scholarly journals Fluorinated rhamnosides inhibit cellular fucosylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Johan F. A. Pijnenborg ◽  
Emiel Rossing ◽  
Jona Merx ◽  
Marek J. Noga ◽  
Willem H. C. Titulaer ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
De Novo ◽  
Genetic Disorders ◽  
Living Cells ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Inflammation ◽  
Mannose Derivatives ◽  
Potential Therapeutics

AbstractThe sugar fucose is expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis via competitive GMDS inhibition. We demonstrate that cell permeable fluorinated rhamnose 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

scholarly journals Fluorinated Mannosides Inhibit Cellular Fucosylation.

2020 ◽  
Author(s):  
Johan Pijnenborg ◽  
Emiel Rossing ◽  
Marek Noga ◽  
Willem Titulaer ◽  
Raisa Veizaj ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
De Novo ◽  
Genetic Disorders ◽  
Living Cells ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Inflammation ◽  
Mannose Derivatives ◽  
Potential Therapeutics

Fucose sugars are expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a novel class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis. We demonstrate that cell permeable fluorinated mannoside 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

scholarly journals Fluorinated Mannosides Inhibit Cellular Fucosylation.

2020 ◽  
Author(s):  
Johan Pijnenborg ◽  
Emiel Rossing ◽  
Marek Noga ◽  
Willem Titulaer ◽  
Raisa Veizaj ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
De Novo ◽  
Genetic Disorders ◽  
Living Cells ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Inflammation ◽  
Mannose Derivatives ◽  
Potential Therapeutics

Fucose sugars are expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a novel class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis. We demonstrate that cell permeable fluorinated mannoside 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

scholarly journals Maternal mosaicism for a missense variant in the SMS gene that causes Snyder-Robinson syndrome

2021 ◽  
pp. mcs.a006122
Author(s):  
Mohammad Marhabaie ◽  
Scott E Hickey ◽  
Katherine E Miller ◽  
Olivia Grischow ◽  
Kathleen M Schieffer ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
De Novo ◽  
Genetic Disorders ◽  
Missense Variant ◽  
Hyperinsulinemic Hypoglycemia ◽  
Spermine Synthase ◽  
Genetic Mosaicism ◽  
The Family ◽  
Bilateral Sensorineural Hearing Loss

There is increasing recognition for the contribution of genetic mosaicism to human disease, particularly as high-throughput sequencing has enabled detection of sequence variants at very low allele frequencies. Here, we describe an infant male who presented at 9 months of age with hypotonia, dysmorphic features, congenital heart disease, hyperinsulinemic hypoglycemia, hypothyroidism, and bilateral sensorineural hearing loss. Whole-genome sequencing of the proband and the parents uncovered an apparent de novo mutation in the X-linked SMS gene. SMS encodes spermine synthase, which catalyzes the production of spermine from spermidine. Inactivation of the SMS gene disrupts the spermidine/spermine ratio, resulting in Snyder-Robinson syndrome. The variant in our patient is absent from the gnomAD and ExAC databases and causes a missense change (p.Arg130Cys) predicted to be damaging by most in silico tools. While Sanger sequencing confirmed the de novo status in our proband, PCR and deep targeted resequencing to ~84,000-175,000x depth revealed that the variant is present in blood from the unaffected mother at ~3% variant allele frequency. Our findings thus provided a long-sought diagnosis for the family while highlighting the role of parental mosaicism in severe genetic disorders.

scholarly journals The Expanding Role of Vesicles Containing Aquaporins

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 179 ◽  
Author(s):  
M Martinez-Ballesta ◽  
Paula Garcia-Ibañez ◽  
Lucía Yepes-Molina ◽  
Juan Rios ◽  
Micaela Carvajal
Keyword(s):  
Environmental Changes ◽  
Cell Communication ◽  
Membrane Vesicles ◽  
Living Cells ◽  
Biotechnological Applications ◽  
Future Perspectives ◽  
Physiological Processes ◽  
Communication Processes ◽  
Other Substances

In animals and plants, membrane vesicles containing proteins have been defined as key for biological systems involving different processes such as trafficking or intercellular communication. Docking and fusion of vesicles to the plasma membrane occur in living cells in response to different stimuli, such as environmental changes or hormones, and therefore play an important role in cell homeostasis as vehicles for certain proteins or other substances. Because aquaporins enhance the water permeability of membranes, their role as proteins immersed in vesicles formed of natural membranes is a recent topic of study. They regulate numerous physiological processes and could hence serve new biotechnological purposes. Thus, in this review, we have explored the physiological implications of the trafficking of aquaporins, the mechanisms that control their transit, and the proteins that coregulate the migration. In addition, the importance of exosomes containing aquaporins in the cell-to-cell communication processes in animals and plants have been analyzed, together with their potential uses in biomedicine or biotechnology. The properties of aquaporins make them suitable for use as biomarkers of different aquaporin-related diseases when they are included in exosomes. Finally, the fact that these proteins could be immersed in biomimetic membranes opens future perspectives for new biotechnological applications.

scholarly journals Role of the Cation-Chloride-Cotransporters in Cardiovascular Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2293 ◽  
Author(s):  
Nur Farah Meor Azlan ◽  
Jinwei Zhang
Keyword(s):  
Cardiovascular Disease ◽  
Potassium Chloride ◽  
Genetic Disorders ◽  
Ion Homeostasis ◽  
Cell Volume Regulation ◽  
Renal Cells ◽  
Sodium Potassium ◽  
Physiological Processes ◽  
Cation Chloride Cotransporters

The SLC12 family of cation-chloride-cotransporters (CCCs) is comprised of potassium chloride cotransporters (KCCs), which mediate Cl− extrusion and sodium-potassium chloride cotransporters (N[K]CCs), which mediate Cl− loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. The functions of CCCs influence a variety of physiological processes, many of which overlap with the pathophysiology of cardiovascular disease. Although not all of the cotransporters have been linked to Mendelian genetic disorders, recent studies have provided new insights into their functional role in vascular and renal cells in addition to their contribution to cardiovascular diseases. Particularly, an imbalance in potassium levels promotes the pathogenesis of atherosclerosis and disturbances in sodium homeostasis are one of the causes of hypertension. Recent findings suggest hypothalamic signaling as a key signaling pathway in the pathophysiology of hypertension. In this review, we summarize and discuss the role of CCCs in cardiovascular disease with particular emphasis on knowledge gained in recent years on NKCCs and KCCs.

scholarly journals Serum/Plasma MicroRNAs as Biomarkers for HBV-Related Hepatocellular Carcinoma in China

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Wen Yin ◽  
Yan Zhao ◽  
Yong-Jing Ji ◽  
Li-Ping Tong ◽  
Ya Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Regulation Of Gene Expression ◽  
Chinese Patients ◽  
Aberrant Expression ◽  
Diagnosis And Prognosis ◽  
Physiological Processes ◽  
Serum Mirnas ◽  
Proliferation And Differentiation ◽  
Plasma Mirnas

MicroRNAs (miRNAs) are a group of small RNAs with a fundamental role in the regulation of gene expression. These RNAs have been shown to participate in various cellular and physiological processes, including cellular development, apoptosis, proliferation, and differentiation. Aberrant expression of several miRNAs was found to be involved in a large variety of neoplasms, including hepatocellular carcinoma (HCC). Previous studies have shown the existence of a large amount of stable miRNAs in human serum/plasma, which laid the foundation for studying the role of serum/plasma miRNAs in the diagnosis and prognosis of HCC. Here, we review the recent progress in research on serum miRNAs as biomarkers for HCC in Chinese patients.

scholarly journals MicroRNAs and Their Targetomes in Tumor-Immune Communication

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2025
Author(s):  
Sunglim Cho ◽  
Jesse W. Tai ◽  
Li-Fan Lu
Keyword(s):  
Gene Regulation ◽  
Immune System ◽  
Target Identification ◽  
Genetic Disorders ◽  
Aberrant Expression ◽  
Cancer Tumor ◽  
Experimental Approaches ◽  
Non Coding Rnas ◽  
Multiple Step

The development of cancer is a complex and dynamically regulated multiple-step process that involves many changes in gene expression. Over the last decade, microRNAs (miRNAs), a class of short regulatory non-coding RNAs, have emerged as key molecular effectors and regulators of tumorigenesis. While aberrant expression of miRNAs or dysregulated miRNA-mediated gene regulation in tumor cells have been shown to be capable of directly promoting or inhibiting tumorigenesis, considering the well-reported role of the immune system in cancer, tumor-derived miRNAs could also impact tumor growth through regulating anti-tumor immune responses. Here, we discuss howmiRNAs can function as central mediators that influence the crosstalk between cancer and the immune system. Moreover, we also review the current progress in the development of novel experimental approaches for miRNA target identification that will facilitate our understanding of miRNA-mediated gene regulation in not only human malignancies, but also in other genetic disorders.

scholarly journals Cracking the Monoubiquitin Code of Genetic Diseases

2020 ◽  
Vol 21 (9) ◽  
pp. 3036 ◽  
Author(s):  
Raj Nayan Sewduth ◽  
Maria Francesca Baietti ◽  
Anna A. Sablina
Keyword(s):  
Genetic Disorders ◽  
Genetic Diseases ◽  
Post Translational Modification ◽  
Binding Properties ◽  
Polyubiquitin Chains ◽  
Target Proteins ◽  
Therapeutic Implications ◽  
Physiological Processes ◽  
The Stability

Ubiquitination is a versatile and dynamic post-translational modification in which single ubiquitin molecules or polyubiquitin chains are attached to target proteins, giving rise to mono- or poly-ubiquitination, respectively. The majority of research in the ubiquitin field focused on degradative polyubiquitination, whereas more recent studies uncovered the role of single ubiquitin modification in important physiological processes. Monoubiquitination can modulate the stability, subcellular localization, binding properties, and activity of the target proteins. Understanding the function of monoubiquitination in normal physiology and pathology has important therapeutic implications, as alterations in the monoubiquitin pathway are found in a broad range of genetic diseases. This review highlights a link between monoubiquitin signaling and the pathogenesis of genetic disorders.

scholarly journals Players in Mitochondrial Dynamics and Female Reproduction

2021 ◽  
Vol 8 ◽  
Author(s):  
Weiwei Zou ◽  
Dongmei Ji ◽  
Zhiguo Zhang ◽  
Li Yang ◽  
Yunxia Cao
Keyword(s):  
Mitochondrial Dynamics ◽  
Reproductive Function ◽  
Metabolic Function ◽  
Female Reproduction ◽  
Therapeutic Approaches ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Dynamic ◽  
Aberrant Expression ◽  
Physiological Processes

Mitochondrial dynamics (fission and fusion) are essential physiological processes for mitochondrial metabolic function, mitochondrial redistribution, and mitochondrial quality control. Various proteins are involved in regulating mitochondrial dynamics. Aberrant expression of these proteins interferes with mitochondrial dynamics and induces a range of diseases. Multiple therapeutic approaches have been developed to treat the related diseases in recent years, but their curative effects are limited. Meanwhile, the role of mitochondrial dynamics in female reproductive function has attracted progressively more attention, including oocyte development and maturation, fertilization, and embryonic development. Here, we reviewed the significance of mitochondrial dynamics, proteins involved in mitochondrial dynamics, and disorders resulting from primary mitochondrial dynamic dysfunction. We summarized the latest therapeutic approaches of hereditary mitochondrial fusion–fission abnormalities and reviewed the recent advances in female reproductive mitochondrial dynamics.

scholarly journals Lipoic Acid Metabolism in Microbial Pathogens

2010 ◽  
Vol 74 (2) ◽  
pp. 200-228 ◽  
Author(s):  
Maroya D. Spalding ◽  
Sean T. Prigge
Keyword(s):  
Lipoic Acid ◽  
Acid Metabolism ◽  
De Novo ◽  
Living Cells ◽  
Microbial Pathogens ◽  
Pentanoic Acid ◽  
Free Living ◽  
Oxidative Defense ◽  
Intermediate Metabolism

SUMMARY Lipoic acid [(R)-5-(1,2-dithiolan-3-yl)pentanoic acid] is an enzyme cofactor required for intermediate metabolism in free-living cells. Lipoic acid was discovered nearly 60 years ago and was shown to be covalently attached to proteins in several multicomponent dehydrogenases. Cells can acquire lipoate (the deprotonated charge form of lipoic acid that dominates at physiological pH) through either scavenging or de novo synthesis. Microbial pathogens implement these basic lipoylation strategies with a surprising variety of adaptations which can affect pathogenesis and virulence. Similarly, lipoylated proteins are responsible for effects beyond their classical roles in catalysis. These include roles in oxidative defense, bacterial sporulation, and gene expression. This review surveys the role of lipoate metabolism in bacterial, fungal, and protozoan pathogens and how these organisms have employed this metabolism to adapt to niche environments.

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