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Cells Sep 2022Alpha-2-macroglobulin (A2M) is a protease inhibitor that regulates extracellular matrix (ECM) stability and turnover. Here, we show that A2M is expressed by endothelial...
Alpha-2-macroglobulin (A2M) is a protease inhibitor that regulates extracellular matrix (ECM) stability and turnover. Here, we show that A2M is expressed by endothelial cells (ECs) from human eye choroid. We demonstrate that retinal pigment epithelium (RPE)-conditioned medium induces A2M expression specifically in ECs. Experiments using chemical inhibitors, blocking antibodies, and recombinant proteins revealed a key role of VEGF-A in RPE-mediated A2M induction in ECs. Furthermore, incubation of ECs with RPE-conditioned medium reduces matrix metalloproteinase-2 gelatinase activity of culture supernatants, which is partially restored after A2M knockdown in ECs. We propose that dysfunctional RPE or choroidal blood vessels, as observed in retinal diseases such as age-related macular degeneration, may disrupt the crosstalk mechanism we describe here leading to alterations in the homeostasis of choroidal ECM, Bruch's membrane and visual function.
Topics: Antibodies, Blocking; Culture Media, Conditioned; Endothelial Cells; Female; Gelatinases; Humans; Matrix Metalloproteinase 2; Pregnancy; Pregnancy-Associated alpha 2-Macroglobulins; Protease Inhibitors; Recombinant Proteins; Retinal Pigment Epithelium; Transcription Factors; Vascular Endothelial Growth Factor A
PubMed: 36230937
DOI: 10.3390/cells11192975 -
Neural Regeneration Research Apr 2023Protein quality control involves many processes that jointly act to regulate the expression, localization, turnover, and degradation of proteins, and has been... (Review)
Review
Protein quality control involves many processes that jointly act to regulate the expression, localization, turnover, and degradation of proteins, and has been highlighted in recent studies as critical to the differentiation of stem cells during regeneration. The roles of constitutively secreted extracellular chaperones in neuronal injury and disease are poorly understood. Extracellular chaperones are multifunctional proteins expressed by many cell types, including those of the nervous system, known to facilitate protein quality control processes. These molecules exert pleiotropic effects and have been implicated as playing important protective roles in a variety of stress conditions, including tissue damage, infections, and local tissue inflammation. This article aims to provide a critical review of what is currently known about the functions of extracellular chaperones in neuronal repair and regeneration and highlight future directions for this important research area. We review what is known of four constitutively secreted extracellular chaperones directly implicated in processes of neuronal damage and repair, including transthyretin, clusterin, α2-macroglobulin, and neuroserpin, and propose that investigation into the effects of these and other extracellular chaperones on neuronal repair and regeneration has the potential to yield valuable new therapies.
PubMed: 36204835
DOI: 10.4103/1673-5374.353483 -
Frontiers in Medicine 2022Although Fanconi syndrome (FS) induced by valproate (VPA) has occasionally been reported, the detailed clinical features of the disease remain unclear. The aim of this...
OBJECTIVE
Although Fanconi syndrome (FS) induced by valproate (VPA) has occasionally been reported, the detailed clinical features of the disease remain unclear. The aim of this study was to elucidate the clinical features of patients with VPA-induced FS.
METHODS
We searched Chinese and English databases for all original studies, clinical reports, and case reports on VPA-induced FS published before March 2022.
RESULTS
A total of 29 articles including 54 patients (28 males and 24 females) were included. The patients had a median age of 7 years (range 2-34 years), had severely disabled (87.0%), tube feeding (64.8%), and received an average of 1.8 medications other than VPA. The median duration of VPA treatment was 4 years (range 0.7-15.5). Pathological fractures (25.9%), unexplained fever (11.1%), muscle weakness (9.3%), and edema (9.3%) were the most common symptoms, while 18 patients were diagnosed in incidental laboratory tests. Blood tests revealed hypokalemia (69.2%), hypophosphatemia (98.0%), and hypouricemia (93.3%). Urinalysis revealed glucosuria (96.1%), proteinuria (100.0%), generalized hyperaminoaciduria (100.0 %), β2 macroglobulin (100.0%). Decreased percent total reabsorption of phosphate (%TRP) found in 94.1% of patients, and increased fractional excretion of uric acid (FEUA) were found in 100% of patients. The median time to resolution of FS after discontinuation of drug therapy was 3 months (range 0.25-18).
CONCLUSIONS
The possibility of FS needs to be considered with long-term VPA administration, especially in young, tube-fed, severely disabled patients who are co-administered with anticonvulsants. Patients receiving VPA should have regular blood and urine tests. Abnormal laboratory values returned to normal levels after VPA discontinuation.
PubMed: 36186816
DOI: 10.3389/fmed.2022.945244 -
Frontiers in Oncology 2022Extracellular vesicles (EVs) derived from urine are promising tools for the diagnosis of urogenital cancers. Urinary EVs (uEVs) are considered potential biomarkers for...
Extracellular vesicles (EVs) derived from urine are promising tools for the diagnosis of urogenital cancers. Urinary EVs (uEVs) are considered potential biomarkers for bladder cancer (BC) because urine is in direct contact with the BC tumor microenvironment and thus reflects the current state of the disease. However, challenges associated with the effective isolation and analysis of uEVs complicate the clinical detection of uEV-associated protein biomarkers. Herein, we identified uEV-derived alpha-2-macroglobulin (a2M) as a novel diagnostic biomarker for BC through comparative analysis of uEVs obtained from patients with BC pre- and post-operation using an antibody array. Furthermore, enzyme-linked immunosorbent assay of uEVs isolated from patients with BC (n=60) and non-cancer control subjects (n=23) validated the significant upregulation of a2M expression in patient uEVs (p<0.0001). There was no significant difference in whole urine a2M levels between patients with BC and controls (p=0.317). We observed that compared to classical differential centrifugation, ExoDisc, a centrifugal microfluidic tangential flow filtration device, was a significantly more effective separation method for uEV protein analysis. We expect that our approach for EV analysis will provide an efficient route for the identification of clinically meaningful uEV-based biomarkers for cancer diagnosis.
PubMed: 36176383
DOI: 10.3389/fonc.2022.976407 -
Frontiers in Pharmacology 2022Post-traumatic osteoarthritis is a special type of osteoarthritis and a common disease, with few effective treatments available. α2-Macroglobulin (α2M) is important to...
α2-macroglobulin-rich serum as a master inhibitor of inflammatory factors attenuates cartilage degeneration in a mini pig model of osteoarthritis induced by "idealized" anterior cruciate ligament reconstruction.
Post-traumatic osteoarthritis is a special type of osteoarthritis and a common disease, with few effective treatments available. α2-Macroglobulin (α2M) is important to chondral protection in post-traumatic osteoarthritis. However, its injection into xenogeneic joint cavities involves safety hazards, limiting clinical applications. Exploring serum α2M-enriching strategies and the therapeutic effect and mechanism of α2M-rich serum (α2MRS) autologous joint injection to treat post-traumatic osteoarthritis has significant value. In the present study, a unique filtration process was used to obtain α2MRS from human and mini pig serum. We evaluated the potential of α2MRS in protecting against post-surgery cartilage degeneration. We identify the potential of α2MRS in reducing the expression of inflammatory cytokines and factors that hasten cartilage degeneration in post-operative conditions leading to post-traumatic osteoarthritis. The potential of α2MRS was analyzed in interleukin-1β induced human chondrocytes and mini pig models. In the chondrocyte model, α2MRS significantly promoted human chondrocyte proliferation and reduced apoptosis and chondrocyte catabolic cytokine gene transcription and secretion. The anterior cruciate ligament autograft reconstruction model of mini pigs was randomized into groups, operated on, and injected with α2MRS or saline. The results showed that α2MRS injection significantly suppressed the levels of inflammatory factors, improved gait, and showed significantly lower cartilage degeneration than the groups that did not receive α2MRS injections. This study highlights the chondroprotective effects of α2MRS, elucidated its potential applications against cartilage degeneration, and could provide a basis for the clinical translation of α2MRS.
PubMed: 36133821
DOI: 10.3389/fphar.2022.849102 -
Journal of Inflammation Research 2022Cognitive impairment associated with human immunodeficiency virus (HIV)-related cryptococcal meningitis (HCM) in the context of immune reconstitution inflammatory...
PURPOSE
Cognitive impairment associated with human immunodeficiency virus (HIV)-related cryptococcal meningitis (HCM) in the context of immune reconstitution inflammatory syndrome is difficult to address. This study was a follow-up of lenalidomide treatment outcomes in patients with HCM and cognitive impairment after complete cryptococcal clearance.
PATIENTS AND METHODS
Seven HCM patients with neuroinflammation and cognitive impairment after complete cryptococcal clearance were enrolled in this prospective study. Neurocognitive assessment, clinical examination and cerebrospinal fluid (CSF) assays were performed before and after lenalidomide treatment.
RESULTS
After lenalidomide treatment, the Montreal Cognitive Assessment [week (W) 0 (median [interquartile range]: 23.0 (13.0-24.0) vs W24: 26.0 (24.0-28.00), P=0.018] and International HIV Dementia Scale scores [W0: 9.0 (2.5-10.5) vs W24: 11.0 (10.00-12.0), P=0.028] improved significantly, mainly in the domain of memory function. There was no significant difference in the Center for Epidemiological Research Depression scores for anxiety and depression before and after treatment. Further stratified analyses revealed that the patients with cognitive improvement group had higher levels of CSF white blood cells [94.0 (44.0-180.0) vs 0 (0-1.5), P=0.032], CSF protein [4.9 (3.0-6.6) vs 0.6 (0.5-0.7), P=0.034], CSF albumin [318.5 (190.9-346.5) vs 33.5 (30.4-46.2), P=0.034], and CSF IgG [160.5 (73.8-256. 0) vs 4.7 (4.3-7.4), P=0.034] but a lower CSF glucose level [2.4 (2.0-2.7) vs 2.8 (2.8-3.9), P=0.032] than the patients with cognitive non-improvement group before treatment. CSF inflammatory cytokines of the growth-related oncogene, interleukin [IL]-10, granulocyte-colony stimulating factor, IL-6, IL-8, complement factor H, tumor necrosis factor-α, and α-2 macroglobulin were obviously decreased in patients with cognitive improvement group after lenalidomide treatment.
CONCLUSION
Lenalidomide potentially reduces cognitive impairment caused by immune reconstitution inflammatory syndrome in patients with HCM after cryptococcal clearance by inhibiting intracranial inflammation.
PubMed: 36131783
DOI: 10.2147/JIR.S374333 -
The Indian Journal of Medical Research Jul 2022Type 2 diabetes mellitus (T2DM) is known to induce inflammation and activation of neutrophils causing the release of neutrophil elastase (NE), a pro-inflammatory...
BACKGROUND & OBJECTIVES
Type 2 diabetes mellitus (T2DM) is known to induce inflammation and activation of neutrophils causing the release of neutrophil elastase (NE), a pro-inflammatory proteinase. The activity of NE is regulated by endogenous inhibitors alpha-antitrypsin (α-AT) and alpha-macroglobulin (α-MG). Disrupted proteolytic homeostasis in T2DM patients is one of the causes for vascular complications. This study was carried out for evaluating the levels of plasma NE, α-AT, α-MG and NE-α-AT complex to understand their roles in the pathophysiology of diabetic nephropathy (DN) and diabetic retinopathy (DR).
METHODS
A total of 240 participants (Control, n=60; T2DM, n=60; DN, n=60; and DR, n=60) were recruited after recording history, clinical examination and laboratory investigations. Retinopathy was confirmed by fundoscopy and nephropathy by urinary albumin excretion and serum creatinine levels. NE was measured using STANA. α-AT, α-MG and NE-α-AT complex were estimated by ELISA.
RESULTS
Baseline clinical and laboratory findings were confirmatory to the study groups. The mean elastase activity was higher (P<0.0005) in diabetes groups (T2DM=0.73±0.31, DN=0.87±0.35, DR=0.76±0.41) than controls (0.35±0.20). The levels of α-AT were lower in DR (8.77±2.85) than DN (26.26±6.16) and T2DM (41.13±14.06) when juxtaposed with controls (122.95±25.71). The approximate fold decrease of α-AT levels was 15 for DR and four for DN compared to controls. The levels of α-MG were lowered in T2DM (167.29±30.45), DN (144.66±13.72), and DR (104.67±11.47) than controls (208.87±31.16). The NE-α-AT complex levels were: controls (215.83±13.61), T2DM (98.85±23.85), DN (129.26±20.40) and DR (153.25±17.11).
INTERPRETATION & CONCLUSIONS
Homeostasis of NE, α-AT and α-MG is disrupted in T2DM, DN and DR. Strikingly reduced levels of α-AT observed in DR are indicative of its possible role in the pathophysiology of retinopathy and emphasizes α-AT as a plausible therapeutic target.
Topics: Humans; Diabetic Retinopathy; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Neutrophils
PubMed: 36124492
DOI: 10.4103/ijmr.IJMR_1293_19 -
Frontiers in Immunology 2022Chronic lymphocytic leukemia (CLL), the most common adult's leukemia in the western world, is caused in 95% of the cases by uncontrolled proliferation of monoclonal...
Chronic lymphocytic leukemia (CLL), the most common adult's leukemia in the western world, is caused in 95% of the cases by uncontrolled proliferation of monoclonal B-lymphocytes. The complement system in CLL is chronically activated at a low level the classical pathway (CP). This chronic activation is induced by IgG-hexamers, which are formed after binding to alpha-2-macroglobulin (A2M). The study investigated for the first time the serum levels of A2M in CLL patients, their association with the disease severity, and A2M production by the malignant B-lymphocytes. Blood samples were collected from 65 CLL patients and 30 normal controls (NC) subjects, and used for quantifications of the A2M levels, the complement activation marker (sC5b-9), the complement components C2, C3 and C4, and clinical biochemistry and hematology parameters. The production of A2M was studied in B-lymphocytes isolated from blood samples as well as in CLL and non-CLL cell lines.The serum A2M levels were significantly higher in CLL patients vs NCs, showing values of 3.62 ± 0.22 and 1.97 ± 0.10 mg/ml, respectively. Within the CLL group, A2M levels correlated significantly with the disease stage, with sC5b-9, and with clinical indicators of the disease severity. Increased A2M production was showed in three out of four CLL B-lymphocytic lines that were studied, as compared to non-CLL lines, to a non-lymphocytic line, and to blood-derived primary B-lymphocytes. A2M production was further increased both in primary cells and in the CLL cell-line after incubation with CLL sera, compared to NC sera. This study shows for the first time that serum A2M levels in CLL are significantly increased, likely due to A2M production by the malignant B-lymphocytes, and are correlated with the disease severity and with chronic complement activation. The moderate change in A2M production after incubation with NC sera supports the hypothesis that inhibition of excess A2M production can be achieved, and that this may potentially down-regulate the IgG-hexamerization and the resulting chronic CP activation. This may also help restore complement system activity, and eventually improve complement activity and immunotherapy outcomes in CLL.
Topics: Adult; B-Lymphocytes; Female; Humans; Immunoglobulin G; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Pregnancy; Pregnancy-Associated alpha 2-Macroglobulins; Transcription Factors
PubMed: 36119042
DOI: 10.3389/fimmu.2022.953644 -
Sao Paulo Medical Journal = Revista... 2022Chronically elevated alpha-2-macroglobulin (A2MG) in the blood has been correlated with diabetes and the HbA1c profile; however, no systematic review has been conducted... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronically elevated alpha-2-macroglobulin (A2MG) in the blood has been correlated with diabetes and the HbA1c profile; however, no systematic review has been conducted to evaluate the association of A2MG salivary levels and glycemia or HbA1c levels in diabetes mellitus type 2 (DM2) patients.
OBJECTIVE
To evaluate whether A2MG salivary levels are related to the glycemia or HbA1c levels in DM2 patients.
DESIGN AND SETTING
Systematic review developed at Universidade Federal de Uberlândia (UFU), Brazil.
METHODS
Eight databases were used as research sources. The eligibility criteria included studies that reported data regarding mean salivary A2MG and the correlation between glycemia and/or HbA1c levels of DM2 subjects (uncontrolled and well-controlled) and non-diabetic subjects. The risk of bias of the studies selected was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools for use in JBI systematic reviews. Pooled correlation coefficients were estimated using the Hunter-Schmidt method. Study estimates were weighted according to their sample size, and heterogeneity was calculated using the chi-square statistic.
RESULTS
Four studies on DM2 patients were included in this systematic review after careful analysis of 1482 studies. Three studies compared A2MG with HbA1c and glycemia. Overall, the correlation between A2MG and HbA1c was strong (r = 0.838). In contrast, the correlation between A2MG and glycemia was low (r = 0.354).
CONCLUSION
The strong association between HbA1C and salivary A2MG suggests that this salivary protein has the potential to be a surrogate for HbA1C, if corroboratory further evidence is obtained through large-scale studies.
Topics: Humans; Blood Glucose; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Pregnancy-Associated alpha 2-Macroglobulins
PubMed: 36102452
DOI: 10.1590/1516-3180.2021.0816.R2.19052022 -
International Journal of Molecular... Sep 2022Biological material is one of the most important aspects that allow for the correct diagnosis of the disease, and tears are an interesting subject of research because of... (Review)
Review
Biological material is one of the most important aspects that allow for the correct diagnosis of the disease, and tears are an interesting subject of research because of the simplicity of collection, as the well as the relation to the components similar to other body fluids. In this review, biomarkers for Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) in tears are investigated and analyzed. Records were obtained from the PubMed and Google Scholar databases in a timeline of 2015-2022. The keywords were: tear film/tear biochemistry/tear biomarkers + diseases (AD, PD, or MS). The recent original studies were analyzed, discussed, and biomarkers present in tears that can be used for the diagnosis and management of AD, PD, and MS diseases were shown. α-synTotal and α-synOligo, lactoferrin, norepinephrine, adrenaline, epinephrine, dopamine, α-2-macroglobulin, proteins involved in immune response, lipid metabolism and oxidative stress, apolipoprotein superfamily, and others were shown to be biomarkers in PD. For AD as potential biomarkers, there are: lipocalin-1, lysozyme-C, and lacritin, amyloid proteins, t-Tau, p-Tau; for MS there are: oligoclonal bands, lipids containing choline, free carnitine, acylcarnitines, and some amino acids. Information systematized in this review provides interesting data and new insight to help improve clinical outcomes for patients with neurodegenerative disorders.
Topics: Alzheimer Disease; Biomarkers; Humans; Lacrimal Apparatus Diseases; Multiple Sclerosis; Parkinson Disease; Tears
PubMed: 36077520
DOI: 10.3390/ijms231710123