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Query Topic: A2M

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alpha 2 macroglobulin(13)

Neurogenic Thoracic Outlet Syndrome and other Forms of Cervical Brachial Syndrome Treated with Plasma Concentrate Enriched for Alpha 2 Macroglobulin.
Existing therapies for myofascial and neuralgic forms of cervicobrachial pain may have unsatisfactory outcomes. Alternative therapies may be considered, particularly for individuals who have failed to respond. Contemporary conceptualizations of chronic pain mechanisms include the contribution of inflammatory factors; therefore, locally targeted antiinflammatory administrations may play a role in treatment of cervicobrachial pain.Alpha 2 macroglobulin (A2M) is a plasma protein that acts as a molecular trap for inflammatory factors such as tumor necrosis factor. After plasma is enriched for A2M, it may be considered as a possible injectable agent to counteract inflammation that may occur with a cervicobrachial pain syndrome. This retrospective review evaluates patient response to the use of plasma concentrate enriched for alpha 2 macroglobulin (A2M-PPP) in treatment of neurogenic thoracic outlet syndrome (TOS) and other forms of cervical brachial syndrome. Observational Study. Outpatient interventional neurology practice. There were 62 patients, including 46 women and 16 men ages 23-77 years. Twenty-three of these patients were diagnosed with complex regional pain syndrome (CRPS) or fibromyalgia, 18 with TOS, and 21 with musculotendinous pain (MTP). At baseline, 1 month, 3 months, and 6 months, patient status was evaluated with a Brief Pain Inventory (BPI) that included a composite pain score and a functional interference score. Patients were asked to estimate overall satisfaction with a Patient Global Impression of Change (PGIC) scale. Criterion for clinically significant improvement included >30% betterment in the BPI pain and functional interference subscales and a PGIC of > 5 at the 3-month mark. Three patients, one with CRPS and 2 with TOS, complained of several days of worsened pain or dysesthesias. No serious or permanent complications were encountered. For patients with TOS at the 3-month mark, 61% achieved clinical endpoints of success compared with 35% with CRPS/fibromyalgia and 24% for patients with MTP (P < 0.05, chi-square). By 6 months, 22% of individuals in the neuropathic TOS group had > 30% improvements in pain and functional interference scores compared with 13% of the individuals in the CRPS/fibromyalgia group and 18% in the MTP group. This article does not differentiate the added benefit of A2M-PPP from hydrodissection alone. Additionally, this article does not evaluate the actual benefit of the A2M molecule apart from other factors present in the platelet-poor concentrate such as exosomes and cytokines. With the advent of pure engineered A2M, more focused studies will be possible. Also, an independent assay was not done, and therefore we cannot be precisely sure about the exact quantity of platelets, if any, which were contained in the platelet-poor concentration. Results suggest that A2M-PPP, when injected into muscle, tendon, and epineurium with live ultrasound guidance, appears to be relatively safe and free of postinjection inflammatory reactions that are often seen after platelet-poor plasma injection. A2M-PPP appears to be associated more frequently with good outcomes when injected into brachial plexus targets in patients with TOS compared with outcomes observed after injection of the plexus in patients with CRPS/fibromyalgia. Plasma concentrate enriched for alpha 2 macroglobulin, neurogenic thoracic outlet syndrome, cervical brachial syndrome.
Publication Date: 2020-03-28
Journal: Pain physician

low-density lipoprotein receptor-related(11)

Substituting the Thiol Ester of Human A2M or C3 with a Disulfide Produces Native Proteins with Altered Proteolysis-Induced Conformational Changes.
Most proteins in the α-macroglobulin (αM) superfamily contain reactive thiol esters that are required for their biological function. Here, we have characterized the human α2-macroglobulin (A2M) and complement component C3 mutants A2M Q975C and C3 Q1013C, which replace the CGEQ thiol ester motifs of the original proteins with the disulfide-forming sequence CGEC. Mass spectrometry showed that the intended disulfide was formed in both proteins. The correct folding and native conformation of A2M Q975C were shown by its assembly to a tetramer, an initially slow electrophoretic mobility with a demonstrable conformational collapse induced by proteolysis, functional protease trapping, and conformation-dependent interactions with low-density lipoprotein receptor-related protein 1. However, A2M Q975C had a decreased capacity to inhibit trypsin and was more susceptible to cleavage by trypsin or thermolysin when compared to wild-type A2M. C3 Q1013C also folded correctly and was initially in a native conformation, as demonstrated by its cation exchange elution profile, electrophoretic mobility, and interaction with complement factor B, although it assumed a conformation that was distinct from native C3, C3b, or C3(H
Publication Date: 2020-12-11
Journal: Biochemistry

deletion polymorphism(14)

The genetic association between alpha-2-macroglobulin (A2M) gene deletion polymorphism and low serum A2M concentration in overweight/obese Thais.
The study subjects were 192 overweight and obese Thais (BMI > 25.00 kg/m2), and 103 Thai controls (BMI = 18.50-24.99 kg/m2), whose ages ranged from 18-60 years. All subjects were evaluated for serum Alpha-2-macroglobulin (A2M), globulin, albumin concentration, and polymorphic variation in the A2M gene. Serum A2M and albumin were significantly lower in the overweight/obese group (P < 0.05). For the overweight/obese and control group, the median ages were 38 and 37 years, serum A2M 200.2; 252.0 (mg/L), albumin 4.4; 4.5 (g/dL), and globulin 3.0; 2.95 (g/dL), respectively. A2M deletion polymorphism genotyping showed no association between A2M deletion polymorphism and the two groupings. At serum A2M concentration < 250 mg/L, there was no relationship between A2M deletion polymorphism and age. Serum A2M had a significant negative correlation with age in all subjects (R = 0.09, P < 0.05). The results did not support the hypothesis that A2M deletion polymorphism is associated with a low A2M concentration in overweight/obese subjects. However, serum A2M had a significant negative correlation with age; serum A2M can possibly be used to indicate the aging of cells in vivo, including the brain. Further studies are needed to investigate other A2M genes located on chromosome 12 to prove A2M gene polymorphism's association with low serum A2M and aging.
Publication Date: 2006-08-17
Journal: Nutritional neuroscience

present study(12)

Tissue specific alpha-2-Macroglobulin (A2M) splice isoform diversity in Hilsa shad, Tenualosa ilisha (Hamilton, 1822).
The present study, for the first time, reported twelve A2M isoforms in Tenualosa ilisha, through SMRT sequencing. Hilsa shad, T. ilisha, an anadromous fish, faces environmental stresses and is thus prone to diseases. Here, expression profiles of different A2M isoforms in four tissues were studied in T. ilisha, for the tissue specific diversity of A2M. Large scale high quality full length transcripts (>0.99% accuracy) were obtained from liver, ovary, testes and gill transcriptomes, through Iso-sequencing on PacBio RSII. A total of 12 isoforms, with complete putatative proteins, were detected in three tissues (7 isoforms in liver, 4 in ovary and 1 in testes). Complete structure of A2M mRNA was predicted from these isoforms, containing 4680 bp sequence, 35 exons and 1508 amino acids. With Homo sapiens A2M as reference, six functional domains (A2M_N,A2M_N2, A2M, Thiol-ester_cl, Complement and Receptor domain), along with a bait region, were predicted in A2M consensus protein. A total of 35 splice sites were identified in T. ilisha A2M consensus transcript, with highest frequency (55.7%) of GT-AG splice sites, as compared to that of Homo sapiens. Liver showed longest isoform (X1) consisting of all domains, while smallest (X10) was found in ovary with one Receptor domain. Present study predicted five putative markers (I-212, I-269, A-472, S-567 and Y-906) for EUS disease resistance in A2M protein, which were present in MG2 domains (A2M_N and A2M_N2), by comparing with that of resistant and susceptible/unknown response species. These markers classified fishes into two groups, resistant and susceptible response. Potential markers, predicted in T. ilisha, placed it to be EUS susceptible category. Putative markers reported in A2M protein may serve as molecular markers in diagnosis of EUS disease resistance/susceptibility in fishes and may have a potential for inclusion in the marker panel for pilot studies. Further, challenging studies are required to confirm the role of particular A2M isoforms and markers identified in immune protection against EUS disease.
Publication Date: 2019-07-25
Journal: PloS one

transferrin trf(10)

Harmonization of units and reference intervals of plasma proteins: state of the art from an External Quality Assessment Scheme.
The need to harmonize laboratory information is particularly intense in the field of plasma proteins, considering their clinical impact and relevance in monitoring diseases. We evaluated units and reference intervals (RIs) utilized by participants of the External Quality Assessment Scheme (EQAS) for plasma proteins of the Centre of Biomedical Research. Moreover, we evaluated inter-laboratory analytical variability from 2001 to 2017. The census of participants' units employed in 2017 showed that for albumin (ALB), ~66% of laboratories still used dL instead of L, and for most other proteins, ~70% still expressed the results in mg/dL. Laboratories primarily used the RIs reported in the packaging inserts of their analytical systems, but for each protein, there was a wide variability of RIs, also among laboratories using the same analytical method. Mean CVs% of the 13 certified proteins in the last five EQA cycles ranged from 3.8% of haptoglobin (HPT) to 12.4% of α1-antitrypsin (AAT) and decreased from 2001 to 2017 for most of them, in particular for C3, ALB, α2-macroglobulin (A2M), HPT and transferrin (TRF). In the face of a reduction in inter-laboratory variability for a lot of proteins, there has not been a substantial change in the units and in the RIs used by the participants. To change old habits is difficult and requires coordination and collaboration. The EQAS plays an important role in the assessment and monitoring of all elements that contribute to the formulation of laboratory information and may be useful to contribute to their harmonization.
Publication Date: 2018-05-12
Journal: Clinical chemistry and laboratory medicine

α-2-macroglobulin a2m(10)

Integrative Multi-Omics Analysis in Calcific Aortic Valve Disease Reveals a Link to the Formation of Amyloid-Like Deposits.
Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in the developed world, yet no pharmacological therapy exists. Here, we hypothesize that the integration of multiple omic data represents an approach towards unveiling novel molecular networks in CAVD. Databases were searched for CAVD omic studies. Differentially expressed molecules from calcified and control samples were retrieved, identifying 32 micro RNAs (miRNA), 596 mRNAs and 80 proteins. Over-representation pathway analysis revealed platelet degranulation and complement/coagulation cascade as dysregulated pathways. Multi-omics integration of overlapping proteome/transcriptome molecules, with the miRNAs, identified a CAVD protein-protein interaction network containing seven seed genes (apolipoprotein A1 (APOA1), hemoglobin subunit β (HBB), transferrin (TF), α-2-macroglobulin (A2M), transforming growth factor β-induced protein (TGFBI), serpin family A member 1 (SERPINA1), lipopolysaccharide binding protein (LBP), inter-α-trypsin inhibitor heavy chain 3 (ITIH3) and immunoglobulin κ constant (IGKC)), four input miRNAs (miR-335-5p, miR-3663-3p, miR-21-5p, miR-93-5p) and two connector genes (amyloid beta precursor protein (APP) and transthyretin (TTR)). In a metabolite-gene-disease network, Alzheimer's disease exhibited the highest degree of betweenness. To further strengthen the associations based on the multi-omics approach, we validated the presence of APP and TTR in calcified valves from CAVD patients by immunohistochemistry. Our study suggests a novel molecular CAVD network potentially linked to the formation of amyloid-like structures. Further investigations on the associated mechanisms and therapeutic potential of targeting amyloid-like deposits in CAVD may offer significant health benefits.
Publication Date: 2020-09-30
Journal: Cells

95 ci(9)

Inflammatory and metalloproteinases profiles predict three-month poor outcomes in ischemic stroke treated with thrombolysis.
Inflammatory mediators and metalloproteinases are altered in acute ischemic stroke (AIS) and play a detrimental effect on clinical severity and hemorrhagic transformation of the ischemic brain lesion. Using data from the Italian multicenter observational MAGIC (MArker bioloGici nell'Ictus Cerebrale) Study, we evaluated the effect of inflammatory and metalloproteinases profiles on three-month functional outcome, hemorrhagic transformation and mortality in 327 patients with AIS treated with intravenous thrombolys in according to SITS-MOST (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy) criteria. Circulating biomarkers were assessed at baseline and 24 h after thrombolysis. Adjusting for age, sex, baseline glycemia and National Institute of Health Stroke Scale, history of atrial fibrillation or congestive heart failure, and of inflammatory diseases or infections, baseline alpha-2macroglobulin (A2M), baseline serum amyloid protein (SAP) and pre-post tissue-plasminogen activator (tPA) variations (Δ) of metalloproteinase 9, remained significantly and independently associated with three-month death [OR (95% CI):A2M:2.99 (1.19-7.53); SAP:5.46 (1.64-18.74); Δmetalloproteinase 9:1.60 (1.12-2.27)]. The addition of baseline A2M and Δmetalloproteinase 9 or baseline SAP and Δmetalloproteinase 9 (model-2 or model-3) to clinical variables (model-1) significantly improved the area under curve for prediction of death [model-2 with A2M: p = 0.0205; model-3 with SAP: p = 0.001]. In conclusion, among AIS patients treated with thrombolysis, circulating A2M, SAP and Δmetalloproteinase 9 are independent markers of poor outcome. These results may prompt controlled clinical research about agents antagonizing their effect.
Publication Date: 2017-03-08
Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

α2-macroglobulin a2m(9)

Early supplemental α2-macroglobulin attenuates cartilage and bone damage by inhibiting inflammation in collagen II-induced arthritis model.
To determine if early supplemental intra-articular α2-macroglobulin (A2M) has a chondroprotective effect in a collagen II-induced arthritis (CIA) mice model. DBA/1 mice were randomized into four groups (n = 15/group): (a) CIA + 1.2 μg of A2M; (b) CIA + 0.8 μg of A2M; (c) CIA + 0.4 μg of A2M; (d) vehicle + phosphate-buffered saline (PBS). A2M was injected into right ankles and PBS was injected into the left ankles simultaneously as internal control at days 36, 43 and 50. The CIA inflammation clinical score and ankle thickness were recorded every other day starting on day 21 until sacrifice. Changes in inflammation were monitored by in vivo fluorescence molecular tomography (FMT). Inflammation, cartilage and bone damage were assessed with X-ray, histology and immunohistochemistry. Cartilage and inflammation-related gene expression was quantified by real-time polymerase chain reaction (PCR). All mice showed ankle inflammation on day 33. After day 43, lower clinical scores, ankle thickness and Sharp/van der Heijde method scores in A2M-treated ankles compared with PBS-treated ankles. FMT data indicated that the inflammation markers MMPSense and ProSense were significantly elevated in the PBS-treated ankles than A2M-treated ankles. Histology and X-ray analyses indicated that A2M administration resulted in lower levels of inflammatory infiltration and synovial hyperplasia, as well as more typical cartilage and bone organization with increased COL II and Aggrecan staining when compared with PBS-treated ankles. In addition, real-time PCR showed that,matrix metalloproteinase-3, -9, -13, COL X and Runx2 were significantly less expressed in A2M-treated groups than PBS-treated animals. Early supplemental intra-articular A2M exerts an anti-inflammatory effect and attenuates cartilage and bone damage in a CIA model.
Publication Date: 2019-01-05
Journal: International journal of rheumatic diseases

g2m g3m(9)

Human Gm, Km, and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism.
Human immunoglobulin allotypes are antigenic determinants (or "markers") determined serologically, classically by hemagglutination inhibition, on the human immunoglobulin (IG) heavy and light chains. The allotypes have been identified on the gamma1, gamma2, gamma3, and alpha2 heavy chains (they are designated as G1m, G2m, G3m, and A2m allotypes, respectively), and on the kappa light chain (Km allotypes). Gm-Am allotypes are inherited in fixed combinations, or Gm-Am haplotypes, owing to the linkage of the human IGHC genes (IGHG3, IGHG1, IGHA1, IGHG2, IGHG4, IGHE, and IGHA2 from 5' to 3' in the IGH locus on chromosome 14). Gm and Am allotypes have been one of the most powerful tools in population genetics and very instrumental in molecular characterization of the human IGHC genes (gene conversion, copy number variation, gene order). They represent a major system for understanding immunogenicity of the polymorphic IG chains, in relation with amino acid and conformational changes. The correlation between G3m allotypes and amino acid changes has been possible with the sequencing of many alleles of the IGHG3 gene, from individuals from different populations and with known allotypes. In this chapter, we integrate genetics and sequence data and provide an updated overview of the Gm-Am haplotypes and Km allotypes. We propose, for the first time, a complete elucidation of the G3m allotypes, illustrated by the "IMGT G3m allele butterfly" concept that allows a graphical representation of the G3m alleles (variants of a gene expressing a given set of allotypes). Knowledge of allotypes is important in antibody engineering and humanization of monoclonal antibodies to improve immunotherapy.
Publication Date: 2012-06-06
Journal: Methods in molecular biology (Clifton, N.J.)

a2m deletion(9)

Functional analysis of plasma alpha(2)-macroglobulin from Alzheimer's disease patients with the A2M intronic deletion.
alpha(2)-Macroglobulin (alpha(2)M) is an abundant plasma/extracellular space protein implicated in clearance of amyloid beta (Abeta), a key constituent of Alzheimer's disease (AD) plaques. alpha(2)M also regulates proteinase and growth factor activities. In recent years, there have been >30 genetic studies debating the controversial role of a five-base-pair intronic deletion in the A2M gene in late-onset AD. However, little is known about potential effects of the deletion upon alpha(2)M function. In this study, we examined the subunit and conformational structure of alpha(2)M in AD plasma samples, and its capacity to bind trypsin, transforming growth factor-beta1, and Abeta. Plasma from patients homozygous for the deletion (DD) showed normal alpha(2)M subunit size, conformation, and proteinase inhibitory activity. Interestingly, plasma alpha(2)M from two DD patients showed markedly increased TGF-beta1 binding. Moreover, methylamine-treated DD plasma samples showed modest, but significant, elevations in Abeta binding to alpha(2)M* compared with samples from patients lacking the deletion. These observations suggest a possible functional basis by which the A2M deletion may influence multifactorial AD pathogenesis.
Publication Date: 2003-12-18
Journal: Neurobiology of disease

1 allotype(8)

Molecular genetics in IgA nephropathy.
Evidence from both genotypic and phenotypic perspectives is considered that patients may be genetically predisposed to IgA nephropathy (IgAN) or Henoch-Schönlein purpura (HSP) or that a factor(s) might exclusively contribute to their progression to chronic renal failure. In contrast to most other renal diseases, both IgAN and HSP are uncommon in blacks; this is unexplained but is not due to their low frequency of the A2m(1) allotype. The association of these diseases or their progression with a variety of abnormalities of IgA immunobiology in patients and their families has not been linked to any genotype; similarly, no HLA antigen has been positively or negatively associated in any consistent way. Although complement factor 3 universally accompanies IgA glomerular deposition, complement pathway abnormalities are only sporadically reported with either IgA deposition or disease progression. Whether angiotensin-related polymorphism including the converting enzyme alleles have a specific predictable role, particularly in the progression of renal failure in IgAN, remains problematic. The promising possibility that a structural defect in IgA1 due to an as yet unidentified genetic defect accounts for the deposition of IgA is considered in some detail. Nevertheless, the genetic mechanism(s) of progressive renal failure, whether exclusive to IgAN or to glomerular diseases generally, is of paramount importance.
Publication Date: 2001-06-16
Journal: Nephron

ceruloplasmin cpl(8)

Immunological profiles in workers occupationally exposed to inorganic mercury.
Forty-one male mercury-exposed workers were examined for the serum concentration levels of immunoglobulins (IgG, IgA, IgM), alpha-1-antitrypsin (A1AT), alpha-2-macroglobulin (A2M), ceruloplasmin (CPL) and orosomucoid (ORO). In the period preceding this investigation the mercury concentrations in workplace air ranged from 0.106 to 0.783 mg.m-3, the range of urinary mercury concentrations was from 0.029 to 0.545 mg.1(-1). All but two (IgG and A1AT) of the immune parameters tested were at the levels that were evidently higher than those found in a control group of 55 workers matched by age who lived in a relatively clean area. The percentage of individuals with no value out of the range of normal physiological limits was in the controls almost 80%, in the exposed 36.6% only. These findings confirm the literature data which show that an inhalation exposure to inorganic mercury may evidently have a stimulating effect on some serum proteins in humans.
Publication Date: 1990-01-01
Journal: Journal of hygiene, epidemiology, microbiology, and immunology

2 allotype(8)

Isotypic and allotypic analysis with monoclonal antibodies and jacalin of 309 serum monoclonal IgA from French and Japanese myeloma patients.
The subclass and allotype distribution of serum monoclonal IgA from myeloma patients was determined by ELISA with monoclonal antibodies in two French and one Japanese laboratory. In addition, the French sera were tested for their reactivity with the lectin jacalin. No significant difference in the isotypic distribution between French and Japanese series could be demonstrated: kappa/lambda ratios were 0.99 and 1.17, and the IgA1 subclass accounted for 93.9% and 91% of cases in the French and Japanese studies, respectively. Five out of 7 myeloma IgA2 from Japan and only one of the 12 IgA2 from France belonged to the A2m(2) allotype (P less than 0.01). All 219 IgA1 tested reacted with jacalin by immunoelectrophoresis (IEP), although with variable intensities. Among IgA2 proteins, only one (of the A2m(1) allotype) yielded a precipitating line with jacalin by IEP. Molecular analysis demonstrated that this protein was an IgA1-IgA2 hybrid bearing most of the A2m(1) epitopes.
Publication Date: 1992-03-01
Journal: Immunology letters

igg iga(8)

Immunoglobulins and some serum proteins in children with altered resistance coming from areas with variously polluted atmosphere.
In four areas with different types of atmospheric pollution 534 children of school age were examined for serum immunoglobulins (IgG, IgA, IgM and IgE), saliva IgA (sIgA), lysozymes (LYS) and acute phase reactants (alfa-l-antitrypsin - A1AT, alfa-2-macroglobulin -A2M, ceruloplasmin -CPL, transferrin - TRF). The children were divided into two groups: those with altered resistance (AR) comprising allergoses of all types and recurrent or persistent infections and those without the above health problems, i.e. healthy (H). There were more children with AR in areas with higher atmospheric pollution than in control areas. The frequency of AR was higher among boys than among girls. In the control area BN, a number of parameters in the AR group differed significantly from those in the H group. In areas with substantial atmospheric pollution these differences were generally less pronounced. Significant differences were found between the control and polluted areas in many indicators. In the area KO characterized by an intermediate degree of industrial pollution the means of the tested parameters were habitually elevated, whereas in the heavily polluted areas they were decreased. The most sensitive tests for evaluating differences between the areas were the levels of A1AT, LYS, and IgE, while the variations of sIgA, sLYS and CPL were less pronounced.
Publication Date: 1990-01-01
Journal: Journal of hygiene, epidemiology, microbiology, and immunology

apoe a2m(6)

Silencing HIF-1α aggravates non-alcoholic fatty liver disease in vitro through inhibiting PPAR-α/ANGPTL4 singling pathway.
Non-alcoholic fatty liver disease (NAFLD) is an aberrant lipid metabolism disease. Hypoxia inducible factor-1 (HIF-1α) is a transcription factor which plays an important part in adapting lower oxygen condition. Here, we aimed to clarify the relationship between HIF-1α and NAFLD. HepG2 cells was stimulated by oleic acid (OA) and palmitic acid (PA) to establish in vitro model of NAFLD. The expression of lipid metabolism-related genes, the binding of PPARα to HIF-1α promoter, the lipid deposition, and oxidative stress were detected by qRT-PCR, western blot, Chip assay, Oil Red O staining and ELISA assays, respectively. HIF-1α silence promoted lipid accumulation in NAFLD cells, accompanying by the significantly increased contents of TG (triglyceride) and ApoB (apolipoprotein B). In HepG2 cells treated with OA/PA, the expression of lipid metabolism-related genes and proteins, including APOE, A2m, TNFRSF11B, LDLr, and SREBP2, and the intracellular lipid deposition were up-regulated and further aggravated after silencing HIF-1α. In addition, the loss of HIF-1α could remarkably elevate MDA contents while inhibit the activities of beneficial antioxidant enzymes SOD and GSH-Px to activate oxidative stress, and promote the secretion of pro-inflammatory IL-6 and TNF-α to aggravate inflammation in NDFLD cells. PPARα positively bound to HIF-1α promoter. The silence of PPARα aggravated lipid deposition under normal or hypoxic environment in NAFLD cells. In addition, PPAR-α silence could decrease the expression of HIF-1α and ANGPTL4 in NAFLD cell model; moreover, the expression of APOE, A2m and TNFRSF11B and the production of TG and MDA were increased by PPAR-α suppression. HIF-1α plays a crucial role in the regulation of lipid metabolism through activating PPAR-α/ANGPTL4 signaling pathway in NAFLD.
Publication Date: 2020-12-05
Journal: Gastroenterologia y hepatologia

haptoglobin hp(6)

The Acute Phase Proteins Reaction in Children Suffering from Pseudocroup.
The aim of the study was to evaluate the inflammatory reaction in children with pseudocroup and compare it with other laryngological diseases according to the available literature data. The study group included 51 children hospitalized because of pseudocroup. The measurements of the acute phase proteins (APP), such as C-reactive protein (CRP), alpha-1-antitrypsin (AT), alpha-1-antichymotrypsin (ACT), alpha-1-acid glycoprotein (AGP), ceruloplasmin (Cp), transferrin (Tf), alpha-2-macroglobulin (A2M), and haptoglobin (Hp) were obtained at 3 time points. The glycosylation profiles of AGP, ACT, and Tf were completed. An increased AGP level was observed in girls. The AGP glycosylation revealed the advantage of the W0 variant over the W1 variant. W1 and W2 were decreased in boys. W3 emerged in boys. The Tf concentration and T4 variant were lower compared to the control group. The A2M level was lower after treatment. The Hp and AT levels were decreased a few weeks later. The ACT glycosylation revealed a decrease of the A4 variant in boys. In conclusion, the inflammatory reaction during pseudocroup was of low intensity. The APP glycosylation suggested a chronic process. In a follow-up investigation, no normalization of the parameters was noted, but signs of persistent inflammation were observed.
Publication Date: 2019-05-03
Journal: Mediators of inflammation

g3m b0(5)

Immunoglobulin allotypes in Jewish populations living in Israel and the United States.
The ongoing interest in the interrelationships of Jewish populations justifies inclusion of the immunoglobulin allotypes in an ethnohistorical analysis. A total of 2,184 serum specimens obtained from unrelated Israeli Jewish and self-identified Milwaukee, WI, Jewish blood donors were classified as Ashkenazi, Sephardi, Asiatic, or North African and tested for G1m (a, x, z, and f), G3m (b0, b1, b3, b5, g), A2m (1 and 2), and Km (1). Selected sera were also tested for G3m (s, t, c3, c5). The estimated maximum likelihood Gm-Am haplotype frequencies were used in a heterogeneity chi-square analysis. The results indicate that there is less heterogeneity within Jewish populations from Europe, Middle East, and North Africa than in corresponding non-Jewish populations representing the same geographical areas. In order to avoid the hazards of a univariate focus, previously published data were incorporated into two additional analyses: 15 populations with information on 16 genetic loci and 24 populations with information on five genetic loci. Both sets of data were analyzed using principal-components and cluster analysis. In both sets of analyses, with the exception of the Yemenite Jews, Jewish populations grouped together. These analyses support the belief that Jewish populations appear to be derived from a common gene pool, and there has been some genetic drift and minimal gene flow with surrounding populations.
Publication Date: 1985-07-01
Journal: American journal of physical anthropology

ps1 ps2(5)

Genomic characterization of Alzheimer's disease and genotype-related phenotypic analysis of biological markers in dementia.
More than 180 genes distributed across the human genome are potentially involved in the pathogenesis of Alzheimer's disease (AD). The AD population shows a higher genetic variation rate than the control population. Significant differences in allelic distribution and frequency exist when AD-related polygenic clusters are compared with other forms of dementia, indicating that the genetic component in neurodegenerative dementia differs from that of other CNS disorders. The characterization of AD genotype-related phenotypic profiles reveals substantial differences in biological markers among AD clusters associated with different genes and/or allelic combinations. AD and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in their major phenotypic and genotypic profiles, as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometric values, cardiovascular function, blood pressure, lipid metabolism, uric acid metabolism, peripheral calcium homeostasis, liver function, alkaline phosphatase, lactate dehydrogenase, red and white blood cells, regional brain atrophy, and brain blood flow velocity. Functional genomic studies incorporating apolipoprotein E (APOE)-related changes in biological markers extended the difference between AD and DVC by up to 57%. Structural genomic studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS, and PRNP, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate in the range of 30-80%, depending upon genes and genetic clusters. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1 to 3%. The main phenotypic differences in AD are genotype dependent, indicating a powerful influence of polygenic factors on the AD phenotypic profile. All these genotypic and phenotypic variations bring about important consequences for the pharmacogenomics of AD.
Publication Date: 2004-12-09
Journal: Pharmacogenomics

c3 c5(4)

Obese dogs with and without obesity-related metabolic dysfunction - a proteomic approach.
Approximately 20 % of obese dogs have metabolic disturbances similar to those observed in human metabolic syndrome, a condition known as obesity-related metabolic dysfunction. This condition is associated with insulin resistance and decreased circulating adiponectin concentrations, but clinical consequences have not been reported. In order to define better the metabolic changes associated with obesity-related metabolic dysfunction (ORMD), we compared the plasma proteomes of obese dogs with and without ORMD. A proteomic analysis was conducted on plasma samples from 8 obese male dogs, 4 with ORMD and 4 without ORMD. The samples were first treated for the depletion of high-abundance proteins and subsequently analysed by using 2-DE DIGE methodology. Using mass spectrometry, 12 proteins were identified: albumin, apoliprotein A-I, C2, C3, C5, C4BPA, A2M, Uncharacterised protein (Fragment) OS = Canis familiaris, fibrinogen, IGJ, ITIH2, and glutathione peroxidase. In obese dogs with ORMD, the relative amounts of ten proteins (albumin, apoliprotein A-I, C2, C3, C5, C4BPA, A2M, Uncharacterised protein (Fragment) OS = Canis familiaris, fibrinogen, and ITIH2) were increased and two proteins (IGJ and glutathione peroxidase) were decreased, compared with obese dogs without ORMD. Specific assays were then used to confirm differences in serum albumin, apoliprotein A-I and glutathione peroxidase in a separate group of 20 overweight dogs, 8 with ORMD and 12 without ORMD. The current study provides evidence that, in obese dogs with ORMD, there are changes in expression of proteins involved in lipid metabolism, immune response, and antioxidant status. The clinical significance of these changes remains to be defined.
Publication Date: 2016-09-21
Journal: BMC veterinary research

e g(4)

The anti-tumorigenic activity of A2M-A lesson from the naked mole-rat.
Cancer resistance is a major cause for longevity of the naked mole-rat. Recent liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M) and cell adhesion molecules, which contribute to the naked mole-rat's cancer resistance. Notably, A2M is known to dramatically decrease with age in humans. We hypothesize that this might facilitate tumour development. Here we found that A2M modulates tumour cell adhesion, migration and growth by inhibition of tumour promoting signalling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR-21, in vitro and in tumour xenografts. A2M increases the expression of CD29 and CD44 but did not evoke EMT. Transcriptome analysis of A2M-treated tumour cells, xenografts and mouse liver demonstrated a multifaceted regulation of tumour promoting signalling pathways indicating a less tumorigenic environment mediated by A2M. By virtue of these multiple actions the naturally occurring A2M has strong potential as a novel therapeutic agent.
Publication Date: 2017-12-28
Journal: PloS one

g2m n(4)

Association between leprosy and immunoglobulin allotypes: Gm-A2m and Km frequencies in Vietnamese.
The relationship between immunoglobulin allotypes and leprosy was studied in 91 unrelated patients and 100 healthy controls from Vietnam. Twenty Vietnamese patients with tuberculosis were also typed for the Gm, A2m and Km allotypes. The results were compared with those from the healthy controls. No significant association was found for the allotypes G1m(z,a,x,f) G2m(n), G3m(g,b), A2m(1,2) and Km(1,3) between the two groups of patients and the controls. Heterogeneity in the distribution of G2m(n), G3m(b), A2m(2) and Km(3) was found when 60 polar-lepromatous (LL) patients and 27 borderline-tuberculoid (BT) patients were separated out of the 91 leprosy patients. In the LL patients there appeared to be a significantly higher frequency of G2m(n), G3m(b) and A2m(2) in comparison with the BT patients (P less than 0.05). A significantly lower frequency of Km(3) was found in the LL patients in comparison with the healthy control group (P less than 0.05). The frequencies of the Gm-A2m haplotypes and of the occurrence of the Km(1) and Km(3) in the Vietnamese population were calculated on the basis of the results in the 100 samples of healthy controls. The main haplotype is Gmaf;n;b (frequency 0.676), occurring with A2m1 (0.200), as well as with A2m2 (0.476).
Publication Date: 1984-06-01
Journal: Journal of immunogenetics

albumin alb(4)

Multiple-Cycle Polymeric Extracellular Vesicle Precipitation and Its Evaluation by Targeted Mass Spectrometry.
The multiple roles of extracellular vesicles (EVs) in pathogenesis have received much attention, as they are valuable as diagnostic and prognostic biomarkers. We employed polymeric EV precipitation to isolate EVs from clinical specimens to overcome the limitations of ultracentrifugation (UC), such as low protein yields, a large volume of specimens used, and time requirements. Multiple-cycle polymeric EV precipitation was applied to enhance the purity of the EV fractions with a small sample volume. Then, the purity was assessed using a multiple reaction monitoring (MRM) panel consisting of alpha-2-macroglobulin (A2M), thrombospondin 1 (THBS 1), galectin 3 binding protein (LGALS3BP), and serum albumin (ALB). For purity evaluation, the EV fractions isolated from blood specimens were subjected to shotgun proteomics and MRM-based targeted proteomics analyses. We demonstrate that the modified method is an easy and convenient method compared with UC. In the shotgun proteomics analysis, the proteome profile of EV fraction contains 89% EV-related proteins by matching with the EVpedia database. In conclusion, we suggest that multiple-cycle polymeric EV precipitation is not only a more effective method for EV isolation for further proteomics-based experiments, but may also be useful for further clinical applications due to the higher EV yield and low sample requirements.
Publication Date: 2021-05-01
Journal: International journal of molecular sciences

transthyretin ttr(3)

Differential protein expression in patients with urosepsis.
Urosepsis in adults comprises approximately 25% of all sepsis cases, and is due to complicated urinary tract infections in most cases. However, its mechanism is not fully clarified. Urosepsis is a very complicated disease with no effective strategy for early diagnosis and treatment. This study aimed to identify possible target-related proteins involved in urosepsis using proteomics and establish possible networks using bioinformatics. Fifty patients admitted to the Urology Unit of Lanzhou General PLA (Lanzhou, China), from October 2012 to October 2015, were enrolled in this study. The patients were further divided into shock and matched-pair non-shock groups. 2-DE technique, mass spectrometry and database search were used to detect differentially expressed proteins in serum from the two groups. Six proteins were found at higher levels in the shock group compared with non-shock individuals, including serum amyloid A-1 protein (SAA1), apolipoprotein L1 (APOL1), ceruloplasmin (CP), haptoglobin (HP), antithrombin-III (SERPINC1) and prothrombin (F2), while three proteins showed lower levels, including serotransferrin (TF), transthyretin (TTR) and alpha-2-macroglobulin (A2M). Nine proteins were differentially expressed between uroseptic patients (non-shock groups) and severe uroseptic patients (shock groups), compared with non-shock groups, serum SAA1, APOL1,CP, HP, SERPINC1and F2 at higher levels, while TF, TTR and A2M at lower levels in shock groups.these proteins were mainly involved in platelet activation, signaling and aggregation, acute phase protein pathway, lipid homeostasis, and iron ion transport, deserve further research as potential candidates for early diagnosis and treatment. (The conclusion seems too simple and vague, please re-write it. You may focus at what proteins have been expressed and introduce more detail about its significance.).
Publication Date: 2018-10-21
Journal: Chinese journal of traumatology = Zhonghua chuang shang za zhi

a2m protein(3)

Differentially expressed serum proteins associated with calcium regulation and hypocalcemia in dairy cows.
Hypocalcemia is an important metabolic disease of dairy cows during the transition period, although the effect of hypocalcemia on biological function in dairy cows remains unknown. In this study, proteomic, mass spectrum, bioinformatics and western blotting were employed to identify differentially expressed proteins related to serum Ca concentration. Serum samples from dairy cows were collected at three time points: 3rd days before calving (day -3), the day of calving (day 0), and 3rd days after calving (day +3). According to the Ca concentration on day 0, a total of 27 dairy cows were assigned to one of three groups (clinical, subclinical, and healthy). Samples collected on day -3 were used for discovery of differentially expressed proteins, which were separated and identified via proteomic analysis and mass spectrometry. Bioinformatics analysis was performed to determine the function of the identified proteins (gene ontology and pathway analysis). The differentially expressed proteins were verified by western blot analysis. There were 57 differential spots separated and eight different proteins were identified. Vitamin D-binding protein precursor (group-specific component, GC), alpha-2-macroglobulin (A2M) protein, and apolipoprotein A-IV were related to hypocalcemia by bioinformatics analysis. Due to its specific expression (up-regulated in clinical hypocalcemia and down-regulated in subclinical hypocalcemia), A2M was selected for validation. The results were consistent with those of proteomic analysis. A2M was as an early detection index for distinguishing clinical and subclinical hypocalcemia. The possible pathogenesis of clinical hypocalcemia caused by GC and apolipoprotein A-IV was speculated. The down-regulated expression of GC was a probable cause of the decrease in calcium concentration.
Publication Date: 2016-11-04
Journal: Asian-Australasian journal of animal sciences

transferrin tf(3)

Effects of ultrasound therapy on the synovial fluid proteome in a rabbit surgery-induced model of knee osteoarthritis.
Ultrasound (US) therapy may improve osteoarthritis symptoms. We investigated the effects of US on the synovial fluid (SF) proteome in a rabbit knee osteoarthritis (KOA) model to explore its therapeutic mechanisms. Sixteen healthy 6-month-old New Zealand white rabbits (eight male, eight female), weighing 2.5-3.0 kg, were randomly divided into groups A and B with eight rabbits per group. Both groups were subjected to right anterior cruciate ligament transaction. Six weeks after surgery, we treated the operated knee joint of group A rabbits with US and of group B rabbits with sham US for 2 weeks. The proteomes of knee joint SF from groups A and B rabbits were then analyzed using a label-free mass spectrometry (MS) quantification method. We identified 19 protein sequences annotated by 361 Gene Ontology (GO) items. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database of rabbit protein sequences, we then annotated the KO numbers of homologous/similar proteins to 32 relevant KEGG pathways. We extracted 10 significantly differentially expressed proteins among the 32 relevant KEGG messages/metabolism pathways. The proteins whose levels were decreased were apolipoprotein A-I (AopA-1), transferrin (TF), carboxypeptidase B2 (CBP2), arylesterase/paraoxonase (PON), fibrinogen alpha chain, and alpha-2-macroglobulin (A2M). The proteins whose levels were increased were molecular chaperone HtpG/heat shock proteins (htpG, HSP90A), decorin (DCN), pyruvate kinase (PK, pyk), and fatty acid-binding protein 4/adipocyte (FABP4, aP2). US therapy can alter protein levels in SF, which can decrease AopA-1, TF, CBP2, PON, fibrinogen alpha chain and A2M protein levels, and increase HtpG/HSP90A, DCN, PK/PKY, and FABP4/aP2 protein levels in SF of KOA, suggesting that the therapeutic mechanisms of US therapy on KOA may occur through changes in the SF proteome.
Publication Date: 2019-02-24
Journal: Biomedical engineering online

alpha-1 antitrypsin(3)

Peripheral blood gene expression of acute phase proteins in people with first episode psychosis.
There is a growing interest in the association between schizophrenia and the activation of inflammatory system with signs of acute phase (AP) response. Majority of such studies had focused on C-reactive protein (CRP). The aims of the present study were (i) to examine the gene expression profiles of other acute phase proteins (APP), namely haptoglobin (HP), alpha-1 antitrypsin (A1T), and alpha-2 macroglobulin (A2M) in patients with first episode psychosis (FEP) over a period of three months and (ii) to explore the association between APP levels and severity of symptoms. In this study, HP, A1T and A2M gene expression levels from whole blood were measured at recruitment, 1- and 3-month follow-up visits using quantitative PCR (qPCR) in 43 patients with FEP and in 57 healthy controls. Diagnoses was ascertained on the Structured Clinical Interview for DSM-IV-TR. Severity of symptoms in patients was assessed on the Positive and Negative Syndrome Scale (PANSS) and a previously validated 5-factor PANSS structure was applied in the subsequent analyses. The FEP sample comprised of 28 (65.1%) individuals with schizophrenia, 12 (27.9%) with schizophreniform disorder and 3 (7%) with schizoaffective disorder. HP gene expression level was noted to be significantly higher in patients than controls at all three time points: recruitment (P=0.049), 1-month follow up (P=0.002) and 3-month follow up (P=0.005). PANSS positive, depression, and excitement symptom factors showed significant associations with HP (P=0.002), A1T (P=0.016) and A2M (P=0.034), respectively. These findings remained significant after controlling for age, gender, smoking status and accumulated chlorpromazine dosage. The current study provides information on HP, A1T and A2M gene expression profiles in FEP patients and their associations with psychopathology. This provides support for the hypothesis that inflammation is related to schizophrenia and further encourages studies on immune-inflammatory markers to understand the relationship between inflammation and schizophrenia.
Publication Date: 2017-06-20
Journal: Brain, behavior, and immunity

a2m r-pa-pu(2)

An altered state of a specific en regulatory element induced in a maize tiller.
There are numerous states of the regulatory element, Enhancer (En). With specific receptor alleles, such as a2m(r-pa-pu) or a2m(r), specific mutability patterns are expressed. One specific derivative En allele, En-v (En-variable), was originally identified with a coarse pattern of mutability with the a2m(r-pa-pu) allele and giving progeny with varied En expression (standard to reduced within an ear progeny). Derivatives of En-v were subsequently found on numerous occasions to give only a very reduced expression (fewer mutant spots) with the a2m(r-pa-pu) allele in the ears derived from the main stalk of the corn plant. When a comparison is made of the effect of this changed En-v state between tiller ears and main stalk ears of the same plant, the tiller ears show an increased level of En-v expression (coarse pattern), while the main-stalk ears continue to show the very reduced level of En-v expression (low frequency of very late variegation). This increased level of mutability of the tiller ears is maintained when transmitted through the main-stalk ear in the subsequent generation. These results indicate that heritable alterations of controlling elements can be produced by endogenous environmental factors present during normal plant development.
Publication Date: 1978-12-01
Journal: Genetics

mg l(2)

The Mutual Relationship Between Peritonitis and Peritoneal Transport.
♦ Preservation of the peritoneum is required for long-term peritoneal dialysis (PD). We investigated the effect of multiple peritonitis episodes on peritoneal transport. ♦ Prospectively collected data from 479 incident PD patients treated between 1990 and 2010 were analyzed, using strict inclusion criteria: follow-up of at least 3 years with the availability of a Standard Peritoneal Permeability Analysis (SPA) in the first year after start of PD and within the third year of PD, without peritonitis preceding the first SPA. For the purpose of the study, we only included patients who remained peritonitis-free (n = 28) or who experienced 3 or more peritonitis episodes (n = 16). ♦ At baseline the groups were similar with regard to small solute and fluid transport. However, the frequent peritonitis group had lower peritoneal protein clearances compared to the no peritonitis group, resulting in lower dialysate concentrations of proteins: albumin 196.5 mg/L vs 372.5 mg/L, IgG 36.4 mg/L vs 65.0 mg/L, and α-2-macroglobulin (A2M) 1.9 mg/L vs 3.6 mg/L, p <0.01. No differences in serum concentrations were present. A comparison between the transport slopes over time in both groups showed a positive time trend of mass transfer area coefficient (MTAC) creatinine (p = 0.03) and glucose absorption (p = 0.09) and a negative trend of transcapillary ultrafiltration (p = 0.06), when compared to the no peritonitis group. Frequent peritonitis did not affect free water transport. ♦ Slow initial peritoneal transport rates of serum proteins result in lower dialysate concentrations, and likely a lower opsonic activity, which is a risk factor for peritonitis. Patients with frequent peritonitis show an increase in small solute transport and a concomitant decrease of ultrafiltration. In long-term peritonitis-free PD patients, small solute transport decreased, while ultrafiltration increased. This suggests that frequent peritonitis leads to an increase of the vascular peritoneal surface area without all the structural membrane alterations that may develop after long-term PD.
Publication Date: 2014-11-15
Journal: Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis


Meta-analyses of 8 polymorphisms associated with the risk of the Alzheimer's disease.
The aim of this study was to evaluate the combined contribution of 8 polymorphisms to the risk of Alzheimer's disease (AD). Through a comprehensive literature search for genetic variants involved in the AD association study, we harvested a total of 6 genes (8 polymorphisms) for the current meta-analyses. These genes consisted of A2M (5bp I/D and V1000I), ABCA2 (rs908832), CHAT (1882G >A, 2384G >A), COMT (Val158Met), HTR6 (267C >T) and LPL (Ser447Ter). A total of 33 studies among 9,453 cases and 10,833 controls were retrieved for the meta-analyses of 8 genetic variants. It was showed that A2M V1000I (odd ratio (OR) = 1.26, 95% confidence interval (CI) = 1.07-1.49, P = 0.007), rs908832 allele of ABCA2 (OR = 1.55, 95% CI = 1.12-2.16, P = 0.009), 2384G >A of CHAT (OR = 1.22, 95% CI = 1.00-1.49, P = 0.05) and Ser447Ter of LPL in the Northern-American population (OR = 0.56, 95% CI = 0.35-0.91, P = 0.02) were significantly associated with the risk of AD. No association was found between the rest of the 5 polymorphisms and the risk of AD. Our results showed that A2M V1000I polymorphism in German, Korean, Chinese, Spanish, Italian and Polish populations, rs90883 of ABCA2 gene in French, American, Swiss, Greek and Japanese populations, 2384G >A of CHAT gene in British and Korean populations and LPL Ser447Ter in the Northern-American population were associated with the risk of AD.
Publication Date: 2013-09-17
Journal: PloS one


Association of polymorphisms in the LRP1 and A2M genes with Alzheimer's disease in the northern Chinese Han population.
Low-density lipoprotein receptor-related protein1 (LRP1) and alpha-2-macroglobulin (A2M) are candidate genes for sporadic Alzheimer's disease (SAD). It is not clear whether the LRP1 exon 3 and A2M exon 24 polymorphisms are associated with SAD. In the present study, we used direct sequencing to genotype the LRP1 C766T (rs1799986) polymorphism in exon 3 and the A2M I1000V (rs669) polymorphism in exon 24 in 364 patients with SAD and 291 healthy control subjects from the Northern Chinese Han population. The distributions of LRP1 genotypes (chi-squared [χ(2)]=7.25, degrees of freedom [d.f.]=2, p=0.027) and alleles (χ(2)=8.154, d.f.=1, p=0.004) were significantly different between patients and controls who were apolipoprotein E (APOE) ε4 positive. The T allele and TT+TC genotype were associated with a reduced risk of developing SAD (T allele: odds ratio [OR]=0.541, 95% confidence interval [CI]=0.368-0.859, p=0.005; TT+TC genotype: OR=0.613, 95% CI=0.315-0.725, p=0.012). There was no statistically significant difference in allele and genotype frequencies between patients with SAD and control subjects for the A2M I1000V polymorphism, even after stratification by age of onset, gender, and APOE ε4 status. We found an interaction between LRP1 and APOE genotypes (p=0.001), but no interaction between LRP1 and A2M genotypes. Our results suggest that the T allele of the LRP1 C766T polymorphism is associated with a decreased risk of SAD in APOE ε4 carriers from the Northern Han Chinese population.
Publication Date: 2012-11-29
Journal: Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia


FoxO1, A2M, and TGF-β1: three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses.
To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues "omics" approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-β1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-β1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful 'hypothesis-free' approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.
Publication Date: 2018-01-06
Journal: Molecular psychiatry


PSA-alpha-2-macroglobulin complex is enzymatically active in the serum of patients with advanced prostate cancer and can degrade circulating peptide hormones.
Prostate cancer cells produce high levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the tumor microenvironment but is presumed to be enzymatically inactive in the blood due to complex formation with serum protease inhibitors α-1-antichymotrypsin and α-2-macroglobulin (A2M). PSA-A2M complexes cannot be measured by standard ELISA assays and are also rapidly cleared from the circulation. Thus the exact magnitude of PSA production by prostate cancer cells is not easily measured. The PSA complexed to A2M is unable to cleave proteins but maintains the ability to cleave small peptide substrates. Thus, in advanced prostate cancer, sufficient PSA-A2M may be in circulation to effect total A2M levels, levels of cytokines bound to A2M and hydrolyze small circulating peptide hormones. Total A2M levels in men with advanced prostate cancer and PSA levels above 1000 ng/mL were measured by ELISA and compared to controls. Additional ELISA assays were used to measure levels of IL-6 and TGF-beta which can bind to A2M. The ability of PSA-A2M complexes to hydrolyze protein and peptide substrates was analyzed ± PSA inhibitor. Enzymatic activity of PSA-A2M in serum of men with high PSA levels was also assayed. Serum A2M levels are inversely correlated with PSA levels in men with advanced prostate cancer. Il-6 Levels are significantly elevated in men with PSA >1000 ng/mL compared to controls with PSA <0.1 ng/mL. PSA-A2M complex in serum of men with PSA levels >1000 ng/mL can hydrolyze small fluorescently labeled peptide substrates but not large proteins that are PSA substrates. PSA can hydrolyze small peptide hormones like PTHrP and osteocalcin. PSA complexed to A2M retains the ability to degrade PTHrP. In advanced prostate cancer with PSA levels >1000 ng/mL, sufficient PSA-A2M is present in circulation to produce enzymatic activity against circulating small peptide hormones. Sufficient PSA is produced in advanced prostate cancer to alter total A2M levels, which can potentially alter levels of a variety of growth factors such as IL-6, TGF-beta, basic FGF, and PDGF. Alterations in levels of these cytokines and proteolytic degradation of small peptide hormones may have profound effect on host-cancer interaction.
Publication Date: 2018-04-17
Journal: The Prostate


Proteomics reveals region-specific hemostatic alterations in response to mechanical ventilation in a preterm lamb model of lung injury.
Preterm infants often require assisted ventilation, however ventilation when applied to the immature lung can initiate ventilator-induced lung injury (VILI). The biotrauma which underscores VILI is largely undefined, and is likely to involve vascular injury responses, including hemostasis. We aimed to use a ventilated, preterm lamb model to: (1) characterize regional alterations in hemostatic mediators within the lung and (2) assess the functional impact of protein alterations on hemostasis by analyzing temporal thrombin generation. Preterm lambs delivered at 124 to 127 days gestation received 90 min of mechanical ventilation (positive end-expiratory pressure = 8 cm H Ventilation was distributed towards the nondependent lung. Significant changes in hemostatic protein abundance, were detected at a two-fold higher rate in the nondependent lung when compared with the gravity-dependent lung. Seven proteins were uniquely altered in non-dependent lung (SERPINA1, MYL12A, RAP1B, RHOA, ITGB1, A2M, GNAI2), compared with a single proteins in gravity-dependent lung (COL1A2). Four proteins were altered in both regions (VTN, FGG, FGA, and ACTB). Tissue protein alterations were mirrored by plasma hypocoagulability at 90-minutes of ventilation. We observed regionally specific, hemostatic alterations within the preterm lung together with disturbed fibrinolysis following a short period of mechanical ventilation.
Publication Date: 2020-10-20
Journal: Thrombosis research