ABSTRACT
Severe alpha-1 antitrypsin deficiency (AATD) is associated with an increased risk of emphysema. However, the clinical manifestations are very heterogeneous, and an individual prognosis is very difficult to establish. Intravenous augmentation therapy with alpha-1 antitrypsin (AAT) from pooled blood donors is the only specific treatment available, but it requires weekly or biweekly administration for life. Several guidelines provide the indication criteria for the initiation of AAT augmentation therapy. However, in clinical practice, there are situations in which the decision as to when to start treatment becomes uncertain and some studies have shown great variability in the indication of this treatment even among specialists. The usual dilemma is between initiating augmentation therapy in individuals who may not develop significant lung disease or in whom disease will not progress or delaying it in patients who may otherwise rapidly and irreversibly progress. We illustrate this dilemma with five clinical cases: from the case of a patient with normal lung function who requests initiation of therapy to a moderately stable patient without augmentation or a mild patient who, after several years of remaining stable without treatment, deterioration in lung function initiated and, consequently, augmentation therapy was begun. All the nuances associated with the indication of augmentation justify a personalised approach and the decision about initiating augmentation therapy must be made after careful consideration of the pros and cons with the patient in reference centres with experience in treatment. These reference centres can work in collaboration with local hospitals where patients can be closely followed and augmentation therapy can be administered to avoid unnecessary travelling, making periodical administrations more comfortable for the patient.
Subject(s)
Pulmonary Emphysema , alpha 1-Antitrypsin Deficiency , alpha 1-Antitrypsin , Humans , alpha 1-Antitrypsin Deficiency/complications , alpha 1-Antitrypsin Deficiency/diagnosis , alpha 1-Antitrypsin Deficiency/drug therapy , alpha 1-Antitrypsin Deficiency/physiopathology , alpha 1-Antitrypsin/administration & dosage , Pulmonary Emphysema/physiopathology , Pulmonary Emphysema/etiology , Pulmonary Emphysema/diagnosis , Pulmonary Emphysema/therapy , Male , Middle Aged , Female , Severity of Illness Index , Treatment Outcome , Precision Medicine , Adult , Disease Progression , AgedABSTRACT
Alpha-1-antitrypsin (AAT) plays a homeostatic role in attenuating excessive inflammation and augmenting host defense against microbes. We demonstrated previously that AAT binds to the glucocorticoid receptor (GR) resulting in significant anti-inflammatory and antimycobacterial consequences in macrophages. Our current investigation aims to uncover AAT-regulated genes that rely on GR in macrophages. We incubated control THP-1 cells (THP-1control) and THP-1 cells knocked down for GR (THP-1GR-KD) with AAT, performed bulk RNA sequencing, and analyzed the findings. In THP-1control cells, AAT significantly upregulated 408 genes and downregulated 376 genes. Comparing THP-1control and THP-1GR-KD cells, 125 (30.6%) of the AAT-upregulated genes and 154 (41.0%) of the AAT-downregulated genes were significantly dependent on GR. Among the AAT-upregulated, GR-dependent genes, CSF-2 that encodes for granulocyte-monocyte colony-stimulating factor (GM-CSF), known to be host-protective against nontuberculous mycobacteria, was strongly upregulated by AAT and dependent on GR. We further quantified the mRNA and protein of several AAT-upregulated, GR-dependent genes in macrophages and the mRNA of several AAT-downregulated, GR-dependent genes. We also discussed the function(s) of selected AAT-regulated, GR-dependent gene products largely in the context of mycobacterial infections. In conclusion, AAT regulated several genes that are dependent on GR and play roles in host immunity against mycobacteria.
Subject(s)
Macrophages , Receptors, Glucocorticoid , alpha 1-Antitrypsin , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin/metabolism , Receptors, Glucocorticoid/metabolism , Receptors, Glucocorticoid/genetics , Humans , Macrophages/metabolism , Macrophages/immunology , THP-1 Cells , Gene Expression Regulation , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/geneticsABSTRACT
Host proteins released by the activated endothelial cells during SARS-CoV-2 infection are implicated to be involved in coagulation and endothelial dysfunction. However, the underlying mechanism that governs the vascular dysfunction and disease severity in COVID-19 remains obscure. The study evaluated the serum levels of Bradykinin, Kallikrein, SERPIN A, and IL-18 in COVID-19 (N-42 with 20 moderate and 22 severe) patients compared to healthy controls (HC: N-10) using ELISA at the day of admission (DOA) and day 7 post-admission. The efficacy of the protein levels in predicting disease severity was further determined using machine learning models. The levels of bradykinins and SERPIN A were higher (P ≤ 0.001) in both severe and moderate cases on day 7 post-admission compared to DOA. All the soluble proteins studied were found to elevated (P ≤ 0.01) in severe compared to moderate in day 7 and were positively correlated (P ≤ 0.001) with D-dimer, a marker for coagulation. ROC analysis identified that SERPIN A, IL-18, and bradykinin could predict the clinical condition of COVID-19 with AUC values of 1, 0.979, and 1, respectively. Among the models trained using univariate model analysis, SERPIN A emerged as a strong prognostic biomarker for COVID-19 disease severity. The serum levels of SERPIN A in conjunction with the coagulation marker D-dimer, serve as a predictive indicator for COVID-19 clinical outcomes. However, studies are required to ascertain the role of these markers in disease virulence.
Subject(s)
Biomarkers , Bradykinin , COVID-19 , Interleukin-18 , SARS-CoV-2 , Humans , COVID-19/blood , COVID-19/diagnosis , Biomarkers/blood , Female , Male , Middle Aged , Prognosis , Interleukin-18/blood , Bradykinin/blood , Adult , Aged , Fibrin Fibrinogen Degradation Products/metabolism , Fibrin Fibrinogen Degradation Products/analysis , Severity of Illness Index , Endothelium, Vascular/metabolism , Kallikreins/blood , alpha 1-Antitrypsin/bloodABSTRACT
BACKGROUND: Genetic factors contribute to the risk and severity of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the utility of genetic testing in risk stratification remains poorly characterised. AIMS: To examine the influence of genetic risk on advanced fibrosis and cirrhosis in patients with type 2 diabetes mellitus (T2DM) and the utility of a polygenic risk score (PRS) in screening guidelines. METHODS: We prospectively enrolled adults aged ≥50 years with T2DM recruited from clinics. PRS was the sum of risk alleles in PNPLA3, TM6SF2 and SERPINA1 minus the protective variant in HSD17B13. We performed magnetic resonance elastography and vibration-controlled transient elastography to assess for advanced fibrosis and cirrhosis. RESULTS: Of 382 included patients, the mean age and BMI were 64.8 (±8.4) years and 31.7 (±6.2) kg/m2 respectively. The prevalence of advanced fibrosis and cirrhosis were 12.3% and 5.2% respectively; higher PRS was associated with increased risk of cirrhosis (2.7% vs. 7.5%, p = 0.037). High PRS was associated with increased risk of advanced fibrosis among those with fibrosis-4 index (FIB-4) index <1.3 (9.6% vs. 2.3%, p = 0.036) but was not significantly different in other FIB-4 categories. Incorporating PRS determination into the American Gastroenterological Association and American Association for the Study of Liver Diseases screening guidelines prevented approximately 20% of all participants with advanced fibrosis from being inappropriately classified as low risk. CONCLUSIONS: Utilising a well-phenotyped, prospective cohort of adults with T2DM, we found that adding an assessment of genetic risk to recommendations to screen at-risk populations may improve risk prediction.
Subject(s)
Diabetes Mellitus, Type 2 , Elasticity Imaging Techniques , Liver Cirrhosis , Humans , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/complications , Middle Aged , Male , Female , Liver Cirrhosis/genetics , Liver Cirrhosis/epidemiology , Aged , Prospective Studies , Prevalence , Genetic Predisposition to Disease , Membrane Proteins/genetics , Risk Factors , Lipase/genetics , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/epidemiology , Risk Assessment/methods , Acyltransferases , alpha 1-Antitrypsin , 17-Hydroxysteroid Dehydrogenases , Phospholipases A2, Calcium-IndependentABSTRACT
BACKGROUND: The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals with the PI*SS genotype is poorly defined despite its substantial prevalence. Our study aimed to characterize this genotype and its risk for lung disease and compare it with the PI*ZZ and PI*SZ genotypes using data from the European Alpha-1 antitrypsin Deficiency Research Collaboration international registry. METHOD: Demographic, clinical, functional, and quality of life (QoL) parameters were assessed to compare the PI*SS characteristics with the PI*SZ and PI*ZZ controls. A propensity score with 1:3 nearest-neighbour matching was performed for the most important confounding variables. RESULTS: The study included 1007 individuals, with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). The PI*SS population consisted of 58.9% men, with a mean age of 59.2 years and a mean FEV1(% predicted) of 83.4%. Compared to PI*ZZ individuals they had less frequent lung disease (71.4% vs. 82.2%, p = 0.037), COPD (41.4% vs. 60%, p = 0.002), and emphysema (23.2% vs. 51.9%, p < 0.001) and better preserved lung function, fewer exacerbations, lower level of dyspnoea, and better QoL. In contrast, no significant differences were found in the prevalence of lung diseases between PI*SS and PI*SZ, or lung function parameters, exacerbations, dyspnoea, or QoL. CONCLUSIONS: We found that, as expected, the risk of lung disease associated with the PI*SS genotype is significantly lower compared with PI*ZZ, but does not differ from that observed in PI*SZ individuals, despite having higher serum AAT levels. TRIAL REGISTRATION: www. CLINICALTRIALS: gov (ID: NCT04180319).
Subject(s)
Genotype , alpha 1-Antitrypsin Deficiency , alpha 1-Antitrypsin , Humans , Male , Female , Middle Aged , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin Deficiency/genetics , alpha 1-Antitrypsin Deficiency/epidemiology , alpha 1-Antitrypsin Deficiency/diagnosis , Aged , Lung Diseases/genetics , Lung Diseases/epidemiology , Lung Diseases/diagnosis , Risk Factors , Registries , Quality of LifeABSTRACT
The aim of this study was to investigate the plasma proteome in individuals with intracranial aneurysms (IAs) and identify biomarkers associated with the formation and rupture of IAs. Proteomic profiles (N = 1069 proteins) were assayed in plasma (N = 120) collected from patients with ruptured and unruptured intracranial aneurysms (RIA and UIA), traumatic subarachnoid hemorrhage (tSAH), and healthy controls (HC) using tandem mass tag (TMT) labeling quantitative proteomics analysis. Gene ontology (GO) and pathway analysis revealed that these relevant proteins were involved in immune response and extracellular matrix organization pathways. Seven candidate biomarkers were verified by ELISA in a completely separate cohort for validation (N = 90). Among them, FN1, PON1, and SERPINA1 can be utilized as diagnosis biomarkers of IA, with a combined area under the ROC curve of 0.891. The sensitivity was 93.33%, specificity was 75.86%, and accuracy was 87.64%. PFN1, ApoA-1, and SERPINA1 can serve as independent risk factors for predicting aneurysm rupture. The combined prediction of aneurysm rupture yielded an area under the ROC curve of 0.954 with a sensitivity of 96.15%, specificity of 81.48%, and accuracy of 88.68%. This prediction model was more effective than PHASES score. In conclusion, high-throughput proteomics analysis with population validation was performed to assess blood-based protein expression characteristics. This revealed the potential mechanism of IA formation and rupture, facilitating the discovery of biomarkers. SIGNIFICANCE: Although the annual rupture rate of small unruptured aneurysms is believed to be minimal, studies have indicated that ruptured aneurysms typically have an average size of 6.28 mm, with 71.8% of them being <7 mm in diameter. Hence, evaluating the possibility of rupture in UIA and making a choice between aggressive treatment and conservative observation emerges as a significant challenge in the management of UIA. No biomarker or scoring system has been able to satisfactorily address this issue to date. It would be significant to develop biomarkers that could be used for early diagnosis of IA as well as for prediction of IA rupture. After TMT proteomics analysis and ELISA validation in independent populations, we found that FN1, PON1, and SERPINA1 can be utilized as diagnostic biomarkers for IA, and PFN1, ApoA-1, and SERPINA1 can serve as independent risk factors for predicting aneurysm rupture. Especially, when combined with ApoA-1, SERPINA1, and PFN1 for predicting IA rupture, the area under the curve (AUC) was 0.954 with a sensitivity of 96.15%, specificity of 81.48%, and accuracy of 88.68%. This prediction model was more effective than PHASES score.
Subject(s)
Aneurysm, Ruptured , Biomarkers , Intracranial Aneurysm , Proteomics , Humans , Intracranial Aneurysm/blood , Intracranial Aneurysm/diagnosis , Biomarkers/blood , Aneurysm, Ruptured/blood , Aneurysm, Ruptured/diagnosis , Male , Female , Proteomics/methods , Middle Aged , Adult , Aged , alpha 1-Antitrypsin/blood , Proteome/analysis , Subarachnoid Hemorrhage/blood , Subarachnoid Hemorrhage/diagnosisABSTRACT
AIM: To characterize vestibular recovery in a mouse model of unilateral labyrinthotomy under local AAT and dexamethasone treatment. BACKGROUND: Alpha1-antitrypsin (AAT) is a circulating tissue-protective molecule that rises during inflammatory conditions and promotes inflammatory resolution. Its local concentration in human perilymph inversely correlates with the severity of inner ear dysfunction; concomitantly, mice that overexpress AAT and undergo inner ear trauma rapidly restore vestibular function. Locally applied AAT has yet to be examined in this context, nor has it been directly compared with anti-inflammatory corticosteroid treatment. METHODS: Wild-type mice C57BL/6 underwent a unilateral inner ear injury. Nine microliters of saline, clinical-grade AAT (180 µg/site), dexamethasone (4 mg/site), or both were applied locally on Days 0, 1, and 2 (n = 5/group). Vestibular function was assessed for 7 days. An in vitro human epithelial gap closure assay was performed using A549 cells in the presence of AAT and/or dexamethasone. RESULTS: Upon labyrinthotomy, all groups displayed severe vestibular dysfunction. Saline-treated mice showed the longest impairment. That group and the dexamethasone group displayed partial to no recovery, while AAT-treated mice exhibited complete recovery within 7 days; at this time point, dexamethasone-treated mice exhibited 50% recovery. Objective vestibular testing showed similar outcomes. In vitro, cotreatment with AAT and dexamethasone resulted in a gap closure dynamic that was superior to AAT alone at 6 h and superior to DEX alone at 48 h. CONCLUSION: Locally applied AAT treatment is superior to locally applied dexamethasone in promoting vestibular recovery in vivo. Ongoing studies are exploring the potential advantages of AAT combined with early low-dose dexamethasone therapy.
Subject(s)
Dexamethasone , Mice, Inbred C57BL , alpha 1-Antitrypsin , Animals , Mice , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , alpha 1-Antitrypsin/administration & dosage , Vestibular Diseases/drug therapy , Vestibular Diseases/etiology , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacology , Ear, Inner/drug effects , Disease Models, Animal , Recovery of Function/drug effects , Vestibule, Labyrinth/drug effects , Vestibule, Labyrinth/injuries , Humans , MaleABSTRACT
The endoplasmic reticulum (ER) produces proteins destined to organelles of the endocytic and secretory pathways, the plasma membrane, and the extracellular space. While native proteins are transported to their intra- or extracellular site of activity, folding-defective polypeptides are retro-translocated across the ER membrane into the cytoplasm, poly-ubiquitylated and degraded by 26 S proteasomes in a process called ER-associated degradation (ERAD). Large misfolded polypeptides, such as polymers of alpha1 antitrypsin Z (ATZ) or mutant procollagens, fail to be dislocated across the ER membrane and instead enter ER-to-lysosome-associated degradation (ERLAD) pathways. Here, we show that pharmacological or genetic inhibition of ERAD components, such as the α1,2-mannosidase EDEM1 or the OS9 ERAD lectins triggers the delivery of the canonical ERAD clients Null Hong Kong (NHK) and BACE457Δ to degradative endolysosomes under control of the ER-phagy receptor FAM134B and the LC3 lipidation machinery. Our results reveal that ERAD dysfunction is compensated by the activation of FAM134B-driven ERLAD pathways that ensure efficient lysosomal clearance of orphan ERAD clients.
Subject(s)
Endoplasmic Reticulum-Associated Degradation , Endoplasmic Reticulum , Lysosomes , Membrane Proteins , Lysosomes/metabolism , Humans , Endoplasmic Reticulum/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Amyloid Precursor Protein Secretases/metabolism , alpha 1-Antitrypsin/metabolism , alpha 1-Antitrypsin/genetics , Animals , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Protein Folding , Protein Transport , Lectins/metabolism , Aspartic Acid Endopeptidases/metabolism , Aspartic Acid Endopeptidases/genetics , Mice , HeLa CellsABSTRACT
INTRODUCTION: Renal ischemia reperfusion injury is a major cause of perioperative acute kidney injury. Alpha-1-antitrypsin (AAT), a protease inhibitor, might improve outcomes by reducing inflammation and apoptosis. We investigated the effects of a single intravenous dose of AAT immediately before ischemia in a rat bilateral renal clamping model. METHODS: Both renal pedicles of male Sprague-Dawley rats were clamped (45 min). Plasma and renal tissue were collected at 3 h, 24 h, and 7 d. Intravenous AAT (60 mg/kg) was administered 5 min before clamping. Controls received saline. Shams underwent surgery without clamping or injection. Kidney function was assessed by plasma creatinine; injury by aspartate aminotransferase, heart-type-fatty-acid-binding-protein, and histopathology. Renal gene expression of tumor necrosis factor α, interleukin (IL)-6, heat shock protein 70, Chemokine (C-X-C motif) ligand 2, cyclo-oxygenase 2, endothelin-1, IL-10, heme oxygenase 1, B-cell lymphoma 2, and bcl-2-like protein 4 were determined by quantitative reverse transcriptase polymerase chain reaction. RESULTS: None of the 3 h and 24 h end points were different between Control and AAT. In Sham, survival was 100% (6/6), 33% in Control (2/6), and 83% (5/6) in AAT (overall log-rank 0.03). At 7 d, plasma creatinine was lower with higher glomerular filtration rate in surviving AAT treated animals compared to Control (P < 0.001, P 0.03, respectively). These also had lower tumor necrosis factor α and IL-6 gene expression (P 0.001, P < 0.001, respectively). CONCLUSIONS: These data suggest that a single intravenous dose of AAT immediately before ischemia might affect proinflammatory gene expression, glomerular filtration rate and animal survival at 1 wk after reperfusion despite an absence of improvement in early renal function and injury. These findings deserve further investigating in sufficiently powered studies including both sexes.
Subject(s)
Kidney , Reperfusion Injury , alpha 1-Antitrypsin , Animals , Male , Rats , Acute Kidney Injury/etiology , Acute Kidney Injury/prevention & control , alpha 1-Antitrypsin/administration & dosage , Disease Models, Animal , Kidney/blood supply , Kidney/pathology , Kidney/drug effects , Rats, Sprague-Dawley , Reperfusion Injury/prevention & control , Reperfusion Injury/pathology , Reperfusion Injury/etiologyABSTRACT
Patients with predominantly antibody deficiencies (PADs) display hypogammaglobulinemia with a high prevalence of infections, along with autoimmune manifestations, benign and malignant lymphoproliferation and granulomatous disease. It is noteworthy that PAD patients, even those with defects in the same causative genes, display a variable clinical phenotype, suggesting that additional genetic polymorphisms, located in either immune-related or non-immune-related genes, may affect their clinical and laboratory phenotype. In this context, we analyzed 80 PAD patients, including 70 with common variable immunodeficiency (CVID) for SERPINA1 defects, in order to investigate the possible contribution to PAD clinical phenotype. Ten CVID patients carried heterozygous pathogenic SERPINA1 defects with normal alpha-1 antitrypsin levels. Interestingly, the presence of the Z allele (rs28929474), which was found in three patients, was significantly associated with liver disease; hepatic complications were also observed in patients carrying the p.Leu23Gln (rs1379209512) and the p.Phe76del (rs775982338) alleles. Conversely, no correlation of SERPINA1 defective variants with respiratory complications was observed, although patients with pathogenic variants exhibit a reduced probability of developing autoimmune diseases. Therefore, we recommend SERPINA1 genetic analysis in PAD in order to identify patients with a higher risk for liver disease.
Subject(s)
Common Variable Immunodeficiency , Heterozygote , alpha 1-Antitrypsin , Humans , alpha 1-Antitrypsin/genetics , Male , Female , Common Variable Immunodeficiency/genetics , Common Variable Immunodeficiency/immunology , Adult , Middle Aged , Phenotype , Alleles , Adolescent , Child , Young Adult , Aged , Agammaglobulinemia/genetics , Agammaglobulinemia/immunology , Genetic Predisposition to DiseaseABSTRACT
Currently, there are no accurate means to predict spontaneous preterm birth (SPTB). Recently, we observed low expression of alpha-1 antitrypsin (AAT) in SPTB placentas. Present aim was to compare the concentrations of maternal serum AAT in pregnancies with preterm and term deliveries. Serum C-reactive protein (CRP) was used as a reference inflammatory marker. Two populations were studied. The first population comprised women who eventually gave birth spontaneously preterm (SPTB group) or term (control group). The second population included pregnant women shortly before delivery and nonpregnant women. We observed that serum AAT levels were higher in the SPTB group than in the controls, and a similar difference was observed when serum CRP was considered in multivariable analysis. However, the overlap in the AAT concentrations was considerable. No statistical significance was observed in serum AAT levels between preterm and term pregnancies at delivery. However, AAT levels were higher at delivery compared to nonpregnant controls. We did not observe a strong correlation between serum AAT and CRP in early pregnancy samples and at labor. We propose that during early pregnancy, complicated by subsequent SPTB, modest elevation of serum AAT associates with SPTB.
Subject(s)
C-Reactive Protein , Premature Birth , alpha 1-Antitrypsin , Humans , Female , Pregnancy , alpha 1-Antitrypsin/blood , Premature Birth/blood , Adult , C-Reactive Protein/metabolism , C-Reactive Protein/analysis , Biomarkers/blood , Infant, Newborn , Term Birth/blood , Case-Control StudiesABSTRACT
BACKGROUND: Alpha-1 antitrypsin deficiency is an underdiagnosed genetic condition that predisposes to pulmonary complications and is mainly caused by rs28929474 (PI*Z allele) and rs17580 (PI*S allele) mutations in the SERPINA1 gene. OBJECTIVE: Development of a homogeneous genotyping test for detection of PI*S and PI*Z alleles based on the principles of allele-specific PCR and amplicon melting analysis with a fluorescent dye. METHODS: Sixty individuals, which included all possible genotypes that result from combinations of rs28929474 and rs17580 single nucleotide variants, were assayed with tailed allele-specific primers and SYBR Green dye in a real-time PCR machine. RESULTS: A clear discrimination of mutant and wild-type variants was achieved in the genetic loci that define PI*S and PI*Z alleles. Specific amplicons showed a difference of 2.0 °C in melting temperature for non-S and S variants and of 2.9 °C for non-Z and Z variants. CONCLUSIONS: The developed genotyping method is robust, fast, and easily scalable on a standard real-time PCR platform. While it overcomes the handicaps of non-homogeneous approaches, it greatly reduces genotyping costs compared with other homogeneous approaches.
Subject(s)
Alleles , Benzothiazoles , Diamines , Organic Chemicals , Quinolines , Real-Time Polymerase Chain Reaction , alpha 1-Antitrypsin , alpha 1-Antitrypsin/genetics , Humans , Real-Time Polymerase Chain Reaction/methods , alpha 1-Antitrypsin Deficiency/genetics , Polymorphism, Single Nucleotide , Genotyping Techniques/methods , Genotype , Fluorescent Dyes/chemistryABSTRACT
Alpha 1antitrypsin (AAT) deficiency represents a complex genetic disorder and necessitates an interdisciplinary approach in the clinical practice. This article provides an overview of the epidemiology, genetics, symptoms, diagnostics and treatment of AAT deficiency. Knowledge and an in-depth understanding of AAT deficiency are indispensable to improve the early recognition of AAT, to optimize the quality of life of those affected and to enable targeted treatment interventions.
Subject(s)
alpha 1-Antitrypsin Deficiency , alpha 1-Antitrypsin Deficiency/genetics , alpha 1-Antitrypsin Deficiency/therapy , alpha 1-Antitrypsin Deficiency/diagnosis , alpha 1-Antitrypsin Deficiency/epidemiology , Humans , alpha 1-Antitrypsin/genetics , Quality of LifeABSTRACT
Alzheimer's disease (AD) is a progressive neurological disorder featuring abnormal protein aggregation in the brain, including the pathological hallmarks of amyloid plaques and hyperphosphorylated tau. Despite extensive research efforts, understanding the molecular intricacies driving AD development remains a formidable challenge. This study focuses on identifying key protein conformational changes associated with the progression of AD. To achieve this, we employed quantitative cross-linking mass spectrometry (XL-MS) to elucidate conformational changes in the protein networks in cerebrospinal fluid (CSF). By using isotopically labeled cross-linkers BS3d0 and BS3d4, we reveal a dynamic shift in protein interaction networks during AD progression. Our comprehensive analysis highlights distinct alterations in protein-protein interactions within mild cognitive impairment (MCI) states. This study accentuates the potential of cross-linked peptides as indicators of AD-related conformational changes, including previously unreported site-specific binding between α-1-antitrypsin (A1AT) and complement component 3 (CO3). Furthermore, this work enables detailed structural characterization of apolipoprotein E (ApoE) and reveals modifications within its helical domains, suggesting their involvement in MCI pathogenesis. The quantitative approach provides insights into site-specific interactions and changes in the abundance of cross-linked peptides, offering an improved understanding of the intricate protein-protein interactions underlying AD progression. These findings lay a foundation for the development of potential diagnostic or therapeutic strategies aimed at mitigating the negative impact of AD.
Subject(s)
Alzheimer Disease , Apolipoproteins E , Mass Spectrometry , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/diagnosis , Humans , Apolipoproteins E/chemistry , Apolipoproteins E/metabolism , Cross-Linking Reagents/chemistry , Protein Conformation , alpha 1-Antitrypsin/chemistry , alpha 1-Antitrypsin/metabolism , Cognitive Dysfunction/metabolismABSTRACT
Subject(s)
Asthma , Genotype , Phenotype , Severity of Illness Index , alpha 1-Antitrypsin Deficiency , alpha 1-Antitrypsin , Humans , Female , alpha 1-Antitrypsin Deficiency/genetics , alpha 1-Antitrypsin Deficiency/complications , alpha 1-Antitrypsin Deficiency/epidemiology , alpha 1-Antitrypsin Deficiency/diagnosis , Male , Middle Aged , Adult , alpha 1-Antitrypsin/genetics , Retrospective Studies , Italy/epidemiology , PrevalenceABSTRACT
Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.
Subject(s)
Islets of Langerhans Transplantation , Pancreatectomy , Pancreatitis, Chronic , Transplantation, Autologous , alpha 1-Antitrypsin , Humans , Islets of Langerhans Transplantation/methods , Pancreatitis, Chronic/surgery , Pancreatitis, Chronic/therapy , alpha 1-Antitrypsin/therapeutic use , Male , Female , Pancreatectomy/methods , Middle Aged , Transplantation, Autologous/methods , Adult , Double-Blind Method , C-Peptide/blood , C-Peptide/metabolism , Prospective StudiesABSTRACT
Background and Objective: Rheumatoid arthritis (RA) is an autoimmune disease in which joints are gradually destroyed. Early diagnosis and treatment before joint deformation or destruction is important. The detection of novel RA biomarkers in saliva may facilitate early detection of RA before disease onset. This study aimed to evaluate salivary concentration of α1-antitrypsin (A1AT) in healthy patients and those with RA, and to assess the diagnostic value of salivary A1AT. Materials and Methods: In total, 80 participants were included: 20 healthy participants, and 60 patients with RA. Saliva and serum samples were obtained from all the patients. Levels of A1AT and cytokines, including interleukin-1 beta (IL-1ß), IL-6, and IL-10 in saliva and serum, were evaluated using an enzyme-linked immunosorbent assay kit and Luminex assay. Data were analyzed using SPSS for Windows. Results: There was a higher level of A1AT in the saliva of patients with RA (median: 2388.66 ng/mL) than that in healthy controls (1579.06 ng/mL). There was a positive mild-to-moderate accuracy (area under the curve: 0.57-0.85) of A1AT in saliva to diagnose RA. The cut-off level (ng/mL) of A1AT in saliva for detecting RA was 1689.0. Conclusions: The obtained data can promote the application of the measurements of A1AT in saliva to diagnose RA.