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Journal of Inherited Metabolic Disease May 2020Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an...
Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.
Topics: Animals; Disease Models, Animal; Galactokinase; Galactose; Galactosemias; Genotype; Humans; Oxidative Stress; Phenotype; UDPglucose 4-Epimerase; UTP-Hexose-1-Phosphate Uridylyltransferase
PubMed: 31808946
DOI: 10.1002/jimd.12202 -
European Neuropsychopharmacology : the... Aug 2022Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are major mental disorders that affect a significant proportion of the global population....
Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are major mental disorders that affect a significant proportion of the global population. Advancing our knowledge of the pathophysiology of these disorders and identifying biomarkers are urgent needs for developing objective diagnostic tests and new therapeutics. In this study, we performed a systematic review and then extracted, curated, and analyzed proteomics data from published studies, aiming to assess the proteome in peripheral blood of individuals with SZ, BD, or MDD. Then, we performed pathway and network analyses to illuminate the biological themes concatenated by the differentially expressed proteins by systematically interrogating the literature to uncover biological pathways with more robust biological meaning. We identified 486 differentially expressed proteins from 51 studies across the three disorders with 9,423 participants. The great majority of pathways were common to SZ, BD, and MDD. They were related to the immune system, including signaling by interleukins, Toll-like receptor signaling pathway, and complement cascade, and to signal transduction, notably MAPK1/MAPK3 signaling, PI3K-Akt Signaling Pathway, Focal Adhesion-PI3K-Akt-mTOR-signaling, rhodopsin-like receptors, GPCR signaling, and the JAK-STAT signaling pathway. Other shared pathways included advanced glycosylation end-product receptor signaling, Regulation of Insulin-like Growth Factor, cholesterol metabolism, and IL-17 signaling pathway. Pathways shared between SZ and BD were integrin cell-surface interactions, GRB2:SOS provides linkage to MAPK signaling for integrins, and syndecan interactions. Shared between BD and MDD were the NRF2 pathway and signaling by EGFR pathways. Our findings advance our understanding of the protein variations and associations with these disorders, which are useful for accelerating biomarker development and drug discovery.
Topics: Biomarkers; Depressive Disorder, Major; Drug Discovery; Humans; Mental Disorders; Phosphatidylinositol 3-Kinases; Proteome; Proto-Oncogene Proteins c-akt
PubMed: 35763977
DOI: 10.1016/j.euroneuro.2022.06.001 -
Microorganisms Apr 2022Genomic characterization of circulating influenza type-A viruses (IAVs) directs the selection of appropriate vaccine formulations and early detection of potentially... (Review)
Review
Genomic characterization of circulating influenza type-A viruses (IAVs) directs the selection of appropriate vaccine formulations and early detection of potentially pandemic virus strains. However, longitudinal data on the genomic evolution and transmission of IAVs in Africa are scarce, limiting Africa's benefits from potential influenza control strategies. We searched seven databases: African Journals Online, Embase, Global Health, Google Scholar, PubMed, Scopus, and Web of Science according to the PRISMA guidelines for studies that sequenced and/or genomically characterized Africa IAVs. Our review highlights the emergence and diversification of IAVs in Africa since 1993. Circulating strains continuously acquired new amino acid substitutions at the major antigenic and potential N-linked glycosylation sites in their hemagglutinin proteins, which dramatically affected vaccine protectiveness. Africa IAVs phylogenetically mixed with global strains forming strong temporal and geographical evolution structures. Phylogeographic analyses confirmed that viral migration into Africa from abroad, especially South Asia, Europe, and North America, and extensive local viral mixing sustained the genomic diversity, antigenic drift, and persistence of IAVs in Africa. However, the role of reassortment and zoonosis remains unknown. Interestingly, we observed substitutions and clades and persistent viral lineages unique to Africa. Therefore, Africa's contribution to the global influenza ecology may be understated. Our results were geographically biased, with data from 63% (34/54) of African countries. Thus, there is a need to expand influenza surveillance across Africa and prioritize routine whole-genome sequencing and genomic analysis to detect new strains early for effective viral control.
PubMed: 35630344
DOI: 10.3390/microorganisms10050900 -
Frontiers in Endocrinology 2021To comprehensively evaluate and compare the therapeutic effects of various hypoglycemic agents in NAFLD patients with or without diabetes. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To comprehensively evaluate and compare the therapeutic effects of various hypoglycemic agents in NAFLD patients with or without diabetes.
METHODS
All literature from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Clinical Trials was searched, and the language was limited to English. Two reviewers independently assessed study eligibility, continuous data extraction, and independent assessment of bias risk. Our primary outcomes were alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride levels, while our secondary outcomes were high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels, body weight, BMI, and fasting glucose and glycosylated hemoglobin (HbA1c) levels.
RESULTS
The review identified 20 eligible trials that met the inclusion criteria. We found that, compared to other drugs, thiazolidinediones, especially pioglitazone, had a greater effect on the levels of ALT (-8.01 (95% CI -14.3 to 2.02)) and AST (-5.0 (95% CI -9.21 to -1,22)) and other biological indicators, but they were also associated with an increased risk of weight gain (3.62 (95% CI 2.25 to 4.99) and increased BMI (0.59 (95% Cl -0.13 to 1.29). GLP1 RAs and metformin also had better therapeutic effects than other drugs as measured by the levels of ALT (liraglutide: -9.36 (95% Cl -18 to -0.34), metformin: -2.84 (95% CI -11.09 to 5.28)) and AST (liraglutide: -5.14 (95% CI -10.69 to 0.37), metformin: -2.39 (95% CI -7.55, 2.49)) and other biological indicators.
CONCLUSION
Despite the significant risk of weight gain, thiazolidinediones, especially pioglitazone, are beneficial in normalizing liver and glucose metabolism in NAFLD patients. In clinical practice, we believe that GLP1 RAs such as liraglutide and exenatide or metformin can be used in combination to offset the risk of weight gain associated with thiazolidinediones. However, long-term studies are still needed to verify the efficacy and safety of individual hypoglycemic agents.
SYSTEMATIC REVIEW REGISTRATION
[PROSPERO], identifier [CRD42020212025].
Topics: Alanine Transaminase; Aspartate Aminotransferases; Bayes Theorem; Blood Glucose; Body Mass Index; Body Weight; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Glycated Hemoglobin; Glycosylation; Humans; Hypoglycemic Agents; Lipoproteins, HDL; Lipoproteins, LDL; Metformin; Network Meta-Analysis; Non-alcoholic Fatty Liver Disease; Pioglitazone; Reproducibility of Results; Risk; Treatment Outcome
PubMed: 33841337
DOI: 10.3389/fendo.2021.649018 -
Annals of Gastroenterology 2022A minimally invasive tool to promptly predict hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) is currently needed. In this study, we aimed via a...
Baseline serum Mac-2 binding protein glycosylation isomer as a predictor of hepatocellular carcinoma in chronic hepatitis B patients: a systematic review and meta-analysis.
BACKGROUND
A minimally invasive tool to promptly predict hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) is currently needed. In this study, we aimed via a meta-analysis to identify the serum Mac-2 binding protein glycosylation isomer (M2BPGi) as a novel glycoprotein-based liver fibrosis marker for predicting HCC in CHB patients.
METHODS
We conducted a systematic search on PubMed, Scopus, ProQuest, Wiley Online Library, and CINAHL Plus (via EBSCOhost). The articles were screened based on several eligibility criteria and were further assessed for study qualities using the Newcastle-Ottawa Scale. The outcomes were presented as standard mean difference (SMD), hazard ratio (HR), and predictive accuracy parameters of a baseline cutoff index (COI) for serum M2BPGi.
RESULTS
Fourteen studies involving 5918 CHB patients were included in this systematic review and meta-analysis. Baseline COI serum M2BPGi was significantly higher in CHB patients who developed HCC than in those who did not (SMD 1.32, 95% confidence interval [CI] 0.91-1.72). A significant HCC risk prediction was also observed (multivariate HR 1.18, 95%CI 1.05-1.32). Baseline COI serum M2BPGi could predict HCC with a pooled sensitivity of 74% (95%CI 50-89%), specificity of 80% (95%CI 65-90%), and area under the summary receiver operating characteristic curve of 0.84 (95%CI 0.81-0.87).
CONCLUSION
High baseline COI serum M2BPGi may predict the development of HCC in CHB patients with moderate-to-high accuracy.
PubMed: 36406974
DOI: 10.20524/aog.2022.0751 -
Journal of Pediatric Gastroenterology... Oct 2021An ever-increasing number of disturbances in glycosylation have been described to underlie certain unexplained liver diseases presenting either almost isolated or in a...
An ever-increasing number of disturbances in glycosylation have been described to underlie certain unexplained liver diseases presenting either almost isolated or in a multi-organ context. We aimed to update previous literature screenings which had identified up to 23 forms of congenital disorders of glycosylation (CDG) with associated liver disease. We conducted a comprehensive literature search of three scientific electronic databases looking at articles published during the last 20 years (January 2000-October 2020). Eligible studies were case reports/series reporting liver involvement in CDG patients. Our systematic review led us to point out 41 forms of CDG where the liver is primarily affected (n = 7) or variably involved in a multisystem disease with mandatory neurological abnormalities (n = 34). Herein we summarize individual clinical and laboratory presentation characteristics of these 41 CDG and outline their main presentation and diagnostic cornerstones with the aid of two synoptic tables. Dietary supplementation strategies have hitherto been investigated only in seven of these CDG types with liver disease, with a wide range of results. In conclusion, the systematic review recognized a liver involvement in a somewhat larger number of CDG variants corresponding to about 30% of the total of CDG so far reported, and it is likely that the number may increase further. This information could assist in an earlier correct diagnosis and a possibly proper management of these disorders.
Topics: Congenital Disorders of Glycosylation; Glycosylation; Humans; Liver Diseases
PubMed: 34173795
DOI: 10.1097/MPG.0000000000003209 -
Cells Feb 2020Glycosylation is the most commonly occurring post-translational modifications, and is believed to modify over 50% of all proteins. The process of glycan modification is...
Glycosylation is the most commonly occurring post-translational modifications, and is believed to modify over 50% of all proteins. The process of glycan modification is directed by different glycosyltransferases, depending on the cell in which it is expressed. These small carbohydrate molecules consist of multiple glycan families that facilitate cell-cell interactions, protein interactions, and downstream signaling. An alteration of several types of O-glycan core structures have been implicated in multiple cancers, largely due to differential glycosyltransferase expression or activity. Consequently, aberrant O-linked glycosylation has been extensively demonstrated to affect biological function and protein integrity that directly result in cancer growth and progression of several diseases. Herein, we provide a comprehensive review of several initiating enzymes involved in the synthesis of O-linked glycosylation that significantly contribute to a number of different cancers.
Topics: Animals; Disease Progression; Glycosylation; Humans; Neoplasm Metastasis; Neoplasms; Polysaccharides; Protein Processing, Post-Translational
PubMed: 32075174
DOI: 10.3390/cells9020446 -
Arteriosclerosis, Thrombosis, and... Mar 2020Post-translational modifications of fibrinogen influence the occurrence and progression of thrombotic diseases. In this systematic review, we assessed the current...
OBJECTIVE
Post-translational modifications of fibrinogen influence the occurrence and progression of thrombotic diseases. In this systematic review, we assessed the current literature on post-translational modifications of fibrinogen and their effects on fibrin formation and clot characteristics. Approach and Results: A systematic search of Medline, Embase, Cochrane Library, and Web of Science was performed to find studies reporting post-translational modifications of fibrinogen and the effects on clot formation and structure. Both in vitro studies and ex vivo studies using patient material were included. One hundred five articles were included, describing 11 different modifications of fibrinogen. For the best known and studied modifications, conclusions could be drawn about their effect on clot formation and structure. Oxidation, high levels of nitration, and glycosylation inhibit the rate of polymerization, resulting in dense clots with thinner fibers, while low levels of nitration increase the rate of polymerization. Glycation showed different results for polymerization, but fibrinolysis was found to be decreased, as a consequence of increased density and decreased permeability of clots. Acetylation also decreases the rate of polymerization but results in increased fiber diameters and susceptibility to fibrinolysis. Other modifications were studied less or contrasting results were found. Therefore, substantial gaps in the knowledge about the effect of post-translational modifications remain.
CONCLUSIONS
Overall, post-translational modifications do affect clot formation and characteristics. More studies need to be performed to reveal the effects of all post-translational modifications and the effects on thrombotic diseases. Expanding the knowledge about modifications of fibrinogen can ultimately contribute to optimizing treatments for thrombotic diseases.
Topics: Acetylation; Animals; Fibrinogen; Fibrinolysis; Glycosylation; Humans; Oxidation-Reduction; Polymerization; Protein Processing, Post-Translational; Thrombosis
PubMed: 31914791
DOI: 10.1161/ATVBAHA.119.313626 -
Frontiers in Medicine 2021The coronavirus disease (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), prompted a global health crisis, with no available...
The coronavirus disease (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), prompted a global health crisis, with no available specific treatments. Convalescent plasma (CP) with neutralizing antibodies could be a promising therapeutic approach to reduce mortality. To evaluate the therapeutic potential of CP for COVID-19 and to assess its safety and efficacy in reducing the patients' mortality. We retrieved clinical trial references from multiple Databases (e.g., PubMed, B-On, SCOPUS), for complete studies until November 26th 2020. We included Randomized controlled trials (RCT) and controlled non-randomized trials (CNRT), that assessed the efficacy of CP to treat hospitalized COVID-19 patients. Trials were included regardless of concomitant medications in the intervention's arms. Eleven trials met our eligibility criteria. This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We defined a methodological protocol to extract and evaluate all pertinent baseline demographics and interventions' characteristics from trials. The primary outcomes were the safety profile of CP, measured by the type, frequency and severity of adverse events, and CP effectiveness in reducing mortality, measured by the number of deaths registered for this therapy. We assessed 11 trials (5 RCT and 6 CNRT) with 3,098 participants, of whom 923 patients were treated with CP. Only 32 (3.5%) of the treated patients suffered adverse events (from which 9.4% serious transfusion-related adverse events). The overall mortality rates were significantly decreased by CP administration {risk ratio (RR) 0.71, = 0.005, 95% confidence interval (Cl) [0.57-0.90]}, with low heterogeneity. In the sub-analysis by period of transfusion, CP transfusion within a week of hospitalization contributed to diminished mortality rate (RR = 0.71, = 0.03, 95%Cl [0.53-0.96]). CP therapy also led to significantly reduced viral loads at 72 h after transfusion (RR = 0.61, = 0.04, 95%Cl [0.38-0.98]), despite high heterogeneity due to disease severity. This meta-analysis established CP as a safe and potentially effective therapy for COVID-19, decreasing the mortality rates and promoting a swift viral clearance. Further studies are necessary to provide stronger evidence.
PubMed: 33889590
DOI: 10.3389/fmed.2021.660688 -
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