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International Journal of Molecular... May 2023Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by... (Review)
Review
Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.
Topics: Humans; Cardiomyopathies; Metabolic Diseases; Heart Defects, Congenital; Glycosylation; Carbohydrates; Sugars; Chondroitinsulfatases; Pentosyltransferases; Mannosyltransferases; Acetyltransferases
PubMed: 37239976
DOI: 10.3390/ijms24108632 -
Biotechnology Advances 2023Polyphenolic compounds (such as quercetin and resveratrol) possess potential medicinal values due to their various bioactivities, but poor water solubility hinders their... (Review)
Review
Polyphenolic compounds (such as quercetin and resveratrol) possess potential medicinal values due to their various bioactivities, but poor water solubility hinders their health benefits to humankind. Glycosylation is a well-known post-modification method to biosynthesize natural product glycosides with improved hydrophilicity. Glycosylation has profound effects on decreasing toxicity, increasing bioavailability and stability, together with changing bioactivity of polyphenolic compounds. Therefore, polyphenolic glycosides can be used as food additives, therapeutics, and nutraceuticals. Engineered biosynthesis provides an environmentally friendly and cost-effective approach to generate polyphenolic glycosides through the use of various glycosyltransferases (GTs) and sugar biosynthetic enzymes. GTs transfer the sugar moieties from nucleotide-activated diphosphate sugar (NDP-sugar) donors to sugar acceptors such as polyphenolic compounds. In this review, we systematically review and summarize the representative polyphenolic O-glycosides with various bioactivities and their engineered biosynthesis in microbes with different biotechnological strategies. We also review the major routes towards NDP-sugar formation in microbes, which is significant for producing unusual or novel glycosides. Finally, we discuss the trends in NDP-sugar based glycosylation research to promote the development of prodrugs that positively impact human health and wellness.
Topics: Humans; Glycosides; Carbohydrates; Glycosylation; Glycosyltransferases; Sugars; Nucleotides
PubMed: 37028465
DOI: 10.1016/j.biotechadv.2023.108146 -
Autoimmunity Reviews Sep 2023Psoriatic arthritis (PsA) is an inflammatory complex condition. Posttranslational modifications influence almost all aspects of normal cell biology and pathogenesis. The... (Review)
Review
BACKGROUND AND AIMS
Psoriatic arthritis (PsA) is an inflammatory complex condition. Posttranslational modifications influence almost all aspects of normal cell biology and pathogenesis. The aim of this systematic review was to collect all published evidence regarding posttranslational modifications in PsA, and the main outcome was to evaluate an association between disease outcomes and specific posttranslational modifications in PsA.
METHODS
A systematic electronic search was performed in Medline, PubMed, Cochrane, Virtual Health Library, and Embase databases. A total of 587 articles were identified; 59 were evaluated after removing duplicates and scanning, of which 47 were included. A descriptive analysis was conducted, with results grouped according to the type of posttranslational modification evaluated. The protocol was registered at the PROSPERO database.
RESULTS
Seven posttranslational modifications were identified: citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress. Anti-citrullinated peptide and anti-carbamylated protein have been evaluated in rheumatoid arthritis. There is now information suggesting that these antibodies may be helpful in improving the diagnosis of PsA and that they may demonstrate a correlation with worse disease progression (erosions, polyarticular involvement, and poor treatment response). Glycosylation was associated with increased inflammation and phosphorylation products related to the expression of SIRT2 and pSTAT3 or the presence of Th17 and cytokine interleukin-22, suggesting a possible therapeutic target.
CONCLUSIONS
Posttranslational modifications often play a key role in modulating protein function in PsA and correlate with disease outcomes. Citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress were identified as associated with diagnosis and prognosis.
Topics: Humans; Arthritis, Psoriatic; Protein Processing, Post-Translational; Citrullination; Glycosylation; Arthritis, Rheumatoid
PubMed: 37487969
DOI: 10.1016/j.autrev.2023.103393 -
International Journal of Molecular... Aug 2022Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid... (Review)
Review
Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders' views on AI for therapy discovery in CDG.
Topics: Artificial Intelligence; Biomarkers; Congenital Disorders of Glycosylation; Drug Repositioning; Humans; Rare Diseases
PubMed: 35955863
DOI: 10.3390/ijms23158725 -
Molecules (Basel, Switzerland) Mar 2020Chitosan derivatives, and more specifically, glycosylated derivatives, are nowadays attracting much attention within the scientific community due to the fact that this... (Review)
Review
Chitosan derivatives, and more specifically, glycosylated derivatives, are nowadays attracting much attention within the scientific community due to the fact that this set of engineered polysaccharides finds application in different sectors, spanning from food to the biomedical field. Overcoming chitosan (physical) limitations or grafting biological relevant molecules, to mention a few, represent two cardinal strategies to modify parent biopolymer; thereby, synthetizing high added value polysaccharides. The present review is focused on the introduction of oligosaccharide side chains on the backbone of chitosan. The synthetic aspects and the effect on physical-chemical properties of such modifications are discussed. Finally, examples of potential applications in biomaterials design and drug delivery of these novel modified chitosans are disclosed.
Topics: Animals; Biocompatible Materials; Chitosan; Drug Delivery Systems; Glycosylation; Humans; Molecular Dynamics Simulation; Nanoparticles; Oligosaccharides; Tissue Engineering
PubMed: 32230971
DOI: 10.3390/molecules25071534 -
Thrombosis Research Sep 2022Ranging from bleeding to thrombosis, the clinical features of congenital fibrinogen qualitative disorders, including dysfibrinogenemia and hypodysfibrinogenemia, are... (Review)
Review
Ranging from bleeding to thrombosis, the clinical features of congenital fibrinogen qualitative disorders, including dysfibrinogenemia and hypodysfibrinogenemia, are highly heterogeneous. Although the associations between some specific fibrinogen mutations and the thrombotic phenotypes have been well elucidated, the underlying mechanism between fibrinogen variants and bleeding events remains underestimated. After systematically reviewing the literature of (hypo-)dysfibrinogenemia patients with bleeding phenotypes, we identified several well-characterized bleeding-related fibrinogen variants in those patients. Several possible pathomechanisms are proposed to explain the genotype-phenotype associations: 1, mutations in the NH-terminal portion of the Aα chain hamper fibrinogen fitting into the active site cleft of thrombin and drastically slow the conversion of fibrinogen into monomeric fibrin; 2, mutations adding new N-linked glycosylation sites introduce bulky and negatively charged carbohydrate side chains and undermine the alignment of fibrin monomers during polymerization; 3, mutations generating unpaired cysteine form extra disulfide bonds between the abnormal fibrinogen chains and produce highly branched and fragile fibrin networks; 4, truncation mutations in the fibrinogen αC regions impair the lateral fibril aggregation, as well as factor XIII crosslinking, endothelial cell and platelet binding. These established relationships between specific variants and the bleeding tendency will help manage (hypo-)dysfibrinogenemia patients to avoid adverse bleeding outcomes.
Topics: Afibrinogenemia; Blood Coagulation Tests; Fibrin; Fibrinogen; Fibrinogens, Abnormal; Hemorrhage; Humans; Thrombosis
PubMed: 35853369
DOI: 10.1016/j.thromres.2022.07.005 -
European Journal of Ophthalmology Jan 2022To assess the association between diabetes mellitus and keratoconus. (Meta-Analysis)
Meta-Analysis
PURPOSE
To assess the association between diabetes mellitus and keratoconus.
METHODS
PubMed, Google Scholar, Web of Science, and Scopus databases were searched for literature on the association between diabetes and keratoconus. The last literature search was conducted on April 4, 2021. A secondary form of the literature search was conducted by manually scanning the reference list of retrieved eligible articles. Included studies were cohort, case-control, or cross-sectional study design that used odds ratio or risk ratio to evaluate the relationship between keratoconus and diabetes. Egger's test was used to assess the presence of publication bias. The quality of eligible studies was assessed using the Newcastle-Ottawa Scale.
RESULTS
Nine studies (six case-control and three cohort studies) published between 2000 and 2021 were included. The total number of keratoconus patients and controls were 27,311 and 53,732. respectively. Meta-analysis revealed no significant association between diabetes mellitus and keratoconus; the pooled odds ratio was 0.87 (95% confidence interval: 0.66-1.14; = 0.314). There was significant heterogeneity ( (df = 7) = 33.36, < 0.001; = 79.01, < 0.001). Age of participants ( < 0.0001), study design ( < 0.001), and sample size ( = 0.024) were significant sources of heterogeneity. There was no evidence of publication bias.
CONCLUSION
The current meta-analysis revealed no significant association between diabetes mellitus and keratoconus. Well-designed longitudinal prospective studies are, however, needed to investigate any association between diabetes mellitus and keratoconus.
Topics: Cross-Sectional Studies; Diabetes Mellitus; Humans; Keratoconus; Odds Ratio; Prospective Studies
PubMed: 34761685
DOI: 10.1177/11206721211053167 -
Frontiers in Immunology 2023Galactose-deficient IgA1 (Gd-IgA1) is a critical effector molecule in the pathogenesis of IgA nephropathy (IgAN), a leading renal disease without noninvasive assessment... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Galactose-deficient IgA1 (Gd-IgA1) is a critical effector molecule in the pathogenesis of IgA nephropathy (IgAN), a leading renal disease without noninvasive assessment options. This updated systematic review aimed to determine the diagnostic and prognostic value of Gd-IgA1 assessment in biological fluids in patients with IgAN.
METHODS
PRISMA guidelines were followed in this review. We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc, VIP Information/China Science and Technology Journal Database, and WANFANG for studies published between database inception and January 31, 2023. Eligible studies that evaluated aberrant IgA1 glycosylation in IgAN patients relative to controls were identified, and random effects meta-analyses were used to compare Gd-IgA1 levels in different groups. The quality of the evidence was assessed using the Newcastle-Ottawa Scale. This study was registered on PROSPERO (CRD42022375246).
FINDINGS
Of the 2727 records identified, 50 were eligible and had available data. The mean Newcastle-Ottawa Scale score was 7.1 (range, 6-8). Data synthesis suggested that IgAN patients had higher levels of blood and/or urine Gd-IgA1 compared with healthy controls (standard mean difference [SMD]=1.43, 95% confidence interval [CI]=1.19-1.68, P<0.00001), IgA vasculitis patients (SMD=0.58, 95% CI=0.22-0.94, P=0.002), and other kidney disease patients (SMD=1.06, 95% CI=0.79-1.33, P<0.00001). Moreover, patients with IgAN had similar levels of serum Gd-IgA1 compared to first-degree relatives (SMD=0.38, 95% CI= -0.04-0.81, P=0.08) and IgA vasculitis with nephritis patients (SMD=0.12, 95% CI= -0.04-0.29, P=0.14). In addition, ten studies demonstrated significant differences in serum Gd-IgA1 levels in patients with mild and severe IgAN (SMD= -0.37, 95% CI= -0.64--0.09, P=0.009).
CONCLUSIONS
High serum and urine Gd-IgA1 levels suggest a diagnosis of IgAN and a poor prognosis for patients with this immunological disorder. Future studies should use more reliable and reproducible methods to determine Gd-IgA1 levels.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022375246, identifier CRD42022375246.
Topics: Humans; Glomerulonephritis, IGA; Prognosis; IgA Vasculitis; Immunoglobulin A
PubMed: 37671165
DOI: 10.3389/fimmu.2023.1209394 -
Neurobiology of Disease Jun 2024Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has... (Meta-Analysis)
Meta-Analysis Review
Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has accumulated over recent decades. The aim of this systematic review is to provide a comprehensive review of common mechanisms, which have hitherto been discussed in separate perspectives, and to assemble and evaluate candidate loci and epigenetic modifications contributing to polygenic risk linkages between T2DM and LOAD. For the systematic review on pathophysiological mechanisms, both human and animal studies up to December 2023 are included. For the qualitative meta-analysis of genomic bases, human association studies were examined; for epigenetic mechanisms, data from human studies and animal models were accepted. Papers describing pathophysiological studies were identified in databases, and further literature gathered from cited work. For genomic and epigenomic studies, literature mining was conducted by formalised search codes using Boolean operators in search engines, and augmented by GeneRif citations in Entrez Gene, and other sources (WikiGenes, etc.). For the systematic review of pathophysiological mechanisms, 923 publications were evaluated, and 138 gene loci extracted for testing candidate risk linkages. 3 57 publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight insulin signalling, inflammation and inflammasome pathways, proteolysis, gluconeogenesis and glycolysis, glycosylation, lipoprotein metabolism and oxidation, cell cycle regulation or survival, autophagic-lysosomal pathways, and energy. Documented findings suggest interplay between brain insulin resistance, neuroinflammation, insult compensatory mechanisms, and peripheral metabolic dysregulation in T2DM and LOAD linkage. The results allow for more streamlined longitudinal studies of T2DM-LOAD risk linkages.
Topics: Humans; Diabetes Mellitus, Type 2; Alzheimer Disease; Animals; Epigenesis, Genetic
PubMed: 38643861
DOI: 10.1016/j.nbd.2024.106485 -
Journal of Pharmaceutical and... Sep 2023Glycosylation is a crucial attribute for biotherapeutics with significant impacts on quality, stability, safety, immunogenicity, pharmacokinetics, and efficacy.... (Review)
Review
Glycosylation is a crucial attribute for biotherapeutics with significant impacts on quality, stability, safety, immunogenicity, pharmacokinetics, and efficacy. Therefore, to ensure consistent glycosylation, a systematic review of biotherapeutics is absolutely required including the variable glycan structure (micro-heterogeneity) and different occupancy at individual site (macro-heterogeneity) from drug design to upstream and downstream bioprocesses. Various methods have been used for glyco-characterization of biotherapeutics at the glycan, glycopeptide, and intact protein levels. In particular, intact protein analysis is considered a facile and rapid glycoform monitoring approach used throughout the product development lifecycle to determine suitable glycosylation lead candidates and reproducible product quality. However, intact glycoform characterization of diverse and complex biotherapeutics with multiple N- and O-glycosylation sites can be very challenging. To address this, a robust analytical platform that enables rapid and accurate characterization of a biotherapeutics with highly complex multiple glycosylation using two-step intact glycoform mass spectrometry has been developed. We used darbepoetin alfa, a second-generation EPO bearing multiple N- and O-glycosylation sites, as a model biotherapeutics to obtain integrated information on glycan heterogeneity and site occupancy through step-by-step MS of intact protein and enzyme-treated protein. In addition, we performed a comparative assessment of the heterogeneity from different products, confirming that our new method can efficiently evaluate glycosylation equivalence. This new strategy provides rapid and accurate information on the degree of glycosylation of a therapeutic glycoprotein with multiple glycosylation, which can be used to assess glycosylation similarity between batches and between biosimilar and reference during development and production.
Topics: Glycosylation; Darbepoetin alfa; Mass Spectrometry; Proteins; Polysaccharides
PubMed: 37393692
DOI: 10.1016/j.jpba.2023.115558