Assessment of the levels of some prognostic biomolecules (galectins, ACE2, SCUBE1/2/3) in COVID-19 patients.

Aim: Our aim was to investigate the differences between healthy people and COVID-19 patients in terms of some immunological biomolecules, especially including those related to the inflammation process. Materials & methods: A total of 180 participants (90 healthy controls and 90 COVID-19 patients) were included. The expression levels of eight different inflammation-related biomolecules were measured by the ELISA technique. Results: The mean levels of ACE2, ANG1-7, GAL3, GAL9, SCUBE1, SCUBE2 and SCUBE3 were elevated in COVID-19 patients when compared with healthy controls, while the mean level of GAL2 was lower in COVID-19 patients than controls. Conclusion: To understand the cytokine storm mechanism and related parameters, more detailed studies should be performed investigating more related biomolecules and related signaling pathways.

Assessment of galectins -1, -3, -4, -8, and -9 expression in ovarian carcinoma patients with clinical implications.

BACKGROUND AND AIM: Galectins have been recently tackled by many researchers in the field of cancer due to their role in tumorigenesis, disease progression, and metastasis. Thus, they are currently involved in biomarkers research on several types of cancer. In ovarian cancers, few studies were carried out to evaluate galectins expression profiling. Hence, our present study was executed to evaluate the mRNA expression of galectins -1, -3, -4, -8, and -9 in epithelial ovarian cancers. METHODS: Fifty-six tumor samples of ovarian carcinomas were analyzed for mRNA expression using qRT-PCR, and fold-changes were calculated in comparison to tissue samples of 26 women with normal ovaries. RESULTS: The results of the present paper emphasize the importance of galectins as predictors for targeted therapy. LGALS1, LGALS3, LGALS4, LGALS8, and LGALS9 were found to be mostly overexpressed in ovarian carcinoma patients with the following percentage: 78.6%, 92.9%, 66.1%, 87.5%, and 85.7% respectively. Moreover, galectins -3 and -9 were found to be significantly elevated with lymph node metastasis (p = 0.044 and p = 0.011). Also, upregulation of galectin-1 and -9 were statistically significant in stages IIB, IIC, and IIIB (p = 0.002) in FIGO staging. CA19.9 is positively correlated to galectin-4 expression (p = 0.039). CONCLUSION: Our findings strengthen the role of galectins in carcinogenesis, disease progression, and lymphnode metastasis in ovarian carcinomas. And since these galectins are mostly overexpressed, they could be promising markers for targeted therapy to reduce disease progression and metastasis process.

Value of galectin-3 in the diagnosis of acute coronary syndrome and the assessment of coronary artery lesions.

Aim: To investigate the value of galectin-3 in the diagnosis of acute coronary syndrome (ACS) and the assessment of coronary artery lesions. Methodology: This study recruited 157 patients with coronary artery disease where 102 and 55 of them were subsequently grouped as ACS and non-ACS, respectively. The severity of coronary artery lesions was evaluated by Gensini score and the number of vessels involved. Results: Receiver operator characteristics analyses of galectin-3 yielded an area under the curve of 0.679 in diagnosing ACS. The galectin-3 levels were correlated with Gensini score and the number of vessels involved. Conclusion: Our study demonstrated that galectin-3 is an effective auxiliary biomarker for the diagnosis of ACS and assessment of coronary artery lesions.

Assessment of prognostic and diagnostic value of some biomarkers in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an increasing problem worldwide. Determining a prognosis is important for the management of HCC. AIM: We aimed to investigate the impact of interleukin (IL)-29, galectin-3, leptin, fibronectin and protease-activated receptor-1 on the prognosis and diagnosis of patients with HCC. MATERIALS AND METHODS: 60 HCC patients (75% male) and 20 healthy volunteers (70% male) were enrolled in this prospective study. Serum samples were obtained during the first admission before any adjuvant or metastatic treatments were administered. Serum biomarkers were determined using ELISA kits. RESULTS: All patients had cirrhosis, and the Child - Pugh stages were as follows: 61.5% Child - Pugh A, 35.9% Child - Pugh B and 2.6% Child - Pugh C (61.7% hepatitis B virus, 11.7% hepatitis C virus, 6.7% hepatitis B virus + hepatitis C virus, 11.7% alcoholic and 8.3% cryptogenic). Fifty-three percent of the HCC patients died within a median of 7.5 months. The mean serum level of IL-29 in patients with HCC was higher than that in the control group (32.55 pg/ml vs 11.46 pg/ml, p < 0.015). Galectin-3 levels were significantly higher in the HCC group (6.7 ng/ml vs 1.38 ng/ml, p < 0.001). Fibronectin levels were higher in the control group than in the HCC group (260 635 ng/ml vs 257 353 ng/ml). However, the mean protease-activated receptor-1 and leptin levels were similar between the two groups (p > 0.05). The biomarkers were divided into two groups according to their median level. In the log rank analysis, biomarkers had no effect on survival (p > 0.05). CONCLUSIONS: IL-29 and galectin-3 levels were significantly higher in HCC patients. Although IL-29 and galectin-3 can be used as diagnostic markers for HCC, they had no prognostic value in HCC patients.

Galectins for Diagnosis and Prognostic Assessment of Human Diseases: An Overview of Meta-Analyses.

An increasing number of studies have explored the activities and functions of galectins. However, translation of these researches into clinical practice seems to be lacking. As compared to scattered individual studies, meta-analyses can provide a more comprehensive review of current evidence and reach a more unbiased and powered conclusion by synthesizing data from diverse studies. In this paper, findings from meta-analyses were reviewed to establish the role of galectins in diagnosis and prognostic assessment of various human diseases. First, in patients with cancer, galectin-1 expression is often associated with poorer survival, but galectin-9 expression is associated with better survival. Galectin-3 is a diagnostic biomarker for thyroid cancer and a predictor of worse survival in patients with colorectal cancer and improved survival in patients with gastric cancer. Second, galectin-3 is useful for diagnosis and prognostic assessment of heart failure and prediction of atrial fibrillation and its recurrence. Third, in chronic kidney disease, galectin-3 is valuable for predicting poor survival. Fourth, during pregnancy, galectin-13 is potentially helpful for identifying patients who do not have preeclampsia.

Association of Cardiac Biomarkers With the Kansas City Cardiomyopathy Questionnaire in Patients With Chronic Kidney Disease Without Heart Failure.

Background The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a measure of heart failure (HF) health status. Worse KCCQ scores are common in patients with chronic kidney disease (CKD), even without diagnosed heart failure (HF). Elevations in the cardiac biomarkers GDF-15 (growth differentiation factor-15), galectin-3, sST2 (soluble suppression of tumorigenesis-2), hsTnT (high-sensitivity troponin T), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) likely reflect subclinical HF in CKD. Whether cardiac biomarkers are associated with low KCCQ scores is not known. Methods and Results We studied participants with CKD without HF in the multicenter prospective CRIC (Chronic Renal Insufficiency Cohort) Study. Outcomes included (1) low KCCQ score <75 at year 1 and (2) incident decline in KCCQ score to <75. We used multivariable logistic regression and Cox regression models to evaluate the associations between baseline cardiac biomarkers and cross-sectional and longitudinal KCCQ scores. Among 2873 participants, GDF-15 (adjusted odds ratio 1.42 per SD; 99% CI, 1.19-1.68) and galectin-3 (1.28; 1.12-1.48) were significantly associated with KCCQ scores <75, whereas sST2, hsTnT, and NT-proBNP were not significantly associated with KCCQ scores <75 after multivariable adjustment. Of the 2132 participants with KCCQ ≥75 at year 1, GDF-15 (adjusted hazard ratio, 1.36 per SD; 99% CI, 1.12-1.65), hsTnT (1.20; 1.01-1.44), and NT-proBNP (1.30; 1.08-1.56) were associated with incident decline in KCCQ to <75 after multivariable adjustment, whereas galectin-3 and sST2 did not have significant associations with KCCQ decline. Conclusions Among participants with CKD without clinical HF, GDF-15, galectin-3, NT-proBNP, and hsTnT were associated with low KCCQ either at baseline or during follow-up. Our findings show that elevations in cardiac biomarkers reflect early symptomatic changes in HF health status in CKD patients.

Imaging, biomarker and invasive assessment of diffuse left ventricular myocardial fibrosis in atrial fibrillation.

BACKGROUND: Using cardiovascular magnetic resonance imaging (CMR), it is possible to detect diffuse fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF), which may be independently associated with recurrence of AF after ablation. By conducting CMR, clinical, electrophysiology and biomarker assessment we planned to investigate LV myocardial fibrosis in patients undergoing AF ablation. METHODS: LV fibrosis was assessed by T1 mapping in 31 patients undergoing percutaneous ablation for AF. Galectin-3, coronary sinus type I collagen C terminal telopeptide (ICTP), and type III procollagen N terminal peptide were measured with ELISA. Comparison was made between groups above and below the median for LV extracellular volume fraction (ECV), followed by regression analysis. RESULTS: On linear regression analysis LV ECV had significant associations with invasive left atrial pressure (Beta 0.49, P = 0.008) and coronary sinus ICTP (Beta 0.75, P < 0.001), which remained significant on multivariable regression. CONCLUSION: LV fibrosis in patients with AF is associated with left atrial pressure and invasively measured levels of ICTP turnover biomarker.

Assessment of serum Tim-3 and Gal-9 levels in predicting the risk of infection after kidney transplantation.

Infection remains a major cause of morbidity and mortality after kidney transplantation (KT). Reliable biomarkers to predict post-transplant infection are lacking. We investigated the predictive performance of pre- and post-transplant levels of T-cell immunoglobulin and mucin domain-3 (Tim-3) and Galectin-9 (Gal-9), two pleiotropic immunomodulatory molecules, in early identification of infection. Serum Tim-3 and Gal-9 were paired measured before and 30 days after transplantation (PTD 30) in 95 KT recipients (KTRs). The decline rates of Tim-3 and Gal-9 were calculated relative to pre-transplant levels. KTRs with infection history had significantly higher levels of PTD 30 Tim-3 and Gal-9, and slower decrease rates of Gal-9 compared to non-infected recipients, while no difference was observed between two groups regarding pre-transplant levels. The AUCs for predicting 1-year post-transplant infection were 0.653 and 0.711 for post-transplant Tim-3 and Gal-9, 0.664 and 0.670 for relative Tim-3 and Gal-9, respectively. After adjusting for potential confounders, PTD 30 Tim-3, Gal-9 and relative Gal-9 remained as independent risk factors for post-transplant infection. Our results suggested that PTD 30 Tim-3 and Gal-9 and relative decrease of Gal-9 were promising predictors for identifying KTRs with high risk of infection, while pre-transplant Tim-3 and Gal-9 showed no predictive power to infection.

Assessment of serum galectin-3, methylated arginine and Hs-CRP levels in type 2 diabetes and prediabetes.

PURPOSE: Galectin-3 is associated with the process of inflammation and fibrosis. The aim of this study was both to evaluate of galectin-3, methylated arginines and hs-CRP in subjects with type 2 diabetes and prediabetes and to investigate a relation between serum galectin-3, methylated arginines and hs-CRP levels. METHODS: In this study, all subjects were defined as the control group, type 2 diabetes (n = 84) by fasting plasma glucose and prediabetes (n = 34) by 75-g oral glucose tolerance test. Also, participants with type 2 diabetes were divided into as group I (HbA1c ≤7%, n = 40) and group II (HbA1c ≥7%, n = 44). The analysis of serum methylated arginines levels was analyzed by tandem mass spectrometry. Galectin-3 levels were determined via chemiluminescent microparticle immunoassay (CMIA). RESULTS: Serum galectin-3, ADMA, L-NMMA and SDMA levels were significantly lower in the control group (13.3 ±â€¯3.42; 0.630 (0.13-1.36); 0.176 (0.02-0.53); 0.115 (0.04-0.26), respectively) compared to diabetic subjects (15.71 ±â€¯4.22; 0.825 (0.23-2.80); 0.366 (0.08-1.41); 0.1645 (0.06-0.47), p = 0.002, p = 0.01, p = 0.001 and p = 0.006, respectively). Galectin-3 was positively correlated with hs-CRP (r = 0.295 p = 0.001), L-NMMA (r = 0.181 p = 0.022), HbA1c (r = 0.247 p = 0.002), neopterin (r = 0.160 p = 0.045) and FPG (r = 0.207 p = 0.001) respectively. Also, there was positively correlated ADMA with FPG (r = 0.192 p = 0.016) and eAG (r = 0.235 p = 0.003). CONCLUSIONS: Thus, galectin-3 might be a useful prognostic marker in the population with prediabetes and diabetes. Moreover, it can be a marker showing the condition of developing complications in diabetic patients.

Ultrasound Risk Assessment Combined with Molecular Markers of Galectin-3, c-MET, HBME-1 and CK19 for Diagnosis of Malignant and Benign Thyroid Nodules.

To investigate the effect of ultrasound combined with expression of Galectin-3, c-Met, HBME-1 and CK19 in differentiating malignant from benign thyroid nodules. Forty-six patients with thyroid nodules were studied with ultrasound and immunohistochemical staining of excised thyroid nodules. The data were classified and compared. The immunohistochemical staining revealed 8 benign and 41 malignant thyroid lesions. In ultrasound risk assessment, the malignancy risk was low in four nodules, medium in five and high in 37 with lymphatic metastasis in 26. A significant (P < 0.05) association existed in the expression of Galectin-3 with nodule boundary and lymphatic metastasis, in HBME-1 with nodule micro-calcification and in c-Met with nodule micro-calcification and lymphatic metastasis. CK19 expression was not significantly (P > 0.05) associated with any of ultrasound features of nodule. Galectin-3, c-Met, HBME-1 and CK19 were significantly (P < 0.05) different in malignant and benign thyroid lesions, with a significant (P < 0.01) tendency in all the molecular markers in predicting the malignant from benign lesions. The ultrasound characteristics could significantly (P < 0.001) predict malignant nodules with a significant (P < 0.05) prediction tendency. The scores of Galectin-3, c-Met and CK19 significantly (P < 0.05) increased with increase of ultrasound malignancy risk degree. In malignant and benign lesions differentiated by ultrasound, no significant (P > 0.05) difference existed in HBME-1 expression, however, with ultrasound malignancy risk increase, the score of HBME-1 expression increased significantly (P = 0.03). Galectin-3, c-Met, HBME-1 and CK19 have significantly greater expressions in thyroid malignant than benign lesions and their expression increases with increase of ultrasound malignancy risk. The combination of both ultrasound and molecular markers can be used to differentiate malignant and benign thyroid lesions.

Stochastic phenotypic interconversion in tumors can generate heterogeneity.

Phenotype variations define heterogeneity in biological and molecular systems, and play a crucial mechanistic role, and heterogeneity has been demonstrated in tumor cells. In this work, cells from blood of patients affected by colon cancer were analyzed and sorted using a microfluidic assay based on galactose-active moieties and incubated for culturing in severe combined immunodeficiency (SCID) mice. Based on the results of these experiments, a model based on Markov theory is implemented and discussed to explain the equilibrium existing between phenotypes of cell subpopulations sorted using the microfluidic assay. In combination with the experimental results, the model has many implications for tumor heterogeneity; For example, it displays interconversion of phenotypes, confirming the experiments. Such interconversion generates metastatic cells and implies that targeting circulating tumor cells (CTC) will not be an efficient method for prevention of tumor recurrence. Most importantly, understanding the transitions between cell phenotypes in the cell population can improve understanding of tumor generation and growth.

Intra- and intermolecular interactions of human galectin-3: assessment by full-assignment-based NMR.

Galectin-3 is an adhesion/growth-regulatory protein with a modular design comprising an N-terminal tail (NT, residues 1-111) and the conserved carbohydrate recognition domain (CRD, residues 112-250). The chimera-type galectin interacts with both glycan and peptide motifs. Complete (13)C/(15)N-assignment of the human protein makes NMR-based analysis of its structure beyond the CRD possible. Using two synthetic NT polypeptides covering residues 1-50 and 51-107, evidence for transient secondary structure was found with helical conformation from residues 5 to 15 as well as proline-mediated, multi-turn structure from residues 18 to 32 and around PGAYP repeats. Intramolecular interactions occur between the CRD F-face (the 5-stranded ß-sheet behind the canonical carbohydrate-binding 6-stranded ß-sheet of the S-face) and NT in full-length galectin-3, with the sequence P(23)GAW(26)…P(37)GASYPGAY(45) defining the primary binding epitope within the NT. Work with designed peptides indicates that the PGAX motif is crucial for self-interactions between NT/CRD. Phosphorylation at position Ser6 (and Ser12) (a physiological modification) and the influence of ligand binding have minimal effect on this interaction. Finally, galectin-3 molecules can interact weakly with each other via the F-faces of their CRDs, an interaction that appears to be assisted by their NTs. Overall, our results add insight to defining binding sites on galectin-3 beyond the canonical contact area for ß-galactosides.

Assessment of Galectin-3 Polymorphism in Subjects with Chronic Chagas Disease / Avaliação do Polimorfismo da Galectina-3 em Indivíduos com Doença de Chagas Crônica

AbstractBackground:Galectin-3, a β-galactoside binding lectin, has been described as a mediator of cardiac fibrosis in experimental studies and as a risk factor associated with cardiovascular events in subjects with heart failure. Previous studies have evaluated the genetic susceptibility to Chagas disease in humans, including the polymorphisms of cytokine genes, demonstrating correlations between the genetic polymorphism and cardiomyopathy development in the chronic phase. However, the relationship between the galectin-3 single nucleotide polymorphism (SNP) and phenotypic variations in Chagas disease has not been evaluated.Objective:The present study aimed to determine whether genetic polymorphisms of galectin-3 may predispose to the development of cardiac forms of Chagas disease.Methods:Fifty-five subjects with Chagas disease were enrolled in this observational study. Real-time polymerase chain reaction (PCR) was used for genotyping the variants rs4644 and rs4652 of the galectin-3 gene.Results:For the SNP rs4644, the relative risk for the cardiac form was not associated with the genotypes AA (OR = 0.79, p = 0.759), AC (OR = 4.38, p = 0.058), or CC (OR = 0.39, p = 0.127). Similarly, for the SNP rs4652, no association was found between the genotypes AA (OR = 0.64, p = 0.571), AC (OR = 2.85, p = 0.105), or CC (OR = 0.49, p = 0.227) and the cardiac form of the disease.Conclusion:Our results showed no association between the different genotypes for both SNPs of the galectin-3 gene and the cardiac form of Chagas disease. (Arq Bras Cardiol. 2015; [online].ahead print, PP.0-0).

ResumoFundamento:A galectina-3, uma lectina de ligação à β-galactosidase, foi descrita como um mediador de fibrose cardíaca em estudos experimentais e um fator de risco associado com eventos cardiovasculares em indivíduos com insuficiência cardíaca. Estudos prévios avaliaram a susceptibilidade genética para doença de Chagas em humanos, incluindo polimorfismos dos genes de citocinas, demonstrando correlações entre o polimorfismo genético e o desenvolvimento de cardiomiopatia na fase crônica. No entanto, a relação entre polimorfismos de nucleotídeo único (single nucleotide polymorphism, SNP) e variações fenotípicas na doença de Chagas ainda não foi avaliada.Objetivo:O presente estudo teve como objetivo determinar se os polimorfismos genéticos da galectina-3 podem predispor ao desenvolvimento de formas cardíacas da doença de Chagas.Métodos:Cinquenta e cinco indivíduos com doença de Chagas foram incluídos neste estudo observacional. A genotipagem das variantes rs4644 e rs4652 do gene da galectina-3 foi realizada por PCR (reação em cadeia de polimerase).Resultados:Para o SNP rs4644, não houve associação entre o risco relativo para a forma cardíaca e os genótipos AA (OR = 0,79, p = 0,759), AC (OR = 4,38, p = 0,058), ou CC (OR = 0,39, p = 0,127). Similarmente, para o SNP rs4652, não foi encontrada associação entre os genótipos AA (OR = 0,64, p = 0,571), AC (OR = 2,85, p = 0,105), ou CC (OR = 0,49, p = 0,227) e a forma cardíaca da doença.Conclusão:Nossos resultados não mostraram associação entre os diferentes genótipos para ambos SNPs do gene da galectina-3 e a forma cardíaca da doença de Chagas. (Arq Bras Cardiol. 2015; [online].ahead print, PP.0-0).

Assessment of Galectin-3 Polymorphism in Subjects with Chronic Chagas Disease.

BACKGROUND: Galectin-3, a ß-galactoside binding lectin, has been described as a mediator of cardiac fibrosis in experimental studies and as a risk factor associated with cardiovascular events in subjects with heart failure. Previous studies have evaluated the genetic susceptibility to Chagas disease in humans, including the polymorphisms of cytokine genes, demonstrating correlations between the genetic polymorphism and cardiomyopathy development in the chronic phase. However, the relationship between the galectin-3 single nucleotide polymorphism (SNP) and phenotypic variations in Chagas disease has not been evaluated. OBJECTIVE: The present study aimed to determine whether genetic polymorphisms of galectin-3 may predispose to the development of cardiac forms of Chagas disease. METHODS: Fifty-five subjects with Chagas disease were enrolled in this observational study. Real-time polymerase chain reaction (PCR) was used for genotyping the variants rs4644 and rs4652 of the galectin-3 gene. RESULTS: For the SNP rs4644, the relative risk for the cardiac form was not associated with the genotypes AA (OR = 0.79, p = 0.759), AC (OR = 4.38, p = 0.058), or CC (OR = 0.39, p = 0.127). Similarly, for the SNP rs4652, no association was found between the genotypes AA (OR = 0.64, p = 0.571), AC (OR = 2.85, p = 0.105), or CC (OR = 0.49, p = 0.227) and the cardiac form of the disease. CONCLUSION: Our results showed no association between the different genotypes for both SNPs of the galectin-3 gene and the cardiac form of Chagas disease.

Ras inhibition boosts galectin-7 at the expense of galectin-1 to sensitize cells to apoptosis.

Galectins are a family of ß-galactoside-binding lectins that exert diverse extracellular and intracellular effects. Galectin-7 and galectin-1 show opposing effects on proliferation and survival in different cell types. Galectin-7 is a p53-induced gene and an enhancer of apoptosis, whereas galectin-1 induces tumorigenicity and resistance to apoptosis in several types of cancers. We show here that in cells derived from neurofibromin-deficient (Nf1(-/-)) malignant peripheral nerve sheath tumors (MPNSTs), Ras inhibition by S-trans,trans-farnesylthiosalicylic-acid (FTS; Salirasib) shifts the pattern of galectin expression. Whereas FTS decreased levels of both active Ras and galectin-1 expression, it dramatically increased both the mRNA and protein expression levels of galectin-7. Galectin-7 accumulation was mediated through JNK inhibition presumably resulting from the observed induction of p53, and was negatively regulated by the AP-1 inhibitor JDP2. Expression of galectin-7 by itself decreased Ras activation in ST88-14 cells and rendered them sensitive to apoptosis. This observed shift in galectin expression pattern together with the accompanying shift from cell proliferation to apoptosis represents a novel pattern of Ras inhibition by FTS. This seems likely to be an important phenomenon in view of the fact that both enhanced cell proliferation and defects of apoptosis constitute major hallmarks of human cancers and play a central role in the resistance of MPNSTs to anti-cancer treatments. These findings suggest that FTS, alone or in combination with chemotherapy agents, may be worth developing as a possible treatment for MPNSTs.

Placental protein 13 (PP13): a new biological target shifting individualized risk assessment to personalized drug design combating pre-eclampsia.

BACKGROUND: Pre-eclampsia affects 2-7% of all pregnant women and is a major cause of maternal and fetal morbidity and mortality. The etiology of pre-eclampsia is still unknown but it is well documented that impaired placentation is a major contributor to its development. One of the placenta-specific proteins is placental protein 13 (PP13). Lower first trimester levels of maternal serum PP13 and its encoding placental mRNA are associated with the development of both early and late-onset severe pre-eclampsia. In cases where this protein is mutated, the frequency of pre-eclampsia is higher. METHODS: 19 out of 68 studies on PP13, published between January 2006 and September 2012, were used to evaluate the value of maternal blood PP13 as a marker of pre-eclampsia. RESULTS: A meta-analysis presented in this review shows that low serum levels of PP13 in the first trimester of pregnancy can predict the development of pre-eclampsia later in pregnancy. Although some functions of this protein have been assessed in in vitro experiments, the in vivo functions of PP13 are still unknown, especially when circulating in the maternal bloodstream. A recent pilot study has shown that in gravid rats PP13 causes significant vasodilatation, reduced blood pressure and increased maternal uterine artery remodeling. CONCLUSION: Reviewing these effects of PP13, the authors propose the use of PP13 as a new drug candidate. Replenishing PP13 in those women with low serum levels early in pregnancy may help prepare their vasculature for pregnancy. This novel pharmacological approach to combat pre-eclampsia is presented as a new direction to transfer from individualized risk to personalized prevention.

PP13, maternal ABO blood groups and the risk assessment of pregnancy complications.

BACKGROUND: Placental Protein 13 (PP13), an early biomarker of preeclampsia, is a placenta-specific galectin that binds beta-galactosides, building-blocks of ABO blood-group antigens, possibly affecting its bioavailability in blood. METHODS AND FINDINGS: We studied PP13-binding to erythrocytes, maternal blood-group effect on serum PP13 and its performance as a predictor of preeclampsia and intrauterine growth restriction (IUGR). Datasets of maternal serum PP13 in Caucasian (n = 1078) and Hispanic (n = 242) women were analyzed according to blood groups. In vivo, in vitro and in silico PP13-binding to ABO blood-group antigens and erythrocytes were studied by PP13-immunostainings of placental tissue-microarrays, flow-cytometry of erythrocyte-bound PP13, and model-building of PP13--blood-group H antigen complex, respectively. Women with blood group AB had the lowest serum PP13 in the first trimester, while those with blood group B had the highest PP13 throughout pregnancy. In accordance, PP13-binding was the strongest to blood-group AB erythrocytes and weakest to blood-group B erythrocytes. PP13-staining of maternal and fetal erythrocytes was revealed, and a plausible molecular model of PP13 complexed with blood-group H antigen was built. Adjustment of PP13 MoMs to maternal ABO blood group improved the prediction accuracy of first trimester maternal serum PP13 MoMs for preeclampsia and IUGR. CONCLUSIONS: ABO blood group can alter PP13-bioavailability in blood, and it may also be a key determinant for other lectins' bioavailability in the circulation. The adjustment of PP13 MoMs to ABO blood group improves the predictive accuracy of this test.

Synthesis of bivalent lactosides based on terephthalamide, N,N'-diglucosylterephthalamide, and glycophane scaffolds and assessment of their inhibitory capacity on medically relevant lectins.

Glycan recognition by lectins initiates clinically relevant processes such as toxin binding or tumor spread. Thus, the development of potent inhibitors has a medical perspective. Toward this goal, we report the synthesis of both rigid and flexible bivalent lactosides on scaffolds that include secondary and tertiary terephthalamides and N,N'-diglucosylterephthalamides. Construction of these compounds involved Schmidt-Michel glycosidation, and amide coupling or Ugi reactions of relevant glycosyl amines in key steps. A glycocluster based on a rigid glycophane was also prepared from coupling of a glucuronic acid derivative and p-xylylenediamine with subsequent ring-closing metathesis. Finally, a more flexible bivalent lactoside was produced from lactosyl azide with use of the copper-catalyzed azide-alkyne cycloaddition. Distances between lactose residues were analyzed computationally as were their orientations for the relatively rigid subset of compounds. Distinct spacing properties were revealed by varying the structure of the scaffold or by varying the location of the lactose residue on the scaffold. To relate these features to bioactivity a plant toxin and human adhesion/growth-regulatory galectins were used as sensors in three types of assay, i.e. measuring agglutination of erythrocytes, binding to glycans of a surface-immobilized glycoprotein, or binding to human cells. Methodologically, the common hemeagglutination assay was found to be considerably less sensitive than both solid-phase and cell assays. The bivalent compounds were less effective at interfering with glycoprotein binding to the plant toxin than to human lectins. Significantly, a constrained compound was identified that displayed selectivity in its inhibitory potency between galectin-3 and its proteolytically processed form. Conversely, compounds with a high degree of flexibility showed notable ability to protect human cells from plant toxin binding. The applied conjugation chemistry thus is compatible with the long-term aim to produce potent and selective lectin inhibitors.