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Journal of Clinical Immunology Jun 2024Magnesium transporter 1 (MAGT1) gene loss-of-function variants lead to X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-glycosylation...
Magnesium transporter 1 (MAGT1) gene loss-of-function variants lead to X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-glycosylation defect (XMEN), a condition with a variety of clinical and immunological effects. In addition, MAGT1 deficiency has been classified as a congenital disorder of glycosylation (CDG) due to its unique role in glycosylation of multiple substrates including NKG2D, necessary for viral protection. Due to the predisposition for EBV, this etiology has been linked with hemophagocytic lymphohistiocytosis (HLH), however only limited literature exists. Here we present a complex case with HLH and EBV-driven classic Hodgkin lymphoma (cHL) as the presenting manifestation of underlying immune defect. However, the patient's underlying immunodeficiency was not identified until his second recurrence of Hodgkin disease, recurrent episodes of Herpes Zoster, and after he had undergone autologous hematopoietic stem cell transplant (HSCT) for refractory Hodgkin lymphoma. This rare presentation of HLH and recurrent lymphomas without some of the classical immune deficiency manifestations of MAGT1 deficiency led us to review the literature for similar presentations and to report the evolving spectrum of disease in published literature. Our systematic review showcased that MAGT1 predisposes to multiple viruses (including EBV) and adds risk of viral-driven neoplasia. The roles of MAGT1 in the immune system and glycosylation were highlighted through the multiple organ dysfunction showcased by the previously validated Immune Deficiency and Dysregulation Activity (IDDA2.1) score and CDG-specific Nijmegen Pediatric CDG Rating Scale (NPCRS) score for the patient cohort in the systematic review.
Topics: Humans; Male; Cation Transport Proteins; Epstein-Barr Virus Infections; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Hodgkin Disease; Lymphohistiocytosis, Hemophagocytic; Recurrence
PubMed: 38896122
DOI: 10.1007/s10875-024-01749-y -
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 Nephrology Mar 2024IgA nephropathy (IgAN) is a common primary glomerular disease. The O-glycosylation status of IgA1 plays a crucial role in disease pathophysiology. The level of... (Review)
Review
BACKGROUND
IgA nephropathy (IgAN) is a common primary glomerular disease. The O-glycosylation status of IgA1 plays a crucial role in disease pathophysiology. The level of poorly-O-galactosylated IgA1, or galactose-deficient IgA1 (Gd-IgA1), has also been identified as a potential biomarker in IgAN. We sought to examine the value of serum Gd-IgA1 as a biomarker in IgAN, by investigating its association with clinical, laboratory, and histopathological features of IgAN.
METHODS
The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and was registered in PROSPERO (CRD42021287423). The literature search was conducted in PubMed, Web of Science, Cochrane, and Scopus, and the selected articles were evaluated for eligibility based on predefined criteria. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Statistical analysis was performed to calculate effect sizes and assess heterogeneity among the studies.
RESULTS
This review analyzed 29 out of 1,986 studies, conducted between 2005 and 2022, with participants from multiple countries. Gd-IgA1 levels were not associated with age and gender, while associations with hypertension, hematuria, and proteinuria were inconsistent. In the meta-analyses, a correlation between serum Gd-IgA1 and estimated glomerular filtration rate was identified, however, the relationships between Gd-IgA1 levels and chronic kidney disease (CKD) stage and progression to kidney failure were inconsistent.
CONCLUSIONS
Serum Gd-IgA1 levels were not associated with validated prognostic risk factors, but were negatively correlated with kidney function. Further research in larger studies using standardized assays are needed to establish the value of Gd-IgA1 as a prognostic risk factor in IgAN.
PubMed: 38427309
DOI: 10.1007/s40620-023-01874-8 -
Comprehensive Reviews in Food Science... Nov 2023Liubao tea (LBT) is a unique microbial-fermented tea that boasts a long consumption history spanning 1500 years. Through a specific post-fermentation process, LBT...
Liubao tea (LBT) is a unique microbial-fermented tea that boasts a long consumption history spanning 1500 years. Through a specific post-fermentation process, LBT crafted from local tea cultivars in Liubao town Guangxi acquires four distinct traits, namely, vibrant redness, thickness, aging aroma, and purity. The intricate transformations that occur during post-fermentation involve oxidation, degradation, methylation, glycosylation, and so forth, laying the substance foundation for the distinctive sensory traits. Additionally, LBT contains multitudinous bioactive compounds, such as ellagic acid, catechins, polysaccharides, and theabrownins, which contributes to the diverse modulation abilities on oxidative stress, metabolic syndromes, organic damage, and microbiota flora. However, research on LBT is currently scattered, and there is an urgent need for a systematical recapitulation of the manufacturing process, the dominant microorganisms during fermentation, the dynamic chemical alterations, the sensory traits, and the underlying health benefits. In this review, current research progresses on the peculiar tea varieties, the traditional and modern process technologies, the substance basis of sensory traits, and the latent bioactivities of LBT were comprehensively summarized. Furthermore, the present challenges and deficiencies that hinder the development of LBT, and the possible orientations and future perspectives were thoroughly discussed. By far, the productivity and quality of LBT remain restricted due to the reliance on labor and experience, as well as the incomplete understanding of the intricate interactions and underlying mechanisms involved in processing, organoleptic quality, and bioactivities. Consequently, further research is urgently warranted to address these gaps.
Topics: Tea; Camellia sinensis; China; Catechin; Oxidative Stress
PubMed: 37850384
DOI: 10.1111/1541-4337.13254 -
PloS One 2023The high prevalence of oral potentially-malignant disorders exhibits diverse severity and risk of malignant transformation, which mandates a Point-of-Care diagnostic... (Meta-Analysis)
Meta-Analysis
The high prevalence of oral potentially-malignant disorders exhibits diverse severity and risk of malignant transformation, which mandates a Point-of-Care diagnostic tool. Low patient compliance for biopsies underscores the need for minimally-invasive diagnosis. Oral cytology, an apt method, is not clinically applicable due to a lack of definitive diagnostic criteria and subjective interpretation. The primary objective of this study was to identify and evaluate the efficacy of biomarkers for cytology-based delineation of high-risk oral lesions. A comprehensive systematic review and meta-analysis of biomarkers recognized a panel of markers (n: 10) delineating dysplastic oral lesions. In this observational cross sectional study, immunohistochemical validation (n: 131) identified a four-marker panel, CD44, Cyclin D1, SNA-1, and MAA, with the best sensitivity (>75%; AUC>0.75) in delineating benign, hyperplasia, and mild-dysplasia (Low Risk Lesions; LRL) from moderate-severe dysplasia (High Grade Dysplasia: HGD) along with cancer. Independent validation by cytology (n: 133) showed that expression of SNA-1 and CD44 significantly delineate HGD and cancer with high sensitivity (>83%). Multiplex validation in another cohort (n: 138), integrated with a machine learning model incorporating clinical parameters, further improved the sensitivity and specificity (>88%). Additionally, image automation with SNA-1 profiled data set also provided a high sensitivity (sensitivity: 86%). In the present study, cytology with a two-marker panel, detecting aberrant glycosylation and a glycoprotein, provided efficient risk stratification of oral lesions. Our study indicated that use of a two-biomarker panel (CD44/SNA-1) integrated with clinical parameters or SNA-1 with automated image analysis (Sensitivity >85%) or multiplexed two-marker panel analysis (Sensitivity: >90%) provided efficient risk stratification of oral lesions, indicating the significance of biomarker-integrated cytopathology in the development of a Point-of-care assay.
Topics: Humans; Hyperplasia; Automation; Biological Assay; Biopsy; Glycosylation; Hyaluronan Receptors; Observational Studies as Topic
PubMed: 37747904
DOI: 10.1371/journal.pone.0291972 -
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 -
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 -
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 -
Neurological Sciences : Official... Oct 2023Variants of the NUS1 gene have been associated with an extensive spectrum of phenotypes, including epilepsy, intellectual disability, cerebellar ataxia, Parkinson's... (Review)
Review
BACKGROUND
Variants of the NUS1 gene have been associated with an extensive spectrum of phenotypes, including epilepsy, intellectual disability, cerebellar ataxia, Parkinson's disease, dystonia, and congenital disorder of glycosylation. It is rarely reported in progressive myoclonus epilepsy (PME).
METHODS AND RESULTS
Herein, we report the case of PME caused by a novel de novo NUS1 missense variant (c.302T>A, p.Met101Lys). In addition, we reviewed the current literature of NUS1-associated PME. At present, five patients with NUS1 variants and PME have been reported in the literature. Due to limited cases reported, the relationship between NUS1 variants and PME is not well-established.
CONCLUSIONS
Our case provides further evidence of the role of NUS1 variants in PME. These findings expand the clinical phenotypes of NUS1 variants, which should be included in the PME genetic screening panel.
Topics: Humans; East Asian People; Mutation, Missense; Myoclonic Epilepsies, Progressive; Myoclonus; Receptors, Cell Surface
PubMed: 37249665
DOI: 10.1007/s10072-023-06851-4 -
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