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  • Glutamine Skipping the Q into Mitochondria
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-12-19
    Zachary E. Stine; Chi V. Dang

    Imported across the plasma membrane by SLC1A5, glutamine has emerged as a metabolic fuel that is catabolized by mitochondrial glutaminase to support tumor growth. The missing link between cytoplasmic and mitochondrial glutamine metabolism is now provided by Yoo et al., identifying the mitochondrial glutamine importer as a variant of SLC1A5.

  • Do Two Mitochondrial Wrongs Help Make Cells Right?
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-12-05
    Ajit S. Divakaruni; Anne N. Murphy

    Using an unbiased genetic screen, To et al. map genes that enhance or suppress growth defects in response to different mitochondrial inhibitors to model mitochondrial disease. The findings have novel implications for the interconnectivity of bioenergetic pathways, and suggest a provocative strategy to treat primary mitochondrial disorders.

  • Regulation of Mitochondrial ATP Production: Ca2+ Signaling and Quality Control
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-22
    Liron Boyman; Mariusz Karbowski; W. Jonathan Lederer

    Cardiac ATP production primarily depends on oxidative phosphorylation in mitochondria and is dynamically regulated by Ca2+ levels in the mitochondrial matrix as well as by cytosolic ADP. We discuss mitochondrial Ca2+ signaling and its dysfunction which has recently been linked to cardiac pathologies including arrhythmia and heart failure. Similar dysfunction in other excitable and long-lived cells including neurons is associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Central to this new understanding is crucial Ca2+ regulation of both mitochondrial quality control and ATP production. Mitochondria-associated membrane (MAM) signaling from the sarcoplasmic reticulum (SR) and the endoplasmic reticulum (ER) to mitochondria is discussed. We propose future research directions that emphasize a need to define quantitatively the physiological roles of MAMs, as well as mitochondrial quality control and ATP production.

  • Mitochondria–Lysosome Crosstalk: From Physiology to Neurodegeneration
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-29
    Cláudia M. Deus; King Faisal Yambire; Paulo J. Oliveira; Nuno Raimundo

    Cellular function requires coordination between different organelles and metabolic cues. Mitochondria and lysosomes are essential for cellular metabolism as major contributors of chemical energy and building blocks. It is therefore pivotal for cellular function to coordinate the metabolic roles of mitochondria and lysosomes. However, these organelles do more than metabolism, given their function as fundamental signaling platforms in the cell that regulate many key processes such as autophagy, proliferation, and cell death. Mechanisms of crosstalk between mitochondria and lysosomes are discussed, both under physiological conditions and in diseases that affect these organelles.

  • Drug Development for the Therapy of Mitochondrial Diseases
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-11
    Volkmar Weissig

    Mitochondrial diseases are a heterogeneous group of inherited or acquired devastating disorders that affect the energy metabolism of the body. Many strategies have been investigated, but currently there is no FDA-approved drug that can alleviate disease symptoms or slow disease progression. This review analyzes to what extent growing knowledge over the past two decades about the etiology and pathogenesis of mitochondrial diseases is reflected in the design and development of new experimental drugs for the therapy of these disorders. All currently registered clinical trials involving new experimental drug entities are reviewed to evaluate how far away we are from the first FDA-approved drug therapy for mitochondrial disease.

  • Mitochondrial Defects Drive Degenerative Retinal Diseases
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-23
    Deborah A. Ferrington; Cody R. Fisher; Renu A. Kowluru

    Mitochondrial dysfunction is involved in the pathology of two major blinding retinal diseases, diabetic retinopathy (DR) and age-related macular degeneration (AMD). These diseases accumulate mitochondrial defects in distinct retinal subcellular structures, the vascular/neural network in DR and the retinal pigment epithelium (RPE) in AMD. These mitochondrial defects cause a metabolic crisis that drives disease. With no treatments to stop these diseases, coupled with an increasing population suffering from AMD and DR, there is an urgent need to develop new therapeutics targeting the mitochondria to prevent or reverse disease-specific pathology.

  • Cardiac Glycosides as Senolytic Compounds
    Trends Mol. Med. (IF 11.028) Pub Date : 2020-01-23
    Nadine Martin; Olivier Soriani; David Bernard

    The identification of senolytics, compounds that eliminate senescent cells, is presently a key priority given their therapeutic promise in cancer and aging-associated diseases. Two recent papers by Triana-Martínez et al. and Guerrero et al. report the senolytic activity of cardiac glycosides (CGs) and their efficacy in these pathophysiological contexts.

  • Commercialization of Organoids
    Trends Mol. Med. (IF 11.028) Pub Date : 2020-01-22
    Deepak Choudhury; Aswathi Ashok; May Win Naing

    Organoids have been successfully exploited for drug screening, disease modeling, pathogenesis, and regenerative medicine. Herein, we discuss the progress achieved in the commercialization of organoids in the last few years. We further elaborate on the concept of organoid biobank and highlight ethical and regulatory issues surrounding organoid research and commercialization.

  • Glymphatic System Impairment in Alzheimer’s Disease and Idiopathic Normal Pressure Hydrocephalus
    Trends Mol. Med. (IF 11.028) Pub Date : 2020-01-18
    Benjamin C. Reeves; Jason K. Karimy; Adam J. Kundishora; Humberto Mestre; H. Mert Cerci; Charles Matouk; Seth L. Alper; Iben Lundgaard; Maiken Nedergaard; Kristopher T. Kahle

    Approximately 10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer’s disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and amyloid-β (Aβ) plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte aquaporin-4 (AQP4). The glia–lymphatic (glymphatic) system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics.

  • Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-12-17
    Amit Bar-Or; Michael P. Pender; Rajiv Khanna; Lawrence Steinman; Hans-Peter Hartung; Tap Maniar; Ed Croze; Blake T. Aftab; Gavin Giovannoni; Manher J. Joshi

    New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein–Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.

  • Vitamins for the Gut Microbiome
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-12-17
    Robert E. Steinert; Yuan-Kun Lee; Wilbert Sybesma

    A main target in microbiome research is the understanding and ability to safely and effectively modulate the microbiome to improve health. Hereto, we discuss the role of vitamins in relation to the gut microbiome and present a rationale for the modulation of gut microbial communities via selected systemic and colon-targeted vitamin administration.

  • Resolving Spliceosomal Malfunctions Advances RNA-Based Therapeutics
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-12-10
    Zhao Zhang, Shengli Li, Leng Han

    Spliceosomes comprise small nuclear (sn)RNAs and proteins. Through genome-wide analyses in large-scale tumor samples, recent studies by Shuai et al., Suzuki et al., and Inoue et al. have identified recurrent spliceosomal mutations that induced genome-wide splicing alterations of cancer-related genes to promote malignancy. These discoveries suggest novel RNA-based therapeutics in anticancer treatment.

  • Missing Pieces to the Endocannabinoid Puzzle
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-12-07
    Mauro Maccarrone

    The most bioactive ingredient of cannabis (Cannabis sativa or indica) extracts, Δ9-tetrahydrocannabinol (THC), was identified in the 1960s as one of more than 110 phytocannabinoids. It activates receptors of chemically different endogenous ligands (endocannabinoids) that, unlike THC, are metabolized by several enzymes of the endocannabinoid system. Here, the complexity of the plant-derived and endogenous cannabinoids (eCBs) is discussed, to better appreciate the challenge of: (i) dissecting their mutual interactions; (ii) understanding their impact on human pathophysiology; and (iii) exploiting them for human disease. To this aim, missing pieces to the eCB puzzle must be urgently found, by solving the 3D structures of key components, and interrogating noncanonical modes of regulation and trafficking of these lipid signals.

  • Editing Cytoprotective Autophagy in Glioma: An Unfulfilled Potential for Therapy
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-29
    Ilya Ulasov, Jawad Fares, Petr Timashev, Maciej S. Lesniak

    Glioblastoma (GBM) resistance to the standard of care is prompting scientists to develop better targeted therapeutic strategies. Autophagy is one of the many signaling mechanisms that regulate tumor regrowth. Despite the extensive in vitro and in vivo studies published, knowledge on autophagic modulation remains scarce. This hinders the development of novel treatment modalities that employ autophagic mechanisms for the clinical benefit of patients with GBM. Clinical trials for GBM continue to fall short of showing significant survival or clinical benefit, with the complex glioma heterogeneity often being the reason to blame. Here, we propose that a combination therapy of current antiglioma regimens and autophagic mediators or suppressors can allow us to overcome GBM regrowth in the context of tumor heterogeneity.

  • CRISPR Diagnosis and Therapeutics with Single Base Pair Precision
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-29
    Seung Hwan Lee, Young-Ho Park, Yeung Bae Jin, Sun-Uk Kim, Junho K. Hur

    Clustered regularly interspaced short palindromic repeats, or CRISPR, has been widely accepted as a versatile genome editing tool with significant potential for medical application. Reliable allele specificity is one of the most critical elements for successful application of this technology to develop high-precision therapeutics and diagnostics. CRISPR-based genome editing tools achieve high-fidelity distinction of single-base differences in target genomic loci by structural identification of CRISPR-associated (Cas) proteins and sequences of the guide RNAs. In this review, we describe the structural features of ribonucleoprotein complex formation by CRISPR proteins and guide RNAs that eventually recognize target DNA sequences. This structural understanding provides the basis for the recent applications of enhanced single-base precision genome editing technologies for effective distinction of specific alleles.

  • Microbe–MUC1 Crosstalk in Cancer-Associated Infections
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-18
    Mukulika Bose, Pinku Mukherjee

    Infection-associated cancers account for ∼20% of all malignancies. Understanding the molecular mechanisms underlying infection-associated malignancies may help in developing diagnostic biomarkers and preventative vaccines against malignancy. During infection, invading microbes interact with host mucins lining the glandular epithelial cells and trigger inflammation. MUC1 is a transmembrane mucin glycoprotein that is present on the surface of almost all epithelial cells, and is known to interact with invading microbes. This interaction can trigger pro- or anti-inflammatory responses depending on the microbe and the cell type. In this review we summarize the mechanisms of microbe and MUC1 interactions, and highlight how MUC1 plays contrasting roles in different cells. We also share perspectives on future research that may support clinical advances in infection-associated cancers.

  • Self-DNA Sensing Fuels HIV-1-Associated Inflammation
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-07-09
    Martin Heil, Norbert H. Brockmeyer

    Inflammation, over-reacting innate immunity, and CD4+ T cell depletion are hallmarks of HIV-1 infection. Self-DNA is usually not considered in the context of HIV-1-associated inflammation, although self-DNA contributes to inflammation in diverse pathologies, including autoimmune diseases, cancer, multiorgan failure after trauma, and even virus infections. Cells undergoing HIV-1-associated pyroptotic bystander cell death release self-DNA and other damage-associated molecular patterns (DAMPs), including chaperones and histones. In complexes with such DAMPs or extracellular vesicles, self-DNA gains immunogenic potential and becomes accessible to intracellular DNA sensors. Therefore, we hypothesize that self-DNA can contribute to HIV-1-associated inflammation. Self-DNA might not only drive HIV-1-associated ‘inflamm-ageing’ but also provide new opportunities for ‘shock and kill’ strategies aimed at eliminating latent HIV-1.

  • DNA Methylation-Based Point-of-Care Cancer Detection: Challenges and Possibilities
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-06-25
    Abu Ali Ibn Sina, Laura G. Carrascosa, Matt Trau

    Eukaryotic cell DNA conserves a distinct genomic methylation pattern, which acts as a molecular switch to control the transcriptional machinery of the cell. However, pathological processes can alter this methylation pattern, leading to the onset of diseases such as cancer. Recent advances in methylation analysis provide a more precise understanding of the consequence of DNA methylation changes towards cancer progression. Consequently, the discoveries of numerous methylation-based biomarkers have inspired the development of simple tests for cancer detection. In this opinion article, we systematically discuss the benefits and challenges associated with the promising methylation-based approaches and develop a point-of-care index to evaluate their potential in terms of point-of-care cancer diagnostics.

  • PRMTs and Arginine Methylation: Cancer’s Best-Kept Secret?
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-06-20
    James Jarrold, Clare C. Davies

    Post-translational modification (PTM) of proteins is vital for increasing proteome diversity and maintaining cellular homeostasis. If the writing, reading, and removal of modifications are not controlled, cancer can develop. Arginine methylation is an understudied modification that is increasingly associated with cancer progression. Consequently protein arginine methyltransferases (PRMTs), the writers of arginine methylation, have rapidly gained interest as novel drug targets. However, for clinical success a deep mechanistic understanding of the biology of PRMTs is required. In this review we focus on advances made regarding the role of PRMTs in stem cell biology, epigenetics, splicing, immune surveillance and the DNA damage response, and highlight the rapid rise of specific inhibitors that are now in clinical trials for cancer therapy.

  • Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-07-25
    Jian Chen, Julian A. Gingold, Xiaoping Su

    Hepatocellular carcinoma (HCC) is an inflammation-induced and chemotherapy-resistant cancer. Dysregulated signaling in the transforming growth factor beta (TGF-β) pathway plays a central role in inflammation, fibrogenesis, and immunomodulation in the HCC microenvironment. This review dissects the genetic landscape of the TGF-β superfamily genes in HCC and discusses the essential effects of this pathway on the tumor immune microenvironment. We highlight the TGF-β signature as a potential biomarker for identifying individualized immunotherapeutic approaches in HCC. An improved understanding of the detailed mechanisms of liver cancer immunogenicity and the specific role of TGF-β in mediating immunotherapy resistance in HCC will provide important insights into HCC immune escape and promote the development of biomarker-derived combination immunotherapies for HCC.

  • Molecular Underpinnings Governing Genetic Complexity of ETS-Fusion-Negative Prostate Cancer
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-07-25
    Vipul Bhatia, Bushra Ateeq

    Inter- and intra-patient molecular heterogeneity of primary and metastatic prostate cancer (PCa) confers variable clinical outcome and poses a formidable challenge in disease management. High-throughput integrative genomics and functional approaches have untangled the complexity involved in this disease and revealed a spectrum of diverse aberrations prevalent in various molecular subtypes, including ETS fusion negative. Emerging evidence indicates that SPINK1 upregulation, mutations in epigenetic regulators or chromatin modifiers, and SPOP are associated with the ETS-fusion negative subtype. Additionally, patients with defects in a DNA-repair pathway respond to poly-(ADP-ribose)-polymerase (PARP) inhibition therapies. Furthermore, a new class of immunogenic subtype defined by CDK12 biallelic loss has also been identified in ETS-fusion-negative cases. This review focuses on the emerging molecular underpinnings driving key oncogenic aberrations and advancements in therapeutic strategies of this disease.

  • Mitophagy and Neuroprotection
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-07-30
    Guofeng Lou, Konstantinos Palikaras, Sofie Lautrup, Morten Scheibye-Knudsen, Nektarios Tavernarakis, Evandro F. Fang

    Neurodegenerative diseases are strongly age-related and currently cannot be cured, with a surge of patient numbers in the coming decades in view of the emerging worldwide ageing population, bringing healthcare and socioeconomic challenges. Effective therapies are urgently needed, and are dependent on new aetiological mechanisms. In neurons, efficient clearance of damaged mitochondria, through the highly evolutionary conserved cellular process termed mitophagy, plays a fundamental role in mitochondrial and metabolic homeostasis, energy supply, neuronal survival, and health. Conversely, defective mitophagy leads to accumulation of damaged mitochondria and cellular dysfunction, contributing to ageing and age-predisposed neurodegeneration. Here, we discuss the contribution of defective mitophagy in these diseases, and underlying molecular mechanisms, and highlight novel therapeutics based on new discovered mitophagy-inducing strategies.

  • The Mitochondrion as an Emerging Therapeutic Target in Cancer
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-07-18
    Katherine G. Roth, Isa Mambetsariev, Prakash Kulkarni, Ravi Salgia

    Mitochondria have emerged as important pharmacological targets because of their key role in cellular proliferation and death. In tumor tissues, mitochondria can switch metabolic phenotypes to meet the challenges of high energy demand and macromolecular synthesis. Furthermore, mitochondria can engage in crosstalk with the tumor microenvironment, and signals from cancer-associated fibroblasts can impinge on mitochondria. Cancer cells can also acquire a hybrid phenotype in which both glycolysis and oxidative phosphorylation (OXPHOS) can be utilized. This hybrid phenotype can facilitate metabolic plasticity of cancer cells more specifically in metastasis and therapy-resistance. In light of the metabolic heterogeneity and plasticity of cancer cells that had until recently remained unappreciated, strategies targeting cancer metabolic dependency appear to be promising in the development of novel and effective cancer therapeutics.

  • Mitochondrial Regulation of Stem Cells in Bone Homeostasis
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-05-21
    Chen-Xi Zheng, Bing-Dong Sui, Xin-Yu Qiu, Cheng-Hu Hu, Yan Jin

    Mitochondria have emerged as key contributors to the organismal homeostasis, in which mitochondrial regulation of stem cells is becoming increasingly important. Originated from mesenchymal stem cell (MSC) and hematopoietic stem cell (HSC) lineage commitments and interactions, bone is a representative organ where the mitochondrial essentiality to stem cell function has most recently been discovered, underlying skeletal health, aging, and diseases. Furthermore, mitochondrial medications based on modulating stem cell specification are emerging to provide promising therapies to counteract bone aging and pathologies. Here we review the cutting-edge knowledge regarding mitochondrial regulation of stem cells in bone homeostasis, highlighting mechanistic insights as well as mitochondrial strategies for augmented bone healing and tissue regeneration.

  • Staying in Healthy Contact: How Peroxisomes Interact with Other Cell Organelles
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-11
    Yelena Sargsyan, Sven Thoms

    Peroxisomes share extensive metabolic connections with other cell organelles. Membrane contact sites (MCSs) establish and maintain such interactions, and they are vital for organelle positioning and motility. In the past few years peroxisome interactions and MCSs with other cellular organelles have been explored extensively, resulting in the identification of new MCSs, the tethering molecules involved, and their functional characterization. Defective tethering and compartmental communication can lead to pathological conditions that can be termed ‘organelle interaction diseases’. We review peroxisome–organelle interactions in mammals and summarize the most recent knowledge of mammalian peroxisomal organelle contacts in health and disease.

  • Crosstalk between Sertoli and Germ Cells in Male Fertility
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-11
    Siwen Wu, Ming Yan, Renshan Ge, C. Yan Cheng

    Spermatogenesis is supported by intricate crosstalk between Sertoli cells and germ cells including spermatogonia, spermatocytes, haploid spermatids, and spermatozoa, which takes place in the epithelium of seminiferous tubules. Sertoli cells, also known as ‘mother’ or ‘nurse’ cells, provide nutrients, paracrine factors, cytokines, and other biomolecules to support germ cell development. Sertoli cells facilitate the generation of several biologically active peptides, which include F5-, noncollagenous 1 (NC1)-, and laminin globular (LG)3/4/5-peptide, to modulate cellular events across the epithelium. Here, we critically evaluate the involvement of these peptides in facilitating crosstalk between Sertoli and germ cells to support spermatogenesis and thus fertility. Modulating or mimicking the activity of F5-, NC1-, and LG3/4/5-peptide could be used to enhance the transport across the blood–testis barrier (BTB) of contraceptive drugs or to treat male infertility.

  • Strengthening Causal Inference for Complex Disease Using Molecular Quantitative Trait Loci
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-09
    Sonja Neumeyer, Gibran Hemani, Eleftheria Zeggini

    Large genome-wide association studies (GWAS) have identified loci that are associated with complex traits and diseases, but index variants are often not causal and reside in non-coding regions of the genome. To gain a better understanding of the relevant biological mechanisms, intermediate traits such as gene expression and protein levels are increasingly being investigated because these are likely mediators between genetic variants and disease outcome. Genetic variants associated with intermediate traits, termed molecular quantitative trait loci (molQTLs), can then be used as instrumental variables in a Mendelian randomization (MR) approach to identify the causal features and mechanisms of complex traits. Challenges such as pleiotropy and the non-specificity of molQTLs remain, and further approaches and methods need to be developed.

  • Glucocorticoid Maturation of Fetal Cardiovascular Function
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-09
    Juanita K. Jellyman, Andrew J.W. Fletcher, Abigail L. Fowden, Dino A. Giussani

    The last decade has seen rapid advances in the understanding of the central role of glucocorticoids in preparing the fetus for life after birth. However, relative to other organ systems, maturation by glucocorticoids of the fetal cardiovascular system has been ignored. Here, we review the effects of glucocorticoids on fetal basal cardiovascular function and on the fetal cardiovascular defense responses to acute stress. This is important because glucocorticoid-driven maturational changes in fetal cardiovascular function under basal and stressful conditions are central to the successful transition from intra- to extrauterine life. The cost–benefit balance for the cardiovascular health of the preterm baby of antenatal glucocorticoid therapy administered to pregnant women threatened with preterm birth is also discussed.

  • Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-07
    Sarah E. Lee, Monica Duran-Martinez, Sabina Khantsis, Diana W. Bianchi, Faycal Guedj

    While preclinical studies have reported improvement of behavioral deficits in the Ts65Dn mouse model of Down syndrome (DS), translation to human clinical trials to improve cognition in individuals with DS has had a poor success record. Timing of the intervention, choice of animal models, strategy for drug selection, and lack of translational endpoints between animals and humans contributed to prior failures of human clinical trials. Here, we focus on in vitro cell models from humans with DS to identify the molecular mechanisms underlying the brain phenotype associated with DS. We emphasize the importance of using these cell models to screen for therapeutic molecules, followed by validating them in the most suitable animal models prior to initiating human clinical trials.

  • MCL1 as a Therapeutic Target in Parkinson's Disease?
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-06
    Edward J. Robinson, Sebastian Aguiar, Marten P. Smidt, Lars P. van der Heide

    Dopamine neurons in the substantia nigra (SN) pars compacta are selectively lost during the progression of Parkinson’s disease (PD). Recent work performed on the role of the Bcl2 family (highly specialized proteins which control cellular survival and death) in midbrain dopamine neurons has led to the identification of the Bcl2 factor Mcl1 as a weak link in the survival of these neurons. We hypothesize that the regulation of BCL2 proteins may explain this selective vulnerability, and may even provide a novel therapeutic opportunity – strengthening weak links such as MCL1 could result in a delay or complete abrogation of cell death during PD.

  • Visualizing Mitochondrial Form and Function within the Cell
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-06
    Brian Glancy

    The specific cellular role of mitochondria is influenced by the surrounding environment because effective mitochondrial function requires the delivery of inputs (e.g., oxygen) and export of products (e.g., signaling molecules) to and from other cellular components, respectively. Recent technological developments in mitochondrial imaging have led to a more precise and comprehensive understanding of the spatial relationships governing the function of this complex organelle, opening a new era of mitochondrial research. Here, I highlight current imaging approaches for visualizing mitochondrial form and function within complex cellular environments. Increasing clarity of mitochondrial behavior within cells will continue to lend mechanistic insights into the role of mitochondria under normal and pathological conditions and point to spatially regulated processes that can be targeted to improve cellular function.

  • Applications of Spherical Nucleic Acid Nanoparticles as Delivery Systems
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-06
    Ahad Mokhtarzadeh, Hassan Vahidnezhad, Leila Youssefian, Jafar Mosafer, Behzad Baradaran, Jouni Uitto

    Spherical nucleic acids (SNAs) are nanostructures consisting of highly oriented, dense layers of oligonucleotides arranged in a spherical 3D geometry. Owing to their unique properties and function, SNAs occupy a material space distinct from 'DNA nanotechnology' and DNA origami. Over the past two decades SNAs have revolutionized gene regulation, drug delivery, gene therapy, and molecular diagnostics, and show promise for both antisense and RNAi therapy. We focus here on recent advances in the synthesis and application of SNAs in gene and drug delivery, diagnostics, and immunomodulation, as well as on the utility of nanoflares as intracellular mRNA detection systems.

  • Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-05
    Sergio Linares-Fernández, Céline Lacroix, Jean-Yves Exposito, Bernard Verrier

    mRNA vaccine platforms present numerous advantages, such as versatility, rapid production, and induction of cellular and humoral responses. Moreover, mRNAs have inherent adjuvant properties due to their complex interaction with pattern recognition receptors (PRRs). This recognition can be either beneficial in activating antigen-presenting cells (APCs) or detrimental by indirectly blocking mRNA translation. To decipher this Janus effect, we describe the different innate response mechanisms triggered by mRNA molecules and how each element from the 5′ cap to the poly-A tail interferes with innate/adaptive immune responses. Then, we emphasize the importance of some critical steps such as production, purification, and formulation as key events to further improve the quality of immune responses and balance innate and adaptive immunity.

  • Organotypic Neurovascular Models: Past Results and Future Directions
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-04
    Daniel A. Balikov, Emma H. Neal, Ethan S. Lippmann

    The high failure rates of clinical trials in neurodegeneration, perhaps most apparent in recent high-profile failures of potential Alzheimer’s disease therapies, have partially motivated the development of improved human cell-based models to bridge the gap between well-plate assays and preclinical efficacy studies in mice. Recently, cerebral organoids derived from stem cells have gained significant traction as 3D models of central nervous system (CNS) regions. Although this technology is promising, several limitations still exist; most notably, improper structural organization of neural cells and a lack of functional glia and vasculature. Here, we provide an overview of the cerebral organoid field and speculate how engineering strategies, including biomaterial fabrication and templating, might be used to overcome existing challenges.

  • Nrf2: Redox and Metabolic Regulator of Stem Cell State and Function
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-11-01
    Xiaozhen Dai, Xiaoqing Yan, Kupper A. Wintergerst, Lu Cai, Bradley B. Keller, Yi Tan

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, and excessive nutrient/metabolite supply. Because the production and fate of stem cells are often modulated by cellular redox and metabolic homeostasis, important roles of Nrf2 have emerged in the regulation of stem cell quiescence, survival, self-renewal, proliferation, senescence, and differentiation. In a rapidly advancing field, this review summarizes Nrf2 signaling in the context of stem cell state and function and provides a rationale for Nrf2 as a therapeutic target in stem cell-based regenerative medicine.

  • The 3D Genome as a Target for Anticancer Therapy
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-10-31
    Omar L. Kantidze, Katerina V. Gurova, Vasily M. Studitsky, Sergey V. Razin

    The role of 3D genome organization in the precise regulation of gene expression is well established. Accordingly, the mechanistic connections between 3D genome alterations and disease development are becoming increasingly apparent. This opinion article provides a snapshot of our current understanding of the 3D genome alterations associated with cancers. We discuss potential connections of the 3D genome and cancer transcriptional addiction phenomenon as well as molecular mechanisms of action of 3D genome-disrupting drugs. Finally, we highlight issues and perspectives raised by the discovery of the first pharmaceutical strongly affecting 3D genome organization.

  • Modeling Parkinson’s Disease Heterogeneity to Accelerate Precision Medicine
    Trends Mol. Med. (IF 11.028) Pub Date : 2019-10-30
    Gonzalo H. Olivares, Patricio Olguín, Andrés D. Klein

    A mechanistic understanding of the diverse clinical manifestations of Parkinson’s disease (PD) and variable patient response to treatments is lacking. Genetically diverse PD model organisms can be used to map modifier genes and understand clinically relevant phenotypes of varying severity. This strategy can accelerate the pace of discoveries for precision medicine purposes.

  • Mitochondria - A Powerful Therapeutic Target.
    Trends Mol. Med. (IF 11.028) Pub Date : null
    Claudia Willmes

  • Soluble amyloid precursor proteins and secretases as Alzheimer's disease biomarkers.
    Trends Mol. Med. (IF 11.028) Pub Date : 2014-02-14
    Robert Perneczky,Panagiotis Alexopoulos,Alexander Kurz

    Recently revised diagnostic guidelines for Alzheimer's disease (AD) emphasise the use of biomarkers, heralding a paradigm shift towards a more biological definition of the disorder. Currently available biomarkers offer added diagnostic accuracy in certain situations, but their performance in terms of early diagnostic sensitivity and specificity does not fully live up to the desired standards. One feasible approach to improve the diagnostic and prognostic performance of AD biomarkers is to measure upstream events of amyloid precursor protein (APP) processing, which are at the core of the initial phase of AD pathogenesis. Here we review evidence on the APP processing enzymes and their cleavage products and discuss possible applications and limitations in their use as AD biomarkers.

  • von Hippel-Lindau tumor suppressor: not only HIF's executioner.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-05-28
    Maria F Czyzyk-Krzeska,Jaroslaw Meller

    Loss of von Hippel-Lindau (VHL) protein function results in an autosomal-dominant cancer syndrome known as VHL disease, which manifests as angiomas of the retina, hemangioblastomas of the central nervous system, renal clear-cell carcinomas and pheochromocytomas. VHL tumor suppressor is a specific substrate-recognition component of the E3 ubiquitin complex, which regulates proteasomal degradation of the subunit of the hypoxia inducible transcription factor (HIF). Impaired VHL complex function leads to accumulation of HIF, overexpression of various HIF-induced gene products and formation of highly vascular neoplasia. However, the ubiquitylating role of the VHL complex extends beyond its function in regulating HIF, as it appears to regulate the stability of other proteins that might be involved in various steps of oncogenic processes.

  • Role of eNOS in neovascularization: NO for endothelial progenitor cells.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-05-28
    Dan G Duda,Dai Fukumura,Rakesh K Jain

    Nitric oxide (NO) is a gaseous molecule with an astonishingly wide range of physiological and pathophysiological activities, including the regulation of vessel tone and angiogenesis in wound healing, inflammation, ischaemic cardiovascular diseases and malignant diseases. Recent data have revealed the predominant role of endothelial nitric oxide synthase (eNOS), an endothelial-cell-specific isoform of NO producing enzyme, in both angiogenesis (the development of new blood vessels derived from existing vessels) and vasculogenesis (blood vessel formation de novo from progenitor cells). In addition, successes in gene therapy, together with the recent development of an eNOS-specific inhibitor, suggest that the modulation of eNOS might be a potent new strategy for the control of pathological neovascularization.

  • Beta-adrenoceptor polymorphisms and heart failure.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-04-27
    Martin J Lohse

    Many polymorphisms have been described for the genes encoding the beta 1, beta 2, and alpha 2c-adrenoceptors that result in altered signaling and/or regulatory properties of the receptors. Several studies have investigated whether these properties affect the cardiovascular function of these receptors in mice or in humans, but have yielded mixed results. Some studies suggest that adrenoceptor polymorphisms might alter the risk for heart failure and the response to treatment with beta-blockers. However, the complex haplotypes resulting from combinations of individual polymorphisms have not yet been investigated, and firm conclusions or recommendations cannot be made because of the low patient numbers in each of the study programs.

  • Recent advances in early-onset severe retinal degeneration: more than just basic research.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-04-27
    Markus N Preising,Steffen Heegaard

    Successful treatment of early-onset sever retinal degeneration (EOSRD) in an animal model of the disease has provided the first proof-o-principle for retinal gene therapy of higher mammals. Currently, large sets of DNA samples are screened to identify patients with Leber's congenital amaurosis (LCA) carrying mutations in RPE65 as possible candidates for gene therapy trials. Research into EOSRD and LCA aims to identify the function of proteins involved or phenotypic changes upon mutation. These data will be used to describe the disease phenotype and identify parameters that can predict the outcome of gene therapy trials.

  • Altered states: selectively drugging the Hsp90 cancer chaperone.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-04-27
    Paul Workman

    The molecular chaperone Hsp90 is an exciting cancer drug target. The first Hsp90 inhibitor to enter clinical trials--the geldanamycin derivative 17AAG--has recently demonstrated proof-of-concept for successful target modulation, with sighs of therapeutic benefit. An important property of Hsp90 inhibitors is their ability to cause simultaneous, combinatorial blockade of multiple cancer-causing pathways by promoting the degradation of many oncogenic client proteins. However, the reason for therapeutic selectivity in cancer cells versus normal cells is unclear. New research now shows that Hsp90 exists in cancer cells in a heightened, activated state that is highly susceptible to inhibition by 17AAG.

  • Brain targeting through the autonomous nervous system: lessons from prion diseases.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-04-27
    Stépahne Haïk,Baptiste A Faucheux,Jean-Jacques Hauw

    The human central nervous system (CNS) is targeted by diverse pathogens that use distinct pathways to bypass the blood-brain barrier, such as trafficking into the brain via infected blood cells or using retrograde axonal transport through sensory or motor fibers. Prions are transmissible agents that induce a devastating subacute neurodegeneration when they successfully reach the CNS. Two recent studies focusing on pathways of prion neuroinvasion provide converging evidence that, in the case of peripheral transmission, such as human consumption of contaminated tissue, the infectious agent uses the sympathetic noradrenergic neurons to reach the CNS after early replication in lymphoid tissues.

  • Establishing a connection between cilia and Bardet-Biedl Syndrome.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-04-27
    Kirk Mykytyn,Val C Sheffield

    Bardet-Biedl Syndrome (BBS) is a gentic disorder with primary features of retinal dystrophy, obesity, polydactyly, structural and functional renal abnormalities, and learning disabilities. In addition to displaying remarkable pleiotropy, BBS is a heterogeneous disorder with linkage to at least eight loci. The identification of the first five BBS genes provided little insight into BBS protein function. Ansley at al. have now identified a sixth BBS gene (BBS8) and provide evidence that the BBS8 protein and other BBS proteins localize to the basal body of ciliated cells, suggesting that BBS is a ciliary dysfunction disorder.

  • Unravelling the role of Humanin.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-04-27
    Ikuo Nishimoto,Masaaki Matsuoka,Takako niikura

    Humanin (HN), a recently identified neuroprotective factor against Alzheimer's disease-related insults, has been reported to function as an anti cell-death factor through multiple mechanisms. One mechanism, revealed in a glioblastoma cell line, involves the apoptosis-inducing protein Bax. This, in addition to the fact that HN is produced in certain normal tissues, such as testis, implies a potential role of HN in oncogenesis. A second mechanism, in neuronal cells, is via a putative cell-surface receptor. It is through this mechanism that HN exhibits its neuroprotective activity.

  • Malaria sporozoite: migrating for a living.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-04-27
    Olivier Silvie,Jean-François Franetich,Luarent Rénia,Dominique Mazier

    Plasmodium sporozoite invasion of host hepatocytes is an initial key step in infection by malaria parasite. Sporozoites can enter hepatocytes via two distinct pathways: by disruption of the plasma membrane followed by parasite migration through cells, or by the formation of a vacuole essential for further differentiation of the parasite. For Plasmodium falciparum, this differentiation requires the presence of CD81 on the hepatocyte surface. Recent findings with rodent parasites also suggest that migration through cells has an effect on both the sporozoite infectivity and the permissiveness of surrounding cells.

  • Cell fusion and reprogramming: resolving our transdifferences.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-04-27
    Nemanja Rodić,Michael S Rutenberg,Naohiro Terada

    Bone marrow-derived cells (BMDCs) can contribute to the regeneration of diverse adult tissues, including brain, liver and heart, following bone marrow transplantation. These unexpected events were initially considered a result of transdifferentiation of BMDCs, supporting the emerging idea of extended plasticity of adult stem cells. Although studies have now clearly demonstrated that spontaneous cell fusion, rather than transdifferentiation, was the primary cause for unexpected cell fate-switches of BMDCs into hepatocytes, Purkinje cells and cardiac myocytes in vivo.

  • Learning from PD-1 Resistance: New Combination Strategies.
    Trends Mol. Med. (IF 11.028) Pub Date : 2016-05-14
    Xia Bu,Kathleen M Mahoney,Gordon J Freeman

    Only a minority of cancer patients respond to anti PD-1 immunotherapy. A recent study demonstrates that PD-1 therapy-resistant melanoma patients present distinct signatures of upregulated genes involved in immunosuppression, angiogenesis, monocyte and macrophage chemotaxis, extracellular matrix remodeling, and epithelial-mesenchymal transition (EMT). Combination targeting of these pathways with PD-1 may help overcome PD-1 resistance, thus producing effective antitumor immunity.

  • The K/BxN mouse: a model of human inflammatory arthritis.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-01-15
    Henrik J Ditzel

  • The GPIbalpha-thrombin interaction: far from crystal clear.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-01-15
    Karen Vanhoorelbeke,Hans Ulrichts,Roland A Romijn,Eric G Huizinga,Hans Deckmyn

  • Molecular oncology in the post-genomic era: the challenge of proteomics.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-01-15
    Simone Mocellin,Carlo Riccardo Rossi,Pietro Traldi,Donato Nitti,Mario Lise

  • Molecular mechanisms of the modulatory effects of HCMV infection in tumor cell biology.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-01-15
    Jindrich Cinatl,Martin Scholz,Rouslan Kotchetkov,Jens-Uwe Vogel,Hans Wilhelm Doerr

  • IDO and tolerance to tumors.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-01-15
    David H Munn,Andrew L Mellor

  • 更新日期:2019-11-01
  • TGF-beta, T-cell tolerance and anti-CD3 therapy.
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-01-15
    Ramireddy Bommireddy,Thomas Doetschman

  • P-selectin modulation in haemostasis: one size fits all?
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-01-15
    Martin Grünewald,Martin Griesshammer

  • VEGF and ALS: the luckiest growth factor?
    Trends Mol. Med. (IF 11.028) Pub Date : 2004-01-15
    David A Greenberg,Kunlin Jin

  • Molecular aspects of bile formation and cholestasis.
    Trends Mol. Med. (IF 11.028) Pub Date : 2003-12-09
    Marco Arrese,Michael Trauner

    Recent insights into the cellular and molecular mechanisms that control the function and regulation of hepatobiliary transport have led to a greater understanding of the physiological significance of bile secretion. Individual carriers for bile acids and other organic anions in both liver and intestine have now been cloned from several species. In addition, complex networks of signals that regulate key enzymes and membrane transporters located in cells that participate in the metabolism or transport of biliary constituents are being unraveled. This knowledge has major implications for the pathogenesis of cholestatic liver diseases. Here, we review recent information on molecular aspects of hepatobiliary secretory function and its regulation in cholestasis. Potential implications of this knowledge for the design of new therapies of cholestatic disorders are also discussed.

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上海纽约大学William Glover