bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2022‒12‒25
29 papers selected by
Silvia Radenkovic
Frontiers in Congenital Disorders of Glycosylation Consortium
  1. CRISPR-Based Tools for Fighting Rare Diseases.
  2. Protein Glutathionylation and Glutaredoxin: Role in Neurodegenerative Diseases.
  3. Insights into Manganese Superoxide Dismutase and Human Diseases.
  4. The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease.
  5. Metabolic Myopathies.
  6. Recent advances in characterization of citrullination and its implication in human disease research: From method development to network integration.
  7. Emerging Roles of the Unique Molecular Chaperone Cosmc in the Regulation of Health and Disease.
  8. Extracellular Vesicle-Based Therapeutics in Neurological Disorders.
  9. Therapeutic tools for inherited neuropathies.
  10. Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases.
  11. Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy.
  12. Emerging Perspectives on Gene Therapy Delivery for Neurodegenerative and Neuromuscular Disorders.
  13. Succinate at the Crossroad of Metabolism and Angiogenesis: Roles of SDH, HIF1α and SUCNR1.
  14. S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases.
  15. Genetic-Based Treatment Strategies for Muscular Dystrophy and Congenital Myopathies.
  16. Islet cilia and glucose homeostasis.
  17. Proteomic Insights into Cardiac Fibrosis: From Pathophysiological Mechanisms to Therapeutic Opportunities.
  18. The multiple facets of acetyl-CoA metabolism: Energetics, biosynthesis, regulation, acylation and inborn errors.
  19. Glucocorticoid Effects on Proteoglycans and Glycosaminoglycans.
  20. Liquid chromatography-tandem mass spectrometry for clinical diagnostics.
  21. Lysosomal Acid Lipase Deficiency: Genetics, Screening, and Preclinical Study.
  22. The Glycosylation of Immune Checkpoints and Their Applications in Oncology.
  23. Protein Targeting to Glycogen (PTG): A Promising Player in Glucose and Lipid Metabolism.
  24. Facioscapulohumeral Muscular Dystrophy.
  25. Functional investigation of SLC1A2 variants associated with epilepsy.
  26. Extracellular Vesicles as Biomarkers in Liver Disease.
  27. Rare diseases and space health: optimizing synergies from scientific questions to care.
  28. The Limb-Girdle Muscular Dystrophies.
  29. Mitochondrial Dysfunction: Pathophysiology and Mitochondria-Targeted Drug Delivery Approaches.
  1. Life (Basel). 2022 Nov 24. pii: 1968. [Epub ahead of print]12(12):
    CRISPR-Based Tools for Fighting Rare Diseases.
    Qingyang Li, Yanmin Gao, Haifeng Wang.
      Rare diseases affect the life of a tremendous number of people globally. The CRISPR-Cas system emerged as a powerful genome engineering tool and has facilitated the comprehension of the mechanism and development of therapies for rare diseases. This review focuses on current efforts to develop the CRISPR-based toolbox for various rare disease therapy applications and compares the pros and cons of different tools and delivery methods. We further discuss the therapeutic applications of CRISPR-based tools for fighting different rare diseases.
    Keywords:  CRISPR-Cas; delivery system; gene therapy; rare disease
    DOI:  https://doi.org/10.3390/life12121968
  2. Antioxidants (Basel). 2022 Nov 25. pii: 2334. [Epub ahead of print]11(12):
    Protein Glutathionylation and Glutaredoxin: Role in Neurodegenerative Diseases.
    Haseena P A, Latha Diwakar, Vijayalakshmi Ravindranath.
      Oxidative stress has been implicated in the pathogenesis and progression of many neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. One of the major enzyme systems involved in the defense against reactive oxygen species are the tripeptide glutathione and oxidoreductase glutaredoxin. Glutathione and glutaredoxin system are very important in the brain because of the oxidative modification of protein thiols to protein glutathione mixed disulfides with the concomitant formation of oxidized glutathione during oxidative stress. Formation of Pr-SSG acts as a sink in the brain and is reduced back to protein thiols during recovery, thus restoring protein functions. This is unlike in the liver, which has a high turnover of glutathione, and formation of Pr-SSG is very minimal as liver is able to quickly quench the prooxidant species. Given the important role glutathione and glutaredoxin play in the brain, both in normal and pathologic states, it is necessary to study ways to augment the system to help maintain the protein thiol status. This review details the importance of glutathione and glutaredoxin systems in several neurodegenerative disorders and emphasizes the potential augmentation of this system as a target to effectively protect the brain during aging.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; glutaredoxin; glutathione; ischemia; oxidative stress; protein thiol
    DOI:  https://doi.org/10.3390/antiox11122334
  3. Int J Mol Sci. 2022 Dec 14. pii: 15893. [Epub ahead of print]23(24):
    Insights into Manganese Superoxide Dismutase and Human Diseases.
    Mengfan Liu, Xueyang Sun, Boya Chen, Rongchen Dai, Zhichao Xi, Hongxi Xu.
      Redox equilibria and the modulation of redox signalling play crucial roles in physiological processes. Overproduction of reactive oxygen species (ROS) disrupts the body's antioxidant defence, compromising redox homeostasis and increasing oxidative stress, leading to the development of several diseases. Manganese superoxide dismutase (MnSOD) is a principal antioxidant enzyme that protects cells from oxidative damage by converting superoxide anion radicals to hydrogen peroxide and oxygen in mitochondria. Systematic studies have demonstrated that MnSOD plays an indispensable role in multiple diseases. This review focuses on preclinical evidence that describes the mechanisms of MnSOD in diseases accompanied with an imbalanced redox status, including fibrotic diseases, inflammation, diabetes, vascular diseases, neurodegenerative diseases, and cancer. The potential therapeutic effects of MnSOD activators and MnSOD mimetics are also discussed. Targeting this specific superoxide anion radical scavenger may be a clinically beneficial strategy, and understanding the therapeutic role of MnSOD may provide a positive insight into preventing and treating related diseases.
    Keywords:  MnSOD; MnSOD mimetics; ROS; human diseases; oxidative stress
    DOI:  https://doi.org/10.3390/ijms232415893
  4. Genes (Basel). 2022 Dec 09. pii: 2319. [Epub ahead of print]13(12):
    The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease.
    Christina Del Greco, Anthony Antonellis.
      Aminoacyl-tRNA synthetases (ARSs) are highly conserved essential enzymes that charge tRNA with cognate amino acids-the first step of protein synthesis. Of the 37 nuclear-encoded human ARS genes, 17 encode enzymes are exclusively targeted to the mitochondria (mt-ARSs). Mutations in nuclear mt-ARS genes are associated with rare, recessive human diseases with a broad range of clinical phenotypes. While the hypothesized disease mechanism is a loss-of-function effect, there is significant clinical heterogeneity among patients that have mutations in different mt-ARS genes and also among patients that have mutations in the same mt-ARS gene. This observation suggests that additional factors are involved in disease etiology. In this review, we present our current understanding of diseases caused by mutations in the genes encoding mt-ARSs and propose explanations for the observed clinical heterogeneity.
    Keywords:  aminoacyl-tRNA synthetases; mitochondrial biology; neurological disease; protein synthesis; tRNA biology
    DOI:  https://doi.org/10.3390/genes13122319
  5. Continuum (Minneap Minn). 2022 Dec 01. 28(6): 1752-1777
    Metabolic Myopathies.
    Mark A Tarnopolsky.
      PURPOSE OF REVIEW: Metabolic myopathies are disorders that affect skeletal muscle substrate oxidation. Although some drugs and hormones can affect metabolism in skeletal muscle, this review will focus on the genetic metabolic myopathies.RECENT FINDINGS: Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/oxidation (fatty acid oxidation defects), and mitochondrial metabolism (mitochondrial myopathies) represent most metabolic myopathies; however, they often overlap clinically with structural genetic myopathies, referred to as pseudometabolic myopathies. Although metabolic myopathies can present in the neonatal period with hypotonia, hypoglycemia, and encephalopathy, most cases present clinically in children or young adults with exercise intolerance, rhabdomyolysis, and weakness. In general, the glycogen storage diseases manifest during brief bouts of high-intensity exercise; in contrast, fatty acid oxidation defects and mitochondrial myopathies usually manifest during longer-duration endurance-type activities, often with fasting or other metabolic stressors (eg, surgery, fever). The neurologic examination is often normal between events (except in the pseudometabolic myopathies) and evaluation requires one or more of the following tests: exercise stress testing, blood (eg, creatine kinase, acylcarnitine profile, lactate, amino acids), urine (eg, organic acids, myoglobin), muscle biopsy (eg, histology, ultrastructure, enzyme testing), and targeted (specific gene) or untargeted (myopathy panels) genetic tests.
    SUMMARY: Definitive identification of a specific metabolic myopathy often leads to specific interventions, including lifestyle, exercise, and nutritional modifications; cofactor treatments; accurate genetic counseling; avoidance of specific triggers; and rapid treatment of rhabdomyolysis.
    DOI:  https://doi.org/10.1212/CON.0000000000001182
  6. Proteomics. 2022 Dec 22. e2200286
    Recent advances in characterization of citrullination and its implication in human disease research: From method development to network integration.
    Bin Wang, Lauren Fields, Lingjun Li.
      Post-translational modifications (PTM) of proteins increase the functional diversity of the proteome and have been implicated in the pathogenesis of numerous diseases. The most widely understood modifications include phosphorylation, methylation, acetylation, O-linked/N-linked glycosylation, and ubiquitination, all of which have been extensively studied and documented. Citrullination is a historically less explored, yet increasingly studied, protein PTM which has profound effects on protein conformation and protein-protein interactions. Dysregulation of protein citrullination has been associated with disease development and progression. Identification and characterization of citrullinated proteins is highly challenging, complicated by the low cellular abundance of citrullinated proteins, making it difficult to identify and quantify the extent of citrullination in samples, coupled with challenges associated with development of mass spectrometry (MS)-based methods, as the corresponding mass shift is relatively small, +0.984 Da, and identical to the mass shift of deamidation. The focus of this review is to discuss recent advancements of citrullination-specific MS approaches and integration of the potential methodology for improved citrullination identification and characterization. In addition, the association of citrullination in disease networks is also highlighted. This article is protected by copyright. All rights reserved.
    Keywords:  Citrullination; PTM; disease network; mass spectrometry; methodology; proteomics; quantitation
    DOI:  https://doi.org/10.1002/pmic.202200286
  7. Biomolecules. 2022 Nov 23. pii: 1732. [Epub ahead of print]12(12):
    Emerging Roles of the Unique Molecular Chaperone Cosmc in the Regulation of Health and Disease.
    Ting Xiang, Muchuan Qiao, Jiangbo Xie, Zheng Li, Hailong Xie.
      The core-1 β1-3galactosyltransferase-specific chaperone 1 (Cosmc) is a unique molecular chaperone of core-1 β1-3galactosyltransferase(C1GALT1), which typically functions inside the endoplasmic reticulum (ER). Cosmc helps C1GALT1 to fold correctly and maintain activity. It also participates in the synthesis of the T antigen, O-glycan, together with C1GALT1. Cosmc is a multifaceted molecule with a wide range of roles and functions. It involves platelet production and the regulation of immune cell function. Besides that, the loss of function of Cosmc also facilitates the development of several diseases, such as inflammation diseases, immune-mediated diseases, and cancer. It suggests that Cosmc is a critical control point in diseases and that it should be regarded as a potential target for oncotherapy. It is essential to fully comprehend Cosmc's roles, as they may provide critical information about its involvement in disease development and pathogenesis. In this review, we summarize the recent progress in understanding the role of Cosmc in normal development and diseases.
    Keywords:  C1GALT1; Cosmc; O-glycosylation; Tn antigen; chaperonin
    DOI:  https://doi.org/10.3390/biom12121732
  8. Pharmaceutics. 2022 Nov 30. pii: 2652. [Epub ahead of print]14(12):
    Extracellular Vesicle-Based Therapeutics in Neurological Disorders.
    Yiwen Yuan, Jian Sun, Tongyao You, Weiwei Shen, Wenqing Xu, Qiang Dong, Mei Cui.
      Neurological diseases remain some of the major causes of death and disability in the world. Few types of drugs and insufficient delivery across the blood-brain barrier limit the treatment of neurological disorders. The past two decades have seen the rapid development of extracellular vesicle-based therapeutics in many fields. As the physiological and pathophysiological roles of extracellular vesicles are recognized in neurological diseases, they have become promising therapeutics and targets for therapeutic interventions. Moreover, advanced nanomedicine technologies have explored the potential of extracellular vesicles as drug delivery systems in neurological diseases. In this review, we discussed the preclinical strategies for extracellular vesicle-based therapeutics in neurological disorders and the struggles involved in their clinical application.
    Keywords:  drug delivery; extracellular vesicles; mesenchymal stem cells; neurodegenerative diseases; neurological disorders; therapeutics
    DOI:  https://doi.org/10.3390/pharmaceutics14122652
  9. Rev Neurol (Paris). 2022 Dec 16. pii: S0035-3787(22)00842-6. [Epub ahead of print]
    Therapeutic tools for inherited neuropathies.
    Y Péréon.
      Inherited neuropathies are a genetically and phenotypically heterogenous group of disorders leading to sensory and motor dysfunction. For years, these neuropathies have been considered as non-treatable diseases, as no drug is able to induce nerve regrowth. Progress in molecular tools has changed this view and several neuropathies can now be efficiently treated. Some more will be treatable in the upcoming years. Basically, these new treatments can be divided into four categories, depending on the target: gene therapy; gene expression therapy; protein modification or replacement (enzyme replacement therapy, ERT); downstream therapies. In this short review, we will provide a few examples for each of them in the field of peripheral neuropathies.
    Keywords:  Antisense oligonucleotides; Gene expression therapy; Gene therapy; SiRNA
    DOI:  https://doi.org/10.1016/j.neurol.2022.12.001
  10. Int J Mol Sci. 2022 Dec 16. pii: 16053. [Epub ahead of print]23(24):
    Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases.
    Yu Liu, Yuejia Huang, Chong Xu, Peng An, Yongting Luo, Lei Jiao, Junjie Luo, Yongzhi Li.
      High mortality rates due to cardiovascular diseases (CVDs) have attracted worldwide attention. It has been reported that mitochondrial dysfunction is one of the most important mechanisms affecting the pathogenesis of CVDs. Mitochondrial DNA (mtDNA) mutations may result in impaired oxidative phosphorylation (OXPHOS), abnormal respiratory chains, and ATP production. In dysfunctional mitochondria, the electron transport chain (ETC) is uncoupled and the energy supply is reduced, while reactive oxygen species (ROS) production is increased. Here, we discussed and analyzed the relationship between mtDNA mutations, impaired mitophagy, decreased OXPHOS, elevated ROS, and CVDs from the perspective of mitochondrial dysfunction. Furthermore, we explored current potential therapeutic strategies for CVDs by eliminating mtDNA mutations (e.g., mtDNA editing and mitochondrial replacement), enhancing mitophagy, improving OXPHOS capacity (e.g., supplement with NAD+, nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nano-drug delivery), and reducing ROS (e.g., supplement with Coenzyme Q10 and other antioxidants), and dissected their respective advantages and limitations. In fact, some therapeutic strategies are still a long way from achieving safe and effective clinical treatment. Although establishing effective and safe therapeutic strategies for CVDs remains challenging, starting from a mitochondrial perspective holds bright prospects.
    Keywords:  cardiovascular disease; mitochondrial DNA mutation; mitochondrial dysfunction; mitophagy; oxidative phosphorylation; reactive oxygen species; therapeutic strategy
    DOI:  https://doi.org/10.3390/ijms232416053
  11. Int J Mol Sci. 2022 Dec 16. pii: 16006. [Epub ahead of print]23(24):
    Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy.
    Andreas Kronbichler, Vladimir Tesar.
      Years of standing still have ended, and the field of nephrology has seen a plethora of clinical trials, changing the therapeutic landscape of chronic kidney disease (CKD) and immune-mediated kidney disease management [...].
    DOI:  https://doi.org/10.3390/ijms232416006
  12. J Pers Med. 2022 Nov 30. pii: 1979. [Epub ahead of print]12(12):
    Emerging Perspectives on Gene Therapy Delivery for Neurodegenerative and Neuromuscular Disorders.
    Cintia Gomez Limia, Megan Baird, Maura Schwartz, Smita Saxena, Kathrin Meyer, Nicolas Wein.
      Neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD) and Parkinson's Disease (PD), are a group of heterogeneous diseases that mainly affect central nervous system (CNS) functions. A subset of NDDs exhibit CNS dysfunction and muscle degeneration, as observed in Gangliosidosis 1 (GM1) and late stages of PD. Neuromuscular disorders (NMDs) are a group of diseases in which patients show primary progressive muscle weaknesses, including Duchenne Muscular Dystrophy (DMD), Pompe disease, and Spinal Muscular Atrophy (SMA). NDDs and NMDs typically have a genetic component, which affects the physiological functioning of critical cellular processes, leading to pathogenesis. Currently, there is no cure or efficient treatment for most of these diseases. More than 200 clinical trials have been completed or are currently underway in order to establish safety, tolerability, and efficacy of promising gene therapy approaches. Thus, gene therapy-based therapeutics, including viral or non-viral delivery, are very appealing for the treatment of NDDs and NMDs. In particular, adeno-associated viral vectors (AAV) are an attractive option for gene therapy for NDDs and NMDs. However, limitations have been identified after systemic delivery, including the suboptimal capacity of these therapies to traverse the blood-brain barrier (BBB), degradation of the particles during the delivery, high reactivity of the patient's immune system during the treatment, and the potential need for redosing. To circumvent these limitations, several preclinical and clinical studies have suggested intrathecal (IT) delivery to target the CNS and peripheral organs via cerebrospinal fluid (CSF). CSF administration can vastly improve the delivery of small molecules and drugs to the brain and spinal cord as compared to systemic delivery. Here, we review AAV biology and vector design elements, different therapeutic routes of administration, and highlight CSF delivery as an attractive route of administration. We discuss the different aspects of neuromuscular and neurodegenerative diseases, such as pathogenesis, the landscape of mutations, and the biological processes associated with the disease. We also describe the hallmarks of NDDs and NMDs as well as discuss current therapeutic approaches and clinical progress in viral and non-viral gene therapy and enzyme replacement strategies for those diseases.
    Keywords:  CSF delivery; gene therapies; molecular biology; neurodegenerative diseases; neuromuscular diseases; therapeutic strategies
    DOI:  https://doi.org/10.3390/jpm12121979
  13. Biomedicines. 2022 Dec 01. pii: 3089. [Epub ahead of print]10(12):
    Succinate at the Crossroad of Metabolism and Angiogenesis: Roles of SDH, HIF1α and SUCNR1.
    Reham Atallah, Andrea Olschewski, Akos Heinemann.
      Angiogenesis is an essential process by which new blood vessels develop from existing ones. While adequate angiogenesis is a physiological process during, for example, tissue repair, insufficient and excessive angiogenesis stands on the pathological side. Fine balance between pro- and anti-angiogenic factors in the tissue environment regulates angiogenesis. Identification of these factors and how they function is a pressing topic to develop angiogenesis-targeted therapeutics. During the last decade, exciting data highlighted non-metabolic functions of intermediates of the mitochondrial Krebs cycle including succinate. Among these functions is the contribution of succinate to angiogenesis in various contexts and through different mechanisms. As the concept of targeting metabolism to treat a wide range of diseases is rising, in this review we summarize the mechanisms by which succinate regulates angiogenesis in normal and pathological settings. Gaining a comprehensive insight into how this metabolite functions as an angiogenic signal will provide a useful approach to understand diseases with aberrant or excessive angiogenic background, and may provide strategies to tackle them.
    Keywords:  angiogenesis; hypoxia-inducible factor 1-alpha (HIF1α); succinate; succinate dehydrogenase (SDH); succinate receptor-1 (SUCNR1)
    DOI:  https://doi.org/10.3390/biomedicines10123089
  14. Int J Mol Sci. 2022 Dec 13. pii: 15849. [Epub ahead of print]23(24):
    S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases.
    Sofia Vrettou, Brunhilde Wirth.
      Redox post-translational modifications are derived from fluctuations in the redox potential and modulate protein function, localization, activity and structure. Amongst the oxidative reversible modifications, the S-glutathionylation of proteins was the first to be characterized as a post-translational modification, which primarily protects proteins from irreversible oxidation. However, a growing body of evidence suggests that S-glutathionylation plays a key role in core cell processes, particularly in mitochondria, which are the main source of reactive oxygen species. S-nitrosylation, another post-translational modification, was identified >150 years ago, but it was re-introduced as a prototype cell-signaling mechanism only recently, one that tightly regulates core processes within the cell's sub-compartments, especially in mitochondria. S-glutathionylation and S-nitrosylation are modulated by fluctuations in reactive oxygen and nitrogen species and, in turn, orchestrate mitochondrial bioenergetics machinery, morphology, nutrients metabolism and apoptosis. In many neurodegenerative disorders, mitochondria dysfunction and oxidative/nitrosative stresses trigger or exacerbate their pathologies. Despite the substantial amount of research for most of these disorders, there are no successful treatments, while antioxidant supplementation failed in the majority of clinical trials. Herein, we discuss how S-glutathionylation and S-nitrosylation interfere in mitochondrial homeostasis and how the deregulation of these modifications is associated with Alzheimer's, Parkinson's, amyotrophic lateral sclerosis and Friedreich's ataxia.
    Keywords:  Alzheimer’s; Friedreich’s ataxia; Parkinson’s; amyotrophiclateralsclerosis; glutathionylation; mitochondria; neurodegeneration; nitrosylation; redox
    DOI:  https://doi.org/10.3390/ijms232415849
  15. Continuum (Minneap Minn). 2022 Dec 01. 28(6): 1800-1816
    Genetic-Based Treatment Strategies for Muscular Dystrophy and Congenital Myopathies.
    Andrew R Findlay, Conrad C Weihl.
      PURPOSE OF REVIEW: This article discusses the foundational concepts of genetic treatment strategies employed in neuromuscular medicine, as well as the importance of genetic testing as a requirement for applying gene-based therapy.RECENT FINDINGS: Gene therapies have become a reality for several neuromuscular disorders. Exon-skipping and (in Europe) ribosomal read-through approaches are currently available to a subset of patients with Duchenne muscular dystrophy. Microdystrophin gene replacement has shown promise and is nearing the final stages of clinical trials. Numerous gene-based therapies for other muscular dystrophies and congenital myopathies are progressing toward approval as well.
    SUMMARY: Muscular dystrophies and congenital myopathies are a heterogenous group of hereditary muscle disorders. Confirming a diagnosis with genetic testing is not only critical for guiding management, but also an actual prerequisite for current and future gene therapies. Recessive loss-of-function or dominant haploinsufficiency disorders may be treated with gene replacement strategies, whereas dominant negative and toxic gain-of-function disorders are best addressed with a variety of knockdown approaches. It is important to recognize that many therapeutics are mutation specific and will only benefit a subset of individuals with a specific disease.
    DOI:  https://doi.org/10.1212/CON.0000000000001203
  16. Front Cell Dev Biol. 2022 ;10 1082193
    Islet cilia and glucose homeostasis.
    Isabella Melena, Jing W Hughes.
      Diabetes is a growing pandemic affecting over ten percent of the U.S. population. Individuals with all types of diabetes exhibit glucose dysregulation due to altered function and coordination of pancreatic islets. Within the critical intercellular space in pancreatic islets, the primary cilium emerges as an important physical structure mediating cell-cell crosstalk and signal transduction. Many events leading to hormone secretion, including GPCR and second-messenger signaling, are spatiotemporally regulated at the level of the cilium. In this review, we summarize current knowledge of cilia action in islet hormone regulation and glucose homeostasis, focusing on newly implicated ciliary pathways that regulate insulin exocytosis and intercellular communication. We present evidence of key signaling proteins on islet cilia and discuss ways in which cilia might functionally connect islet endocrine cells with the non-endocrine compartments. These discussions aim to stimulate conversations regarding the extent of cilia-controlled glucose homeostasis in health and in metabolic diseases.
    Keywords:  beta cells; glucose regulation; pancreatic islets; paracrine signaling; primary cilia
    DOI:  https://doi.org/10.3389/fcell.2022.1082193
  17. Molecules. 2022 Dec 11. pii: 8784. [Epub ahead of print]27(24):
    Proteomic Insights into Cardiac Fibrosis: From Pathophysiological Mechanisms to Therapeutic Opportunities.
    Ruiqiang Qi, E Lin, Juan Song, Yan Wang, Ling Lin.
      Cardiac fibrosis is a common pathophysiologic process in nearly all forms of heart disease which refers to excessive deposition of extracellular matrix proteins by cardiac fibroblasts. Activated fibroblasts are the central cellular effectors in cardiac fibrosis, and fibrotic remodelling can cause several cardiac dysfunctions either by reducing the ejection fraction due to a stiffened myocardial matrix, or by impairing electric conductance. Recently, there is a rising focus on the proteomic studies of cardiac fibrosis for pathogenesis elucidation and potential biomarker mining. This paper summarizes the current knowledge of molecular mechanisms underlying cardiac fibrosis, discusses the potential of imaging and circulating biomarkers available to recognize different phenotypes of this lesion, reviews the currently available and potential future therapies that allow individualized management in reversing progressive fibrosis, as well as the recent progress on proteomic studies of cardiac fibrosis. Proteomic approaches using clinical specimens and animal models can provide the ability to track pathological changes and new insights into the mechanisms underlining cardiac fibrosis. Furthermore, spatial and cell-type resolved quantitative proteomic analysis may also serve as a minimally invasive method for diagnosing cardiac fibrosis and allowing for the initiation of prophylactic treatment.
    Keywords:  cardiac fibrosis; cell-type resolved proteomics; circulating biomarkers; extracellular matrix; fibroblast activation; therapeutic strategies
    DOI:  https://doi.org/10.3390/molecules27248784
  18. Mol Genet Metab. 2022 Nov 30. pii: S1096-7192(22)00442-5. [Epub ahead of print]138(1): 106966
    The multiple facets of acetyl-CoA metabolism: Energetics, biosynthesis, regulation, acylation and inborn errors.
    Youlin Wang, Hao Yang, Chloé Geerts, Alexandra Furtos, Paula Waters, Denis Cyr, Shupei Wang, Grant A Mitchell.
      Acetyl-coenzyme A (Ac-CoA) is a core metabolite with essential roles throughout cell physiology. These functions can be classified into energetics, biosynthesis, regulation and acetylation of large and small molecules. Ac-CoA is essential for oxidative metabolism of glucose, fatty acids, most amino acids, ethanol, and of free acetate generated by endogenous metabolism or by gut bacteria. Ac-CoA cannot cross lipid bilayers, but acetyl groups from Ac-CoA can shuttle across membranes as part of carrier molecules like citrate or acetylcarnitine, or as free acetate or ketone bodies. Ac-CoA is the basic unit of lipid biosynthesis, providing essentially all of the carbon for the synthesis of fatty acids and of isoprenoid-derived compounds including cholesterol, coenzyme Q and dolichols. High levels of Ac-CoA in hepatocytes stimulate lipid biosynthesis, ketone body production and the diversion of pyruvate metabolism towards gluconeogenesis and away from oxidation; low levels exert opposite effects. Acetylation changes the properties of molecules. Acetylation is necessary for the synthesis of acetylcholine, acetylglutamate, acetylaspartate and N-acetyl amino sugars, and to metabolize/eliminate some xenobiotics. Acetylation is a major post-translational modification of proteins. Different types of protein acetylation occur. The most-studied form occurs at the epsilon nitrogen of lysine residues. In histones, lysine acetylation can alter gene transcription. Acetylation of other proteins has diverse, often incompletely-documented effects. Inborn errors related to Ac-CoA feature a broad spectrum of metabolic, neurological and other features. To date, a small number of studies of animals with inborn errors of CoA thioesters has included direct measurement of acyl-CoAs. These studies have shown that low levels of tissue Ac-CoA correlate with the development of clinical signs, hinting that shortage of Ac-CoA may be a recurrent theme in these conditions. Low levels of Ac-CoA could potentially disrupt any of its roles.
    Keywords:  Acetyl-CoA; Acetylation; Acylation; Energy metabolism; Inborn errors
    DOI:  https://doi.org/10.1016/j.ymgme.2022.106966
  19. Int J Mol Sci. 2022 Dec 10. pii: 15678. [Epub ahead of print]23(24):
    Glucocorticoid Effects on Proteoglycans and Glycosaminoglycans.
    Anastasia V Strokotova, Elvira V Grigorieva.
      Glucocorticoids are steroid hormones that play diverse roles in numerous normal and pathological processes. They are actively used to treat a wide variety of diseases, including neurodegenerative and inflammatory diseases, cancers, and COVID-19, among others. However, the long-term use of glucocorticoids is associated with numerous side effects. Molecular mechanisms of these negative side effects are not completely understood. Recently, arguments have been made that one such mechanisms may be related to the influence of glucocorticoids on O-glycosylated components of the cell surface and extracellular matrix, in particular on proteoglycans and glycosaminoglycans. The potential toxic effects of glucocorticoids on these glycosylated macromolecules are particularly meaningful for brain physiology because proteoglycans/glycosaminoglycans are the main extracellular components of brain tissue. Here, we aim to review the known effects of glucocorticoids on proteoglycan expression and glycosaminoglycan content in different tissues, with a specific focus on the brain.
    Keywords:  brain; chondroitin sulfate; extracellular matrix; glucocorticoid; glycosaminoglycan; heparan sulfate; proteoglycan; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms232415678
  20. Nat Rev Methods Primers. 2022 ;2(1): 96
    Liquid chromatography-tandem mass spectrometry for clinical diagnostics.
    Stefani N Thomas, Deborah French, Paul J Jannetto, Brian A Rappold, William A Clarke.
      Mass spectrometry is a powerful analytical tool used for the analysis of a wide range of substances and matrices; it is increasingly utilized for clinical applications in laboratory medicine. This Primer includes an overview of basic mass spectrometry concepts, focusing primarily on tandem mass spectrometry. We discuss experimental considerations and quality management, and provide an overview of some key applications in the clinic. Lastly, the Primer discusses significant challenges for implementation of mass spectrometry in clinical laboratories and provides an outlook of where there are emerging clinical applications for this technology.
    Keywords:  Mass spectrometry; Medical research
    DOI:  https://doi.org/10.1038/s43586-022-00175-x
  21. Int J Mol Sci. 2022 Dec 08. pii: 15549. [Epub ahead of print]23(24):
    Lysosomal Acid Lipase Deficiency: Genetics, Screening, and Preclinical Study.
    Ryuichi Mashima, Shuji Takada.
      Lysosomal acid lipase (LAL) is a lysosomal enzyme essential for the degradation of cholesteryl esters through the endocytic pathway. Deficiency of the LAL enzyme encoded by the LIPA gene leads to LAL deficiency (LAL-D) (OMIM 278000), one of the lysosomal storage disorders involving 50-60 genes. Among the two disease subtypes, the severe disease subtype of LAL-D is known as Wolman disease, with typical manifestations involving hepatomegaly, splenomegaly, vomiting, diarrhea, and hematopoietic abnormalities, such as anemia. In contrast, the mild disease subtype of this disorder is known as cholesteryl ester storage disease, with hypercholesterolemia, hypertriglyceridemia, and high-density lipoprotein disappearance. The prevalence of LAL-D is rare, but several treatment options, including enzyme replacement therapy, are available. Accordingly, a number of screening methodologies have been developed for this disorder. This review summarizes the current discussion on LAL-D, covering genetics, screening, and the tertiary structure of human LAL enzyme and preclinical study for the future development of a novel therapy.
    Keywords:  biochemistry; genetics; lysosome acid lipase; screening
    DOI:  https://doi.org/10.3390/ijms232415549
  22. Pharmaceuticals (Basel). 2022 Nov 23. pii: 1451. [Epub ahead of print]15(12):
    The Glycosylation of Immune Checkpoints and Their Applications in Oncology.
    Linlin Zheng, Qi Yang, Feifei Li, Min Zhu, Haochi Yang, Tian Tan, Binghuo Wu, Mingxin Liu, Chuan Xu, Jun Yin, Chenhui Cao.
      Tumor therapies have entered the immunotherapy era. Immune checkpoint inhibitors have achieved tremendous success, with some patients achieving long-term tumor control. Tumors, on the other hand, can still accomplish immune evasion, which is aided by immune checkpoints. The majority of immune checkpoints are membrane glycoproteins, and abnormal tumor glycosylation may alter how the immune system perceives tumors, affecting the body's anti-tumor immunity. Furthermore, RNA can also be glycosylated, and GlycoRNA is important to the immune system. Glycosylation has emerged as a new hallmark of tumors, with glycosylation being considered a potential therapeutic approach. The glycosylation modification of immune checkpoints and the most recent advances in glycosylation-targeted immunotherapy are discussed in this review.
    Keywords:  GlycoRNA; cancer therapy; glycosylation; immune checkpoints; post-translational modifications
    DOI:  https://doi.org/10.3390/ph15121451
  23. Biomolecules. 2022 Nov 26. pii: 1755. [Epub ahead of print]12(12):
    Protein Targeting to Glycogen (PTG): A Promising Player in Glucose and Lipid Metabolism.
    Xia Deng, Chenxi Wang, Yue Xia, Guoyue Yuan.
      Protein phosphorylation and dephosphorylation are widely considered to be the key regulatory factors of cell function, and are often referred to as "molecular switches" in the regulation of cell metabolic processes. A large number of studies have shown that the phosphorylation/dephosphorylation of related signal molecules plays a key role in the regulation of liver glucose and lipid metabolism. As a new therapeutic strategy for metabolic diseases, the potential of using inhibitor-based therapies to fight diabetes has gained scientific momentum. PTG, a protein phosphatase, also known as glycogen targeting protein, is a member of the protein phosphatase 1 (PP1) family. It can play a role by catalyzing the dephosphorylation of phosphorylated protein molecules, especially regulating many aspects of glucose and lipid metabolism. In this review, we briefly summarize the role of PTG in glucose and lipid metabolism, and update its role in metabolic regulation, with special attention to glucose homeostasis and lipid metabolism.
    Keywords:  glucose metabolism; glycogen synthesis; lipid metabolism; protein phosphatase 1α (PP1α); protein targeting to glycogen (PTG)
    DOI:  https://doi.org/10.3390/biom12121755
  24. Continuum (Minneap Minn). 2022 Dec 01. 28(6): 1735-1751
    Facioscapulohumeral Muscular Dystrophy.
    Karlien Mul.
      PURPOSE OF REVIEW: This article reviews the current knowledge on the clinical characteristics and disease mechanism of facioscapulohumeral muscular dystrophy (FSHD), as well as advances in targeted therapy development.RECENT FINDINGS: FSHD has a wide range of severity, yet a distinct phenotype characterized by weakness of the facial, shoulder, and upper arm muscles, followed by weakness of the trunk and leg muscles. It can be caused by two genetic mechanisms that share a common downstream pathway, namely, the epigenetic derepression and subsequent misexpression of the myotoxic DUX4 transcription factor. Treatment is currently supportive and outlined in evidence-based guidelines. Advances in the understanding of the pathogenic mechanism of FSHD are paving the way for targeted therapy development. Approaches for targeted therapies to reduce DUX4 expression that are currently being explored include small molecules, antisense oligonucleotides, vector-based RNA interference, and gene therapy. In anticipation of more clinical trials, "clinical trial preparedness," including the development of sensitive biomarkers and clinical outcome measures, are needed.
    SUMMARY: The cornerstones of the diagnosis of FSHD are clinical observation and genetic testing. Management is currently supportive, but progress in the understanding of the disease mechanism has shifted the field of FSHD toward targeted therapy development.
    DOI:  https://doi.org/10.1212/CON.0000000000001155
  25. Cell Death Dis. 2022 Dec 21. 13(12): 1063
    Functional investigation of SLC1A2 variants associated with epilepsy.
    Qi Qu, Wenlong Zhang, Ji Wang, Dongmei Mai, Siqiang Ren, Shaogang Qu, Yunlong Zhang.
      Epilepsy is a common neurological disorder and glutamate excitotoxicity plays a key role in epileptic pathogenesis. Astrocytic glutamate transporter GLT-1 is responsible for preventing excitotoxicity via clearing extracellular accumulated glutamate. Previously, three variants (G82R, L85P, and P289R) in SLC1A2 (encoding GLT-1) have been clinically reported to be associated with epilepsy. However, the functional validation and underlying mechanism of these GLT-1 variants in epilepsy remain undetermined. In this study, we reported that these disease-linked mutants significantly decrease glutamate uptake, cell membrane expression of the glutamate transporter, and glutamate-elicited current. Additionally, we found that these variants may disturbed stromal-interacting molecule 1 (STIM1)/Orai1-mediated store-operated Ca2+ entry (SOCE) machinery in the endoplasmic reticulum (ER), in which GLT-1 may be a new partner of SOCE. Furthermore, knock-in mice with disease-associated variants showed a hyperactive phenotype accompanied by reduced glutamate transporter expression. Therefore, GLT-1 is a promising and reliable therapeutic target for epilepsy interventions.
    DOI:  https://doi.org/10.1038/s41419-022-05457-6
  26. Int J Mol Sci. 2022 Dec 19. pii: 16217. [Epub ahead of print]23(24):
    Extracellular Vesicles as Biomarkers in Liver Disease.
    Rocío Muñoz-Hernández, Ángela Rojas, Sheila Gato, Javier Gallego, Antonio Gil-Gómez, María José Castro, Javier Ampuero, Manuel Romero-Gómez.
      Extracellular vesicles (EVs) are membrane-derived vesicles released by a variety of cell types, including hepatocytes, hepatic stellate cells, and immune cells in normal and pathological conditions. Depending on their biogenesis, there is a complex repertoire of EVs that differ in size and origin. EVs can carry lipids, proteins, coding and non-coding RNAs, and mitochondrial DNA causing alterations to the recipient cells, functioning as intercellular mediators of cell-cell communication (auto-, para-, juxta-, or even endocrine). Nevertheless, many questions remain unanswered in relation to the function of EVs under physiological and pathological conditions. The development and optimization of methods for EV isolation are crucial for characterizing their biological functions, as well as their potential as a treatment option in the clinic. In this manuscript, we will comprehensively review the results from different studies that investigated the role of hepatic EVs during liver diseases, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, fibrosis, and hepatocellular carcinoma. In general, the identification of patients with early-stage liver disease leads to better therapeutic interventions and optimal management. Although more light needs to be shed on the mechanisms of EVs, their use for early diagnosis, follow-up, and prognosis has come into the focus of research as a high-potential source of 'liquid biopsies', since they can be found in almost all biological fluids. The use of EVs as new targets or nanovectors in drug delivery systems for liver disease therapy is also summarized.
    Keywords:  biomarkers; extracellular vesicles; liver disease
    DOI:  https://doi.org/10.3390/ijms232416217
  27. NPJ Microgravity. 2022 Dec 22. 8(1): 58
    Rare diseases and space health: optimizing synergies from scientific questions to care.
    Maria Puscas, Gabrielle Martineau, Gurjot Bhella, Penelope E Bonnen, Phil Carr, Robyn Lim, John Mitchell, Matthew Osmond, Emmanuel Urquieta, Jaime Flamenbaum, Giuseppe Iaria, Yann Joly, Étienne Richer, Joan Saary, David Saint-Jacques, Nicole Buckley, Etienne Low-Decarie.
      Knowledge transfer among research disciplines can lead to substantial research progress. At first glance, astronaut health and rare diseases may be seen as having little common ground for such an exchange. However, deleterious health conditions linked to human space exploration may well be considered as a narrow sub-category of rare diseases. Here, we compare and contrast research and healthcare in the contexts of rare diseases and space health and identify common barriers and avenues of improvement. The prevalent genetic basis of most rare disorders contrasts sharply with the occupational considerations required to sustain human health in space. Nevertheless small sample sizes and large knowledge gaps in natural history are examples of the parallel challenges for research and clinical care in the context of both rare diseases and space health. The two areas also face the simultaneous challenges of evidence scarcity and the pressure to deliver therapeutic solutions, mandating expeditious translation of research knowledge into clinical care. Sharing best practices between these fields, including increasing participant involvement in all stages of research and ethical sharing of standardized data, has the potential to contribute to humankind's efforts to explore ever further into space while caring for people on Earth in a more inclusive fashion.
    DOI:  https://doi.org/10.1038/s41526-022-00224-5
  28. Continuum (Minneap Minn). 2022 Dec 01. 28(6): 1698-1714
    The Limb-Girdle Muscular Dystrophies.
    Nicholas E Johnson, Jeffrey M Statland.
      PURPOSE OF REVIEW: The limb-girdle muscular dystrophies (LGMDs) are a group of inherited muscle disorders with a common feature of limb-girdle pattern of weakness, caused by over 29 individual genes. This article describes the classification scheme, common subtypes, and the management of individuals with LGMD.RECENT FINDINGS: Advances in genetic testing and next-generation sequencing panels containing all of the LGMD genes have led to earlier genetic confirmation, but also to more individuals with variants of uncertain significance. The LGMDs include disorders with autosomal recessive inheritance, which are often due to loss-of-function mutations in muscle structural or repair proteins and typically have younger ages of onset and more rapidly progressive presentations, and those with autosomal dominant inheritance, which can have older ages of presentation and chronic progressive disease courses. All cause progressive disability and potential loss of ability to walk or maintain a job due to progressive muscle wasting. Certain mutations are associated with cardiac or respiratory involvement. No disease-altering therapies have been approved by the US Food and Drug Administration (FDA) for LGMDs and standard treatment uses a multidisciplinary clinic model, but recessive LGMDs are potentially amenable to systemic gene replacement therapies, which are already being tested in clinical trials for sarcoglycan and FKRP mutations. The dominant LGMDs may be amenable to RNA-based therapeutic approaches.
    SUMMARY: International efforts are underway to better characterize LGMDs, help resolve variants of uncertain significance, provide consistent and improved standards of care, and prepare for future clinical trials.
    DOI:  https://doi.org/10.1212/CON.0000000000001178
  29. Pharmaceutics. 2022 Nov 30. pii: 2657. [Epub ahead of print]14(12):
    Mitochondrial Dysfunction: Pathophysiology and Mitochondria-Targeted Drug Delivery Approaches.
    Tanzeel Khan, Rashid Waseem, Zainy Zehra, Ayesha Aiman, Priyanka Bhardwaj, Jaoud Ansari, Md Imtaiyaz Hassan, Asimul Islam.
      Mitochondria are implicated in a wide range of functions apart from ATP generation, and, therefore, constitute one of the most important organelles of cell. Since healthy mitochondria are essential for proper cellular functioning and survival, mitochondrial dysfunction may lead to various pathologies. Mitochondria are considered a novel and promising therapeutic target for the diagnosis, treatment, and prevention of various human diseases including metabolic disorders, cancer, and neurodegenerative diseases. For mitochondria-targeted therapy, there is a need to develop an effective drug delivery approach, owing to the mitochondrial special bilayer structure through which therapeutic molecules undergo multiple difficulties in reaching the core. In recent years, various nanoformulations have been designed such as polymeric nanoparticles, liposomes, inorganic nanoparticles conjugate with mitochondriotropic moieties such as mitochondria-penetrating peptides (MPPs), triphenylphosphonium (TPP), dequalinium (DQA), and mitochondrial protein import machinery for overcoming barriers involved in targeting mitochondria. The current approaches used for mitochondria-targeted drug delivery have provided promising ways to overcome the challenges associated with targeted-drug delivery. Herein, we review the research from past years to the current scenario that has identified mitochondrial dysfunction as a major contributor to the pathophysiology of various diseases. Furthermore, we discuss the recent advancements in mitochondria-targeted drug delivery strategies for the pathologies associated with mitochondrial dysfunction.
    Keywords:  drug delivery; mitochondrial dysfunction; nanoparticles; pathophysiology
    DOI:  https://doi.org/10.3390/pharmaceutics14122657
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