Chemical Strike against a Dominant-Inherited MUC1-Frameshifted Protein Associated with Progressive Kidney Disease.
Abstract In a recent paper by Dvela-Levitt et al., chemical screening using an immunofluorescent assay identified a compound that caused removal of a dominant-inherited misfolded secretory protein, mucin1-frameshifted, from an intracellular location in immortalized renal epithelial cells of a patient affected with progressive medullary cystic kidney disease. This illustrates the power of chemical screening at the cellular level to address specific proteinopathies and the utility of such compounds to illuminate novel cellular pathways that can clear toxic proteins. PMID: 31521560 [PubMed - as supplied by publi...
Source: Trends in Molecular Medicine - September 11, 2019 Category: Molecular Biology Authors: Thomas G, Horwich A Tags: Trends Mol Med Source Type: research

Hijacking of GABAA Receptors by Mutant Glycine Receptors.
Abstract Startle disease results from mutations in genes encoding inhibitory GlyR α1 and β subunits or the presynaptic glycine transporter GlyT2. However, the most effective therapies are benzodiazepines that potentiate inhibitory GABAAR function. A recent publication by Zou et al. adds further complexity by suggesting that dominant GlyR α1 mutants assemble into pre- and extrasynaptic GABAARs. PMID: 31521561 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - September 11, 2019 Category: Molecular Biology Authors: Harvey RJ Tags: Trends Mol Med Source Type: research

Checkpoint Inhibition and Infectious Diseases: A Good Thing?
Abstract The mammalian immune system has evolved the capacity to detect and destroy tumor cells. Tumors utilize multiple strategies to evade host immune surveillance, including the induction of the checkpoint molecules cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) to suppress antitumor immunity. Pharmacologic blockade of these molecules with checkpoint inhibitors (CPIs) restores T cell function and prolongs survival in patients with various malignancies. Emerging evidence suggests that the same checkpoint pathways may play a crucial role during infections. Indeed, ...
Source: Trends in Molecular Medicine - September 4, 2019 Category: Molecular Biology Authors: Abers MS, Lionakis MS, Kontoyiannis DP Tags: Trends Mol Med Source Type: research

Toward in silico Identification of Tumor Neoantigens in Immunotherapy.
Abstract Cancer immunotherapy includes cancer vaccination, adoptive T cell transfer (ACT) with chimeric antigen receptor (CAR) T cells, and administration of tumor-infiltrating lymphocytes and immune-checkpoint blockade such as anti-CTLA4/anti-PD1 inhibitors that can directly or indirectly target tumor neoantigens and elicit a T cell response. Accurate, rapid, and cost-effective identification of neoantigens, however, is critical for successful immunotherapy. Here, we review computational issues for neoantigen identification by summarizing the various sources of neoantigens and their identification from high-throu...
Source: Trends in Molecular Medicine - September 4, 2019 Category: Molecular Biology Authors: Zhou C, Zhu C, Liu Q Tags: Trends Mol Med Source Type: research

Cisplatin-Induced Ototoxicity: Updates on Molecular Targets.
Abstract Cis-diamminedichloridoplatinum (II) (cisplatin) is a chemotherapeutic drug currently prescribed for the treatment of many types of human cancer, but its use is associated with numerous adverse effects, one of which is ototoxicity. Cisplatin-induced hearing loss is mainly attributed to oxidative stress, but recent data suggest that inflammation could be the trigger event leading to inner ear cell death through endoplasmic reticulum (ER) stress, autophagy, necroptosis, and then intrinsic apoptosis. In this review, we look at the molecular targets of cisplatin, and the intracellular pathways underlying its o...
Source: Trends in Molecular Medicine - August 28, 2019 Category: Molecular Biology Authors: Gentilin E, Simoni E, Candito M, Cazzador D, Astolfi L Tags: Trends Mol Med Source Type: research

The Sweet Kiss Breaching Immunological Self-Tolerance.
Abstract Metabolic alterations leading to overactivation of nutrient-energy-sensing pathways have been linked to altered immunological self-tolerance. Now, Zhang and colleagues (Immunity, 2019) have identified a key role for high glucose consumption in exacerbating autoimmunity in mice via induction of T helper (Th)17 cells. This reveals a novel mechanism underlying effects of diet during autoimmunity development with major translational implications. PMID: 31451384 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - August 22, 2019 Category: Molecular Biology Authors: Galgani M, Matarese G Tags: Trends Mol Med Source Type: research

Deciphering the Ecology of Cystic Fibrosis Bacterial Communities: Towards Systems-Level Integration.
Abstract Despite over a decade of cystic fibrosis (CF) microbiome research, much remains to be learned about the overall composition, metabolic activities, and pathogenicity of the microbes in CF airways, limiting our understanding of the respiratory microbiome's relation to disease. Systems-level integration and modeling of host-microbiome interactions may allow us to better define the relationships between microbiological characteristics, disease status, and treatment response. In this way, modeling could pave the way for microbiome-based development of predictive models, individualized treatment plans, and nove...
Source: Trends in Molecular Medicine - August 19, 2019 Category: Molecular Biology Authors: Bevivino A, Bacci G, Drevinek P, Nelson MT, Hoffman L, Mengoni A Tags: Trends Mol Med Source Type: research

β Cell Senescence as a Common Contributor to Type 1 and Type 2 Diabetes.
β Cell Senescence as a Common Contributor to Type 1 and Type 2 Diabetes. Trends Mol Med. 2019 Aug 15;: Authors: Tian Y, Zhang Y, Fu X Abstract Type 1 (T1D) and type 2 diabetes (T2D), two distinct clinical entities principally driven by autoimmunity and metabolic dysfunction, respectively, are associated with β cell failure. Two studies (Thompson et al., Cell Metab., 2019 and Aguayo-Mazzucato et al., Cell Metab., 2019) now reveal a role for β cell senescence in T1D and T2D, and highlight the potential of senolytic therapy for these diseases. PMID: 31422036 [PubMed - as supplied by p...
Source: Trends in Molecular Medicine - August 15, 2019 Category: Molecular Biology Authors: Tian Y, Zhang Y, Fu X Tags: Trends Mol Med Source Type: research

Applications of CRISPR/Cas9 Technology in the Treatment of Lung Cancer.
This article reviews the current landscape of CRISPR/Cas9 applications for lung cancer treatment as a basis for further studies. Given its promising performance, in-depth and systematic research on the application of CRISPR/Cas9 in lung cancer treatment will be necessary in future studies for its successful implementation in clinical practice. PMID: 31422862 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - August 15, 2019 Category: Molecular Biology Authors: Jiang C, Lin X, Zhao Z Tags: Trends Mol Med Source Type: research

An Organ-On-A-Chip Engineered Platform to Study the Microbiota-Gut-Brain Axis in Neurodegeneration.
Abstract After decades of research, the etiology of neurodegenerative disorders such as Alzheimer's or Parkinson's disease is still mostly unknown. Recent findings indicate that the microorganisms in the human gut might be involved in neurodegenerative pathways. Here, we discuss an innovative groundbreaking bioengineering approach that could make a difference in this intriguing scenario. PMID: 31422037 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - August 14, 2019 Category: Molecular Biology Authors: Raimondi MT, Albani D, Giordano C Tags: Trends Mol Med Source Type: research

The Advent of Human Life Data Economics: (Trends in Molecular Medicine 25, 566-570; 2019).
PMID: 31399335 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - August 6, 2019 Category: Molecular Biology Authors: Zhavoronkov A, Church G Tags: Trends Mol Med Source Type: research

Targeting GPCRs Activated by Fatty Acid-Derived Lipids in Type 2 Diabetes.
Abstract G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, because of their diversity, cell-specific expression, and druggable sites accessible at the cell surface. Preclinical and clinical studies suggest that targeting GPCRs activated by fatty acid-derived lipids may have potential to improve glucose homeostasis and reduce complications in patients with type 2 diabetes (T2D). Despite the discontinued development of fasiglifam (TAK-875), the first FFA1 agonist to reach late-stage clinical trials, lipid-sensing receptors remain a viable target, albeit with a need for further charac...
Source: Trends in Molecular Medicine - July 31, 2019 Category: Molecular Biology Authors: Gendaszewska-Darmach E, Drzazga A, Koziołkiewicz M Tags: Trends Mol Med Source Type: research

Mitophagy and Neuroprotection.
Abstract 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 ...
Source: Trends in Molecular Medicine - July 30, 2019 Category: Molecular Biology Authors: Lou G, Palikaras K, Lautrup S, Scheibye-Knudsen M, Tavernarakis N, Fang EF Tags: Trends Mol Med Source Type: research

Direct Lineage Reprogramming for Brain Repair: Breakthroughs and Challenges.
Abstract Injury to the human central nervous system (CNS) is devastating because our adult mammalian brain lacks intrinsic regenerative capacity to replace lost neurons and induce functional recovery. An emerging approach towards brain repair is to instruct fate conversion of brain-resident non-neuronal cells into induced neurons (iNs) by direct lineage reprogramming. Considerable progress has been made in converting various source cell types of mouse and human origin into clinically relevant iNs. Recent achievements using transcriptomics and epigenetics have shed light on the molecular mechanisms underpinning neu...
Source: Trends in Molecular Medicine - July 29, 2019 Category: Molecular Biology Authors: Vignoles R, Lentini C, d'Orange M, Heinrich C Tags: Trends Mol Med Source Type: research

Molecular Underpinnings Governing Genetic Complexity of ETS-Fusion-Negative Prostate Cancer.
Abstract 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,...
Source: Trends in Molecular Medicine - July 25, 2019 Category: Molecular Biology Authors: Bhatia V, Ateeq B Tags: Trends Mol Med Source Type: research

Immunomodulatory TGF- β Signaling in Hepatocellular Carcinoma.
Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma. Trends Mol Med. 2019 Jul 25;: Authors: Chen J, Gingold JA, Su X Abstract 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 t...
Source: Trends in Molecular Medicine - July 25, 2019 Category: Molecular Biology Authors: Chen J, Gingold JA, Su X Tags: Trends Mol Med Source Type: research

Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond.
Abstract Few therapeutic and diagnostic tools specifically aim at T cells in autoimmune disorders, but are T cells a narrow target in these diseases? Lessons may be learned from celiac disease (CeD), one of the few autoimmune disorders where the T cell driving antigens are known, i.e. dietary gluten proteins. T cell clonotypes specific to gluten are expanded, persist for decades and express a distinct phenotype in CeD patients. Cells with this phenotype are increased also in other autoimmune conditions. Accordingly, disease-specific CD4+ T cells form an immunological scar in CeD and probably other autoimmune disor...
Source: Trends in Molecular Medicine - July 19, 2019 Category: Molecular Biology Authors: Christophersen A, Risnes LF, Dahal-Koirala S, Sollid LM Tags: Trends Mol Med Source Type: research

The Mitochondrion as an Emerging Therapeutic Target in Cancer.
Abstract 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 o...
Source: Trends in Molecular Medicine - July 18, 2019 Category: Molecular Biology Authors: Roth KG, Mambetsariev I, Kulkarni P, Salgia R Tags: Trends Mol Med Source Type: research

Modeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention.
Abstract Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular disease where cardiac dysfunction often associates with mutations in sarcomeric genes. Various models based on tissue explants, isolated cardiomyocytes, skinned myofibrils, and purified actin/myosin preparations have uncovered disease hallmarks, enabling the development of putative therapeutics, with some reaching clinical trials. Newly developed human pluripotent stem cell (hPSC)-based models could be complementary by overcoming some of the inconsistencies of earlier systems, whilst challenging and/or clarifying previous findings...
Source: Trends in Molecular Medicine - July 17, 2019 Category: Molecular Biology Authors: Mosqueira D, Smith JGW, Bhagwan JR, Denning C Tags: Trends Mol Med Source Type: research

CRISPR Craze to Transform Cardiac Biology.
Abstract Clustered regularly interspaced short palindromic repeats (CRISPR) has revolutionized many research areas and has rapidly become the gold standard in genome editing by outrivaling all other available tools. Its unprecedented versatility creates the opportunity to modify any aspect of gene regulation. Even though the cardiac field is starting to appreciate the potential of CRISPR, many applications to study cardiac biology and disease so far have remained untouched. In particular, CRISPR-based strategies that act independent of the homology-directed repair pathway could help circumvent issues of modifying ...
Source: Trends in Molecular Medicine - July 17, 2019 Category: Molecular Biology Authors: van Kampen SJ, van Rooij E Tags: Trends Mol Med Source Type: research

Low Production of Reactive Oxygen Species Drives Systemic Lupus Erythematosus.
l R Abstract Systemic lupus erythematosus (SLE) is a common autoimmune disease. Recent findings have shown that a major single nucleotide variant predisposing to SLE is associated with low production of reactive oxygen species (ROS). A variant amino acid in a frequent NCF1 allele causing deficient ROS production leads to an exaggerated type I interferon (IFN) response, earlier disease onset, and higher susceptibility to SLE. It is the so far strongest identified single nucleotide variant, with an odds ratio (OR) of>3 and an allele frequency of>10%. Its functional role is in sharp contrast to the earlier beli...
Source: Trends in Molecular Medicine - July 11, 2019 Category: Molecular Biology Authors: Urbonaviciute V, Luo H, Sjöwall C, Bengtsson A, Holmdahl R Tags: Trends Mol Med Source Type: research

Self-DNA Sensing Fuels HIV-1-Associated Inflammation.
Abstract 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 immunogen...
Source: Trends in Molecular Medicine - July 9, 2019 Category: Molecular Biology Authors: Heil M, Brockmeyer NH Tags: Trends Mol Med Source Type: research

Molecular Treasures of Cancer Cell Lines.
Abstract Multifaceted characterizations of human cancer cell lines hold huge treasures for cancer research and therapeutic opportunities. Two recent publications in Nature and Nature Medicine describe the expanded Cancer Cell Line Encyclopedia (CCLE), which spans the genome, transcriptome, epigenome, proteome and metabolome, thereby providing copious resources for cancer research. PMID: 31255475 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - June 26, 2019 Category: Molecular Biology Authors: Li S, Zhang Z, Han L Tags: Trends Mol Med Source Type: research

DNA Methylation-Based Point-of-Care Cancer Detection: Challenges and Possibilities.
Abstract 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 discu...
Source: Trends in Molecular Medicine - June 25, 2019 Category: Molecular Biology Authors: Sina AA, Carrascosa LG, Trau M Tags: Trends Mol Med Source Type: research

Assessing Neuroprotective Agents for A β-Induced Neurotoxicity.
Assessing Neuroprotective Agents for Aβ-Induced Neurotoxicity. Trends Mol Med. 2019 Jun 24;: Authors: Forest KH, Nichols RA Abstract Alzheimer's disease (AD) is a relentlessly progressive neurodegenerative disease, currently incurable, which presents one of the largest unmet needs in medicine. AD is histologically characterized by the accumulation of extracellular amyloid-beta (Aβ), evident as senile plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. However, the levels of diffusible extracellular Aβ, a neuropeptide largely present in oligomeric form,...
Source: Trends in Molecular Medicine - June 24, 2019 Category: Molecular Biology Authors: Forest KH, Nichols RA Tags: Trends Mol Med Source Type: research

tRNA Deregulation and Its Consequences in Cancer.
Abstract The expression of transfer RNAs (tRNAs) is deregulated in cancer cells but the mechanisms and functional meaning of such deregulation are poorly understood. The proteome of cancer cells is not fully encoded by their transcriptome, however, the contribution of mRNA translation to such diversity remains to be elucidated. We review data supporting the hypothesis that tRNA expression deregulation and translational error rate is an important contributor to proteome diversity and cell population heterogeneity, genome instability, and drug resistance in tumors. This hypothesis is aligned with recent data in vari...
Source: Trends in Molecular Medicine - June 24, 2019 Category: Molecular Biology Authors: Santos M, Fidalgo A, Varanda AS, Oliveira C, Santos MAS Tags: Trends Mol Med Source Type: research

Shaping Striated Muscles with Ubiquitin Proteasome System in Health and Disease.
Abstract For long-lived contractile cells, such as striated muscle cells, maintaining proteome integrity is a challenging task. These cells require hundreds of components that must be properly synthesized, folded, and incorporated into the basic contractile unit, the sarcomere. Muscle protein quality control in cells is mainly guaranteed by the ubiquitin-proteasome system (UPS), the lysosome-autophagy system, and various molecular chaperones. Recent studies establish the concept of dedicated UPS in the regulation of sarcomere assembly during development and in adult life to maintain the intricate and interwoven or...
Source: Trends in Molecular Medicine - June 21, 2019 Category: Molecular Biology Authors: Hnia K, Clausen T, Moog-Lutz C Tags: Trends Mol Med Source Type: research

ANGPTL4 in Metabolic and Cardiovascular Disease.
ndo C Abstract Alterations in circulating lipids and ectopic lipid deposition impact on the risk of developing cardiovascular and metabolic diseases. Lipoprotein lipase (LPL) hydrolyzes fatty acids (FAs) from triglyceride (TAG)-rich lipoproteins including very low density lipoproteins (VLDLs) and chylomicrons, and regulates their distribution to peripheral tissues. Angiopoietin-like 4 (ANGPTL4) mediates the inhibition of LPL activity under different circumstances. Accumulating evidence associates ANGPTL4 directly with the risk of atherosclerosis and type 2 diabetes (T2D). This review focuses on recent findings on ...
Source: Trends in Molecular Medicine - June 21, 2019 Category: Molecular Biology Authors: Aryal B, Price NL, Suarez Y, Fernández-Hernando C Tags: Trends Mol Med Source Type: research

Iron and Atherosclerosis: The Link Revisited.
Abstract The causal link between iron and atherosclerosis has been debated. Recent studies have revisited the 'iron hypothesis' by showing that dietary iron overload or elevated non-transferrin bound iron (NTBI) aggravates atherosclerosis in mice by driving vascular dysfunction, thus identifying NTBI as a risk factor and therapeutic target for atherosclerosis. PMID: 31230908 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - June 20, 2019 Category: Molecular Biology Authors: Xu S Tags: Trends Mol Med Source Type: research

PRMTs and Arginine Methylation: Cancer's Best-Kept Secret?
Abstract 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 adv...
Source: Trends in Molecular Medicine - June 20, 2019 Category: Molecular Biology Authors: Jarrold J, Davies CC Tags: Trends Mol Med Source Type: research

miRNAs Identify Shared Pathways in Alzheimer's and Parkinson's Diseases.
Abstract Despite the identification of several dozens of common genetic variants associated with Alzheimer's disease (AD) and Parkinson's disease (PD), most of the genetic risk remains uncharacterised. Therefore, it is important to understand the role of regulatory elements, such as miRNAs. Dysregulated miRNAs are implicated in AD and PD, with potential value in dissecting the shared pathophysiology between the two disorders. miRNAs relevant to both neurodegenerative diseases are related to axonal guidance, apoptosis, and inflammation, therefore, AD and PD likely arise from similar underlying biological pathway de...
Source: Trends in Molecular Medicine - June 17, 2019 Category: Molecular Biology Authors: Sadlon A, Takousis P, Alexopoulos P, Evangelou E, Prokopenko I, Perneczky R Tags: Trends Mol Med Source Type: research

Tools for Bioimaging Pancreatic β Cells in Diabetes.
Tools for Bioimaging Pancreatic β Cells in Diabetes. Trends Mol Med. 2019 Jun 06;: Authors: Kang NY, Soetedjo AAP, Amirruddin NS, Chang YT, Eriksson O, Teo AKK Abstract When diabetes is diagnosed, the majority of insulin-secreting pancreatic β cells are already dysfunctional or destroyed. This β cell dysfunction/destruction usually takes place over many years, making timely detection and clinical intervention difficult. For this reason, there is immense interest in developing tools to bioimage β cell mass and/or function noninvasively to facilitate early diagnosis of diabetes as we...
Source: Trends in Molecular Medicine - June 6, 2019 Category: Molecular Biology Authors: Kang NY, Soetedjo AAP, Amirruddin NS, Chang YT, Eriksson O, Teo AKK Tags: Trends Mol Med Source Type: research

Staphylococcus aureus Orchestrates Type 2 Airway Diseases.
This article reviews the role of S. aureus in chronic inflammatory airway diseases and discusses possible therapeutic approaches to target S. aureus. PMID: 31176612 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - June 5, 2019 Category: Molecular Biology Authors: Teufelberger AR, Bröker BM, Krysko DV, Bachert C, Krysko O Tags: Trends Mol Med Source Type: research

Do Microglial Sex Differences Contribute to Sex Differences in Neurodegenerative Diseases?
Abstract Sex differences have been clinically documented in numerous neurodegenerative diseases and yet the reasons for these differences are not well understood. Recent studies have found that microglia, the innate immune cells of the central nervous system, are a key cell type involved in neurodegenerative diseases. This cell type displays sex differences in their expression profiles and function. Could these sex differences in microglia explain the sex differences seen in neurodegenerative diseases? How can we further probe these differences to better understand disease mechanisms? In this Opinion, we highlight...
Source: Trends in Molecular Medicine - June 3, 2019 Category: Molecular Biology Authors: Kodama L, Gan L Tags: Trends Mol Med Source Type: research

Endocannabinoid and Prostanoid Crosstalk in Pain.
Abstract Interfering with endocannabinoid (eCB) metabolism to increase their levels is a proven anti-nociception strategy. However, because the eCB and prostanoid systems are intertwined, interfering with eCB metabolism will affect the prostanoid system and inversely. Key to this connection is the production of the cyclooxygenase (COX) substrate arachidonic acid upon eCB hydrolysis as well as the ability of COX to metabolize the eCBs anandamide (AEA) and 2-arachidonoylglycerol (2-AG) into prostaglandin-ethanolamides (PG-EA) and prostaglandin-glycerol esters (PG-G), respectively. Recent studies shed light on the ro...
Source: Trends in Molecular Medicine - May 31, 2019 Category: Molecular Biology Authors: Buisseret B, Alhouayek M, Guillemot-Legris O, Muccioli GG Tags: Trends Mol Med Source Type: research

A Single Human Neuron Approach to Synapse Function.
Abstract To understand human neuronal function, it is crucial to obtain knowledge of how human synapses operate. New approaches are necessary to define the unique properties of human synapses. Recently, new culturing approaches have been developed to obtain cultures of single human neurons for the first time (Rhee et al., Cell Rep. 2019, Meijer et al., Cell Rep. 2019, and Fenske et al., Sci. Rep. 2019). PMID: 31155337 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - May 30, 2019 Category: Molecular Biology Authors: Fenske P, Rosenmund C Tags: Trends Mol Med Source Type: research

Abandoning the Notion of Non-Small Cell Lung Cancer.
Abstract Non-small cell lung cancers (NSCLCs) represent 85% of lung tumors. NSCLCs encompass multiple cancer types, such as adenocarcinomas (LUADs), squamous cell cancers (LUSCs), and large cell cancers. Among them, LUADs and LUSCs are the largest NSCLC subgroups. LUADs and LUSCs appear sharply distinct at the transcriptomic level, as well as for cellular control networks. LUADs show distinct genetic drivers and divergent prognostic profiles versus LUSCs. Therapeutic clinical trials in NSCLC indicate differential LUAD versus LUSC response to treatments. Hence, LUAD and LUSC appear to be vastly distinct diseases at...
Source: Trends in Molecular Medicine - May 30, 2019 Category: Molecular Biology Authors: Relli V, Trerotola M, Guerra E, Alberti S Tags: Trends Mol Med Source Type: research

Immunometabolism around the Clock.
Abstract Almost every cell has a molecular clock, which controls gene expression on a 24-h cycle, providing circadian rhythmicity. An example of a circadian behaviour common to most organisms is the feeding/fasting cycle, which shapes whole-body metabolism. However, the exact mechanisms by which the clock controls cellular metabolism have only recently become clear. The molecular clock and related metabolic pathways are also key drivers of immunity. Thus, a natural convergence of circadian biology, metabolism, and immunology has emerged to form a new field that we term 'circadian immunometabolism'. Expanding our u...
Source: Trends in Molecular Medicine - May 29, 2019 Category: Molecular Biology Authors: Carroll RG, Timmons GA, Cervantes-Silva MP, Kennedy OD, Curtis AM Tags: Trends Mol Med Source Type: research

Road Map for Development of Stem Cell-Based Alternative Test Methods.
Abstract Much progress has been made in establishing strategies for differentiation of induced human pluripotent stem cells (hiPSCs). However, differentiated hiPSCs are not yet routinely used for prediction of toxicity. Here, limiting factors are summarised and possibilities for improvement are discussed, with a focus on hepatocytes, cardiomyocytes, tubular epithelial cells, and developmental toxicity. Moreover, we make recommendations for further fine-tuning of differentiation protocols for hiPSCs to hepatocyte-like cells by comparing individual steps of currently available protocols to the mechanisms occurring d...
Source: Trends in Molecular Medicine - May 23, 2019 Category: Molecular Biology Authors: Sachinidis A, Albrecht W, Nell P, Cherianidou A, Hewitt NJ, Edlund K, Hengstler JG Tags: Trends Mol Med Source Type: research

Mitochondrial Regulation of Stem Cells in Bone Homeostasis.
Abstract 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 patho...
Source: Trends in Molecular Medicine - May 21, 2019 Category: Molecular Biology Authors: Zheng CX, Sui BD, Qiu XY, Hu CH, Jin Y Tags: Trends Mol Med Source Type: research

Tackling Aging by Using miRNA as a Target and a Tool.
Abstract miRNA is a class of short noncoding RNA that regulates gene expression at the post-transcriptional level. Evidence of age-associated changes in miRNA expression has been collected in models ranging from nematodes to humans; however, there has been little discussion of how to turn our knowledge of miRNA biology into antiaging therapy. This opinion article provides a snapshot of our current understanding of the roles of miRNA in modulating the aging process. We discuss major chemical techniques for modifying the miRNA structure as well as developing delivery systems for intervention. Finally, technical need...
Source: Trends in Molecular Medicine - May 21, 2019 Category: Molecular Biology Authors: Lai WF, Lin M, Wong WT Tags: Trends Mol Med Source Type: research

Astrocytes: Emerging Therapeutic Targets in Neurological Disorders.
Abstract Astrocytes fulfil several functions that collectively contribute to maintain the optimal microenvironment for neuronal function and survival. The multiplicity and complexity of these activities clearly indicates that the correct performance of astrocytes is crucial for the physiological functioning of the nervous system, and its derangement may contribute to the occurrence and progression of many neurological disorders. Although rectifying astrocyte malfunction has successfully counteracted disease pathogenesis and outcome in many preclinical settings, the translation of this revolutionary approach into c...
Source: Trends in Molecular Medicine - May 20, 2019 Category: Molecular Biology Authors: Valori CF, Guidotti G, Brambilla L, Rossi D Tags: Trends Mol Med Source Type: research

Shape Follows Function: Gastrointestinal Signals for Enterococcal Colonization.
Abstract Vancomycin-resistant Enterococcus faecium (VRE) is a major cause of nosocomial infections. A new study by McKenney et al. (Cell Host Microbe 2019;25:695-705.e5) reports that VRE undergo a morphotype switch in response to lithocholic acid (LCA) to facilitate gastrointestinal (GI) tract colonization. This metabolic cue is a potential target to decrease VRE colonization and subsequent transmission of antibiotic resistance. PMID: 31109795 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - May 17, 2019 Category: Molecular Biology Authors: Nguyen AH, Miller WR, Arias CA Tags: Trends Mol Med Source Type: research

Losing Sense of Self and Surroundings: Hematopoietic Stem Cell Aging and Leukemic Transformation.
te; E Abstract Aging leads to functional decline of the hematopoietic system, manifested by an increased incidence of hematological disease in the elderly. Deterioration of hematopoietic integrity with age originates in part from the degraded functionality of hematopoietic stem cells (HSCs). Here, we review recent findings identifying changes in metabolic programs and loss of epigenetic identity as major drivers of old HSC dysfunction and their role in promoting leukemia onset in the context of age-related clonal hematopoiesis (ARCH). We discuss how inflammatory and growth signals from the aged bone marrow (BM) mi...
Source: Trends in Molecular Medicine - May 17, 2019 Category: Molecular Biology Authors: Verovskaya EV, Dellorusso PV, Passegué E Tags: Trends Mol Med Source Type: research

Modifying the Organ Matrix Pre-engraftment: A New Transplant Paradigm?
Abstract The availability of solid organs for transplantation remains low and there is a substantial need for methods to preserve the viability of grafted tissues. Suppression of solid-organ transplant rejection has traditionally focused on highly effective T cell inhibitors that block host immune lymphocyte responses. However, persistent and destructive innate and acquired immune reactions remain difficult to treat, causing late graft loss. Pretreatment of grafts to reduce organ rejection provides an alternate strategy. Approaches using antithrombotics, stem cells, genetic modifications, modulation of infrastruct...
Source: Trends in Molecular Medicine - May 17, 2019 Category: Molecular Biology Authors: Yaron JR, Kwiecien JM, Zhang L, Ambadapadi S, Wakefield DN, Clapp WL, Dabrowski W, Burgin M, Munk BH, McFadden G, Chen H, Lucas AR Tags: Trends Mol Med Source Type: research

The Role of Reactive Oxygen Species in In Vitro Cardiac Maturation.
Abstract Recent advances in developmental biology and biomedical engineering have significantly improved the efficiency and purity of cardiomyocytes (CMs) generated from pluripotent stem cells (PSCs). Regardless of the protocol used to derive CMs, these cells exhibit hallmarks of functional immaturity. In this Opinion, we focus on reactive oxygen species (ROS), signaling molecules that can potentially modulate cardiac maturation. We outline how ROS impacts nearly every aspect associated with cardiac maturation, including contractility, calcium handling, metabolism, and hypertrophy. Though the precise role of ROS i...
Source: Trends in Molecular Medicine - May 9, 2019 Category: Molecular Biology Authors: Momtahan N, Crosby CO, Zoldan J Tags: Trends Mol Med Source Type: research

Mechanisms of Genomic Instability in Breast Cancer.
Abstract Breast cancer is the most common cancer among women globally. Genomic instability (GI) refers to the increased tendency to accrue genomic alterations. It drives heterogeneity and is a hallmark of cancer. Genomic integrity is closely guarded by several mechanisms, including DNA damage checkpoints, the DNA repair machinery, and the mitotic checkpoint. Alterations in these surveillance mechanisms cause GI. In breast cancer, several pathways maintaining genomic integrity are distinctly altered, including some that have been successfully exploited for therapeutic targeting. In this review, we comprehensively d...
Source: Trends in Molecular Medicine - May 8, 2019 Category: Molecular Biology Authors: Duijf PHG, Nanayakkara D, Nones K, Srihari S, Kalimutho M, Khanna KK Tags: Trends Mol Med Source Type: research

Proteostasis and Beyond: ATF6 in Ischemic Disease.
Abstract Endoplasmic reticulum (ER) stress is a pathological hallmark of numerous ischemic diseases, including stroke and myocardial infarction (MI). In these diseases, ER stress leads to activation of the unfolded protein response (UPR) and subsequent adaptation of cellular physiology in ways that dictate cellular fate following ischemia. Recent evidence highlights a protective role for the activating transcription factor 6 (ATF6) arm of the UPR in mitigating adverse outcomes associated with ischemia/reperfusion (I/R) injury in multiple disease models. This suggests ATF6 as a potential therapeutic target for inte...
Source: Trends in Molecular Medicine - May 8, 2019 Category: Molecular Biology Authors: Glembotski CC, Rosarda JD, Wiseman RL Tags: Trends Mol Med Source Type: research

Epidermal Lipids: Key Mediators of Atopic Dermatitis Pathogenesis.
Abstract The skin barrier keeps the 'inside in' and the 'outside out', forming a protective blanket against external insults. Epidermal lipids, such as ceramides, fatty acids (FAs), triglycerides, and cholesterol, are integral components driving the formation and maintenance of the epidermal permeability barrier (EPB). A breach in this lipid barrier sets the platform for the subsequent onset and progression of atopic dermatitis (AD). Such lipids are also important in the normal functioning of organisms, both plants and animals, and in diseases, including cancer. Given the doubling of the number of cases of AD in r...
Source: Trends in Molecular Medicine - May 1, 2019 Category: Molecular Biology Authors: Bhattacharya N, Sato WJ, Kelly A, Ganguli-Indra G, Indra AK Tags: Trends Mol Med Source Type: research

Vascular Regenerative Cell Exhaustion in Diabetes: Translational Opportunities to Mitigate Cardiometabolic Risk.
Abstract Ischemic cardiovascular complications remain a major cause of mortality in people with type 2 diabetes (T2D). Individuals with T2D may have a reduced ability to revascularize ischemic tissues due to abnormal production of circulating provascular progenitor cells. This 'regenerative cell exhaustion' process is intensified by increasing oxidative stress and inflammation and during T2D progression. Chronic exhaustion may be mediated by changes in the bone marrow microenvironment that dysregulate the wingless related integration site network, a central pathway maintaining the progenitor cell pool. Restoration...
Source: Trends in Molecular Medicine - April 30, 2019 Category: Molecular Biology Authors: Terenzi DC, Trac JZ, Teoh H, Gerstein HC, Bhatt DL, Al-Omran M, Verma S, Hess DA Tags: Trends Mol Med Source Type: research