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Pain Management Jun 2023This case report describes the successful treatment of neuroma pain in the setting of below knee amputations using alpha-2-macroglobulin (A2M). A 34-year-old female...
This case report describes the successful treatment of neuroma pain in the setting of below knee amputations using alpha-2-macroglobulin (A2M). A 34-year-old female patient presented with 9 months of stump pain despite conservative treatment. The exam revealed persistent pain through rest periods and weight-bearing status during therapy. Ultrasound showed neuroma formation with neovascularization. The patient underwent two A2M hydrodissection treatments, 2 weeks apart. The patient reported significant pain relief. Ultrasound showed decreases in neovascularization and cross-sectional area of the neuroma. The patient was able to ambulate pain-free for 2 years and reported no pain since. A2M may be a treatment for patients with neuroma pain in the setting of amputations.
Topics: Female; Pregnancy; Humans; Adult; Amputees; Pregnancy-Associated alpha 2-Macroglobulins; Pain; Neuroma; Knee
PubMed: 37551540
DOI: 10.2217/pmt-2023-0005 -
Biochimie Mar 2024Chandipura Virus is an emerging tropical pathogen with a high mortality rate among children. No mode of treatment or antivirals exists against CHPV infection, due to...
Chandipura Virus is an emerging tropical pathogen with a high mortality rate among children. No mode of treatment or antivirals exists against CHPV infection, due to little information regarding its host interaction. Studying viral pathogen interaction with its host can not only provide valuable information regarding its propagation strategy, but also on which host proteins interact with the virus. Identifying these proteins and understanding their role in the infection process can provide more stable anti-viral targets. In this study, we focused on identifying host factors that interact with CHPV and may play a critical role in CHPV infection. We are the first to report the successful identification of Alpha-2-Macroglobulin (A2M), a secretory protein of the host that interacts with CHPV. We also established that LRP1 (Low-density lipoprotein receptor-related protein 1) and GRP78 (Glucose regulated protein 78), receptors of A2M, also interact with CHPV. Furthermore, we could also demonstrate that knocking out A2M has a severe effect on viral infection. We conclusively show the interaction of these host proteins with CHPV. Our findings also indicate that these host proteins could play a role in viral entry into the host cell.
Topics: Child; Humans; Vesiculovirus; Transcription Factors; Macroglobulins; Low Density Lipoprotein Receptor-Related Protein-1
PubMed: 37517577
DOI: 10.1016/j.biochi.2023.07.019 -
Biomedicines Jun 2023Metastasis is a serious and often life-threatening condition, representing the leading cause of death among women with breast cancer (BC). Although the current clinical...
Metastasis is a serious and often life-threatening condition, representing the leading cause of death among women with breast cancer (BC). Although the current clinical classification of BC is well-established, the addition of minimally invasive laboratory tests based on peripheral blood biomarkers that reflect pathological changes in the body is of utmost importance. In the current study, the serum proteome and lipidome profiles for 50 BC patients with (25) and without (25) metastasis were studied. Targeted proteomic analysis for concertation measurements of 125 proteins in the serum was performed via liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM MS) using the BAK 125 kit (MRM Proteomics Inc., Victoria, BC, Canada). Untargeted label-free lipidomic analysis was performed using liquid chromatography coupled to tandem mass-spectrometry (LC-MS/MS), in both positive and negative ion modes. Finally, 87 serum proteins and 295 lipids were quantified and showed a moderate correlation with tumor grade, histological and biological subtypes, and the number of lymph node metastases. Two highly accurate classifiers that enabled distinguishing between metastatic and non-metastatic BC were developed based on proteomic (accuracy 90%) and lipidomic (accuracy 80%) features. The best classifier (91% sensitivity, 89% specificity, AUC = 0.92) for BC metastasis diagnostics was based on logistic regression and the serum levels of 11 proteins: alpha-2-macroglobulin, coagulation factor XII, adiponectin, leucine-rich alpha-2-glycoprotein, alpha-2-HS-glycoprotein, Ig mu chain C region, apolipoprotein C-IV, carbonic anhydrase 1, apolipoprotein A-II, apolipoprotein C-II and alpha-1-acid glycoprotein 1.
PubMed: 37509426
DOI: 10.3390/biomedicines11071786 -
Journal of Biomolecular Structure &... Jul 2023In the present study, we investigated the interaction of alpha-2-macroglobulin (α2M) with naringenin using multi-spectroscopic, molecular docking, and molecular...
In the present study, we investigated the interaction of alpha-2-macroglobulin (α2M) with naringenin using multi-spectroscopic, molecular docking, and molecular simulation approaches to identify the functional changes and structural variations in the α2M structure. Our study suggests that naringenin compromised α2M anti-proteinase activity. The results of absorption spectroscopy and fluorescence measurement showed that naringenin-α2M formed a complex with a binding constant of (k)∼10, indicative of moderate binding. The value of ΔG° in the binding indicates the process to be spontaneous and the major force responsible to be hydrophobic interaction. The findings of FRET reveal the binding distance between naringenin and the amino acids of α2M was 2.82 nm. The secondary structural analysis of α2M with naringenin using multi-spectroscopic methods like synchronous fluorescence, red-edge excitation shift (REES), FTIR, and CD spectra further confirmed the significant conformational alterations in the protein. Molecular docking approach reveals the interactions between naringenin and α2M to be hydrogen bonds, van der Waals forces, and pi interactions, which considerably favour and stabilise the binding. Molecular dynamics modelling simulations also supported the steady binding with the least RMSD deviations. Our study suggests that naringenin interacts with α2M to alter its confirmation and compromise its activity.Communicated by Ramaswamy H. Sarma.
PubMed: 37498152
DOI: 10.1080/07391102.2023.2240420 -
Biochemical Pharmacology Sep 2023The brain-derived neurotrophic factor (BDNF) has been recently shown to have activating effects in isolated platelets. However, BDNF circulates in plasma and a mechanism...
The brain-derived neurotrophic factor (BDNF) has been recently shown to have activating effects in isolated platelets. However, BDNF circulates in plasma and a mechanism to preclude constant activation of platelets appears necessary. Hence, we investigated the mechanism regulating BDNF bioavailability in blood. Protein-protein interactions were predicted by molecular docking and validated through immunoprecipitation. Platelet aggregation was assessed using light transmission aggregometry with washed platelets in response to classical agonists or BDNF, in the absence or presence of alpha-2-macroglobulin (αM), and in platelet-rich plasma. BDNF signaling was assessed with phospho-blots. As little as 25% autologous plasma was sufficient to completely abolish platelet aggregation in response to BDNF. Docking predicted two forms of BDNF binding to native or activated αM, in parallel and perpendicular arrangements, and the model suggested that the BDNF-αM complex cannot bind to the high-affinity BDNF receptor, tropomyosin receptor kinase B (TrkB). Experimentally, native and activated αM formed stable complexes with BDNF preventing BDNF-induced TrkB activation and signal transduction. Both native and activated αM inhibited BDNF induced-platelet aggregation in a concentration-dependent manner with comparable half-maximal inhibitory concentrations (IC≈ 125-150 nM). Our study implicates αM as a physiological regulator of BDNF bioavailability, and as an inhibitor of BDNF-induced platelet activation in blood.
Topics: Female; Pregnancy; Humans; Brain-Derived Neurotrophic Factor; Platelet Aggregation; Pregnancy-Associated alpha 2-Macroglobulins; Molecular Docking Simulation; Receptor, trkB; Enzyme Inhibitors
PubMed: 37487878
DOI: 10.1016/j.bcp.2023.115701 -
Biomaterials Oct 2023Tumor necrosis factor α (TNF-α) is a leading proinflammatory cytokine as the master regulator of inflammation in chronic inflammation diseases. Although TNF-α...
Tumor necrosis factor α (TNF-α) is a leading proinflammatory cytokine as the master regulator of inflammation in chronic inflammation diseases. Although TNF-α antagonists such as small molecules and peptides are in development, comparable effectiveness in TNF-α neutralization is hardly achieved only with TNF-α capture. In this study, simplified α-macroglobulin (SM) as a novel TNF-α inhibitor was fabricated to relieve inflammation response by TNF-α capture and internalization with lysosomal degradation. SM was prepared by conjugating a TNF-α-targeting peptide with a receptor binding domain (RBD) derived from α-macroglobulin through a synthetic biology strategy. SM exhibited effective capture and bioactivity inhibition of TNF-α. Improved endocytosis of TNF-α into lysosomes was observed with SM in macrophages. Even challenged with LPS/IFNγ, the macrophages showed relieved inflammation response with SM treatment. When administrated in chronic inflammation injury in vivo, SM achieved comparable therapeutic efficacy with Infliximab, showing ameliorated cartilage degeneration with relieved inflammation in osteoarthritis (OA) and preserved cardiac function with mitigated myocardium injury in myocardial infarction (MI). These results suggest that SM functioning in TNF-α capture-internalization mechanism might be promising therapeutic alternatives of TNF-α antibodies.
Topics: Pregnancy; Female; Humans; Tumor Necrosis Factor-alpha; Pregnancy-Associated alpha 2-Macroglobulins; Osteoarthritis; Myocardial Infarction; Inflammation; Immunologic Factors
PubMed: 37487780
DOI: 10.1016/j.biomaterials.2023.122247 -
Thrombosis Research Sep 2023
Topics: Humans; Blood Coagulation; Blood Specimen Collection
PubMed: 37454465
DOI: 10.1016/j.thromres.2023.07.007 -
Cells May 2023This study aimed to compare the proteomic profile of stimulated and unstimulated saliva samples from pregnant women with/without obesity and periodontitis. Pregnant...
This study aimed to compare the proteomic profile of stimulated and unstimulated saliva samples from pregnant women with/without obesity and periodontitis. Pregnant women were allocated into four groups: with obesity and periodontitis (OP); with obesity but without periodontitis (OWP); with normal BMI but with periodontitis (NP); with normal BMI and without periodontitis (NWP). Stimulated saliva (SS) and unstimulated saliva (US) samples were collected, and salivary proteins were extracted and individually processed by proteomic analysis (nLC-ESI-MS/MS). Proteins involved with the immune response process, antioxidant activity, and retina homeostasis were decreased or absent in SS samples from all groups (i.e., , , , , , , , , , ). Additionally, proteins related to the carbohydrate metabolic process and glycolytic and glucose metabolic process were absent in SS, mainly from OP and OWP (i.e., , , ). Saliva stimulation decreased important proteins involved with immune response and inflammation process in all groups. Unstimulated salivary samples seem to be the best choice for the proteomic approach in pregnant women.
Topics: Humans; Female; Pregnancy; Pregnant Women; Tandem Mass Spectrometry; Saliva; Proteomics; Periodontitis; Obesity
PubMed: 37408223
DOI: 10.3390/cells12101389 -
Talanta Dec 2023Recent advances in proteomics technologies have enabled the analysis of thousands of proteins in a high-throughput manner. Mass spectrometry (MS) based proteomics uses a...
Recent advances in proteomics technologies have enabled the analysis of thousands of proteins in a high-throughput manner. Mass spectrometry (MS) based proteomics uses a peptide-centric approach where biological samples undergo specific proteolytic digestion and then only unique peptides are used for protein identification and quantification. Considering the fact that a single protein may have multiple unique peptides and a number of different forms, it becomes essential to understand dynamic protein-peptide relationships to ensure robust and reliable peptide-centric protein analysis. In this study, we investigated the correlation between protein concentration and corresponding unique peptide responses under a conventional proteolytic digestion condition. Protein-peptide correlation, digestion efficiency, matrix-effect, and concentration-effect were evaluated. Twelve unique peptides of alpha-2-macroglobulin (A2MG) were monitored using a targeted MS approach to acquire insights into protein-peptide dynamics. Although the peptide responses were reproducible between replicates, protein-peptide correlation was moderate in protein standards and low in complex matrices. The results suggest that reproducible peptide signal could be misleading in clinical studies and a peptide selection could dramatically change the outcome at protein level. This is the first study investigating quantitative protein-peptide correlations in biological samples using all unique peptides representing the same protein and opens a discussion on peptide-based proteomics.
PubMed: 37392709
DOI: 10.1016/j.talanta.2023.124878 -
Frontiers in Network Physiology 2023The low-density lipoprotein related protein receptor 1 (LRP1), also known as CD91 or α-Macroglobulin-receptor, is a transmembrane receptor that interacts with more than... (Review)
Review
The low-density lipoprotein related protein receptor 1 (LRP1), also known as CD91 or α-Macroglobulin-receptor, is a transmembrane receptor that interacts with more than 40 known ligands. It plays an important biological role as receptor of morphogens, extracellular matrix molecules, cytokines, proteases, protease inhibitors and pathogens. In the CNS, it has primarily been studied as a receptor and clearance agent of pathogenic factors such as Aβ-peptide and, lately, Tau protein that is relevant for tissue homeostasis and protection against neurodegenerative processes. Recently, it was found that LRP1 expresses the Lewis-X (Lex) carbohydrate motif and is expressed in the neural stem cell compartment. The removal of from the cortical radial glia compartment generates a strong phenotype with severe motor deficits, seizures and a reduced life span. The present review discusses approaches that have been taken to address the neurodevelopmental significance of LRP1 by creating novel, lineage-specific constitutive or conditional knockout mouse lines. Deficits in the stem cell compartment may be at the root of severe CNS pathologies.
PubMed: 37383546
DOI: 10.3389/fnetp.2023.1190240