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F1000Research 2020Improved hygiene leading to reduced exposure to microorganisms has been implicated as one possible cause for the recent "epidemic" of chronic inflammatory diseases... (Review)
Review
Improved hygiene leading to reduced exposure to microorganisms has been implicated as one possible cause for the recent "epidemic" of chronic inflammatory diseases (CIDs) in industrialized countries. That is the essence of the hygiene hypothesis that argues that rising incidence of CIDs may be, at least in part, the result of lifestyle and environmental changes that have made us too "clean" for our own good, so causing changes in our microbiota. Apart from genetic makeup and exposure to environmental triggers, inappropriate increase in intestinal permeability (which may be influenced by the composition of the gut microbiota), a "hyper-belligerent" immune system responsible for the tolerance-immune response balance, and the composition of gut microbiome and its epigenetic influence on the host genomic expression have been identified as three additional elements in causing CIDs. During the past decade, a growing number of publications have focused on human genetics, the gut microbiome, and proteomics, suggesting that loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately influencing the close bidirectional interaction between gut microbiome and our immune system. This cross-talk is highly influential in shaping the host gut immune system function and ultimately shifting genetic predisposition to clinical outcome. This observation led to a re-visitation of the possible causes of CIDs epidemics, suggesting a key pathogenic role of gut permeability. Pre-clinical and clinical studies have shown that the zonulin family, a group of proteins modulating gut permeability, is implicated in a variety of CIDs, including autoimmune, infective, metabolic, and tumoral diseases. These data offer novel therapeutic targets for a variety of CIDs in which the zonulin pathway is implicated in their pathogenesis.
Topics: Cholera Toxin; Gastrointestinal Microbiome; Haptoglobins; Humans; Intestinal Mucosa; Permeability; Protein Precursors
PubMed: 32051759
DOI: 10.12688/f1000research.20510.1 -
Plant Biotechnology Journal Apr 2020Gluten-free foods cannot substitute for products made from wheat flour. When wheat products are digested, the remaining peptides can trigger an autoimmune disease in 1%...
Gluten-free foods cannot substitute for products made from wheat flour. When wheat products are digested, the remaining peptides can trigger an autoimmune disease in 1% of the North American and European population, called coeliac disease. Because wheat proteins are encoded by a large gene family, it has been impossible to use conventional breeding to select wheat varieties that are coeliac-safe. However, one can test the properties of protein variants by expressing single genes in coeliac-safe cereals like maize. One source of protein that can be considered as coeliac-safe and has bread-making properties is teff (Eragrostis tef), a grain consumed in Ethiopia. Here, we show that teff α-globulin3 (Etglo3) forms storage vacuoles in maize that are morphologically similar to those of wheat. Using transmission electron microscopy, immunogold labelling shows that Etglo3 is almost exclusively deposited in the storage vacuole as electron-dense aggregates. Of maize seed storage proteins, 27-kDa γ-zein is co-deposited with Etglo3. Etglo3 polymerizes via intermolecular disulphide bonds in maize, similar to wheat HMW glutenins under non-reducing conditions. Crossing maize Etglo3 transgenic lines with α-, β- and γ-zein RNA interference (RNAi) lines reveals that Etglo3 accumulation is only dramatically reduced in γ-zein RNAi background. This suggests that Etglo3 and 27-kDa γ-zein together cause storage vacuole formation and behave similar to the interactions of glutenins and gliadins in wheat. Therefore, expression of teff α-globulins in maize presents a major step in the development of a coeliac-safe grain with bread-making properties.
Topics: Alpha-Globulins; Bread; Eragrostis; Flour; Glutens; Plants, Genetically Modified; Seed Storage Proteins; Triticum; Zea mays
PubMed: 31585498
DOI: 10.1111/pbi.13273 -
Circulation Research Sep 2023Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes.
BACKGROUND
Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes.
METHODS
Two hundred nineteen carotid endarterectomy samples were procured from 120 patients. A sequential protein extraction protocol was employed in conjunction with multiplexed, discovery proteomics. To focus on extracellular proteins, parallel reaction monitoring was employed for targeted proteomics. Proteomic signatures were integrated with bulk, single-cell, and spatial RNA-sequencing data, and validated in 200 patients from the Athero-Express Biobank study.
RESULTS
This extensive proteomics analysis identified plaque inflammation and calcification signatures, which were inversely correlated and validated using targeted proteomics. The inflammation signature was characterized by the presence of neutrophil-derived proteins, such as S100A8/9 (calprotectin) and myeloperoxidase, whereas the calcification signature included fetuin-A, osteopontin, and gamma-carboxylated proteins. The proteomics data also revealed sex differences in atherosclerosis, with large-aggregating proteoglycans versican and aggrecan being more abundant in females and exhibiting an inverse correlation with estradiol levels. The integration of RNA-sequencing data attributed the inflammation signature predominantly to neutrophils and macrophages, and the calcification and sex signatures to smooth muscle cells, except for certain plasma proteins that were not expressed but retained in plaques, such as fetuin-A. Dimensionality reduction and machine learning techniques were applied to identify 4 distinct plaque phenotypes based on proteomics data. A protein signature of 4 key proteins (calponin, protein C, serpin H1, and versican) predicted future cardiovascular mortality with an area under the curve of 75% and 67.5% in the discovery and validation cohort, respectively, surpassing the prognostic performance of imaging and histology.
CONCLUSIONS
Plaque proteomics redefined clinically relevant patient groups with distinct outcomes, identifying subgroups of male and female patients with elevated risk of future cardiovascular events.
Topics: Female; Humans; Male; Proteomics; Sex Characteristics; Versicans; alpha-2-HS-Glycoprotein; Atherosclerosis; Calcinosis
PubMed: 37646165
DOI: 10.1161/CIRCRESAHA.123.322590 -
World Journal of Gastroenterology Dec 2021In this editorial, the roles of orosomucoid (ORM) in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect...
In this editorial, the roles of orosomucoid (ORM) in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect to the publication by Zhu presented in the previous issue of (2020; 26(8): 840-817). ORM, or alpha-1 acid glycoprotein (AGP), is an acute-phase protein that constitutes 1% to 3% of plasma proteins in humans and is mainly synthesized in the liver. ORM exists in serum as two variants: ORM1 and ORM2. Although the variants share 89.6% sequence identity and have similar biological properties, ORM1 constitutes the main component of serum ORM. An interesting feature of ORM is that its biological effects differ according to variations in glycosylation patterns. This variable feature makes ORM an attractive target for diagnosing and monitoring many diseases, including those of the liver. Recent findings suggest that a sharp decrease in ORM level is an important marker for HBV-associated acute liver failure (ALF), and ORM1 plays an important role in liver regeneration. In viral hepatitis, increases in both ORM and its fucosylated forms and the correlation of these increases with fibrosis progression suggest that this glycoprotein can be used with other markers as a noninvasive method in the follow-up assessment of diseases. In addition, similar findings regarding the level of the asialylated form of ORM, called asialo-AGP (AsAGP), have been reported in a follow-up assessment of fibrosis in chronic liver disease. An increase in ORM in serum has also been shown to improve hepatocellular carcinoma (HCC) diagnosis performance when combined with other markers. In addition, determination of the ORM level has been useful in the diagnosis of HCC with AFP concentrations less than 500 ng/mL. For monitoring patients with AFP-negative HCC, a unique trifucosylated tetra-antennary glycan of ORM may also be used as a new potential marker. The fact that there are very few studies investigating the expression of this glycoprotein and its variants in liver tissues constitutes a potential limitation, especially in terms of revealing all the effects of ORM on carcinogenesis and tumor behavior. Current findings indicate that ORM2 expression is decreased in tumors, and this is related to the aggressive course of the disease. Parallel to this finding, in HCC cell lines, ORM2 decreases HCC cell migration and invasion, supporting reports of its tumor suppressor role. In conclusion, the levels of ORM and its different glycosylated variants are promising additional biomarkers for identifying ALF, for monitoring fibrosis in viral hepatitis, and for diagnosing early HCC. Although there is evidence that the loss of ORM2 expression in HCC is associated with poor prognosis, further studies are needed to support these findings. Additionally, investigations of ORM expression in borderline dysplastic nodules and hepatocellular adenomas, which pose diagnostic problems in the differential diagnosis of HCC, especially in biopsy samples, may shed light on whether ORM can be used in histopathological differential diagnosis.
Topics: Biomarkers; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Orosomucoid
PubMed: 34963738
DOI: 10.3748/wjg.v27.i45.7739 -
Blood Apr 2023
Topics: Antithrombins; Factor IXa; Antithrombin III; Anticoagulants
PubMed: 37079331
DOI: 10.1182/blood.2023019793 -
Biosensors Sep 2022Alpha-fetoprotein (AFP) is widely-known as the most commonly used protein biomarker for liver cancer diagnosis at the early stage. Therefore, developing the highly... (Review)
Review
Alpha-fetoprotein (AFP) is widely-known as the most commonly used protein biomarker for liver cancer diagnosis at the early stage. Therefore, developing the highly sensitive and reliable method of AFP detection is of essential demand for practical applications. Herein, two types of aptamer-based AFP detection methods, i.e., optical and electrochemical biosensors, are reviewed in detail. The optical biosensors include Raman spectroscopy, dual-polarization interferometry, resonance light-scattering, fluorescence, and chemiluminescence. The electrochemical biosensors include cyclic voltammetry, electrochemical impedance spectroscopy, and giant magnetic impedance. Looking into the future, methods for AFP detection that are high sensitivity, long-term stability, low cost, and operation convenience will continue to be developed.
Topics: alpha-Fetoproteins; Electrochemical Techniques; Limit of Detection; Biosensing Techniques; Aptamers, Nucleotide
PubMed: 36290918
DOI: 10.3390/bios12100780 -
International Journal of Molecular... Dec 2020Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to... (Review)
Review
Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to protect tissues from enzymes released during inflammation, such as neutrophil elastase and proteinase 3. In addition to its antiprotease activity, AAT interacts with numerous other substances and has various functions, mainly arising from the conformational flexibility of normal variants of AAT. Therefore, AAT has diverse biological functions and plays a role in various pathophysiological processes. This review discusses major molecular forms of AAT, including complex, cleaved, glycosylated, oxidized, and S-nitrosylated forms, in terms of their origin and function.
Topics: Animals; Biomarkers; Disease Susceptibility; Glycosylation; Humans; Ligands; Oxidation-Reduction; Peptides; Protein Binding; Protein Multimerization; Protein Processing, Post-Translational; Proteolysis; Structure-Activity Relationship; alpha 1-Antitrypsin
PubMed: 33276468
DOI: 10.3390/ijms21239187 -
Drug Discovery Today Apr 2017Preeclampsia is a serious pregnancy-specific condition, affecting 10 million women annually worldwide. No specific treatment is currently available. Recent studies have... (Review)
Review
Preeclampsia is a serious pregnancy-specific condition, affecting 10 million women annually worldwide. No specific treatment is currently available. Recent studies have demonstrated abnormal production and accumulation of free fetal hemoglobin in the preeclamptic placenta, and identified subsequent leakage into the maternal circulation as an important factor in the development of preeclampsia. A recombinant version of alpha-1-microglobulin, an endogenous well-characterized heme and radical scavenger, has been developed. Intravenous administration of recombinant alpha-1-microglobulin in animal models has been proved to eliminate or significantly reduce the manifestations of preeclampsia. Recombinant alpha-1-microglobulin has the potential to become the first specific therapy for preeclampsia.
Topics: Alpha-Globulins; Animals; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Recombinant Proteins
PubMed: 27988357
DOI: 10.1016/j.drudis.2016.12.005 -
American Journal of Respiratory Cell... Nov 2020AAT (alpha-1 antitrypsin) deficiency (AATD), characterized by low levels of circulating serine protease inhibitor AAT, results in emphysematous destruction of the lung.... (Review)
Review
AAT (alpha-1 antitrypsin) deficiency (AATD), characterized by low levels of circulating serine protease inhibitor AAT, results in emphysematous destruction of the lung. Inherited serum deficiency disorders, such as hemophilia and AATD, have been considered ideal candidates for gene therapy. Although viral vector-meditated transduction of the liver has demonstrated utility in hemophilia, similar success has not been achieved for AATD. The challenge for AAT gene therapy is achieving protective levels of AAT locally in the lung and mitigating potential liver toxicities linked to systemically administered viral vectors. Current strategies with ongoing clinical trials involve different routes of adeno-associated virus administrations, such as intramuscular and intrapleural injections, to provide consistent therapeutic levels from nonhepatic organ sites. Nevertheless, exploration of alternative methods of nonhepatic sourcing of AAT has been of great interest in the field. In this regard, pulmonary endothelium-targeted adenovirus vector could be a key technical mandate to achieve local augmentation of AAT within the lower respiratory tract, with the potential benefit of circumventing liver toxicities. In addition, incorporation of the CRISPR/Cas9 (CRISPR-associated protein 9) nuclease system into gene-delivery technologies has provided adjunctive technologies that could fully realize a one-time treatment for sustained, lifelong expression of AAT in patients with AATD. This review will focus on the adeno-associated virus- and adenoviral vector-mediated gene therapy strategies for the pulmonary manifestations of AATD and show that endeavoring to use genome-editing techniques will advance the current strategy to one fully compatible with direct human translation.
Topics: Animals; Dependovirus; Gene Editing; Genetic Therapy; Humans; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency
PubMed: 32668173
DOI: 10.1165/rcmb.2020-0159PS -
Biological Chemistry Oct 2014Alpha-1 antitrypsin (AAT) is a circulating serine protease inhibitor (serpin) that inhibits neutrophil elastase in the lung, and AAT deficiency is associated with... (Review)
Review
Alpha-1 antitrypsin (AAT) is a circulating serine protease inhibitor (serpin) that inhibits neutrophil elastase in the lung, and AAT deficiency is associated with early-onset emphysema. AAT is also a liver-derived acute-phase protein that, in vitro and in vivo, reduces production of pro-inflammatory cytokines, inhibits apoptosis, blocks leukocyte degranulation and migration, and modulates local and systemic inflammatory responses. In monocytes, AAT has been shown to increase intracellular cAMP, regulate expression of CD14, and suppress NFκB nuclear translocation. These effects may be mediated by AAT's serpin activity or by other protein-binding activities. In preclinical models of autoimmunity and transplantation, AAT therapy prevents or reverses autoimmune disease and graft loss, and these effects are accompanied by tolerogenic changes in cytokine and transcriptional profiles and T cell subsets. This review highlights advances in our understanding of the immune-modulating effects of AAT and their potential therapeutic utility.
Topics: Adaptive Immunity; Animals; Apoptosis; Humans; Immunity, Innate; Immunologic Factors; Inflammation; Mice; Structure-Activity Relationship; alpha 1-Antitrypsin
PubMed: 24854541
DOI: 10.1515/hsz-2014-0161