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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 -
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 -
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 -
Frontiers in Cardiovascular Medicine 2021The hemoglobin glycation index (HGI) has been proposed as a marker to quantify inter-individual variation in hemoglobin glycosylation. However, whether HGI is...
The hemoglobin glycation index (HGI) has been proposed as a marker to quantify inter-individual variation in hemoglobin glycosylation. However, whether HGI is associated with an increased risk of diabetic complications independent of glycated hemoglobin (HbA1c) remains unclear. This meta-analysis aimed to determine the association between HGI and the risk of all cause mortality and composite cardiovascular disease (CVD). PubMed, and EMBASE databases were searched for related studies up to March 31, 2021. Observational studies reported associations between HGI levels and composite CVD and all cause mortality were included for meta-analysis. A random effect model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CI) for higher HGI. A total of five studies, comprising 22,035 patients with type two diabetes mellitus were included for analysis. The median follow-up duration was 5.0 years. After adjusted for multiple conventional cardiovascular risk factors, an increased level of HGI was associated with a higher risk of composite CVD (per 1 SD increment: HR = 1.14, 95% CI = 1.04-1.26) and all cause mortality (per 1 SD increment: HR = 1.18, 95% CI = 1.05-1.32). However, when further adjusted for HbA1c, the association between HGI and risk of composite CVD (per 1 SD increment of HGI: HR = 1.01, 95% CI = 0.93-1.10) and all cause mortality (per 1 SD increment of HGI: HR = 1.03, 95% CI = 0.96-1.10) became insignificant. High HGI was associated with an increased risk of composite CVD and all cause mortality after adjustment for multiple conventional cardiovascular risk factors. However, the association was mainly mediating by the level of HbA1c.
PubMed: 34124211
DOI: 10.3389/fcvm.2021.690689 -
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 -
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 -
International Journal of Molecular... Mar 2021Pancreatic ductal adenocarcinoma (PDAC) is known as a highly aggressive malignant disease. Prognosis for patients is notoriously poor, despite improvements in surgical...
Pancreatic ductal adenocarcinoma (PDAC) is known as a highly aggressive malignant disease. Prognosis for patients is notoriously poor, despite improvements in surgical techniques and new (neo)adjuvant chemotherapy regimens. Early detection of PDAC may increase the overall survival. It is furthermore foreseen that precision medicine will provide improved prognostic stratification and prediction of therapeutic response. In this review, omics-based discovery efforts are presented that aim for novel diagnostic and prognostic biomarkers of PDAC. For this purpose, we systematically evaluated the literature published between 1999 and 2020 with a focus on protein- and protein-glycosylation biomarkers in pancreatic cancer patients. Besides genomic and transcriptomic approaches, mass spectrometry (MS)-based proteomics and glycomics of blood- and tissue-derived samples from PDAC patients have yielded new candidates with biomarker potential. However, for reasons discussed in this review, the validation and clinical translation of these candidate markers has not been successful. Consequently, there has been a change of mindset from initial efforts to identify new unimarkers into the current hypothesis that a combination of biomarkers better suits a diagnostic or prognostic panel. With continuing development of current research methods and available techniques combined with careful study designs, new biomarkers could contribute to improved detection, prognosis, and prediction of pancreatic cancer.
Topics: Biomarkers, Tumor; Body Fluids; Carcinoma, Pancreatic Ductal; Clinical Decision-Making; Diagnosis, Differential; Early Detection of Cancer; Glycomics; Glycoproteins; Humans; Mass Spectrometry; Neoplasm Proteins; Neoplastic Syndromes, Hereditary; Pancreatic Neoplasms; Pancreatitis, Chronic; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Prognosis; Proteomics; Reproducibility of Results; Risk Factors
PubMed: 33800786
DOI: 10.3390/ijms22052655 -
Molecular & Cellular Proteomics : MCP 2021Intact glycopeptide identification has long been known as a key and challenging barrier to the comprehensive and accurate understanding the role of glycosylation in an...
Intact glycopeptide identification has long been known as a key and challenging barrier to the comprehensive and accurate understanding the role of glycosylation in an organism. Intact glycopeptide analysis is a blossoming field that has received increasing attention in recent years. MS-based strategies and relative software tools are major drivers that have greatly facilitated the analysis of intact glycopeptides, particularly intact N-glycopeptides. This article provides a systematic review of the intact glycopeptide-identification process using MS data generated in shotgun proteomic experiments, which typically focus on N-glycopeptide analysis. Particular attention is paid to the software tools that have been recently developed in the last decade for the interpretation and quality control of glycopeptide spectra acquired using different MS strategies. The review also provides information about the characteristics and applications of these software tools, discusses their advantages and disadvantages, and concludes with a discussion of outstanding tools.
Topics: Animals; Glycopeptides; Humans; Mass Spectrometry; Proteomics; Software
PubMed: 33556625
DOI: 10.1074/mcp.R120.002090 -
Biomedicine & Pharmacotherapy =... Nov 2020The glyoxalase system is a ubiquitous enzymatic network which plays important roles in biological life. It consists of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and...
The glyoxalase system is a ubiquitous enzymatic network which plays important roles in biological life. It consists of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and reduced glutathione (GSH), which perform an essential metabolic function in cells by detoxifying methylglyoxal (MG) and other endogenous harmful metabolites into non-toxic d-lactate. MG and MG-derived advanced glycation endproducts (AGEs) are associated with various diseases, such as diabetes, cardiovascular disease, neurodegenerative disorders and cancer, and GLO1 is a key rate-limiting enzyme in the anti-glycation defense. The abnormal activity and expression of GLO1 in various diseases make this enzyme a promising target for drug design and development. This review focuses on the regulatory mechanism of GLO1 in diverse pathogenic conditions with a thorough discussion of GLO1 regulators since their discovery, including GLO1 activators and inhibitors. The different classes, chemical structure and structure-activity relationship are embraced. Moreover, assays for the discovery of small molecule regulators of the glyoxalase system are also introduced in this article. Compared with spectrophotometer-based assay, microplate-based assay is a more simple, rapid and quantitative high-throughput method. This review will be useful to design novel and potent GLO1 regulators and hopefully provide a convenient reference for researchers.
Topics: Animals; Biological Products; Cardiovascular Diseases; Drug Evaluation, Preclinical; Enzyme Inhibitors; Glycosylation; Humans; Lactoylglutathione Lyase; Neoplasms; Pyruvaldehyde
PubMed: 32858501
DOI: 10.1016/j.biopha.2020.110663