- Decline in FEV1 and hospitalized exacerbations in individuals with severe alpha-1 antitrypsin deficiency. [Journal Article]
- IJInt J Chron Obstruct Pulmon Dis 2019; 14:1075-1083
- CONCLUSIONS: Active smoking, age, respiratory symptoms at baseline and repeated severe exacerbations of COPD are factors associated with an accelerated decline of lung function in individuals with severe AATD.
- Evaluation of Alpha 1-Antitrypsin for the Early Diagnosis of Colorectal Cancer. [Journal Article]
- POPathol Oncol Res 2019 Jun 10
- Previous proteomic studies have identified alpha 1-antitrypsin (A1AT) as a potential serum biomarker for colorectal cancer (CRC). In this case-control study, we evaluated plasma A1AT concentration an…
Previous proteomic studies have identified alpha 1-antitrypsin (A1AT) as a potential serum biomarker for colorectal cancer (CRC). In this case-control study, we evaluated plasma A1AT concentration and activity as a biomarker for the early diagnosis of colorectal cancer in a group of 113 sporadic CRC patients. We also analyzed A1AT gene promoter methylation, and genotypes in this group of CRC patients. The plasma A1AT and CEA concentrations were measured using the nephelometric and ELISA methods, respectively. A1AT activity was determined by Trypsin Inhibitor Capacity assay. The genomic DNA from blood samples were subjected to Z and S genotype analysis using PCR-RFLP method and the gene promoter methylation in tumors and their adjacent normal tissues was determined by methylation specific-PCR assay. The plasma levels of A1AT and CEA in patients (median, 2.3 g/L and 5.96 ng/ml, respectively) were significantly higher than those in healthy controls (medians, 1.43 g/L and 2.57 ng/ml, respectively) (p = 0.0001). The plasma A1AT activity and concentrations were positively correlated with the tumor stage and well-discriminated between early and advanced stages. The A1AT activity in plasma was the most useful marker for CRC diagnosis (median 4.8 mmol/min/ml in cases vs 1.91 mmol/min/ml in controls, p = 0.0001). No deficient Z or S alleles of A1AT was observed in patients' genotype and the gene promoter tends to be more methylated in normal mucosa than in tumor tissues. We conclude that plasma A1AT activity has better sensitivity and specificity than CEA measurement for the early detection of CRC. Promoter demethylation might play a role in increasing plasma A1AT levels in CRC patients.
- Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease? [Review]
- DADrugs Aging 2019 Jun 10
- Alpha-1 antitrypsin (AAT) protects the lung by inhibiting neutrophil proteinases, but AAT has many other non-proteolytic functions that are anti-inflammatory, antiviral and homeostatic. Approximately…
Alpha-1 antitrypsin (AAT) protects the lung by inhibiting neutrophil proteinases, but AAT has many other non-proteolytic functions that are anti-inflammatory, antiviral and homeostatic. Approximately 1 in 1600 to 1 in 5000 people have the homozygous Z mutation, which causes AAT misfolding, accumulation in (predominantly) liver cells and low circulating levels of AAT, leading to AAT deficiency (AATD). AATD is classically a disease of neutrophilic inflammation, with an aggressive and damaging innate immune response contributing to emphysema and other pathologies. AATD is one of the most common genetic disorders but considerably under-recognised. Most patients are diagnosed later in life, by which time they may have accumulated significant lung, liver and multisystem damage. Disease presentation is heterogeneous and not fully explained by deficiency levels alone or exposure to cigarette smoking. This suggests other factors influence AATD-associated pathological processes. Aging itself is associated with organ dysfunction, including emphysema and airflow obstruction, inflammation, altered immune cell responses (termed immunosenescence) and a loss of proteostasis. Many of these processes are present in AATD but at an earlier age and more advanced stage compared with chronological aging alone. Augmentation therapy does not completely abrogate the manifold disease processes present in AATD. New approaches are needed. There is emerging evidence that both age- and AATD-related disease processes are amenable to correction by targeting proteostasis, autophagy, immunosenescence and epigenetic factors. This review explores the impact of the aging process on AATD presentation and discusses novel therapeutic strategies to mitigate low levels of AAT or misfolded AAT in an aging host.
- Greater survival despite increased complication rates following lung transplant for alpha-1-antitrypsin deficiency compared to chronic obstructive pulmonary disease. [Journal Article]
- JTJ Thorac Dis 2019; 11(4):1130-1144
- CONCLUSIONS: A1ATD lung recipients had worse short-term complication-free survival but improved long-term survival compared to COPD patients. A1ATD was associated with greater risk of new GI pathology after transplant. Close monitoring of A1ATD patients with timely evaluation of GI complaints after transplant is warranted.
- A Novel Mass Spectrometry Platform for Multiplexed N-glycoprotein Biomarker Discovery from Patient Biofluids by Antibody Panel Based N-glycan Imaging. [Journal Article]
- ACAnal Chem 2019 Jun 10
- A new platform for N-glycoprotein analysis from serum that combines matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) workflows with antibody slide arrays is described…
A new platform for N-glycoprotein analysis from serum that combines matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) workflows with antibody slide arrays is described. Antibody Panel Based (APB) N-glycan imaging allows for the specific capture of N-glycoproteins by antibodies on glass slides and N-glycan analysis in a protein-specific and multiplexed manner. Development of this technique has focused on characterizing two abundant and well-studied human serum glycoproteins, alpha-1-antitrypsin and immunoglobulin G. Using purified standard solutions and one microliter samples of human serum, both glycoproteins can be immunocaptured and followed by enzymatic release of N-glycans. N-glycans are detected with a MALDI FT-ICR mass spectrometer in a concentration-dependent manner while maintaining specificity of capture. Importantly, the N-glycans detected via slide-based antibody capture were identical to that of direct analysis of the spotted standards. As a proof of concept, this workflow was applied to patient serum samples from individuals with liver cirrhosis to accurately detect a characteristic increase in an IgG N-glycan. This novel approach to protein-specific N-glycan analysis from an antibody panel can be further expanded to include any glycoprotein for which a validated antibody exists. Additionally, this platform can be adapted for analysis of any biofluid or biological sample that can be analyzed by antibody arrays.
- Fractalkine Induces Hepcidin Expression of BV-2 Microglia and Causes Iron Accumulation in SH-SY5Y Cells. [Journal Article]
- CMCell Mol Neurobiol 2019 Jun 06
- Fractalkine (CX3CL1) is a potent inflammatory mediator of the central nervous system, which is expressed by neurons and regulates microglial functions by binding to fractalkine receptor (CX3CR1). It …
Fractalkine (CX3CL1) is a potent inflammatory mediator of the central nervous system, which is expressed by neurons and regulates microglial functions by binding to fractalkine receptor (CX3CR1). It has been demonstrated that neuroinflammation plays an important role in iron accumulation of the brain leading to neuronal cell death. The major regulator of iron homeostasis is the peptide hormone hepcidin. Hepcidin expression is triggered by inflammatory conditions, which may contribute to the neuronal iron accumulation. In the present study, we established a bilaminar co-culture system of differentiated SH-SY5Y cells and BV-2 microglia as a neuronal model to examine the effect of soluble fractalkine on iron homeostasis of microglia and SH-SY5Y cells. We determined the hepcidin expression of fractalkine-treated microglia which showed significant elevation. We examined the relation between increased hepcidin secretion, the known hepcidin regulators and the signalling pathways controlled by fractalkine receptor. Our data revealed that TMPRSS6 and alpha 1-antitrypsin levels decreased due to fractalkine treatment, as well as the activity of NFκB pathway and the tyrosine phosphorylation of STAT5 factor. Moreover, fractalkine-induced hepcidin production of microglia initiated ferroportin internalisation of SH-SY5Y cells, which contributed to iron accumulation of neurons. Our results demonstrate that soluble form of fractalkine regulates hepcidin expression of BV-2 cells through fractalkine-mediated CX3CR1 internalisation. Moreover, fractalkine indirectly contributes to the iron accumulation of SH-SY5Y cells by activating ferroportin internalisation and by triggering the expressions of divalent metal transporter-1, ferritin heavy chain and mitochondrial ferritin.
- European Biological Variation Study (EuBIVAS): Within- and Between-Subject Biological Variation Data for 15 Frequently Measured Proteins. [Journal Article]
- CCClin Chem 2019 Jun 06
- CONCLUSIONS: In addition to new BV estimates for sTfR, this EuBIVAS substudy generated more demanding APS for frequently requested plasma specific proteins. APS for CRP should not be calculated from BV data except when CRP is used as a risk factor for cardiovascular disease.
- Diagnostic Yield of an Algorithm for Neonatal and Infantile Cholestasis Integrating Next-Generation Sequencing. [Journal Article]
- JPedJ Pediatr 2019 May 31
- CONCLUSIONS: This protocol combining clinical and genetic assessment proved to be an effective diagnostic tool for neonatal/infantile cholestasis, identifying inherited disorders with a high detection rate. It also could allow a noninvasive diagnosis in children presenting with colored stools.
- Serum Levels of Alpha1-antitrypsin and Their Relationship With COPD in the General Spanish Population. [Journal Article]
- ABArch Bronconeumol 2019 May 29
- CONCLUSIONS: Increased circulating levels of AAT, similarly to CRP and other markers of systemic inflammation, is an important feature of COPD. Our results highlight a complex interrelationship between levels of AAT and health of respiratory system.
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- The E3 ubiquitin ligase MARCH2 regulates ERGIC3-dependent trafficking of secretory proteins. [Journal Article]
- JBJ Biol Chem 2019 May 29
- The E3 ubiquitin ligase membrane-associated ring-CH-type finger 2 (MARCH2) is known to be involved in intracellular vesicular trafficking, but its role in the early secretory pathway between the endo…
The E3 ubiquitin ligase membrane-associated ring-CH-type finger 2 (MARCH2) is known to be involved in intracellular vesicular trafficking, but its role in the early secretory pathway between the endoplasmic reticulum (ER) and Golgi compartments is largely unknown. Human ER-Golgi intermediate compartment protein 2 (ERGIC2) and ERGIC3 are orthologs of Erv41p and Erv46p in yeast, proteins that form a heteromeric complex, cycle between the ER and Golgi, and function as cargo receptors in both anterograde and retrograde protein trafficking. Here, we report that MARCH2 directs ubiquitination and subsequent degradation of ERGIC3, and that MARCH2 depletion increases endogenous ERGIC3 levels. We provide evidence that the lysine residues at positions 6 and 8 of ERGIC3 are the major sites of MARCH2-mediated ubiquitination. Of note, MARCH2 did not significantly decrease the levels of an ERGIC3 variant with lysine-to-arginine substitutions at residues 6 and 8. We also show that ERGIC3 binds to itself or to ERGIC2, whereas ERGIC2 is unable to interact with itself. Our results indicate that α1-antitrypsin and haptoglobin are likely to be cargo proteins of ERGIC3. We further observed that α1-antitrypsin and haptoglobin specifically bind to ERGIC3 and that ERGIC3 depletion decreases their secretion. Moreover, MARCH2 reduced secretion of α1-antitrypsin and haptoglobin, and co-expression of the ubiquitination-resistant ERGIC3 variant largely restored their secretion, suggesting that MARCH2-mediated ERGIC3 ubiquitination is the major cause of the decrease in trafficking of ERGIC3-binding secretory proteins. Our findings provide detailed insights into the regulation of the early secretory pathway by MARCH2 and into ERGIC3 function.