3-II. By contrast, GFP-LC3 expression had lesser or no effect on autophagy in liver, lung and spleen. Autophagic flux analysis showed that autophagosome formation in GFP-LC3 acinar cells increased 3-fold but was not fully counterbalanced by increased autophagic degradation. Acinar cell (ex vivo) pancreatitis inhibited autophagic flux in WT and essentially blocked it in GFP-LC3 cells. In vivo pancreatitis caused autophagy impairment in WT mice, manifest by upregulation of LC3-II and SQSTM1/p62, increased number and size of autophagic vacuoles, and decreased level of TFEB, all of which were exacerbated in GFP-LC3 mice. GFP-LC3 expression affected key pancreatitis responses; most dramatically, it worsened increases in serum AMY (amylase), a diagnostic marker of acute pancreatitis, in several mouse models. The results emphasize physiological importance of autophagy for acinar cell function, demonstrate organ-specific effects of GFP-LC3 expression, and indicate that application of GFP-LC3 mice in disease models should be done with caution.Abbreviations: AP: acute pancreatitis; Arg-AP: L-arginine-induced acute pancreatitis; ATG: autophagy-related (protein); AVs: autophagic vacuoles; CCK: cholecystokinin-8; CDE: choline-deficient, D,L-ethionine supplemented diet; CER: caerulein (ortholog of CCK); CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; ER: endoplasmic reticulum; LAMP: lysosomal-associated membrane protein; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; TEM: transmission electron microscopy; TFEB: transcription factor EB; ZG: zymogen granule(s).

    更新日期:2020-01-16
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