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International Journal of Biological... Mar 2024P. falciparumerythrocyte membrane protein 1 (PfEMP1) is the major parasite protein responsible for rosetting by binding to host receptors such as heparan sulfate, CR1 on...
P. falciparumerythrocyte membrane protein 1 (PfEMP1) is the major parasite protein responsible for rosetting by binding to host receptors such as heparan sulfate, CR1 on RBC surface. Usually monomeric protein-carbohydrate interactions are weak [1], therefore PfEMP1 binds to plasma proteins like IgM or α2-macroglobulin that facilitate its clustering on parasitized RBC surface and augment rosetting [2,3]. We show that 3D7A expresses PfEMP1, PF3D7_0412900, and employs its CIDRγ2 domain to interact with glycophorin B on uninfected RBC to form large rosettes but more importantly even in the absence of plasma proteins. Overall, we established the role of PF3D7_0412900 in rosetting as antibodies against CIDRγ2 domain reduced rosetting and also identified its receptor, glycophorin B which could provide clue why glycophorin B null phenotype, S-s-U- RBCs prevalent in malaria endemic areas is protective against severe malaria.
Topics: Humans; Plasmodium falciparum; Glycophorins; Protozoan Proteins; Erythrocytes; Blood Proteins; Malaria
PubMed: 38309398
DOI: 10.1016/j.ijbiomac.2024.129868 -
Bioengineered Dec 2024
PubMed: 38299351
DOI: 10.1080/21655979.2024.2302658 -
Cardiovascular Diabetology Jan 2024Type 2 diabetes mellitus (T2DM) increases the risk of coronary heart disease (CHD) by 2-4 fold, and is associated with endothelial dysfunction, dyslipidaemia, insulin...
BACKGROUND
Type 2 diabetes mellitus (T2DM) increases the risk of coronary heart disease (CHD) by 2-4 fold, and is associated with endothelial dysfunction, dyslipidaemia, insulin resistance, and chronic hyperglycaemia. The aim of this investigation was to assess, by a multimarker mass spectrometry approach, the predictive role of circulating proteins as biomarkers of cardiovascular damage progression associated with diabetes mellitus.
METHODS
The study considered 34 patients with both T2DM and CHD, 31 patients with T2DM and without CHD, and 30 patients without diabetes with a diagnosis of CHD. Plasma samples of subjects were analysed through a multiplexed targeted liquid chromatography mass spectrometry (LC-MS)-based assay, namely Multiple Reaction Monitoring (MRM), allowing the simultaneous detection of peptides derived from a protein of interest. Gene Ontology (GO) Analysis was employed to identify enriched GO terms in the biological process, molecular function, or cellular component categories. Non-parametric multivariate methods were used to classify samples from patients and evaluate the relevance of the analysed proteins' panel.
RESULTS
A total of 81 proteins were successfully quantified in the human plasma samples. Gene Ontology analysis assessed terms related to blood microparticles, extracellular exosomes and collagen-containing extracellular matrix. Preliminary evaluation using analysis of variance (ANOVA) of the differences in the proteomic profile among patient groups identified 13 out of the 81 proteins as significantly different. Multivariate analysis, including cluster analysis and principal component analysis, identified relevant grouping of the 13 proteins. The first main cluster comprises apolipoprotein C-III, apolipoprotein C-II, apolipoprotein A-IV, retinol-binding protein 4, lysozyme C and cystatin-C; the second one includes, albeit with sub-grouping, alpha 2 macroglobulin, afamin, kininogen 1, vitronectin, vitamin K-dependent protein S, complement factor B and mannan-binding lectin serine protease 2. Receiver operating characteristic (ROC) curves obtained with the 13 selected proteins using a nominal logistic regression indicated a significant overall distinction (p < 0.001) among the three groups of subjects, with area under the ROC curve (AUC) ranging 0.91-0.97, and sensitivity and specificity ranging from 85 to 100%.
CONCLUSIONS
Targeted mass spectrometry approach indicated 13 multiple circulating proteins as possible biomarkers of cardiovascular damage progression associated with T2DM, with excellent classification results in terms of sensitivity and specificity.
Topics: Humans; Diabetes Mellitus, Type 2; Proteomics; Biomarkers; Peptides; Blood Proteins
PubMed: 38245742
DOI: 10.1186/s12933-024-02125-1 -
Thrombosis Research Feb 2024Hypoxia plays an important role in several pathologies, e.g. chronic obstructive pulmonary disease and obstructive sleep apnea syndrome, and is linked to an increased...
Hypoxia plays an important role in several pathologies, e.g. chronic obstructive pulmonary disease and obstructive sleep apnea syndrome, and is linked to an increased thrombosis risk. Furthermore, oxygen deprivation is associated with hypercoagulability. In this study, we investigated the effect of gender and exercise on the coagulation potential under hypoxic conditions at high altitude by assessing thrombin generation (TG) and platelet activation. Hereto, ten healthy volunteers were included (50 % male, median age of 27.5 years). The measurements were conducted first at sea level and then twice at high altitude (3883 m), first after a passive ascent by cable car and second after an active ascent by a mountain hike. As expected, both the passive and active ascent resulted in a decreased oxygen saturation and an increased heart rate at high altitude. Acute mountain sickness symptoms were observed independently of the ascent method. After the active ascent, platelet, white blood cell and granulocyte count were increased, and lymphocytes were decreased, without a gender-related difference. FVIII and von Willebrand factor were significantly increased after the active ascent for both men and women. Platelet activation was reduced and delayed under hypobaric conditions, especially in women. TG analysis showed a prothrombotic trend at high altitude, especially after the active ascent. Women had a hypercoagulable phenotype, compared to men at all 3 timepoints, indicated by a higher peak height and endogenous thrombin potential (ETP), and shorter lag time and time-to-peak. In addition, ETP and peak inhibition by thrombomodulin was lower in women after the active ascent, compared to men. Interestingly, data normalisation for subject baseline values indicated an opposing effect of altitude-induced hypoxia on α2-macroglobulin levels and TG lag time between men and women, decreasing in men and increasing in women. We conclude that hypoxia increases TG, as well as FVIII and VWF levels in combination with exercise. In contrast, platelets lose their responsiveness at high altitude, which is most pronounced after heavy exercise. Women had a more pronounced prothrombotic phenotype compared to men, which we theorize is counterbalanced under hypobaric conditions by decreased platelet activation.
Topics: Humans; Male; Female; Adult; Altitude; Thrombin; Hypoxia; Altitude Sickness; von Willebrand Factor; Thrombophilia
PubMed: 38241764
DOI: 10.1016/j.thromres.2023.12.018 -
Thrombosis Research Feb 2024α-macroglobulin (αM) is a versatile endopeptidase inhibitor that plays a role in cell growth, inflammation and coagulation. αM is an inhibitor of key coagulation...
BACKGROUND
α-macroglobulin (αM) is a versatile endopeptidase inhibitor that plays a role in cell growth, inflammation and coagulation. αM is an inhibitor of key coagulation enzyme thrombin. Hypercoagulability due to an excess of thrombin production can cause thrombotic events. Therefore, we investigated the association of αM levels and cardiovascular events in a subset of the general Italian population.
METHODS
We determined αM levels in the baseline samples of a prospective cohort (n = 19,688; age: 55 ± 12 years; 47.8 % men) of the Moli-sani study and investigated the association with the cardiovascular events (n = 432, 2.2 %) in the median follow-up period of 4.3 years. Hazard ratios (HR) with 95 % confidence intervals (CI) were calculated by multivariable Cox regression and adjusted for a large panel of confounding factors.
RESULTS
αM levels above the 90th percentile were significantly associated with cardiovascular disease (CVD) events after full adjustment for age, sex, current smoking, BMI, oral contraceptive use, cardiovascular diseases, hypertension, hypercholesterolemia, diabetes and history of cancer (HR: 1.36; CI: 1.06-1.74). Moreover, high αM was associated with coronary heart disease (CHD; HR: 1.47; CI: 1.12-1.91), but not stroke. Stratification for CVD at baseline showed that high αM levels are associated with CHD events in subjects without CVD at baseline (HR: 1.40; CI: 1.00-1.95) and subjects with CVD at baseline (HR: 1.58; CI: 1.02-2.44).
CONCLUSION
We show in a prospective cohort that high levels of αM could be a risk factor for cardiovascular events, especially coronary heart disease events.
Topics: Male; Humans; Adult; Middle Aged; Aged; Female; Cohort Studies; Cardiovascular Diseases; Prospective Studies; Thrombin; Risk Factors; Coronary Disease; Macroglobulins
PubMed: 38198944
DOI: 10.1016/j.thromres.2024.01.001 -
Frontiers in Veterinary Science 2023The relationship between epilepsy and cognitive dysfunction has been investigated in canines, and memory impairment was prevalent in dogs with epilepsy. Additionally,...
INTRODUCTION
The relationship between epilepsy and cognitive dysfunction has been investigated in canines, and memory impairment was prevalent in dogs with epilepsy. Additionally, canines with epilepsy have greater amyloid-β (Aβ) accumulation and neuronal degeneration than healthy controls. The present study investigated plasma Aβ levels and performed proteomic profiling in dogs with refractory epilepsy and healthy dogs.
METHODS
In total, eight dogs, including four healthy dogs and four dogs with epilepsy, were included in the study. Blood samples were collected to analyze Aβ levels and perform proteomic profiling. Changes in the plasma proteomic profiles of dogs were determined by nano liquid chromatography tandem mass spectrometry.
RESULTS AND DISCUSSION
The plasma Aβ level was significantly higher in dogs with epilepsy (99 pg/mL) than in healthy dogs (5.9 pg/mL). In total, 155 proteins were identified, and of these, the expression of 40 proteins was altered in epilepsy. Among these proteins, which are linked to neurodegenerative diseases, 10 (25%) were downregulated in dogs with epilepsy, whereas 12 (30%) were upregulated. The expression of the acute phase proteins haptoglobin and α2-macroglobulin significantly differed between the groups. Complement factor H and ceruloplasmin were only detected in epilepsy dogs, suggesting that neuroinflammation plays a role in epileptic seizures. Gelsolin, which is involved in cellular processes and cytoskeletal organization, was only detected in healthy dogs. Gene Ontology annotation revealed that epilepsy can potentially interfere with biological processes, including cellular processes, localization, and responses to stimuli. Seizures compromised key molecular functions, including catalytic activity, molecular function regulation, and binding. Defense/immunity proteins were most significantly modified during the development of epilepsy. In Kyoto Encyclopedia of Genes and Genomes pathway analysis, complement and coagulation cascades were the most relevant signaling pathways affected by seizures. The findings suggested that haptoglobin, ceruloplasmin, α2-macroglobulin, complement factor H, and gelsolin play roles in canine epilepsy and Aβ levels based on proteomic profiling. These proteins could represent diagnostic biomarkers that, after clinical validation, could be used in veterinary practice as well as proteins relevant to disease response pathways. To determine the precise mechanisms underlying these relationships and their implications in canine epilepsy, additional research is required.
PubMed: 38192726
DOI: 10.3389/fvets.2023.1258244 -
Frontiers in Neuroscience 2023The peripheral immune system changes in amyotrophic lateral sclerosis (ALS), but the causal relationship between the two is still controversial.
INTRODUCTION
The peripheral immune system changes in amyotrophic lateral sclerosis (ALS), but the causal relationship between the two is still controversial.
METHODS
In this study, we aimed to estimate the causal relationship between peripheral immune markers and ALS using a two-sample Mendelian randomization method. Genome-wide association study (GWAS) data on peripheral blood immune traits from European populations were used for exposure, and ALS summary statistics were used as the outcome. The causal relationship was evaluated by inverse variance weighting, MR-Egger, and weighted median methods and verified by multiple sensitivity analysis.
RESULTS
We found that the increase of one standard deviation of lymphocyte count is related to reducing ALS risk. CD3 on effector memory CD4 T cell, HLA DR CD4 T cell, effector memory CD8 T cell, terminally differentiated CD8 T cell and CD28- CD8 T cell is also a protective factor for ALS. Among the circulating immune protein, the increase of one standard deviation of α-2-macroglobulin receptor-associated protein (α-2-MRAP) and C4b showed associated with low risk of ALS, while Interleukin-21 (IL-21) increases the risk of ALS.
DISCUSSION
Our study further reveals the important role of peripheral immune activity in ALS.
PubMed: 38188028
DOI: 10.3389/fnins.2023.1269354 -
Oncology Dec 2023Introduction - Melanoma is the most aggressive skin cancer, with an increasing occurrence. Despite the recent important improvements due to novel immunotherapy...
Introduction - Melanoma is the most aggressive skin cancer, with an increasing occurrence. Despite the recent important improvements due to novel immunotherapy approaches, when late diagnosed, melanoma prognosis is poor due to the metastatic progression and drug-resistance onset. Therefore, there is an urgent need to identify additional therapeutic targets. Melanoma invasive behavior is related to the activity of metalloproteases, able to degrade extracellular matrix leading to tumor dissemination. A recent study suggested that the most potent proteases inhibitor alpha-2-macroglobulin (A2MG) from plasma of hibernating fishes exerts potent anti-proliferative effects. Our previous studies showed significant reduction of A2MG in sera from mice/human melanoma models. Methods - Gene and protein expression studies have been performed by using platforms and databases available online containing expression data form thousands of patients and healthy controls. Results - We carried out an extensive bioinformatics analysis to evaluate the A2MG gene/protein expression on a large cohort of patients affected by many different cancer types, compared to healthy control subjects, and we found highly significant difference of A2MG expression in 20 out of 31 cancers types (including melanoma) compared to healthy controls. Similar results were also confirmed at proteomic level using another platform available online. Further, we found that higher A2MG expression is significantly related to overall survival in different cancers including melanoma. Conclusion - Our results strongly suggest A2MG as a novel molecular target in melanoma therapy, as well as in other cancer types.
PubMed: 38160662
DOI: 10.1159/000536033 -
Anticancer Research Jan 2024Pregnancy zone protein (PZP), encoded by PZP, belongs to the α-2-macroglobulin superfamily, and plays an important role in inflammatory responses and immune cell...
BACKGROUND/AIM
Pregnancy zone protein (PZP), encoded by PZP, belongs to the α-2-macroglobulin superfamily, and plays an important role in inflammatory responses and immune cell activation in cancer. However, the relationship between gastric cancer (GC) and PZP is poorly studied. This study investigated the clinical significance of PZP expression in GC tissues of patients with locally advanced GC after curative resection.
PATIENTS AND METHODS
Using quantitative polymerase chain reaction, we measured PZP expression in GC tissues and adjacent normal gastric mucosa of 253 patients with pStage II/III GC who underwent curative resection. We compared the expression levels of PZP in GC tissues and adjacent normal gastric mucosa and examined the relationship of PZP expression in GC tissues with clinicopathological factors and overall survival (OS).
RESULTS
PZP expression was significantly associated with histology, venous invasion, and pathological stage. The high PZP expression group had significantly worse OS than did the low expression group (5-year survival 48.6% vs. 68.5%, p=0.0003). Furthermore, in multivariate analysis, high PZP expression was an independent factor for poor OS (hazard ratio=1.984, 95% confidence interval=1.307-3.012, p=0.0013).
CONCLUSION
In post-curative resection patients with locally advanced GC, PZP expression in GC tissue may be a useful prognostic marker.
Topics: Humans; Clinical Relevance; Gastrectomy; Prognosis; Stomach Neoplasms; Pregnancy Proteins
PubMed: 38159976
DOI: 10.21873/anticanres.16820 -
Journal of Alzheimer's Disease Reports 2023The relationship between alpha 2-macroglobulin (A2M) gene and Alzheimer's disease (AD) has been widely studied across populations; however, the results are inconsistent.
BACKGROUND
The relationship between alpha 2-macroglobulin (A2M) gene and Alzheimer's disease (AD) has been widely studied across populations; however, the results are inconsistent.
OBJECTIVE
This study aimed to evaluate the association of A2M gene with AD by the application of meta-analysis.
METHODS
Relevant studies were identified by comprehensive searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratio (OR) with corresponding 95% confidence intervals (CI) was calculated using a random-effects or fixed-effects model. The Cochran Q statistic and I metric was used to evaluate heterogeneity, and Egger's test and Funnel plot were used to assess publication bias.
RESULTS
A total of 62 studies were identified and included in the current meta-analysis. The G allele of rs226380 reduced AD risk (OR: 0.64, 95% CI: 0.47-0.87, pFDR = 0.012), but carrier with the TT genotype was more likely to develop AD in Asian populations (OR: 1.56, 95% CI: 1.12-2.19, pFDR = 0.0135). The V allele of the A2M-I/V (rs669) increased susceptibility to AD in female population (OR, 95% CI: 2.15, 1.38-3.35, pFDR = 0.0024); however, the II genotype could be a protective factor in these populations (OR, 95% CI: 0.43, 0.26-0.73, pFDR = 0.003). Sensitivity analyses confirmed the reliability of the original results.
CONCLUSIONS
Existing evidence indicate that A2M single nucleotide polymorphisms (SNPs) may be associated with AD risk in sub-populations. Future studies with larger sample sizes will be necessary to confirm the results.
PubMed: 38143774
DOI: 10.3233/ADR-230131