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Biologicals : Journal of the... Jun 2024Convalescent plasma was proposed for passive immunization against COVID-19; but so far there are conflicting results and still open questions. However, besides...
Convalescent plasma was proposed for passive immunization against COVID-19; but so far there are conflicting results and still open questions. However, besides antibodies, other plasma proteins may be good candidates for further research and application. Thromboinflammation frequently complicates severe COVID-19, and classical anticoagulants like heparins seem to have limited effect. The natural protease inhibitors antithrombin III (ATIII), α-antitrypsin (α-AT) and α-macroglobulin (α-M), which are found decreased in severe COVD-19, play a crucial role in prothrombotic and inflammatory pathways. While ATIII and α-AT are licensed as commercially prepared therapeutic concentrates, there is no preparation of α-M available. The diagnostic, prognostic, and even therapeutic potential of plasma protease inhibitors should be further explored.
PubMed: 38924809
DOI: 10.1016/j.biologicals.2024.101781 -
Pathogens (Basel, Switzerland) Jun 2024This study investigates the impact of Epstein-Barr virus (EBV) infection on children's proteomes across different phases of the disease, utilising seventy-nine blood...
This study investigates the impact of Epstein-Barr virus (EBV) infection on children's proteomes across different phases of the disease, utilising seventy-nine blood samples categorised into three groups: EBV-naive patients, acute infectious mononucleosis (IM) cases, and convalescents followed up for 12 months post-IM. The aim is to identify proteins influenced by EBV infection, shedding light on the chronic processes triggered by the virus. The results reveal thirty-nine proteins distinguishing between naive patients and those with IM, including actin, lumican, peroxiredoxin-2, fibulin-1, gelsolin, and alpha-2-macroglobulin, which are involved in immune responses, cell adhesion, and inflammation. Elevated oxidative stress markers like peroxiredoxin-2 in IM patients suggest potential links to EBV's induction of reactive oxygen species. Increased levels of apolipoproteins A-I, A-IV, C-IV, and M during IM imply associations with viral infection, while complement system proteins (C1q, C1r, and C8 gamma chain) are also elevated, reflecting their role in the immune response and viral clearance. This study's focus on children provides unique insights into EBV's impact on young populations, emphasising proteomics' role in uncovering protein associations and understanding the virus's long-term consequences. However, specific relationships between identified proteins and EBV infection require further investigation.
PubMed: 38921769
DOI: 10.3390/pathogens13060471 -
PloS One 2024Early prognostication of patient outcomes in intracerebral hemorrhage (ICH) is critical for patient care. We aim to investigate protein biomarkers' role in...
Early prognostication of patient outcomes in intracerebral hemorrhage (ICH) is critical for patient care. We aim to investigate protein biomarkers' role in prognosticating outcomes in ICH patients. We assessed 22 protein biomarkers using targeted proteomics in serum samples obtained from the ICH patient dataset (N = 150). We defined poor outcomes as modified Rankin scale score of 3-6. We incorporated clinical variables and protein biomarkers in regression models and random forest-based machine learning algorithms to predict poor outcomes and mortality. We report Odds Ratio (OR) or Hazard Ratio (HR) with 95% Confidence Interval (CI). We used five-fold cross-validation and bootstrapping for internal validation of prediction models. We included 149 patients for 90-day and 144 patients with ICH for 180-day outcome analyses. In multivariable logistic regression, UCH-L1 (adjusted OR 9.23; 95%CI 2.41-35.33), alpha-2-macroglobulin (aOR 5.57; 95%CI 1.26-24.59), and Serpin-A11 (aOR 9.33; 95%CI 1.09-79.94) were independent predictors of 90-day poor outcome; MMP-2 (aOR 6.32; 95%CI 1.82-21.90) was independent predictor of 180-day poor outcome. In multivariable Cox regression models, IGFBP-3 (aHR 2.08; 95%CI 1.24-3.48) predicted 90-day and MMP-9 (aOR 1.98; 95%CI 1.19-3.32) predicted 180-day mortality. Machine learning identified additional predictors, including haptoglobin for poor outcomes and UCH-L1, APO-C1, and MMP-2 for mortality prediction. Overall, random forest models outperformed regression models for predicting 180-day poor outcomes (AUC 0.89), and 90-day (AUC 0.81) and 180-day mortality (AUC 0.81). Serum biomarkers independently predicted short-term poor outcomes and mortality after ICH. Further research utilizing a multi-omics platform and temporal profiling is needed to explore additional biomarkers and refine predictive models for ICH prognosis.
Topics: Humans; Cerebral Hemorrhage; Machine Learning; Male; Female; Biomarkers; Prognosis; Proteomics; Aged; Middle Aged; Algorithms
PubMed: 38829877
DOI: 10.1371/journal.pone.0296616 -
Toxicology Reports Jun 2024Assessing toxicity of complex mixtures of contaminants from industrial sites with historic and ongoing contamination remains a challenge for risk assessors. Groundwater...
Assessing toxicity of complex mixtures of contaminants from industrial sites with historic and ongoing contamination remains a challenge for risk assessors. Groundwater from a pesticide packaging site in Canada containing a complex mixture of known and unknown contaminants was examined in male rats to determine the target organ toxicity. This study determined the time-course of toxicity (7, 14, 28, and 60 days) following oral exposure to 0.05% v/v contaminated groundwater compared to tap water (control) in male Sprague Dawley rats (n=5 /group/time). Exposure to groundwater resulted in inflammation, indicated by a statistically significant increase in plasma lymphocyte and neutrophil counts on days 7 and 60, respectively, but a reduction in the plasma alpha 2 macroglobulin levels by day 60. Gonadotoxicity was indicated by a reduced Johnsen score (grading spermatogenesis) in all exposed groups at all time points, while seminiferous epithelial height was reduced on days 7, 14, and 28 compared to controls. Plasma testosterone was reduced in exposed groups on days 7 and 28, accompanied by elevated testicular lipid peroxidation at all time points compared to control. In contrast, lipid peroxidation in the lungs from exposed rats was elevated on days 7, 14, and 28. Plasma symmetric dimethylarginine was elevated on day 14 in the exposed group indicating renal impairment. Taken together, these results indicate that testes, kidney, immune and lung are target organs for the contaminated groundwater from this industrial site. The current study highlights the challenge in hazard assessment for complex mixtures and highlights the need for effects-directed analysis and the continued, albeit limited, use of animal models in toxicity testing.
PubMed: 38813463
DOI: 10.1016/j.toxrep.2024.05.002 -
General Physiology and Biophysics May 2024Vascular endothelial cell functions affect lower extremity arteriosclerosis obliterans (LEASO), while alpha-2-macroglobulin (A2M) and CCCTC-binding factor (CTCF) are...
Vascular endothelial cell functions affect lower extremity arteriosclerosis obliterans (LEASO), while alpha-2-macroglobulin (A2M) and CCCTC-binding factor (CTCF) are closely related to the function of such cells. This paper aims to identify the influences of CTCF on vascular endothelial cells in LEASO by regulating A2M. A rat model of LEASO was established to measure intima-media ratio, blood lipid, and inflammatory factor levels. By constructing LEASO cell models, cell viability and apoptosis were assayed, while autophagy-related proteins, CTCF and A2M levels in femoral artery tissues and HUVECs were determined. The transcriptional regulation of CTCF on A2M was verified. In LEASO rat models, femoral artery lumen was narrowed and endothelial cells were disordered; levels of total cholesterol, IL-1, and TNF-α enhanced, and HDL-C decreased, with strong expression of A2M and low expression of CTCF. The viability of ox-LDL-treated HUVECs was decreased, together with higher apoptosis, lower LC3II/I expression, and higher p62 expression, which were reversed by sh-A2M transfection. Overexpression of CTCF inhibited A2M transcription, promoted the viability and autophagy of HUVECs, and decreased apoptosis. Collectively, CTCF improves the function of vascular endothelial cells in LEASO by inhibiting A2M transcription.
Topics: Animals; Humans; Male; Rats; Apoptosis; Arteriosclerosis Obliterans; Autophagy; CCCTC-Binding Factor; Cell Survival; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Lower Extremity; Pregnancy-Associated alpha 2-Macroglobulins; Rats, Sprague-Dawley; Transcription, Genetic
PubMed: 38774923
DOI: 10.4149/gpb_2024005 -
Doklady. Biochemistry and Biophysics May 2024We determined natural antibodies (n-Abs) to the regulators of the main systems of biochemical homeostasis: β-endorphin, serotonin, dopamine, histamine, orphanin,...
We determined natural antibodies (n-Abs) to the regulators of the main systems of biochemical homeostasis: β-endorphin, serotonin, dopamine, histamine, orphanin, angiotensin, GABA, glutamate, bradykinin, vasopressin, thrombin, and α-2-macroglobulin in individuals with phantom pain syndrome (PPS), resulting from amputation after injury. It was established that each patient has an individual immunoprofile, but for all of them there was a significant increase in the level of antibodies to serotonin, histamine, and angiotensin, which reflect the chronicity of the pain syndrome and do not depend on the self-assessment of the severity of PPS. Determination of the role of regulators of biochemical homeostasis in the development of phantom pain showed that, at high, moderate, and weak severity of PPS, the biogenic amine and angiotensinergic systems are activated. A decrease in PPS intensity normalizes deviations in all immunological parameters. The levels of n-Abs for the pain (β-endorphin) and analgesic (orphanin) systems are significant only at low PPS. Monitoring the individual profile of n-Abs to endogenous regulators allows us to obtain an objective picture of the pain status of the patient's body.
PubMed: 38744736
DOI: 10.1134/S1607672924700832 -
Biomeditsinskaia Khimiia Apr 2024Antibodies to thyroid peroxidase (AB-TPO), antibodies to thyroglobulin (AB-TG), and the content of α2-macroglobulin (α2-MG) have been studied in serum samples of...
Antibodies to thyroid peroxidase (AB-TPO), antibodies to thyroglobulin (AB-TG), and the content of α2-macroglobulin (α2-MG) have been studied in serum samples of patients with autoimmune thyroiditis (AIT). All the patients were divided into 3 groups depending on age: 25-35, 36-50, 51-65 years. We found a significant change in the thyroid panel parameters in AIT, but without significant changes in the average concentration of α2-MG in the age groups of patients. This may be due to the accumulation and retention of complexes of defective forms of α2-MG in the circulation associated with their decreased ability to bind to receptors.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; alpha-Macroglobulins; Autoantibodies; Iodide Peroxidase; Iron-Binding Proteins; Thyroglobulin; Thyroiditis, Autoimmune
PubMed: 38711412
DOI: 10.18097/PBMC20247002125 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Apr 2024To explore the mechanism underlying the protective effect of α2-macroglobulin (A2M) against glucocorticoid-induced femoral head necrosis.
[α2-macroglobulin alleviates glucocorticoid-induced avascular necrosis of the femoral head in mice by promoting proliferation, migration and angiogenesis of vascular endothelial cells].
OBJECTIVE
To explore the mechanism underlying the protective effect of α2-macroglobulin (A2M) against glucocorticoid-induced femoral head necrosis.
METHODS
In a human umbilical vein endothelial cell (HUVEC) model with injuries induced by gradient concentrations of dexamethasone (DEX; 10-10 mol/L), the protective effects of A2M at 0.05 and 0.1 mg/mL were assessed by examining the changes in cell viability, migration, and capacity of angiogenesis using CCK-8 assay, Transwell and scratch healing assays and angiogenesis assay. The expressions of CD31 and VEGF-A proteins in the treated cells were detected using Western blotting. In BALB/c mouse models of avascular necrosis of the femoral head induced by intramuscular injections of methylprednisolone, the effects of intervention with A2M on femoral trabecular structure, histopathological characteristics, and CD31 expression were examined with Micro-CT, HE staining and immunohistochemical staining.
RESULTS
In cultured HUVECs, DEX treatment significantly reduced cell viability, migration and angiogenic ability in a concentration- and time-dependent manner (<0.05), and these changes were obviously reversed by treatment with A2M in positive correlation with A2M concentration (<0.05). DEX significantly reduced the expression of CD31 and VEGF-A proteins in HUVECs, while treatment with A2M restored CD31 and VEGF-A expressions in the cells (<0.05). The mouse models of femoral head necrosis showed obvious trabecular damages in the femoral head, where a large number of empty lacunae and hypertrophic fat cells could be seen and CD31 expression was significantly decreased (<0.05). A2M treatment of the mouse models significantly improved trabecular damages, maintained normal bone tissue structures, and increased CD31 expression in the femoral head (<0.05).
CONCLUSION
A2M promotes proliferation, migration, and angiogenesis of DEX-treated HUVECs and alleviates methylprednisolone-induced femoral head necrosis by improving microcirculation damages and maintaining microcirculation stability in the femoral head.
Topics: Animals; Mice; Femur Head Necrosis; Human Umbilical Vein Endothelial Cells; Humans; Mice, Inbred BALB C; Glucocorticoids; Cell Movement; Cell Proliferation; Dexamethasone; Vascular Endothelial Growth Factor A; Cell Survival; Femur Head; Platelet Endothelial Cell Adhesion Molecule-1; Angiogenesis
PubMed: 38708505
DOI: 10.12122/j.issn.1673-4254.2024.04.13 -
PeerJ 2024Pulmonary hypertension (PH), a common complication in dogs affected by degenerative mitral valve disease (DMVD), is a progressive disorder characterized by increased...
Pulmonary hypertension (PH), a common complication in dogs affected by degenerative mitral valve disease (DMVD), is a progressive disorder characterized by increased pulmonary arterial pressure (PAP) and pulmonary vascular remodeling. Phosphorylation of proteins, impacting vascular function and cell proliferation, might play a role in the development and progression of PH. Unlike gene or protein studies, phosphoproteomic focuses on active proteins that function as end-target proteins within signaling cascades. Studying phosphorylated proteins can reveal active contributors to PH development. Early diagnosis of PH is crucial for effective management and improved clinical outcomes. This study aimed to identify potential serum biomarkers for diagnosing PH in dogs affected with DMVD using a phosphoproteomic approach. Serum samples were collected from healthy control dogs ( = 28), dogs with DMVD ( = 24), and dogs with DMVD and PH ( = 29). Phosphoproteins were enriched from the serum samples and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Data analysis was performed to identify uniquely expressed phosphoproteins in each group and differentially expressed phosphoproteins among groups. Phosphoproteomic analysis revealed nine uniquely expressed phosphoproteins in the serum of dogs in the DMVD+PH group and 15 differentially upregulated phosphoproteins in the DMVD+PH group compared to the DMVD group. The phosphoproteins previously implicated in PH and associated with pulmonary arterial remodeling, including small nuclear ribonucleoprotein G (SNRPG), alpha-2-macroglobulin (A2M), zinc finger and BTB domain containing 42 (ZBTB42), hemopexin (HPX), serotransferrin (TRF) and complement C3 (C3), were focused on. Their unique expression and differential upregulation in the serum of DMVD dogs with PH suggest their potential as biomarkers for PH diagnosis. In conclusion, this phosphoproteomic study identified uniquely expressed and differentially upregulated phosphoproteins in the serum of DMVD dogs with PH. Further studies are warranted to validate the diagnostic utility of these phosphoproteins.
Topics: Animals; Dogs; Hypertension, Pulmonary; Proteomics; Phosphoproteins; Dog Diseases; Biomarkers; Tandem Mass Spectrometry; Male; Heart Valve Diseases; Female; Mitral Valve; Chromatography, Liquid
PubMed: 38708342
DOI: 10.7717/peerj.17186 -
Research and Practice in Thrombosis and... Mar 2024A State of the Art lecture titled "Platelets and neurotrophins" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Neurotrophins,...
A State of the Art lecture titled "Platelets and neurotrophins" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Neurotrophins, a family of neuronal growth factors known to support cognitive function, are increasingly recognized as important players in vascular health. Indeed, along with their canonical receptors, neurotrophins are expressed in peripheral tissues, particularly in the vasculature. The better-characterized neurotrophin in vascular biology is the brain-derived neurotrophic factor (BDNF). Its largest extracerebral pool resides within platelets, partly inherited from megakaryocytes and also likely internalized from circulation. Activation of platelets releases vast amounts of BDNF into their milieu and interestingly leads to platelet aggregation through binding of its receptor, the tropomyosin-related kinase B, on the platelet surface. As BDNF is readily available in plasma, a mechanism to preclude excessive platelet activation and aggregation appears critical. As such, binding of BDNF to α2-macroglobulin hinders its ability to bind its receptor and limits its platelet-activating effects to the site of vascular injury. Altogether, addition of BDNF to a forming clot facilitates not only paracrine platelet activation but also binding to fibrinogen, rendering the resulting clot more porous and plasma-permeable. Importantly, release of BDNF into circulation also appears to be protective against adverse cardiovascular and cerebrovascular outcomes, which has been reported in both animal models and epidemiologic studies. This opens an avenue for platelet-based strategies to deliver BDNF to vascular lesions and facilitate wound healing through its regenerative properties. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.
PubMed: 38706782
DOI: 10.1016/j.rpth.2024.102398