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  • Relationship between changes in the exon-recognition machinery and SLC22A1 alternative splicing in hepatocellular carcinoma
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-15
    Meraris Soto; Maria Reviejo; Ruba Al-Abdulla; Marta R. Romero; Rocio I.R. Macias; Loreto Boix; Jordi Bruix; Maria A. Serrano; Jose J.G. Marin
    更新日期:2020-01-15
  • Neuroprotection from optic nerve injury and modulation of oxidative metabolism by transplantation of active mitochondria to the retina
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-15
    Gabriel Nascimento-dos-Santos; Eduardo de-Souza-Ferreira; Rafael Lani; Caroline Coelho de Faria; Victor Guedes Araujo; Leandro Coelho Teixeira-Pinheiro; Taliane de Souza Vasconcelos; Thaís Gonçalo Leandro; Marcelo Felippe Santiago; Rafael Linden; Antonio Galina; Hilda Petrs-Silva

    Mitochondrial dysfunctions are linked to a series of neurodegenerative human conditions, including Parkinson's disease, schizophrenia, optic neuropathies, and glaucoma. Recently, a series of studies have pointed mitotherapy – exogenous mitochondria transplant – as a promising way to attenuate the progression of neurologic disorders; however, the neuroprotective and pro-regenerative potentials of isolated mitochondria in vivo have not yet been elucidated. In this present work, we tested the effects of transplants of active (as well-coupled organelles were named), liver-isolated mitochondria on the survival of retinal ganglion cells and axonal outgrowth after optic nerve crush. Our data show that intravitreally transplanted, full active mitochondria incorporate into the retina, improve its oxidative metabolism and electrophysiological activity at 1 day after transplantation. Moreover, mitotherapy increases cell survival in the ganglion cell layer at 14 days, and leads to a higher number of axons extending beyond the injury site at 28 days; effects that are dependent on the organelles' structural integrity. Together, our findings support mitotherapy as a promising approach for future therapeutic interventions upon central nervous system damage.

    更新日期:2020-01-15
  • IL-20 promotes hypoxia/reoxygenation-induced mitochondrial dysfunction and apoptosis in cardiomyocytes by upregulating oxidative stress by activating the PKC/NADPH oxidase pathway
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-15
    Kun-Ling Tsai; Pei-Ling Hsieh; Wan-Ching Chou; Ching-Hsia Hung; Hsin-Lun Yang; Yun-Ching Chang; Pei-Ming Chu; Ming-Shi Chang; Shih-Hung Chan

    Acute myocardial infarction (AMI) is the maximum critical cardiovascular event and causes high morbidity and mortality worldwide. The ischemia and reperfusion that occur in AMI cause apoptosis and cellular dysfunction in cardiomyocytes. IL-20, an IL-10 family member, is involved in various inflammatory diseases. Therefore, we sought to elucidate the role of IL-20 in the infarcted heart following ischemia/reperfusion (I/R) injury. We found that IL-20 and its receptors, IL-20R1 and IL-20R2, were increased in H2C2 cardiomyoblast cells and ventricular tissues subjected to hypoxia/reoxygenation (H/R) stimulation. The presence of IL-20 further inhibited the cell viability of H9C2 cells and primary cardiomyocytes. Our results suggested that IL-20 elicited an increase in Ca2+ and activation of the PKC/NADPH oxidase pathway, leading to the elevation of oxidase stress and downregulation of AKT. Furthermore, we demonstrated that IL-20 was able to mediate H/R-induced apoptosis via PKC/NADPH oxidase/AKT signaling. Our findings implied that IL-20 was responsive to H/R stress in vitro and in rat hearts undergoing I/R injury, and this upregulation of IL-20 may contribute to the apoptosis of cardiomyocytes.

    更新日期:2020-01-15
  • Plasma-derived exosomes contribute to pancreatitis-associated lung injury by triggering NLRP3-dependent pyroptosis in alveolar macrophages
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-15
    Xiao-Bo Wu; Hong-Yu Sun; Zhu-Lin Luo; Long Cheng; Xing-Mei Duan; Jian-Dong Ren
    更新日期:2020-01-15
  • Arachidonic acid inhibits inflammatory responses by binding to myeloid differentiation factor-2 (MD2) and preventing MD2/toll-like receptor 4 signaling activation
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-14
    Yali Zhang; Hongjin Chen; Wenxin Zhang; Yan Cai; Peiren Shan; Di Wu; Bing Zhang; Hui Liu; Khan Zia; Guang Liang
    更新日期:2020-01-14
  • Disturbance of bioenergetics and calcium homeostasis provoked by metabolites accumulating in propionic acidemia in heart mitochondria of developing rats
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-10
    Ana Cristina Roginski; Alessandro Wajner; Cristiane Cecatto; Simone Magagnin Wajner; Roger Frigério Castilho; Moacir Wajner; Alexandre Umpierrez Amaral
    更新日期:2020-01-10
  • Dietary zinc restriction promotes degeneration of the endocrine pancreas in mice
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-09
    Tháyna Sisnande; Cleverton K. Lima; Dayana Cabral da Silva; Thayana Moulin Beninatto; Natália Leão Alves; Mariana J. Amaral; Leandro Miranda-Alves; Luís Maurício T.R. Lima

    Zinc is a key component of several proteins, interacting with the pancreatic hormones insulin and amylin. The role of zinc in insulin oligomerization and crystallinity is well established, although the effects of dietary zinc restriction on both energetic metabolism and β-pancreatic hormonemia and morphology remain unexplored. Here we report the effects of dietary zinc restriction on the endocrine pancreas and metabolic phenotype of mice. Nontransgenic male Swiss mice were fed a low-zinc or control diet for 4 weeks after weanling. Growth, glycemia, insulinemia and amylinemia were lower and pancreatic islets were smaller in the intervention group despite the preserved insulin crystallinity in secretory granules. We found strong immunostaining for insulin, amylin and oligomers in apoptotic pancreatic islet. High production of β-pancreatic hormones in zinc-restricted animals counteracted the reduced islet size caused by apoptosis. These data suggest that zinc deficiency is sufficient to promote islet β-cell hormonal disruption and degeneration.

    更新日期:2020-01-09
  • Duchenne muscular dystrophy is associated with the inhibition of calcium uniport in mitochondria and an increased sensitivity of the organelles to the calcium-induced permeability transition
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-08
    Mikhail V. Dubinin; Eugeny Yu. Talanov; Kirill S. Tenkov; Vlada S. Starinets; Irina B. Mikheeva; Mars G. Sharapov; Konstantin N. Belosludtsev
    更新日期:2020-01-09
  • Future perspectives: What lies ahead for Neuronal Ceroid Lipofuscinosis research?
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-08
    Jonathan D. Cooper; Sara E. Mole

    The increasing pace of progress in all aspects of Neuronal Ceroid Lipofuscinosis (NCL) research is highlighted by the breadth and depth of review articles [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10]] in this Special Issue that provide a helpful snapshot of the field between the previous international meeting, NCL 2018, and the next, NCL 2020. These advances encompass several areas that were previously thought intractable, ranging from basic science, through to a better understanding of the clinical presentation of different forms of NCL, therapeutic development, and new clinical trials that are underway. Increasing numbers of original NCL research papers continue to be published, and this new sense of momentum is greatly encouraging for the field. Here, we make some predictions as to what we can anticipate in the next few years.

    更新日期:2020-01-09
  • Mitochondrial permeability transition pore is involved in oxidative burst and NETosis of human neutrophils
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-08
    Nina Vorobjeva; Ivan Galkin; Olga Pletjushkina; Sergei Golyshev; Roman Zinovkin; Anastasia Prikhodko; Vladimir Pinegin; Irina Kondratenko; Boris Pinegin; Boris Chernyak
    更新日期:2020-01-08
  • Protective effect of curcumin nanoparticles against cardiotoxicity induced by doxorubicin in rat
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-07
    Haitham S. Mohammed; Eman N. Hosny; Yasser A. Khadrawy; Merna Magdy; Yasmen S. Attia; Omnia A. Sayed; Mahmoud AbdElaal

    The present study designed to investigate the protective effect of curcumin nanoparticles (CUR-NPs) on the cardiotoxicity induced by doxorubicin. Rats were divided into four groups; control, rats treated daily with CUR-NPs (50 mg/kg) for 14 days, rats treated with an acute dose of doxorubicin (20 mg/kg) and rats treated daily with CUR-NPs for 14 days injected with doxorubicin on the 10th day. After electrocardiogram (ECG) recording from rats at different groups, rat decapitation was carried out and the heart of each rat was excised out to measure the oxidative stress parameters; lipid peroxidation (MDA), nitric oxide (NO) and reduced glutathione (GSH) and the activities of Na,K,ATPase and acetylcholinesterase (AchE). In addition, the levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) were determined in the cardiac tissues. Lactate dehydrogenase (LDH) activity was measured in the serum. The ECG recordings indicated that daily pretreatment with CUR- NPs has prevented the tachycardia (i.e. increase in heart rate) and ameliorated the changes in ST wave and QRS complex induced by doxorubicin. In addition, CUR-NPs prevented doxorubicin induced significant increase in MDA, NO, DA, AchE and LDH and doxorubicin induced significant decrease in GSH, NE, 5-HT and Na,K,ATPase. According to the present findings, it could be concluded that CUR-NPs have a protective effect against cardiotoxicity induced by doxorubicin. This may shed more light on the importance of CUR-NPs pretreatment before the application of doxorubicin therapy.

    更新日期:2020-01-07
  • A pantothenate kinase-deficient mouse model reveals a gene expression program associated with brain coenzyme a reduction
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-07
    Chitra Subramanian; Jiangwei Yao; Matthew W. Frank; Charles O. Rock; Suzanne Jackowski

    Pantothenate kinase (PanK) is the first enzyme in the coenzyme A (CoA) biosynthetic pathway. The differential expression of the four-active mammalian PanK isoforms regulates CoA levels in different tissues and PANK2 mutations lead to Pantothenate Kinase Associated Neurodegeneration (PKAN). The molecular mechanisms that potentially underlie PKAN pathophysiology are investigated in a mouse model of CoA deficiency in the central nervous system (CNS). Both PanK1 and PanK2 contribute to brain CoA levels in mice and so a mouse model with a systemic deletion of Pank1 together with neuronal deletion of Pank2 was generated. Neuronal Pank2 expression in Pank1−/−Syn-Pank2−/− double knockout mice decreased starting at P9–11 triggering a significant brain CoA deficiency. The depressed brain CoA in the Pank1−/−Syn-Pank2−/− mice correlates with abnormal forelimb flexing and weakness that, in turn, contributes to reduced locomotion and abnormal gait. Biochemical analysis reveals a reduction in short-chain acyl-CoAs, including acetyl-CoA and succinyl-CoA. Comparative gene expression analysis reveals that the CoA deficiency in brain is associated with a large elevation of Hif3a transcript expression and significant reduction of gene transcripts in heme and hemoglobin synthesis. Reduction of brain heme levels is associated with the CoA deficiency. The data suggest a response to oxygen/glucose deprivation and indicate a disruption of oxidative metabolism arising from a CoA deficiency in the CNS.

    更新日期:2020-01-07
  • Glycogen storage in a zebrafish Pompe disease model is reduced by 3-BrPA treatment
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-07
    Cinzia Bragato; Silvia Carra; Flavia Blasevich; Franco Salerno; Alessia Brix; Andrea Bassi; Monica Beltrame; Franco Cotelli; Lorenzo Maggi; Renato Mantegazza; Marina Mora
    更新日期:2020-01-07
  • Chagas disease vaccine design: the search for an efficient Trypanosoma cruzi immune-mediated control
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-03
    Augusto E. Bivona; Andrés Sánchez Alberti; Natacha Cerny; Sebastián N. Trinitario; Emilio L. Malchiodi

    Chagas disease is currently endemic to 21 Latin-American countries and has also become a global concern because of globalization and mass migration of chronically infected individuals. Prophylactic and therapeutic vaccination might contribute to control the infection and the pathology, as complement of other strategies such as vector control and chemotherapy. Ideal prophylactic vaccine would produce sterilizing immunity; however, a reduction of the parasite burden would prevent progression from Trypanosoma cruzi infection to Chagas disease. A therapeutic vaccine for Chagas disease may improve or even replace the treatment with current drugs which have several side effects and require long term treatment that frequently leads to therapeutic withdrawal. Here, we will review some aspects about sub-unit vaccines, the rationale behind the selection of the immunogen, the role of adjuvants, the advantages and limitations of DNA-based vaccines and the idea of therapeutic vaccines. One of the main limitations to advance vaccine development against Chagas disease is the high number of variables that must be considered and the lack of uniform criteria among research laboratories. To make possible comparisons, much of this review will be focused on experiments that kept many variables constant including antigen mass/doses, type of eukaryotic plasmid, DNA-delivery system, mice strain and sex, lethal and sublethal model infection, and similar immunogenicity and efficacy assessments.

    更新日期:2020-01-04
  • Regulation of autophagy and apoptosis by Dp44mT-mediated activation of AMPK in pancreatic cancer cells
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2020-01-02
    S. Krishan; S. Sahni; L.Y.W. Leck; P.J. Jansson; D.R. Richardson
    更新日期:2020-01-02
  • Mitochondrial genetics cooperate with nuclear genetics to selectively alter immune cell development/trafficking
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-30
    T.C. Beadnell; C. Fain; C.J. Vivian; J.C.G. King; R. Hastings; M.A. Markiewicz; D.R. Welch

    The nuclear genome drives differences in immune cell populations and differentiation potentials, in part regulated by changes in metabolism. Despite this connection, the role of mitochondrial DNA (mtDNA) polymorphisms (SNP) in this process has not been examined. Using mitochondrial nuclear exchange (MNX) mice, we and others have shown that mtDNA strongly influences varying aspects of cell biology and disease. Based upon an established connection between mitochondria and immune cell polarization, we hypothesized that mtDNA SNP alter immune cell development, trafficking, and/or differentiation. Innate and adaptive immune cell populations were isolated and characterizated from the peritoneum and spleen. While most differences between mouse strains are regulated by nuclear DNA (nDNA), there are selective changes that are mediated by mtDNA differences (e.g., macrophage (CD11c) differentiation), These findings highlight how nuclear-mitochondrial crosstalk may alter pathology and physiology via regulation of specific components of the immune system.

    更新日期:2019-12-30
  • Inhibition of the proteasome preserves Mitofusin-2 and mitochondrial integrity, protecting cardiomyocytes during ischemia-reperfusion injury
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-28
    Ivonne Olmedo; Gonzalo Pino; Jaime A. Riquelme; Pablo Aránguiz; Magda C. Díaz; Camila López-Crisosto; Sergio Lavandero; Paulina Donoso; Zully Pedrozo; Gina Sánchez

    Cardiomyocyte loss is the main cause of myocardial dysfunction following an ischemia-reperfusion (IR) injury. Mitochondrial dysfunction and altered mitochondrial network dynamics play central roles in cardiomyocyte death. Proteasome inhibition is cardioprotective in the setting of IR; however, the mechanisms underlying this protection are not well-understood. Several proteins that regulate mitochondrial dynamics and energy metabolism, including Mitofusin-2 (Mfn2), are degraded by the proteasome. The aim of this study was to evaluate whether proteasome inhibition can protect cardiomyocytes from IR damage by maintaining Mfn2 levels and preserving mitochondrial network integrity. Using ex vivo Langendorff-perfused rat hearts and in vitro neonatal rat ventricular myocytes, we showed that the proteasome inhibitor MG132 reduced IR-induced cardiomyocyte death. Moreover, MG132 preserved mitochondrial mass, prevented mitochondrial network fragmentation, and abolished IR-induced reductions in Mfn2 levels in heart tissue and cultured cardiomyocytes. Interestingly, Mfn2 overexpression also prevented cardiomyocyte death. This effect was apparently specific to Mfn2, as overexpression of Miro1, another protein implicated in mitochondrial dynamics, did not confer the same protection. Our results suggest that proteasome inhibition protects cardiomyocytes from IR damage. This effect could be partly mediated by preservation of Mfn2 and therefore mitochondrial integrity.

    更新日期:2019-12-29
  • The potential clinical benefit of targeting androgen receptor (AR) in estrogen-receptor positive breast cancer cells treated with Exemestane
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-28
    Cristina Amaral; Tiago Augusto; Marta Almada; Sara C. Cunha; Georgina Correia-da-Silva; Natércia Teixeira

    The development of acquired resistance to the aromatase inhibitors (AIs) used in clinic is being considered the major concern in estrogen-receptor positive (ER+) breast cancer therapy. Recently, androgen receptor (AR) has gained attention in the clinical setting, since it has been implicated in AIs-resistance, although, different roles for AR in cell fate have been described. In this work, our group elucidates, for the first time, the oncogenic role of AR in sensitive and resistant ER+ breast cancer cells treated with the potent third-generation steroidal AI Exemestane (Exe). We demonstrate that Exe promotes an overexpression/activation of AR, which has an oncogenic and pro-survival role in Exe-sensitive and Exe-resistant cells. Moreover, we also disclose that targeting AR with bicalutamide (CDX) in Exe-treated cells, enhances the efficacy of this AI in sensitive cells and re-sensitizes resistant cells to Exe treatment. Furthermore, by targeting AR in Exe-resistant cells, it is also possible to block the activation of the ERK1/2 and PI3K cell survival pathways, hamper ERα activation and increase ERβ expression. Thus, this study, highlights a new mechanism involved in Exe-acquired resistance, implicating AR as a key molecule in this setting and suggesting that Exe-resistant cells may have an AR-dependent but ER-independent mechanism. Hence we propose AR antagonism as a potential and attractive therapeutic strategy to overcome Exe-acquired resistance or to enhance the growth inhibitory properties of Exe on ER+ breast cancer cells, improving breast cancer treatment.

    更新日期:2019-12-29
  • Role of TNFα and leptin signaling in colon cancer incidence and tumor growth under obese phenotype
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-28
    Snahlata Singh; Shyamananda Singh Mayengbam; Surbhi Chouhan; Bhavana Deshmukh; Pranay Ramteke; Dipti Athavale; Manoj Kumar Bhat
    更新日期:2019-12-29
  • c-Myc directly targets an over-expression of pyruvate carboxylase in highly invasive breast cancer
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-23
    Udom Lao-On; Pinnara Rojvirat; Pakkanan Chansonkrow; Phatchariya Phannasil; Siraprapa Siritutsoontorn; Varodom Charoensawan; Sarawut Jitrapakdee

    Here we showed that the c-Myc oncogene is responsible for overexpression of pyruvate carboxylase (PC) in highly invasive MDA-MB-231 cells. Pharmacological inhibition of c-Myc activity with 10074-G5 compound, resulted in a marked reduction of PC mRNA and protein, concomitant with reduced cell growth, migration and invasion. This growth inhibition but not migration and invasion can be partly restored by overexpression of PC, indicating that PC is a c-Myc-regulated pro-proliferating enzyme. Analysis of chromatin immunoprecipitation sequencing of c-Myc bound promoters revealed that c-Myc binds to two canonical c-Myc binding sites, locating at nucleotides −417 to −407 and −301 to −291 in the P2 promoter of human PC gene. Mutation of either c-Myc binding site in the P2 promoter-luciferase construct resulted in 50–60% decrease in luciferase activity while double mutation of c-Myc binding sites further decreased the luciferase activity in MDA-MB-231 cells. Overexpression of c-Myc in HEK293T cells that have no endogenous c-Myc resulted in 250-fold increase in luciferase activity. Mutation of either E-boxes lowered luciferase activity by 50% and 25%, respectively while double mutation of both sites abolished the c-Myc transactivation response. An electrophoretic mobility shift assay using nuclear proteins from MDA-MB-231 confirmed binding of c-Myc to both c-Myc binding sites in the P2 promoter. Bioinformatic analysis of publicly available transcriptomes from the cancer genome atlas (TCGA) dataset revealed an association between expression of c-Myc and PC in primary breast, as well as in lung and colon cancer tissues, suggesting that overexpression of PC is deregulated by c-Myc in these cancers.

    更新日期:2019-12-23
  • Genome-wide translational reprogramming of genes important for myocyte functions in overload-induced heart failure
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-21
    Qianqian Guo; Yongtao Zhang; Shucui Zhang; Jiajia Jin; Shu Pang; Xiao Wu; Wencheng Zhang; Xiaolei Bi; Yun Zhang; Qunye Zhang; Fan Jiang
    更新日期:2019-12-21
  • Quorum sensing molecules as a novel microbial factor impacting muscle cells
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-20
    Anton De Spiegeleer; Dirk Elewaut; Nele Van Den Noortgate; Yorick Janssens; Nathan Debunne; Selien Van Langenhove; Srinath Govindarajan; Bart De Spiegeleer; Evelien Wynendaele

    Skeletal muscle makes up the largest part of human body mass and a good maintenance of this organ is essential for general health. In accordance, muscle wasting, a frequent phenomenon in many diseases, is associated with functional decline and a decrease in quality of life. Unfortunately, due to a lack of knowledge of the underlying pathophysiology, no targeted therapies exist today to encounter muscle wasting. Recent studies suggest a role for the gut microbiome in muscle wasting, without the mediators of this gut-muscle axis being identified. Here we evaluated the possible effects of 75 quorum sensing molecules (QSM), traditionally only seen as intra-bacterial communication molecules, on C2C12 muscle cells, studying viability, differentiation, inflammation, mitochondrial changes and protein degradation as biological outcomes. The responses were evaluated using different approaches: median absolute deviation, quartiles, strictly standardized mean difference and robust strictly standardized mean difference. This study resulted in 30 QSM, with effects observed on C2C12 cells. Known producers of the 27 peptide QSM belong to species of the genus Staphylococcus, Streptococcus, Enterococcus, Bacillus, Lactobacillus and Escherichia, while the 3 non-peptide QSM are produced by a broad range of Gram-positive and Gram-negative bacteria. Altogether, these proof-of-concept findings provide the first evidence that QSM produced by microbiota play a role in the gut-muscle axis, opening new perspectives for diagnostic and therapeutic targets in muscle wasting diseases.

    更新日期:2019-12-20
  • Immune-neuroendocrine and metabolic disorders in human and experimental T. cruzi infection: New clues for understanding Chagas disease pathology
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-19
    Florencia B. González; Silvina R. Villar; M. Florencia Pacini; Oscar A. Bottasso; Ana R. Pérez

    Studies in mice undergoing acute Trypanosoma cruzi infection and patients with Chagas disease, led to identify several immune-neuroendocrine disturbances and metabolic disorders. Here, we review relevant findings concerning such abnormalities and discuss their possible influence on disease physiopathology.

    更新日期:2019-12-20
  • 更新日期:2019-12-20
  • Cardiac pathology in neuronal ceroid lipofuscinoses (NCL): More than a mere co-morbidity
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-19
    Katja Rietdorf; Emily E. Coode; Angela Schulz; Eva Wibbeler; Martin D. Bootman; John R. Ostergaard

    The neuronal ceroid lipofuscinoses (NCLs) are mostly seen as diseases affecting the central nervous system, but there is accumulating evidence that they have co-morbidities outside the brain. One of these co-morbidities is a decline in cardiac function. This is becoming increasingly recognised in teenagers and adolescents with juvenile CLN3, but it may also occur in individuals with other NCLs. The purpose of this review is to summarise the current knowledge of the structural and functional changes found in the hearts of animal models and people diagnosed with NCL. In addition, we present evidence of structural changes that were observed in a systematic comparison of the cardiomyocytes from CLN3Δex7/8 mice.

    更新日期:2019-12-19
  • The interplay of signaling pathway in endothelial cells—Matrix stiffness dependency with targeted-therapeutic drugs
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-19
    Vicki Vania; Lu Wang; Marco Tjakra; Tao Zhang; Juhui Qiu; Youhua Tan; Guixue Wang

    Cardiovascular diseases (CVDs) have been one of the major causes of human deaths in the world. The study of CVDs has focused on cell chemotaxis for decades. With the advances in mechanobiology, accumulating evidence has demonstrated the influence of mechanical stimuli on arterial pathophysiology and endothelial dysfunction that is a hallmark of atherosclerosis development. An increasing number of drugs have been exploited to decrease the stiffness of vascular tissue for CVDs therapy. However, the underlying mechanisms have yet to be explored. This review aims to summarize how matrix stiffness mediates atherogenesis through various important signaling pathways in endothelial cells and cellular mechanophenotype, including RhoA/Rho-associated protein kinase (ROCK), mitogen-activated protein kinase (MAPK), and Hippo pathways. We also highlight the roles of putative mechanosensitive non-coding RNAs in matrix stiffness-mediated atherogenesis. Finally, we describe the usage of tunable hydrogel and its future strategy to improve our knowledge underlying matrix stiffness-mediated CVDs mechanism.

    更新日期:2019-12-19
  • Current status of stem cell research: An editorial
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-17
    P. Hemachandra Reddy

    The purpose of this editorial is to highlight recent developments in molecular biology tools and techniques in stem cell research and their applications to human diseases. Recent advancements in stem cell research and regenerative medicine are offering immense hope to cure human diseases and injuries, such as cancer, diabetes, Alzheimer's disease, Parkinson's disease, and traumatic brain injuries. In the last three decades, especially in the last decade, major breakthroughs have been seen in the conversion of adult stem cells into induced pluripotent stem cells, which in turn has led the way to developing stem cell therapies for human diseases. This article summarizes contributions of research into stem cell therapies.

    更新日期:2019-12-18
  • The transcriptional repressor SNAI2 impairs neuroblastoma differentiation and inhibits response to retinoic acid therapy
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-17
    Kirsten S. Vrenken; Britt M.T. Vervoort; Dorette S. van Ingen Schenau; Yvonne H.W. Derks; Liesbeth van Emst; Pavlo G. Grytsenko; Jeroen A.J. Middelbeek; Frank N. van Leeuwen

    Neuroblastoma is the most common extracranial solid tumor in children and originates from poorly differentiated neural crest progenitors. High-risk neuroblastoma patients frequently present with metastatic disease at diagnosis. Despite intensive treatment, patients often develop refractory disease characterized by poorly differentiated, therapy resistant cells. Although adjuvant therapy using retinoic acid (RA)-induced differentiation may increase event-free survival, in the majority of cases response to RA-therapy is inadequate. Consequently, current research aims to identify novel therapeutic targets that enhance the sensitivity to RA and induce neuroblastoma cell differentiation. The similarities between neural crest development and neuroblastoma progression provide an appealing starting point. During neural crest development the EMT-transcription factor SNAI2 plays an important role in neural crest specification as well as neural crest cell migration and survival. Here, we report that CRISPR/Cas9 mediated deletion as well as shRNA mediated knockdown of the EMT-transcription factor SNAI2 promotes cellular differentiation in a variety of neuroblastoma models. By comparing mRNA expression data from independent patient cohorts, we show that a SNAI2 activity-based gene expression signature significantly correlates with event-free survival. Loss of SNAI2 function reduces self-renewal, 3D invasion, as well as metastatic spread in vivo, while strongly sensitizing neuroblastoma cells to RA-induced growth inhibition. Together, our data demonstrate that SNAI2 maintains progenitor-like features in neuroblastoma cells while interfering with RA-induced growth inhibition. We propose that targeting gene regulatory circuits, such as those controlling SNAI2 function, may allow reversion of RA-therapy resistant neuroblastoma cells to a more differentiated and therapy responsive phenotype.

    更新日期:2019-12-18
  • Betaine/GABA transporter-1 (BGT-1) deficiency in mouse prevents acute liver failure in vivo and hepatocytes apoptosis in vitro
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-09
    Zhenze Liu, Qing Li, Ruling Shen, Lei Ci, Zhipeng Wan, Jiahao Shi, Qin Huang, Xu Yang, Mengjie Zhang, Hua Yang, Ruilin Sun, Zhugang Wang, Fang Huang, Tianfei Lu, Jian Fei

    Betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT-1 or Slc6a12) is a transporter for the neurotransmitter GABA and osmolyte betaine. To date, most studies on BGT-1 have focused on its functions in the nervous system and renal osmotic homeostasis. Despite its dominant distribution in the liver, the function of BGT-1 in hepatic physiology or disease remains unknown. Here, we report that BGT-1 was significantly downregulated in patients with liver failure as well as in mice with experimental acute liver failure (ALF). Furthermore, mice deficient in BGT-1 showed significant resistance to ALF compared with wild type (WT) mice, manifesting as improved survival rate, reduced alanine transaminase/aspartate aminotransferase levels, better histopathological symptoms and fewer apoptotic cells in the liver. Similarly, in primary hepatocytes, BGT-1 deficiency or treatment with a BGT-1 inhibitor, NNC 05-2090, attenuated TNF-α mediated apoptosis. In addition, BGT-1 deficiency or dosing with NNC 05-2090 stimulated the expression of the anti-apoptotic gene, c-Met in the liver, suggesting the involvement of c-Met in the function on hepatocytes of BGT-1 apoptosis. Our findings suggest BGT-1 is a promising candidate drug target to prevent and treat hepatocyte apoptosis related diseases, such as ALF.

    更新日期:2019-12-09
  • The effects of the inactivation of Hydroxyproline dehydrogenase on urinary oxalate and glycolate excretion in mouse models of primary hyperoxaluria
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-07
    Brianna Buchalski, Kyle D. Wood, Anil Challa, Sonia Fargue, Ross P. Holmes, W. Todd Lowther, John Knight
    更新日期:2019-12-07
  • Notch signaling in the pathogenesis of thoracic aortic aneurysms: A bridge between embryonic and adult states
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-06
    Anna Malashicheva, Aleksandra Kostina, Anna Kostareva, Olga Irtyuga, Vladimir Uspensky

    Aneurysms of the thoracic aorta are a “silent killer” with no evident clinical signs until the fatal outcome. Molecular and genetic bases of thoracic aortic aneurysms mainly include transforming growth factor beta signaling, smooth muscle contractile units and metabolism genes, and extracellular matrix genes. In recent studies, a role of Notch signaling, among other pathways, has emerged in disease pathogenesis. Notch is a highly conserved signaling pathway that regulates the development and differentiation of many types of tissues and influences major cellular processes such as cell proliferation, differentiation and apoptosis. Mutations in several Notch signaling components have been associated with a number of heart defects, demonstrating an essential role of Notch signaling both in cardiovascular system development and its maintenance during postnatal life. This review discusses the role of Notch signaling in the pathogenesis of thoracic aortic aneurysms considering development and maintenance of the aortic root and how developmental regulations by Notch signaling may influence thoracic aortic aneurysms.

    更新日期:2019-12-07
  • Differential phenotypic and functional profile of epitope-specific cytotoxic CD8+ T cells in benznidazole-treated chronic asymptomatic Chagas disease patients
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-06
    Adriana Egui, Manuel Carlos López, Inmaculada Gómez, Marina Simón, Manuel Segovia, M. Carmen Thomas

    One of the greatest challenges in Chagas disease research is the search for tools that will enable the assessment of pharmacological treatment efficacy. A recently described set of serological biomarkers composed of four parasite antigens and established criteria of treatment efficacy allowed the evaluation of the impact of benznidazole treatment a short/medium time after the treatment. In addition, cellular immunological parameters have also been described as potential indicators of the treatment response. The cytotoxic CD8+ T cells specific to five epitopes in the PFR2, PFR3, TcCA-2 and KMP11 antigens have been analysed, and these epitopes have been shown to be recognized, processed and presented in the context of a natural T. cruzi infection. In the present manuscript, we characterized these antigen-specific CD8+ T cells in indeterminate chronic Chagas disease patients both before and after (from 11 to 28 months) benznidazole treatment. The results indicate that there is a differential memory CD8+ T cell profile depending on the antigenic epitope and that the benznidazole treatment modulates the memory, differentiation and senescence phenotypes of the epitope-specific CD8+ T cells. Moreover, in these patients, the reactivity of sera against the referred set of biomarkers was evaluated. The data obtained show that the patients who met the established therapeutic efficacy criteria presented a differential phenotypic profile of the antigen-specific CD8+ T cells even prior to treatment compared to the patients who did not meet the therapeutic efficacy criteria, and this behaviour is associated with a better functionality of these CD8+ T cells.

    更新日期:2019-12-07
  • Current nutritional and pharmacological anti-aging interventions
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-06
    Manuel Ros, José María Carrascosa

    Aging is the main risk factor for chronic diseases and disablement in human societies with a great impact in social and health care expenditures. So far, aging and, eventually, death are unavoidable. Nevertheless, research efforts on aging-associated diseases with the aim not only to extend life span but also to increment health span in an attempt to delay, stop and even reverse the aging process have not stopped growing. Caloric restriction extends both health and life span in several short-lived experimental models and has brought to light the role of different molecular effectors involved in nutrient sensing pathways and longevity. This opens the possibility of modulating these molecular effectors also in humans to increase longevity and health span. The difficulty to implement caloric restricted diets in humans has led to the development of new bearable diets such as time-restricted feeding, intermittent fasting or diets with limited amounts of some nutrients and to the search of pharmacological agents, targeted to the effectors that mediate the extension of life and health span in response to these anti-aging diets. Pharmacological approaches that eliminate senescent cells or prevent primary causes of aging such as telomere attrition also emerge as potential anti-aging strategies. In the present article, we review these possible nutritional and pharmacological interventions designed to mitigate and/or delay the aging process and to increase health and life span.

    更新日期:2019-12-07
  • The LRRK2-RAB axis in regulation of vesicle trafficking and α-synuclein propagation
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-06
    Eun-Jin Bae, Seung-Jae Lee

    LRRK2 and SNCA, the gene for α-synuclein, are the two of the most important genetic factors of Parkinson's disease (PD). A-synuclein is aggregated and accumulated in neurons and glia in PD and considered the pathogenic culprit of the disease. A-synuclein aggregates spread from a few discrete regions of the brain to larger areas as the disease progresses through cell-to-cell propagation mechanism. LRRK2 is involved in the regulation of vesicle trafficking, in particular in the endolysosomal and autophagic pathways. Studies also suggest that LRRK2 might regulate the pathogenic actions of α-synuclein. However, the relationship between these two proteins in the pathogenesis of PD remains elusive. Here, we review the current literature on the pathophysiological function of LRRK2 with an emphasis on its role in the endolysosomal and autophagic pathways. We also propose a potential mechanism by which LRRK2 is involved in the regulation of aggregation and the propagation of α-synuclein.

    更新日期:2019-12-06
  • High fat diet consumption results in mitochondrial dysfunction, oxidative stress, and oligodendrocyte loss in the central nervous system
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-06
    Monica R. Langley, Hyesook Yoon, Ha-Neui Kim, Chan-Il Choi, Whitney Simon, Laurel Kleppe, Ian R. Lanza, Nathan K. LeBrasseur, Aleksey Matveyenko, Isobel A. Scarisbrick
    更新日期:2019-12-06
  • The unmet medical need for Trypanosoma cruzi-infected patients: Monitoring the disease status
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-12-04
    Maan Zrein, Eric Chatelain

    Patients infected by Trypanosoma cruzi are typically diagnosed by detecting specific antibodies in serological assays. Persistence of the parasitic infection increases the risk of morbidity and mortality. There are indications that anti-parasitic therapies help to reduce these risks when comparing treated and untreated populations. However, at present, treatment efficacy cannot be properly evaluated on an individual patient basis by available laboratory methods. To monitor parasite clearance, it is essential to change the paradigm of serological methods: analyzing the broad spectrum of antibody diversity is more informative about clinical status than conventional serology tests designed merely for global detection of antibodies.

    更新日期:2019-12-04
  • Stem cells for treatment of musculoskeletal conditions orthopedic/sports medicine applications
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-30
    Mimi Zumwalt, Arubala P. Reddy

    A myriad of musculoskeletal conditions afflicts a vast number of the world's population from birth to death. Countless pathological diseases and traumatic injuries (acute and chronic) contribute to different human disabilities, causing a tremendous financial toll on the economy of healthcare. The medical field is continually searching for novel ways to combat orthopedically related conditions. The immediate goal is the restoration of anatomy then ultimately return of function in hopes of enhancing quality if not the quantity of life. Traditional methods involve surgical correction/reconstruction of skeletal deformities from fractures/soft tissue damage/ruptures or replacement/resection of degenerated joints. Modern research is currently concentrating on innovative procedures to replenish/restore the human body close to its original/natural state [1, 2].

    更新日期:2019-11-30
  • Protective effect of metformin against palmitate-induced hepatic cell death
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-29
    Yana Geng, Alejandra Hernández Villanueva, Asmaa Oun, Manon Buist-Homan, Hans Blokzijl, Klaas Nico Faber, Amalia Dolga, Han Moshage

    Lipotoxicity causes hepatic cell death and therefore plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metformin, a first-line anti-diabetic drug, has shown a potential protective effect against NAFLD. However, the underlying mechanism is still not clear. In this study, we aim to understand the molecular mechanism of the protective effect of metformin in NAFLD, focusing on lipotoxicity. Cell death was studied in HepG2 cells and primary rat hepatocytes exposed to palmitate and metformin. Metformin ameliorated palmitate-induced necrosis and apoptosis (decreased caspase-3/7 activity by 52% and 57% respectively) in HepG2 cells. Metformin also reduced palmitate-induced necrosis in primary rat hepatocytes (P < 0.05). The protective effect of metformin is not due to reducing intracellular lipid content or activation of AMPK signaling pathways. Metformin and a low concentration (0.1 μmol/L) of rotenone showed moderate inhibition on mitochondrial respiration indicated by reduced basal and maximal mitochondrial respiration and proton leak in HepG2 cells. Moreover, metformin and rotenone (0.1 μmol/L) preserved mitochondrial membrane potential in both HepG2 cells and primary rat hepatocytes. In addition, metformin and rotenone (0.1 μmol/L) also reduces reactive oxygen species (ROS) production and increase superoxide dismutase 2 (SOD2) expression. Our results establish that metformin AMPK-independently protects against PA-induced hepatic cell death by moderate inhibition of the mitochondrial respiratory chain, recovering mitochondrial function, decreasing cellular ROS production, and inducing SOD2 expression, indicating that metformin may have beneficial actions beyond its glucose-lowering effect and also suggests that mitochondrial complex І may be a therapeutic target in NAFLD.

    更新日期:2019-11-29
  • Interleukin-6 plays a critical role in aldosterone-induced macrophage recruitment and infiltration in the myocardium
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-28
    Che-Wei Liao, Chia-Hung Chou, Xue-Ming Wu, Zheng-Wei Chen, Ying-Hsien Chen, Yi-Yao Chang, Vin-Cent Wu, Stefan Rose-John, Chi-Sheng Hung, Yen-Hung Lin

    Macrophages play an important role in aldosterone-induced myocardial fibrosis, in which the first key steps are macrophage recruitment and infiltration. We hypothesized that IL-6 may be a key mediator of aldosterone-induced macrophage recruitment and infiltration. To test this hypothesis, we designed cell studies with a human monocytic cell line THP-1 that with monocyte/macrophage functions to explore the signaling pathway of aldosterone-induced macrophage infiltration, and further investigated the phenomenon and consequent pathway in aldosterone-infused mice studies. The results showed that aldosterone induced the expression of IL-6 via mineralocorticoid receptors, and enhanced THP-1 cell migration and infiltration. Further experiments using a protease array and siRNA revealed that expressions of MMP-1 and MMP-9 were associated with aldosterone-induced macrophage infiltration. In addition, aldosterone-induced MMP-1 and MMP-9 expressions were mediated via cyclooxygenase-II and prostaglandin E2/EP-2 and EP-4 receptors. In aldosterone-infused mice, mRNA expressions of MMP-1, MMP-9 and COX-2 in peripheral blood monocytic cells were significantly increased. Moreover, the number of mouse macrophage-restricted F4/80 protein-positive cells in the myocardium was significantly higher in the aldosterone-infused mice compared with control mice. The increase in F4/80-positive cells in the myocardium was suppressed in the aldosterone-infused mice with the aldosterone antagonist eplerenone or anti-IL-6 antibody treatment. In conclusion, interleukin-6 played an important role in aldosterone-induced macrophage recruitment and infiltration in the myocardium.

    更新日期:2019-11-29
  • Matrix stiffness modulates ILK-mediated YAP activation to control the drug resistance of breast cancer cells
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-28
    Xiang Qin, Xiaoying Lv, Ping Li, Rui Yang, Qiong Xia, Yu Chen, Yueting Peng, Li Li, Shun Li, Tingting Li, Ying Jiang, Hong Yang, Chunhui Wu, Chuan Zheng, Jie Zhu, Fengming You, Heng Wang, Jiong Chen, Yiyao Liu

    One of the hallmarks of cancer progression is strong drug resistance during clinical treatments. The tumor microenvironment is closely associated with multidrug resistance, the optimization of tumor microenvironments may have a strong therapeutic effect. In this study, we configured polyacrylamide hydrogels of varying stiffness [low (10 kPa), intermediate (38 kPa) and high (57 kPa)] to simulate tissue physical matrix stiffness across different stages of breast cancer. After treatment with doxorubicin, cell survival rates on intermediate stiffness substrate are significantly higher. We find that high expression of ILK and YAP reduces the survival rates of breast cancer patients. Drug resistance is closely associated with the inactivation of the hippo pathway protein Merlin/MST/LATS and the activation of YAP. These results not only highlight the understanding of drug resistance mechanisms but also serve as a new basis for developing breast cancer treatment delivery systems.

    更新日期:2019-11-29
  • Minor C allele of the SNP rs7873784 associated with rheumatoid arthritis and type-2 diabetes mellitus binds PU.1 and enhances TLR4 expression
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-28
    Kirill V. Korneev, Ekaterina N. Sviriaeva, Nikita A. Mitkin, Alisa M. Gorbacheva, Aksinya N. Uvarova, Alina S. Ustiugova, Oleg L. Polanovsky, Ivan V. Kulakovskiy, Marina A. Afanasyeva, Anton M. Schwartz, Dmitry V. Kuprash

    Toll-like receptor 4 (TLR4) is an innate immunity receptor predominantly expressed on myeloid cells and involved in the development of various diseases, many of them with complex genetics. Here we present data on functionality of single nucleotide polymorphism rs7873784 located in the 3′-untranslated region (3′-UTR) of TLR4 gene and associated with various pathologies involving chronic inflammation. We demonstrate that TLR4 3′-UTR strongly enhanced the activity of TLR4 promoter in U937 human monocytic cell line while minor rs7873784(C) allele created a binding site for transcription factor PU.1 (encoded by SPI1 gene), a known regulator of TLR4 expression. Increased binding of PU.1 further augmented the TLR4 transcription while PU.1 knockdown or complete disruption of the PU.1 binding site abrogated the effect. We hypothesize that additional functional PU.1 site may increase TLR4 expression in individuals carrying minor C variant of rs7873784 and modulate the development of certain pathologies, such as rheumatoid arthritis and type-2 diabetes mellitus.

    更新日期:2019-11-28
  • The contribution of multicellular model organisms to neuronal ceroid lipofuscinosis research
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-26
    Robert J. Huber, Stephanie M. Hughes, Wenfei Liu, Alan Morgan, Richard I. Tuxworth, Claire Russell

    The NCLs (neuronal ceroid lipofuscinosis) are forms of neurodegenerative disease that affect people of all ages and ethnicities but are most prevalent in children. Commonly known as Batten disease, this debilitating neurological disorder is comprised of 13 different subtypes that are categorized based on the particular gene that is mutated (CLN1-8, CLN10-14). The pathological mechanisms underlying the NCLs are not well understood due to our poor understanding of the functions of NCL proteins. Only one specific treatment (enzyme replacement therapy) is approved, which is for the treating the brain in CLN2 disease. Hence there remains a desperate need for further research into disease-modifying treatments. In this review, we present and evaluate the genes, proteins and studies performed in the social amoeba, nematode, fruit fly, zebrafish, mouse and large animals pertinent to NCL. In particular, we highlight the use of multicellular model organisms to study NCL protein function, pathology and pathomechanisms. Their use in testing novel therapeutic approaches is also presented. With this information, we highlight how future research in these systems may be able to provide new insight into NCL protein functions in human cells and aid in the development of new therapies.

    更新日期:2019-11-27
  • Overexpression of Na+–HCO3– Cotransporter contributes to the exacerbation of cardiac remodeling in mice with myocardial infarction by increasing intracellular calcium overload
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-26
    Zhenhuan Chen, Lu Chen, Kaitong Chen, Hairuo Lin, Mengjia Shen, Lin Chen, Hailin Zhu, Yingqi Zhu, Qiancheng Wang, Fang Xi, Xiaobo Huang, Yuegang Wang, Wangjun Liao, Jianping Bin, Masanori Asakura, Jie Liu, Masafumi Kitakaze, Yulin Liao

    The role of the cardiac isoform of the electrogenic sodium-bicarbonate ion cotransporter (NBCe1) in cardiac remodeling is not fully understood. The aim of this study was to assess the effects of NBCe1 overexpression on cardiac remodeling induced by myocardial infarction (MI) in mice. We generated NBCe1 transgenic (Tg) mice and NBCe1 overexpressing adult mouse ventricular myocytes (AMVMs) to investigate the role of NBCe1 on post-MI remodeling and calcium kinetics. Tg mice showed a markedly higher mortality rate and larger infarct size after MI. At 6 weeks after MI, the maximum rising rates of left ventricular pressure (dp/dt), contractility index, and the exponential time constant of relaxation (τ) were markedly lower, and there was higher cardiomyocyte apoptosis, in Tg mice compared with WT mice. In cultured AMVMs, overexpression of NBCe1 decreased sarcomere shortening and calcium amplitude. In WT AMVMs, the rates of the rise and decay phase of calcium transients, indicated by the rising time (Tpeak, time to peak) and decay time constant (τd), and the number of apoptotic cells, were increased following hypoxia, while overexpression of NBCe1 further increased Tpeak and cellular apoptosis, but not τd. Intracellular resting calcium and sodium concentrations were significant increased following both hypoxia and NBCe1 overexpression. Co-treatment with S0859, an NBCe1 antagonist, blocked the hypoxia-induced increase in Tpeak, τd, intracellular resting calcium and sodium concentrations, and apoptosis in cardiomyocytes. These findings indicate that NBCe1 overexpression promotes cardiac remodeling by increasing intracellular calcium overload. Therefore, NBCe1 should be a potential target for treatment of cardiac remodeling.

    更新日期:2019-11-26
  • Metformin reduces TRPC6 expression through AMPK activation and modulates cytoskeleton dynamics in podocytes under diabetic conditions
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-25
    Maria Szrejder, Patrycja Rachubik, Dorota Rogacka, Irena Audzeyenka, Michał Rychłowski, Ewelina Kreft, Stefan Angielski, Agnieszka Piwkowska

    Podocytes have foot processes that comprise an important cellular layer of the glomerular barrier involved in regulating glomerular permeability. The disturbance of podocyte function plays a central role in the development of proteinuria in diabetic nephropathy. AMP-activated protein kinase (AMPK), a key regulator of glucose and fatty acid metabolism, plays a major role in obesity and type 2 diabetes. Accumulating evidence suggests that TRPC6 channels are crucial mediators of calcium transport in podocytes, and these channels are involved in disturbing the glomerular filtration barrier in diabetes. Metformin is an anti-diabetic drug widely used for treating patients with type 2 diabetes. Recent studies have suggested that the therapeutic effect of metformin might be mediated by AMPK. The precise function of metformin on cellular function and intracellular signaling in podocytes under diabetic conditions is not fully understood. In this study, we demonstrated that metformin normalized TRPC6 expression via AMPKα1 activation in podocytes exposed to high glucose concentrations. A quantitative analysis showed that metformin increased the colocalization of TRPC6 and AMPKα1 subunits from 42% to 61% in standard glucose (SG) medium and from 29% to 52% in high glucose (HG) medium. AMPK activation was also necessary for maintaining appropriate levels of Rho-family small GTPase activity in HG conditions. Moreover, metformin through AMPK activation remodeled cytoskeleton dynamics, and consequently, reduced filtration barrier permeability in diabetic conditions.

    更新日期:2019-11-26
  • Genes of the cGMP-PKG-Ca2+ signaling pathway are alternatively spliced in cardiomyopathy: Role of RBFOX2
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-25
    Xianxiu Wan, KarryAnne Belanger, Steven G. Widen, Muge N. Kuyumcu-Martinez, Nisha J. Garg

    Aberrations in the cGMP-PKG-Ca2+ pathway are implicated in cardiovascular complications of diverse etiologies, though involved molecular mechanisms are not understood. We performed RNA-Seq analysis to profile global changes in gene expression and exon splicing in Chagas disease (ChD) murine myocardium. Ingenuity-Pathway-Analysis of transcriptome dataset identified 26 differentially expressed genes associated with increased mobilization and cellular levels of Ca2+ in ChD hearts. Mixture-of-isoforms and Enrichr KEGG pathway analyses of the RNA-Seq datasets from ChD (this study) and diabetic (previous study) murine hearts identified alternative splicing (AS) in eleven genes (Arhgef10, Atp2b1, Atp2a3, Cacna1c, Itpr1, Mef2a, Mef2d, Pde2a, Plcb1, Plcb4, and Ppp1r12a) of the cGMP-PKG-Ca2+ pathway in diseased hearts. AS of these genes was validated by an exon exclusion-inclusion assay. Further, Arhgef10, Atp2b1, Mef2a, Mef2d, Plcb1, and Ppp1r12a genes consisted RBFOX2 (RNA-binding protein) binding-site clusters, determined by analyzing the RBFOX2 CLIP-Seq dataset. H9c2 rat heart cells transfected with Rbfox2 (vs. scrambled) siRNA confirmed that expression of Rbfox2 is essential for proper exon splicing of genes of the cGMP-PKG-Ca2+ pathway. We conclude that changes in gene expression may influence the Ca2+ mobilization pathway in ChD, and AS impacts the genes involved in cGMP/PKG/Ca2+ signaling pathway in ChD and diabetes. Our findings suggest that ChD patients with diabetes may be at increased risk of cardiomyopathy and heart failure and provide novel ways to restore cGMP-PKG regulated signaling networks via correcting splicing patterns of key factors using oligonucleotide-based therapies for the treatment of cardiovascular complications.

    更新日期:2019-11-26
  • In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-23
    Marie Lucienne, Juan Antonio Aguilar-Pimentel, Oana V. Amarie, Lore Becker, Julia Calzada-Wack, Patricia da Silva-Buttkus, Lillian Garrett, Sabine M. Hölter, Philipp Mayer-Kuckuk, Birgit Rathkolb, Jan Rozman, Nadine Spielmann, Irina Treise, Dirk H. Busch, Thomas Klopstock, Carsten Schmidt-Weber, Eckhard Wolf, Wolfgang Wurst, Matthias R. Baumgartner

    Isolated methylmalonic aciduria (MMAuria) is primarily caused by deficiency of methylmalonyl-CoA mutase (MMUT or MUT). Biochemically, MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-carnitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma or even death, with kidney and neurological impairment frequently identified in the long-term. Here, we report a hemizygous mouse model which combines a knock-in (ki) missense allele of Mut with a knock-out (ko) allele (Mut-ko/ki mice) that was fed a 51%-protein diet from day 12 of life, constituting a bespoke model of MMAuria. Under this diet, mutant mice developed a pronounced metabolic phenotype characterized by drastically increased blood levels of MMA and C3 compared to their littermate controls (Mut-ki/wt). With this bespoke mouse model, we performed a standardized phenotypic screen to assess the whole-body impairments associated with this strong metabolic condition. We found that Mut-ko/ki mice show common clinical manifestations of MMAuria, including pronounced failure to thrive, indications of mild neurological and kidney dysfunction, and degenerative morphological changes in the liver, along with less well described symptoms such as cardiovascular and hematological abnormalities. The analyses also reveal so far unknown disease characteristics, including low bone mineral density, anxiety-related behaviour and ovarian atrophy. This first phenotypic screening of a MMAuria mouse model confirms its relevance to human disease, reveals new alterations associated with MUT deficiency, and suggests a series of quantifiable readouts that can be used to evaluate potential treatment strategies.

    更新日期:2019-11-26
  • Apolipoprotein A-I primes beta cells to increase glucose stimulated insulin secretion
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-22
    Oktawia Nilsson, Rita Del Giudice, Mototsugu Nagao, Caitriona Grönberg, Lena Eliasson, Jens O. Lagerstedt

    The increase of plasma levels of high-density lipoproteins and Apolipoprotein A-I (ApoA-I), its main protein component, has been shown to have a positive action on glucose disposal in type 2 diabetic patients. The current study investigates the unexplored function of ApoA-I to prime beta cells for improved insulin secretion. INS-1E rat clonal beta cells as well as isolated murine islets were used to study the effect of ApoA-I on responsiveness of the beta cells to high glucose challenge. Confocal and transmission electron microscopy were used to dissect ApoA-I mechanisms of action. Chemical endocytosis blockers were used to understand the role of ApoA-I internalization in mediating its positive effect. In high glucose environment, pre-incubation of beta cells and isolated murine islets with ApoA-I augmented insulin secretion. This effect appeared to be due to an increased reservoir of insulin granules at the cell membrane, as confirmed by confocal and transmission electron microscopy. Moreover, ApoA-I induced pancreatic and duodenal homeobox 1 (PDX1) shuttling from the cytoplasm to the nucleus, with the subsequent increase in the proinsulin processing enzyme protein convertase 1 (PC1/3). Finally, the blockade of ApoA-I endocytosis in beta cells resulted in a loss of ApoA-I positive action on insulin secretion. The proposed mechanisms of the phenomenon here described include ApoA-I internalization into beta cells, PDX1 nuclear translocation, and increased levels of proinsulin processing enzymes. Altogether, these events lead to an increased number of insulin granules.

    更新日期:2019-11-22
  • Pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency in zebrafish results in fatal seizures and metabolic aberrations
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-21
    Jolita Ciapaite, Monique Albersen, Sanne M.C. Savelberg, Marjolein Bosma, Federico Tessadori, Johan Gerrits, Nico Lansu, Susan Zwakenberg, Jeroen P.W. Bakkers, Fried J.T. Zwartkruis, Gijs van Haaften, Judith J. Jans, Nanda M. Verhoeven-Duif
    更新日期:2019-11-22
  • Mitochondrial remodeling in human skin fibroblasts from sporadic PD male patients uncovers metabolic and mitochondrial bioenergetics defects
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-20
    Cláudia M. Deus, Susana P. Pereira, Teresa Cunha-Oliveira, Francisco B. Pereira, Nuno Raimundo, Paulo J. Oliveira

    Parkinson's Disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra. The exact mechanism by which dopaminergic neurodegeneration occurs is still unknown; however, mitochondrial dysfunction has long been implicated in PD pathogenesis. To investigate the sub-cellular events that lead to disease progression and to develop personalized interventions, non-neuronal cells which are collected in a minimally invasive manner can be key to test interventions aimed at improving mitochondrial function. We used human skin fibroblasts from sporadic PD (sPD) patients as a cell proxy to detect metabolic and mitochondrial alterations which would also exist in a non-neuronal cell type. In this model, we used a glucose-free/galactose- glutamine- and pyruvate-containing cell culture medium, which forces cells to be more dependent on oxidative phosphorylation (OXPHOS) for energy production, in order to reveal hidden metabolic and mitochondrial alterations present in fibroblasts from sPD patients. We demonstrated that fibroblasts from sPD patients show hyperpolarized and elongated mitochondrial networks and higher mitochondrial ROS concentration, as well as decreased ATP levels and glycolysis-related ECAR. Our results also showed that abnormalities of fibroblasts from sPD patients became more evident when stimulating OXPHOS. Under these culture conditions, fibroblasts from sPD cells presented decreased basal respiration, ATP-linked OCR and maximal respiration, and increased mitochondria-targeting phosphorylation of DRP1 when compared to control cells. Our work validates the relevance of using fibroblasts from sPD patients to study cellular and molecular changes that are characteristic of dopaminergic neurodegeneration of PD, and shows that forcing mitochondrial OXPHOS uncovers metabolic defects that were otherwise hidden.

    更新日期:2019-11-21
  • Eicosanoid pathway on host resistance and inflammation during Mycobacterium tuberculosis infection is comprised by LTB4 reduction but not PGE2 increment
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-10-28
    Carlos Arterio Sorgi, Elyara Maria Soares, Rogério Silva Rosada, Claudia Silva Bitencourt, Karina Furlani Zoccal, Priscilla Aparecida Tartari Pereira, Caroline Fontanari, Izaíra Brandão, Ana Paula Masson, Simone Gusmão Ramos, Célio Lopes Silva, Fabiani Gai Frantz, Lúcia Helena Faccioli

    The functions of eicosanoids, a family of potent biologically active lipid mediators, are not restricted to inflammatory responses and they also act as mediators of the pathogenesis process. However, the role of eicosanoids in tuberculosis remains controversial. To investigate the specific role of LTB4 in Mycobacterium tuberculosis (Mtb) infection, we used 5-lipoxygenase-deficient (5-LO−/−) mice and WT (sv129) mice inoculated intranasally with LTB4 (encapsulated in PLGA microspheres). We showed that deficiency of the 5-LO pathway was related to resistance to Mtb infection. LTB4 inoculation increased susceptibility to Mtb in 5-LO−/− mice but not in WT mice, resulting in worsening of lung inflammation and tissue damage. In infected WT mice, most supplementary LTB4 was metabolized to the inactive form 12-oxo-LTB4 in the lung. A high amount of PGE2 was detected during Mtb infection, and pharmacological inhibition of COX-2 induced a significant reduction of bacterial load and an improved innate immune response in the lungs, independently of baseline LTB4 levels. COX-2 inhibition with celecoxib significantly reduced PGE2 levels, enhanced IFN-γ production and NO release, and increased macrophage phagocytosis of Mtb. The results suggest that a balance between PGE2/LTB4 is essential in the pathogenesis process of tuberculosis to prevent severe inflammation. Moreover, optimal levels of PGE2 are required to induce an effective innate response in the early phase of Mtb infection. Thus, pharmacological modulation of eicosanoid production may provide an important host-directed therapy in tuberculosis.

    更新日期:2019-11-18
  • DNA repair fidelity in stem cell maintenance, health, and disease
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-04-04
    Chinnadurai Mani, P. Hemachandra Reddy, Komaraiah Palle

    Stem cells are a sub population of cell types that form the foundation of our body, and have the potential to replicate, replenish and repair limitlessly to maintain the tissue and organ homeostasis. Increased lifetime and frequent replication set them vulnerable for both exogenous and endogenous agents-induced DNA damage compared to normal cells. To counter these damages and preserve genetic information, stem cells have evolved with various DNA damage response and repair mechanisms. Furthermore, upon experiencing irreparable DNA damage, stem cells mostly prefer early senescence or apoptosis to avoid the accumulation of damages. However, the failure of these mechanisms leads to various diseases, including cancer. Especially, given the importance of stem cells in early development, DNA repair deficiency in stem cells leads to various disabilities like developmental delay, premature aging, sensitivity to DNA damaging agents, degenerative diseases, etc. In this review, we have summarized the recent update about how DNA repair mechanisms are regulated in stem cells and their association with disease progression and pathogenesis.

    更新日期:2019-11-18
  • The potential contribution of stromal cell-derived factor 2 (SDF2) in endoplasmic reticulum stress response in severe preeclampsia and labor-onset
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-02-15
    Aline R. Lorenzon-Ojea, Hong Wa Yung, Graham J. Burton, Estela Bevilacqua

    Endoplasmic reticulum (ER) stress occurs when the protein folding machinery in the cell is unable to cope with newly synthesized proteins, which results in an accumulation of misfolded proteins in the ER lumen. In response, the cell activates a cellular signaling pathway known as the Unfolded Protein Response (UPR), aiming to restore cellular homeostasis. Activation and exacerbation of the UPR have been described in several human pathologies, including cancer and neurological disorders, and in some gestational diseases such as preeclampsia and gestational diabetes. This review explores the participation of stromal cell-derived factor 2 (SDF2) in UPR pathways, shows new information and discusses its exacerbation regarding protein expression in severe preeclampsia and labor, both of which are associated with ER stress.

    更新日期:2019-11-18
  • Nicotinamide riboside kinase-2 alleviates ischemia-induced heart failure through P38 signaling
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-16
    Firdos Ahmad, Dhanendra Tomar, Smriti Aryal A C, Adel B. Elmoselhi, Manfred Thomas, John W. Elrod, Douglas G. Tilley, Thomas Force

    Nicotinamide riboside kinase-2 (NRK-2), a muscle-specific β1 integrin binding protein, predominantly expresses in skeletal muscle with a trace amount expressed in healthy cardiac tissue. NRK-2 expression dramatically increases in mouse and human ischemic heart however, the specific role of NRK-2 in the pathophysiology of ischemic cardiac diseases is unknown. We employed NRK2 knockout (KO) mice to identify the role of NRK-2 in ischemia-induced cardiac remodeling and dysfunction. Following myocardial infarction (MI), or sham surgeries, serial echocardiography was performed in the KO and littermate control mice. Cardiac contractile function rapidly declined and left ventricular interior dimension (LVID) was significantly increased in the ischemic KO vs. control mice at 2 weeks post-MI. An increase in mortality was observed in the KO vs. control group. The KO hearts displayed increased cardiac hypertrophy and heart failure reflected by morphometric analysis. Consistently, histological assessment revealed an extensive and thin scar and dilated LV chamber accompanied with elevated fibrosis in the KOs post-MI. Mechanistically, we observed that loss of NRK-2 enhanced p38α activation following ischemic injury. Consistently, ex vivo studies demonstrated that the gain of NRK-2 function suppresses the p38α as well as fibroblast activation (α-SMA expression) upon TGF-β stimulation, and limits cardiomyocytes death upon hypoxia/re‑oxygenation. Collectively our findings show, for the first time, that NRK-2 plays a critical role in heart failure progression following ischemic injury. NRK-2 deficiency promotes post-MI scar expansion, rapid LV chamber dilatation, cardiac dysfunction and fibrosis possibly due to increased p38α activation.

    更新日期:2019-11-18
  • Mechanisms of extracellular vesicle uptake in stressed retinal pigment epithelial cell monolayers
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-15
    Crystal Nicholson, Navjot Shah, Masaaki Ishii, Balasubramaniam Annamalai, Carlene Brandon, Jessalyn Rodgers, Tamara Nowling, Bärbel Rohrer

    Purpose Extracellular vesicles (EVs) can mediate long-distance communication in polarized RPE monolayers. Specifically, EVs from oxidatively stressed donor cells (stress EVs) rapidly reduced barrier function (transepithelial resistance, TER) in naïve recipient monolayers, when compared to control EVs. This effect on TER was dependent on dynamin-mediated EV uptake, which occurred rapidly with EVs from oxidatively stressed donor cells. Here, we further determined molecular mechanisms involved in uptake of EVs by naïve RPE cells. Methods RPE cells were grown as monolayers in media supplemented with 1% FBS followed by transfer to FBS-free media. Cultures were used to collect control or stress EVs upon treatment with H2O2, others served as naïve recipient cells. In recipient monolayers, TER was used to monitor EV-uptake-based activity, live-cell imaging confirmed uptake. EV surface proteins were quantified by protein chemistry. Results Clathrin-independent, lipid raft-mediated internalization was excluded as an uptake mechanism. Known ligand-receptor interactions involved in clathrin-dependent endocytosis include integrins and proteoglycans. Desialylated glycans and integrin-receptors on recipient cells were necessary for EV uptake and subsequent reduction of TER in recipient cells. Protein quantifications confirmed elevated levels of ligands and neuraminidase on stress EVs. However, control EVs could confer activity in the TER assay if exogenous neuraminidase or additional ligand was provided. Conclusions In summary, while EVs from both stressed cells and control contain cargo to communicate stress messages to naive RPE cells, stress EVs contain surface ligands that confer rapid uptake by recipient cells. We propose that EVs potentially contribute to RPE dysfunction in aging and disease.

    更新日期:2019-11-18
  • PF4 antagonizes retinal neovascularization via inhibiting PRAS40 phosphorylation in a mouse model of oxygen-induced retinopathy
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-15
    Siwei Cai, Qianhui Yang, Yunshan Cao, Yahong Li, Juping Liu, Jiantao Wang, Xiaomin Zhang, Liren Liu, Xiaorong Li, Yan Zhang

    Retinal neovascularization (RNV) is a common pathology of blinding proliferative retinopathies. The current treatments to RNV, however, are hindered by limited efficacy, side effects, and drug resistance. A naturally-occurring cytokine in retina that is amicable to immune system and possesses robust anti-neovascular function would facilitate to overcome the hurdles. In this study, retinas from a mouse model of oxygen-induced retinopathy (OIR) underwent a protein array to screen the naturally-occurring cytokines that may antagonize RNV. Among the 62 angiogenesis-associated cytokines, platelet factor 4 (Pf4) stood out with the most prominent upregulation and statistical significance. Moreover, an intravitreal injection of mouse Pf4 demonstrated dramatic anti-vaso-obliteration and anti-neovascularization effects dose dependently in the OIR model; whereas human PF4 inhibited the proliferation, migration, and tubulogenesis of monkey retinal vascular endothelial cells treated with VEGF and TNF-α. These previously undescribed angiostatic effects of PF4 in OIR retinas and retinal vascular endothelial cells support translation of this naturally-occurring chemokine into a therapeutic modality to RNV supplementary to the anti-VEGFs. Mechanistically, a phosphorylation array and western blots indicated that downregulation of proline-rich Akt substrate of 40 kDa (Pras40) and its phosphorylation were necessary for Pf4's anti-neovascular effects in the OIR retinas. Indeed, overexpression of the wildtype Pras40 and the mutant version with deficient phosphorylation abolished and mimicked the Pf4's angiostatic effects in the OIR retinas, respectively. The similar effects were also observed in vitro. This study, for the first time, links PF4's anti-RNV function to an intracellular signaling molecule PRAS40 and its phosphorylation.

    更新日期:2019-11-18
  • Selective inhibition of PKR improves vascular inflammation and remodelling in high fructose treated primary vascular smooth muscle cells
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-15
    Jaspreet Kalra, Sureshbabu Mangali, Audesh Bhat, Kirtikumar Jadhav, Arti Dhar

    Background and objective Double-stranded RNA dependent protein kinase (PKR) is reported to play a critical role in the pathogenesis of diabetes and associated vascular complications. Increased PKR activity is observed in metabolic disorders. Increased PKR activity is reported to induce inflammation and oxidative stress. Inflammation and oxidative stress are implicated in the pathogenesis of vascular disease. There are no studies done so far about the role of PKR in vascular smooth muscle cells (VSMCs) and the underlying molecular mechanism. Thus the aim of the present study is to investigate the role of PKR in high fructose treated VSMCs. Moreover, a selective PKR inhibitor, imoxin (C16) was used to investigate the underlying molecular mechanism. Methods VSMCs were isolated by enzymatic digestion method from thoracic aorta of rats and incubated with high fructose (HF) and PKR inhibitor. Immunocytochemistry and Western blotting were performed for PKR and its downstream markers of inflammation, apoptosis and phenotypic transition (AGEs, MMP-9, and ERK1/2). Oxidative stress was measured using flow cytometry. Cellular hypertrophy and proliferative index were determined by haematoxylin and eosin staining, MTT assay, BrdU labelling assay and agarose gel electrophoresis. Scratch test was done for migratory behaviour. Alizarin red staining was performed for assessing vascular calcification. Mitochondrial membrane potential and chromatin condensation was determined by rhodamine 6G and DAPI staining. Results PKR expression was significantly increased in HF treated VSMCs which was accompanied by increase in levels of gene markers of inflammation, oxidative stress and apoptosis. Moreover, increase in cellular proliferation, phenotypic switch and decrease in membrane potential was observed in HF treated VSMCs. All these effects of HF were attenuated by selective PKR inhibitor, imoxin (C16). Conclusion In conclusion PKR activation plays an important role in the pathogenesis of vascular inflammation and remodelling, and therapeutically targeting PKR could be an effective approach to treat the abnormalities associated with vascular complications.

    更新日期:2019-11-15
  • Deciphering the role of protein kinase CK2 in the maturation/stability of CFTR F508del
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-15
    Claudio D'Amore, Christian Borgo, Valentina Bosello-Travain, Jordi Vilardell, Valentina Salizzato, Lorenzo A. Pinna, Andrea Venerando, Mauro Salvi

    F508del-CFTR, the most common mutation in cystic fibrosis (CF) patients, impairs CFTR trafficking to plasma membrane leading to its premature proteasomal degradation. Several post-translational modifications have been identified on CFTR with multiple roles in stability, localization and channel function, and the possibility to control the enzymes responsible of these modifications has been long considered a potential therapeutic strategy. Protein kinase CK2 has been previously suggested as an important player in regulating CFTR functions and it has been proposed as a pharmacological target in a combinatory therapy to treat CF patients. However, the real implication of CK2 in F508del-CFTR proteostasis, and in particular the hypothesis that its inhibition could be important in CF therapies, is still elusive. Here, by using immortalized cell lines, primary human cells, and knockout cell lines deprived of CK2 subunits, we do not disclose any direct correlation between F508del-CFTR proteostasis and CK2 expression/activity. Rather, our data indicate that the CK2α′ catalytic subunit should be preserved rather than inhibited for F508del rescue by the correctors of class-1, such as VX-809, disclosing new important features in CF therapeutic approaches.

    更新日期:2019-11-15
  • Agonist-induced 4-1BB activation prevents the development of Sjӧgren's syndrome-like sialadenitis in non-obese diabetic mice
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-15
    Jing Zhou, BoRa You, Qing Yu

    Activation of costimulatory receptor 4-1BB enhances T helper 1 (Th1) and CD8 T cell responses in protective immunity, and prevents or attenuates several autoimmune diseases by increasing Treg numbers and suppressing Th17 or Th2 effector response. We undertook this study to elucidate the impact of enforced 4-1BB activation on the development of SS-like sialadenitis in non-obese diabetic (NOD) model of this disease. An anti-4-1BB agnostic antibody was intraperitoneally injected to female NOD mice aged 7 weeks, prior to the disease onset that occurs around 10–11 weeks of age, 3 times weekly for 2 weeks, and the mice were analyzed for SS pathologies at age 11 weeks. The salivary flow rate was markedly higher in the anti-4-1BB-treated NOD mice compared to the IgG-treated controls. Anti-4-1BB treatment significantly reduced the leukocyte infiltration of the submandibular glands (SMGs) and the levels of serum antinuclear antibodies. Flow cytometric analysis showed that the percentages of CD4 T cells, Th17 cells and plasmacytoid dendritic cells among SMG leukocytes were markedly reduced by anti-4-1BB treatment, in conjunction with a reduction in SMG IL-23p19 mRNA levels and serum IL-17 concentrations. Although the proportion of Tregs and IL-10 mRNA levels in SMGs were not altered by 4-1BB activation, IL-10 mRNA levels in submandibular lymph nodes and serum IL-10 concentrations were both markedly increased. While anti-4-1BB treatment did not affect the amount of Th1 cells and IFNγ mRNA, it increased these measurables in submandibular lymph nodes. Hence, agonistic activation of 4-1BB impedes the development of SS-like sialadenitis and hyposalivation.

    更新日期:2019-11-15
  • Liver-specific deletion of Ngly1 causes abnormal nuclear morphology and lipid metabolism under food stress
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-13
    Haruhiko Fujihira, Yuki Masahara-Negishi, Yoshihiro Akimoto, Hiroto Hirayama, Hyeon-Cheol Lee, Benjamin A. Story, William F. Mueller, Petra Jakob, Sandra Clauder-Münster, Lars M. Steinmetz, Senthil K. Radhakrishnan, Hayato Kawakami, Yoshihiro Kamada, Eiji Miyoshi, Takehiko Yokomizo, Tadashi Suzuki

    The cytoplasmic peptide:N-glycanase (Ngly1) is a de-N-glycosylating enzyme that cleaves N-glycans from misfolded glycoproteins and is involved in endoplasmic reticulum-associated degradation. The recent discovery of NGLY1-deficiency, which causes severe systemic symptoms, drew attention to the physiological function of Ngly1 in mammals. While several studies have been carried out to reveal the physiological necessity of Ngly1, the semi-lethal nature of Ngly1-deficient animals made it difficult to analyze its function in adults. In this study, we focus on the physiological function of Ngly1 in liver (hepatocyte)-specific Ngly1-deficient mice generated using the cre-loxP system. We found that hepatocyte-specific Ngly1-deficient mice showed abnormal hepatocyte nuclear size/morphology with aging but did not show other notable defects in unstressed conditions. This nuclear phenotype did not appear to be related to the function of the only gene currently reported to rescue Ngly1-deficient murine lethality so far, endo-β-N-acetylglucosaminidase. We also found that under a high fructose diet induced stress, the hepatocyte-specific Ngly1-deletion resulted in liver transaminases elevation and increased lipid droplet accumulation. We showed that the processing and localization of the transcription factor, nuclear factor erythroid 2-like 1 (Nfe2l1), was impaired in the Ngly1-deficient hepatocytes. Therefore, Nfe2l1, at least partially, contributes to the phenotypes observed in hepatocyte-specific Ngly1-deficient mice. Our results indicate that Ngly1 plays important roles in the adult liver impacting nuclear morphology and lipid metabolism. Hepatocyte-specific Ngly1-deficient mice could thus serve as a valuable animal model for assessing in vivo efficacy of drugs and/or treatment for NGLY1-deficiency.

    更新日期:2019-11-13
  • The deficiency of NRSF/REST enhances the pro-inflammatory function of astrocytes in the model of Parkinson's disease
    BBA Mol. Basis Dis. (IF 4.328) Pub Date : 2019-11-07
    Heng Li, Zhaolin Liu, Yufei Wu, Yajing Chen, Jinghui Wang, Zishan Wang, Dongping Huang, Mo Wang, Mei Yu, Jian Fei, Fang Huang

    Neuroinflammation, as an important pathological characteristic of Parkinson's disease (PD), is primarily mediated by activated astrocytes and microglia. Neuron-restrictive silencer factor/repressor element 1 (RE1)-silencing transcription factor (NRSF/REST) regulates many genes and signal pathways involved in the inflammatory process in astrocytes. In the present study, we established the GFAP-Cre:NRSFflox/flox conditional knockout (cKO) mice. The expression of inflammation-associated molecules were measured in primary astrocytes from wild type (WT) and cKO mice after stimulation by 1-Methyl-4-phenylpyridine (MPP+), LPS, and conditioned medium (CM) of LPS-treated BV-2 microglial cells. The inflammatory molecule expression in BV-2 microglial cells exposed to conditioned medium of MPP+-treated primary astrocytes were also analyzed. Moreover, a subacute regimen of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP) was used to establish mouse PD model and the damages to the nigrostriatal pathway were comprehensively evaluated in WT and cKO mice. We found that MPP+ induced a remarkable increase of NRSF expression in cultured astrocytes. Compared to WT astrocytes, the expression of inflammatory molecules IL-1β, IL-6, COX-2, and iNOS increased dramatically in NRSF deficient astrocytes challenged with CM of LPS-treated BV-2 cells. COX-2 and IL-1β transcripts were significantly elevated in BV-2 microglial cells exposed to CM of MPP+-treated NRSF deficient astrocytes compared to WT astrocytes. In cKO mice, the activation of astrocytes and microglial cells was more obvious, and the nigrostriatal dopaminergic system was more heavily injured compared to their WT counterparts after MPTP administration. Our results suggest that reactive NRSF deficient astrocytes orchestrated with microglial cells aggravate the pathophysiological progress in PD.

    更新日期:2019-11-08
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