Diagnostic Value of Serum Galectin-3 Binding Protein Level in Patients with Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) still lacks effective biomarkers to assist in its diagnosis and prognosis. Galectin-3 binding protein (Gal-3BP) plays a role in immune and inflammatory diseases. OBJECTIVE: This study aimed to evaluate Gal-3BP as a prognostic and predictive factor in patients with PAH. METHODS: From January 2017 to December 2019, we enrolled 167 consecutive PAH patients and 58 healthy controls. Right heart catheterization (RHC) was used to diagnose PAH. Serum Gal-3BP levels were measured by high-sensitivity human enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum Gal-3BP levels in the PAH group were significantly higher compared with the control group (4.87±2.09 vs 2.22±0.86 µg/mL, p<0.001). Gal-3BP level was correlated with several hemodynamic parameters obtained from RHC (p<0.001). Multivariate linear regression analysis showed that Gal-3BP was a risk factor for PAH (odds ratio (OR)=2.947, 95% CI: 1.821-4.767, p<0.001). The optimal cut-off value of serum Gal-3BP level for predicting PAH was 2.89 µg/mL (area under the curve (AUC)=0.860, 95 % CI: 0.811-0.910, p<0.001). Kaplan-Meier analysis showed that Gal-3BP levels above the median (4.87 µg/mL) were associated with an increased risk of death in patients with PAH (hazard ratio (HR)=8.868, 95 % CI: 3.631-21.65, p<0.0001). Cox multivariate risk regression analysis showed that Gal-3BP was a risk factor for death in PAH patients (HR=2.779, 95 % CI: 1.823-4.237, p<0.001). CONCLUSION: Serum Gal-3BP levels were increased in patients with PAH, and levels of Gal-3BP were associated with the severity of PAH. Gal-3BP might have predictive value for the diagnosis and prognosis of PAH.

TNBC-derived Gal3BP/Gal3 complex induces immunosuppression through CD45 receptor.

A preliminary study investigating immunotherapy strategies for aggressive triple negative breast cancer (TNBC) revealed an overexpression of genes involved in the release of extracellular vesicles (EVs). Proteins expressed by EVs play a role in reprogramming the tumor microenvironment and impeding effective responses to immunotherapy. Galectin 3 (Gal3), found in the extracellular space of breast cancer cells, downregulates T-cell receptor expression. Gal3 binds to several receptors, including CD45, which is required for T-cell receptor activation. Previously, we reported a novel tumor escape mechanism, whereby TNBC cells suppress immune cells through CD45 intracellular signals. The objective of this study was to determine the potential association of Gal3 with TNBC-secreted EVs induction of immunosuppression via the CD45 signaling pathway. EVs were isolated from MDA-MB-231 cells and the plasma of patients with TNBC. Mass spectrometry revealed the presence of Gal3 binding protein (Gal3BP) in the isolated small EVs, which interacted with TNBC secreted Gal3. Gal3BP and Gal3 form a complex that induces a significant increase in T-regulatory cells in peripheral blood mononuclear cells (PBMCs). This increase correlates with a significant increase in suppressive interleukins 10 and 35. Blocking the CD45 receptor in PBMCs cultured with tumor-derived EVs impeded the immunosuppression exerted by the Gal3BP/Gal3 complex. This led to an increase in IFN-γ and the activation of CD4, CD8 and CD56 effector cells. This study suggests a tumor escape mechanism that may contribute to the development of a different immunotherapy strategy that complements current therapies used for TNBC.

LGALS3BP is a potential target of antibody-drug conjugates in oral squamous cell carcinoma.

OBJECTIVE: The aim of the present study was to evaluate the expression of intracellular and vesicular LGALS3BP in oral squamous cell carcinoma (OSCC) patients and available cell lines to explore its potential as a target for antibody-drug conjugate (ADC) therapy. METHODS: Free and vesicular LGALS3BP expression levels were evaluated in cancer tissues from a cohort of OSCC patients as well as in a panel of OSCC cell lines through immunohistochemistry, qRT-PCR, Western Blot analysis, and ELISA. RESULTS: LGALS3BP resulted in being highly expressed in the cytoplasm of tumour cells in OSCC patient tissues. A strong correlation was found between high LGALS3BP expression levels and aggressive histological features of OSCC. Biochemistry analysis performed on OSCC cell lines showed that LGALS3BP is expressed in all the tested cell lines and highly enriched in cancer-derived extracellular vesicles. Moreover, LGALS3BP high-expressing HOC621 and CAL27 OSCC cell lines showed high sensitivity to the ADC-payload DM4, with an IC50 around 0.3 nM. CONCLUSIONS: The present study highlights that LGALS3BP is highly expressed in OSCC suggesting a role as a potential diagnostic biomarker and therapeutic target for ADC-based therapy.

Visualizing Galectin-3 Binding Protein Expression with ImmunoPET.

Galectin-3 binding protein (Gal-3BP) is a glycoprotein that is overexpressed and secreted by several cancers and has been implicated as a marker of both tumor progression and poor prognosis in melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and breast cancer. The expression of Gal-3BP by a variety of neoplasms makes it an enticing target for both diagnostics and therapeutics, including immuno-positron emission tomography (immunoPET) probes and antibody-drug conjugates (ADCs). Herein, we report the development, in vitro characterization, and in vivo evaluation of a pair of Gal-3BP-targeting radioimmunoconjugates for 89Zr-immunoPET. A humanized anti-Gal-3BP antibody, 1959, and its corresponding ADC, 1959-sss/DM4 (DM4 = ravtansine), were modified with desferrioxamine (DFO) to yield DFO-1959 and DFO-1959-sss/DM4 immunoconjugates bearing 1-2 DFO/monoclonal antibody. Both DFO-modified immunoconjugates retained their affinity for Gal-3BP in enzyme-linked immunosorbent assay experiments. The chelator-bearing antibodies were radiolabeled with zirconium-89 (t1/2 ≈ 3.3 d) to produce radioimmunoconjugates ─ [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 ─ with high specific activity (>444 MBq/mg, >12 mCi/mg) and stability (>80% intact after 168 h in human serum at 37 °C). In mice bearing subcutaneous Gal-3BP-secreting A375-MA1 xenografts, [89Zr]Zr-DFO-1959 clearly delineated tumor tissue, reaching a maximum tumoral activity concentration (54.8 ± 15.8%ID/g) and tumor-to-background contrast (tumor-to-blood = 8.0 ± 4.6) at 120 h post-injection. The administration of [89Zr]Zr-DFO-1959 to mice bearing subcutaneous Gal-3BP-expressing melanoma patient-derived xenografts produced similarly promising results. [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 exhibited nearly identical pharmacokinetic profiles in the mice bearing A375-MA1 tumors, though the latter produced higher uptake in the spleen and kidneys. Both [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 effectively visualized Gal-3BP-secreting tumors in murine models of melanoma. These results suggest that both probes could play a role in the clinical imaging of Gal-3BP-expressing malignancies, particularly as companion theranostics for the identification of patients likely to respond to Gal-3BP-targeted therapeutics such as 1959-sss/DM4.

90K/Mac-2 BP Is a New Predictive Biomarker of Response to Infliximab Therapy in IBD Patients.

Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and Ulcerative Colitis (UC), are multifactorial disorders characterized by a chronic inflammatory status with the secretion of cytokines and immune mediators. Biologic drugs targeting pro-inflammatory cytokines, such as infliximab, are broadly used in the treatment of IBD patients, but some patients lose responsiveness after an initial success. The research into new biomarkers is crucial for advancing personalized therapies and monitoring the response to biologics. The aim of this single center, observational study is to analyze the relationship between serum levels of 90K/Mac-2 BP and the response to infliximab, in a cohort of 48 IBD patients (30 CD and 18 UC), enrolled from February 2017 to December 2018. In our IBD cohort, high 90K serum levels were found at baseline in patients who then developed anti-infliximab antibodies at the fifth infusion (22 weeks after the first), becoming non-responders (9.76 ± 4.65 µg/mL compared to 6.53 ± 3.29 µg/mL in responder patients, p = 0.005). This difference was significant in the total cohort and in CD, but not significant in UC. We then analyzed the relationship between serum levels of 90K, C-reactive protein (CRP), and Fecal calprotectin. A significant positive correlation was found at baseline between 90K and CRP, the most common serum inflammation marker (R = 0.42, p = 0.0032). We concluded that circulating 90K could be considered a new non-invasive biomarker for monitoring the response to infliximab. Furthermore, 90K serum level determination, before the first infliximab infusion, in association with other inflammatory markers such as CRP, could assist in the choice of biologics for the treatment of IBD patients, thereby obviating the need for a drug switch due to loss of response, and so improving clinical practice and patient care.

Transfer of Galectin-3-Binding Protein via Epididymal Extracellular Vesicles Promotes Sperm Fertilizing Ability and Developmental Potential in the Domestic Cat Model.

Key proteins transferred by epididymal extracellular vesicles (EVs) to the transiting sperm cells contribute to their centrosomal maturation and developmental potential. Although not reported in sperm cells yet, galectin-3-binding protein (LGALS3BP) is known to regulate centrosomal functions in somatic cells. Using the domestic cat model, the objectives of this study were to (1) detect the presence and characterize the transfer of LGALS3BP via EVs between the epididymis and the maturing sperm cells and (2) demonstrate the impact of LGALS3BP transfer on sperm fertilizing ability and developmental potential. Testicular tissues, epididymides, EVs, and spermatozoa were isolated from adult individuals. For the first time, this protein was detected in EVs secreted by the epididymal epithelium. The percentage of spermatozoa with LGALS3BP in the centrosome region increased as cells progressively incorporated EVs during the epididymal transit. When LGALS3BP was inhibited during in vitro fertilization with mature sperm cells, less fertilized oocytes and slower first cell cycles were observed. When the protein was inhibited in epididymal EVs prior to incubation with sperm cells, poor fertilization success further demonstrated the role of EVs in the transfer of LGALS3BP to the spermatozoa. The key roles of this protein could lead to new approaches to enhance or control fertility in clinical settings.

Urine proteomics by mass spectrometry identifies proteins involved in key pathogenic pathways in patients with juvenile dermatomyositis.

OBJECTIVES: To identify and validate biomarkers in JDM patients using a multiplexing tandem mass tag urine proteome profiling approach. METHODS: First morning void urine samples were collected from JDM patients (n = 20) and healthy control subjects (n = 21) and processed for analysis using a standardized liquid chromatography-tandem mass spectrometry approach. Biomarkers with significantly altered levels were correlated with clinical measures of myositis disease activity and damage. A subset of candidate biomarkers was validated using commercially available ELISA kits. RESULTS: In total, 2348 proteins were detected in the samples, with 275 proteins quantified across all samples. Among the differentially altered proteins, cathepsin D and galectin-3 binding protein were significantly increased in the urine of JDM patients (adjusted P < 0.05), supporting previous findings in myositis patients. These two candidate biomarkers were confirmed with ELISAs. Cathepsin D positively correlated with Myositis Damage Index (r = 0.57, P < 0.05) and negatively correlated with the Childhood Myositis Assessment Scale (r = -0.54, P < 0.05). We also identified novel JDM candidate biomarkers involved with key features of myositis, including extracellular matrix remodelling proteins. CONCLUSION: This study confirmed the presence of several proteins in the urine of JDM patients that were previously found to be elevated in the blood of myositis patients and identified novel candidate biomarkers that require validation. These results support the use of urine as a source for biomarker development in JDM.

Predictive plasma biomarker for gestational diabetes: A case-control study in China.

OBJECTIVE: This study aims to find new plasma biomarkers in early pregnancy. DESIGN: The original study enrolled 1219 pregnant women. We investigated protein expression profiles of placental tissues from women with GDM (n = 89) and normal glucose tolerance (NGT) (n = 83). Maternal plasma samples between two groups in early and middle pregnancy were used for validation of candidate biomarkers. METHODS: Differentially expressed proteins (DEPs) were identified by label-free quantitative proteomics from human placenta samples between two groups. Several DEPs were validated in plasma by Luminex assays. An automatic biochemical analyzer was used to detect blood lipid indexes. The associations of GAL-3BP with biochemical indicators were demonstrated by Pearson's correlation analysis. Binary logistic regression was used to model potential predictive indicators in early pregnancy of GDM. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic accuracy of the predictive model and the value of GAL-3BP. RESULTS: 123 DEPs were found in placenta involved in ribosomal function, pancreatic secretion, oxidative phosphorylation, and inflammatory signaling pathway. Plasma GAL-3BP are significantly higher in women with GDM than NGT in the first (p = 0.008) and second (p = 0.026) trimester, but C9 and VWF have no difference. The predictive value of GAL-3BP in the first trimester of pregnancy (AUC 0.64) is better than that in the second trimester (AUC 0.61), and combined predictive model of TG and GAL-3BP at early pregnancy has greater predictive and diagnostic value for GDM (AUC 0.69) than individual GAL-3BP (AUC 0.64). CONCLUSIONS: Plasma TG and GAL-3BP has good predictive and diagnostic value at early pregnancy, suggesting that these two indicators may be used as biomarkers for early prediction and diagnosis of GDM. SIGNIFICANCE: The advantage of this study is that circulating TG and GAL-3BP might differentiate the progress of women with GDM and normal glucose tolerance (NGT) at the early stage of pregnancy. It is the first study to consider the role of GAL-3BP as an early predictive biomarker in the development of GDM during the whole pregnancy. Another advantage is that volunteers in this study were recruited from two provinces in China to eliminate the impacts of environmental confounders. The similar changes of blood glucose/lipid indicators for women with GDM and NGT in both regions was found in the first and second trimester of pregnancy, which added to the reliability of analytical results.

Urine Galectin-3 binding protein reflects nephritis activity in systemic lupus erythematosus.

BACKGROUND: Lupus nephritis (LN) is a major and severe organ involvement in systemic lupus erythematosus (SLE), whose diagnosis and treatment necessitate to perform kidney biopsy, which is an invasive procedure. Non-invasive urine biomarkers are an active area of investigation to support LN diagnosis and management. OBJECTIVE: To investigate the role of urinary galectin-3 binding protein (u-Gal-3BP) as a candidate biomarker of renal disease in biopsy proven LN. PATIENTS AND METHODS: Levels of u-Gal-3BP were investigated in a cross-sectional fashion by ELISA in 270 subjects: 86 LN patients, 63 active SLE patients with no kidney involvement, 73 SLE patients with inactive disease and 48 age and sex-matched population-based controls (PBC). Moreover, urine samples were analysed separately by ELISA for additional markers of kidney pathology: neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), kidney injury molecule-1 (KIM-1) and galectin-3 (Gal-3). The concentrations of all studied molecules were normalized to urine creatinine levels. In 10 patients, post-treatment levels of the biomarkers were measured. RESULTS: Normalized u-Gal-3BP levels were higher in LN patients compared to the other groups (p < .0001). Comparing different LN classes, u-Gal-3BP levels were higher among patients with proliferative (class III/IV) and membranous (class V) as compared to mesangial (class II) forms (p = .04). In proliferative forms, u-Gal-3BP levels correlated with the activity index in renal biopsies (r = 0.42, p = .004). Moreover, in a subset of 10 patients with repeated kidney biopsy and urine sampling before and after induction treatment, a significant decrease of u-Gal-3BP was observed (p = .03). Among the other markers, KIM-1 was also able to discriminate LN from the other groups, while NGAL, OPN and Gal-3 could not in this cohort. CONCLUSION: Given its ability to discriminate LN patients from active non-renal and inactive SLE patients, the observed correlation with the activity index in renal biopsies, and its levels declining following treatment, u-Gal-3BP shows promise as a non-invasive urinary biomarker to help detecting and to monitor renal involvement in SLE patients and should be validated in larger cohorts.

Placental galectin-3 is reduced in early-onset preeclampsia.

Preeclampsia is a disease of pregnancy responsible for significant maternal and neonatal mortality. Galectin-3 is a ß-Galactoside binding protein. This study aimed to characterise galectin-3 in women with preeclampsia and human trophoblast stem cells (hTSCs). Galectin-3 was measured in placental lysates and plasma collected from patients with early-onset preeclampsia (delivered <34 weeks' gestation) and gestation matched controls. Placental galectin-3 protein was significantly reduced in 43 women with early-onset preeclampsia compared to 21 controls. mRNA expression of LGALS3 (galectin-3 encoding gene) was reduced in 29 women with early-onset preeclampsia, compared to 18 controls (p = 0.009). There was no significant difference in plasma galectin-3 protein in 46 women with early-onset preeclampsia compared to 20 controls. In a separate cohort of samples collected at 36 weeks' gestation, circulating galectin-3 was not altered in 23 women who later developed preeclampsia, versus 182 who did not. In syncytialised hTSCs, hypoxia increased mRNA expression of LGALS3 (p = 0.01). Treatment with inflammatory cytokines (TNF-α and IL-6) had no effect on LGALS3 mRNA expression. However, TNF-α treatment caused an increase in mRNA expression of LGALS3BP (galectin-3 binding protein encoding gene) in hTSCs (p = 0.03). This study showed a reduction of galectin-3 in placenta from pregnancies complicated by early-onset preeclampsia. LGALS3 mRNA expression was dysregulated by hypoxia exposure in placental stem cells.

Antibody-mediated blockade for galectin-3 binding protein in tumor secretome abrogates PDAC metastasis.

The major challenges in pancreatic ductal adenocarcinoma (PDAC) management are local or distant metastasis and limited targeted therapeutics to prevent it. To identify a druggable target in tumor secretome and to explore its therapeutic intervention, we performed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis of tumors obtained from a patient-derived xenograft model of PDAC. Galectin-3 binding protein (Gal-3BP) is identified as a highly secreted protein, and its overexpression is further validated in multiple PDAC tumors and primary cells. Knockdown and exogenous treatment of Gal-3BP showed that it is required for PDAC cell proliferation, migration, and invasion. Mechanistically, we revealed that Gal-3BP enhances galectin-3-mediated epidermal growth factor receptor signaling, leading to increased cMyc and epithelial-mesenchymal transition. To explore the clinical impact of these findings, two antibody clones were developed, and they profoundly abrogated the metastasis of PDAC cells in vivo. Altogether, our data demonstrate that Gal-3BP is an important therapeutic target in PDAC, and we propose its blockade by antibody as a therapeutic option for suppressing PDAC metastasis.

Urinary galectin-3 binding protein (G3BP) as a biomarker for disease activity and renal pathology characteristics in lupus nephritis.

OBJECTIVE: There is an urgent need to identify novel biomarkers of LN to reflect renal histological changes. This study aims to investigate urinary G3BP levels in LN patients and their association with renal disease activity both clinically and pathologically. METHODS: This is a cross-sectional study. A total of 119 lupus nephritis patients were recruited. Thirty patients with chronic kidney diseases (CKD) and 27 healthy volunteers were also recruited as controls. Urinary G3BP was tested by ELISA. Renal histopathology was reviewed by an experienced renal pathologist. Other clinical variables were collected through chart review. RESULTS: The levels of uG3BP were significantly increased in active LN patients compared to those in inactive LN (p<0.001), CKD patients (p=0.01), and healthy controls (p<0.001). ROC analysis indicated a good discrimination ability of uG3BP to differentiate active LN from CKD patients (AUC=0.7), inactive LN (AUC=0.76), or healthy controls (AUC=0.87). uG3BP was positively correlated with SLEDAI (ρ=0.352, p<0.001), rSLEDAI (ρ=0.302, p<0.001), and SLICC RAS (ρ=0.465, p<0.001), indicating a role as a biomarker of disease activity. It also correlated with clinical parameters, including 24-h urine protein, ESR, and serum C3 levels. In patients with 24-h urine protein > 3.0 g/24h, uG3BP levels were higher in proliferative LN than in membranous LN (p=0.04). They could discriminate the two pathogenic types of LN (AUC=0.72), and they also positively correlated with AI (ρ=0.389, p=0.008) and scores of hyaline deposits (ρ=0.418, p=0.006). While in patients with 24-h urine protein ≤ 3.0 g/24h, uG3BP levels were not significantly different between proliferative and membranous LN, and there was no apparent relationship between uG3BP levels with AI or with scores of hyaline deposits, but they correlated positively with scores of cellular/fibrocellular crescents (ρ=0.328, p=0.04). CONCLUSION: uG3BP is a non-invasive biomarker for clinically and histologically reflecting disease activity. It is associated with active histological changes and can be used as a surrogate biomarker when the renal biopsy is impractical.

Plasma-Derived Extracellular Vesicles Reveal Galectin-3 Binding Protein as Potential Biomarker for Early Detection of Glioma.

Gliomas are the most common type of the malignant brain tumor, which arise from glial cells. They make up about 40% of all primary brain tumors and around 70% of all primary malignant brain tumors. They can occur anywhere in the central nervous system (CNS) and have a poor prognosis. The average survival of glioma patients is approximately 6-15 months with poor aspects of life. In this edge, identification of proteins secreted by cancer cells is of special interest because it may provide a better understanding of tumor progression and provide early diagnosis of the diseases. Extracellular vesicles (EVs) were isolated from pooled plasma of healthy controls (n=03) and patients with different grades of glioma (Grade I or II or III, n=03 each). Nanoparticle tracking analysis, western blot, and flow cytometry were performed to determine the size, morphology, the concentration of glioma-derived vesicles and EV marker, CD63. Further, iTRAQ-based LC-MS/MS analysis of EV protein was performed to determine the differential protein abundance in extracellular vesicles across different glioma grades. We further verified galectin-3 binding protein (LGALS3BP) by ELISA in individual blood plasma and plasma-derived vesicles from control and glioma patients (n=40 each). Analysis by Max Quant identified 123 proteins from the pooled patient exosomes, out of which 34, 21, and 14 proteins were found to be differentially abundant by more than 1.3-fold in the different grades of glioma grade I, pilocytic astrocytoma; grade II, diffuse astrocytoma; grade III, anaplastic astrocytoma, respectively, in comparison with the control samples. A total of seven proteins-namely, CRP, SAA2, SERPINA3, SAA1, C4A, LV211, and KV112-showed differential abundance in all the three grades. LGALS3BP was seen to be upregulated across the different grades, and ELISA analysis from individual blood plasma and plasma-derived extracellular vesicles confirmed the increased expression of LGALS3BP in glioma patients (p<0.001). The present study provides LGALS3BP as a potential biomarker for early detection of glioma and improve survival outcome of the patient. The present study further provides the information of progression and monitoring the tumor grades (grade 1, grade II, grade III).

Association of Serum Galectin-3-Binding Protein and Metabolic Syndrome in a Chinese Adult Population.

Background: Galectin-3-binding protein (GAL-3BP) is a ubiquitous and multifunctional secreted glycoprotein, which functions in innate immunity and has been highlighted as a potential mediator of adipose inflammation in obesity. In this study, we aimed to identify whether GAL-3BP is a novel biological marker for metabolic syndrome (MetS). Methods: The biochemical and anthropometric variables of the 570 participants in this study were evaluated using standard procedures. Their serum GAL-3BP levels were measured using enzyme-linked immunosorbent assay (ELISA), while the association between the glycoprotein and MetS was analyzed using multiple logistic regression analyses. Moreover, an experimental MetS model was established. The expression of GAL-3BP in serum and adipose tissue was measured using ELISA and western blotting. Lipid accumulation was determined with the use of immunohistochemistry and immunofluorescent staining. Results: The serum GAL-3BP level was found to be positively associated with MetS. The logistic regression analyses demonstrated that participants expressing the upper levels of GAL-3BP were more likely to develop MetS than those expressing less of the glycoprotein (OR = 2.39, 95%CI: 1.49, 3.83). The association between the serum GAL-3BP level and MetS was found preferentially in postmenopausal women (OR = 2.30, 95%CI: 1.31, 4.05). In addition, GAL-3BP was increased in the serum and visceral adipose tissue (VAT) of high fat diet (HFD) mice. Moreover, GAL-3BP was highly expressed in VAT macrophages. Conclusions: This study confirmed serum GAL-3BP to be positively associated with MetS, highlighting it as a useful biological marker of MetS in Chinese participants.

Serum galectin-3 and galectin-3 binding protein levels in systemic lupus erythematosus and cutaneous lupus erythematosus.

INTRODUCTION: The roles of galectin-3 (Gal-3) and galectin-3 binding protein (G3BP) in systemic lupus erythematosus (SLE) are of ongoing interest, but the data are insufficient due to highly limited available studies. There are no data on cutaneous lupus erythematosus (CLE). AIM: To assess serum Gal-3 and G3BP concentrations in SLE patients with and without LE-specific skin lesions, CLE patients and to correlate levels of proteins with clinical and laboratory parameters. MATERIAL AND METHODS: The study included 71 SLE patients with and without LE-specific skin lesions, 23 CLE patients and 40 controls. Gal-3 and G3BP were measured by specific enzyme-linked immunosorbent assays (ELISA). RESULTS: Serum Gal-3 and G3BP concentrations were significantly higher in SLE with and without LE-specific lesions compared to controls, but without differences between SLE groups. Gal-3 and G3BP levels were also elevated in CLE compared to controls (p = 0.001, p = 0.005; respectively). There was a positive correlation between G3BP level and CLASI activity score both in CLE (r = 0.55, p = 0.006) and in SLE patients with LE-specific lesions (r = 0.36, p = 0.02). G3BP and Gal-3 levels did not differ in SLE with LE-specific lesions and CLE. There was a positive correlation between serum G3BP level and the SLEDAI score in SLE patients (r = 0.26, p = 0.03). CONCLUSIONS: Our findings indicate that serum G3BP and Gal-3 are elevated in CLE. Additionally, G3BP might be associated with the extent of skin lesions. There are no differences between G3BP and Gal-3 concentrations in SLE with and without LE-specific skin lesions.

Systemic Lupus Erythematosus Presenting as Pulmonary Embolism After Liposuction: A Clinical Conundrum.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a wide array of presentations and a predilection to affect women of certain ethnic backgrounds. The hallmark of the disease is multisystem involvement, dispersed in time and severity. Usual pulmonary involvement includes pleuritis, pleural effusions, pneumonitis, shrinking lung syndrome, pulmonary hypertension, and alveolar hemorrhage. Pulmonary embolism (PE) is a relatively unusual presentation of SLE. We present the case of a 28-year-old Hispanic female who presented with shortness of breath and chest pain after liposuction and was found to have a PE. Fat embolism was ruled out. The absence of overt signs and symptoms and traditional risk factors prompted a fragmentary workup. This led to the detection of antibodies sensitive and specific for SLE, in the absence of overt signs and symptoms. We revive the concept of latent lupus, a condition construed as early lupus. Since our patient was lost to follow up, we were unable to complete workup for SLE, but firmly suspect direct causation between SLE and PE. Further studies are needed to establish pathogenesis in order to facilitate early diagnosis and prevent morbidity and mortality from PE.

Galectin-3 Binding Protein, Depression, and Younger Age Were Independently Associated With Alexithymia in Adult Patients With Type 1 Diabetes.

Aims: Alexithymia has been linked to cardiovascular disease. The aim was to explore whether the immuno-inflammatory variables galectin-3 binding protein (Gal3BP), soluble (s)CD163 and galectin-3 were independently associated with alexithymia, while controlling for known risk factors for cardiovascular disease, such as depression, anxiety, impaired glycemic control, obesity, smoking, and physical inactivity in patients with type 1 diabetes (T1D). Methods: Cross-sectional design. The participants were consecutively recruited from one diabetes out-patient clinic. Alexithymia, depression and anxiety were assessed by self-report instruments. Blood samples, anthropometrics, and blood pressure were collected, supplemented with data from electronic health records. High Gal3BP was defined as ≥3.3 µg/ml, high sCD163 as ≥0.6 µg/ml, high galectin-3 as ≥2.6 ng/ml, impaired glycemic control as HbA1c >70 mmol/mol (>8.6%) and abdominal obesity as waist circumference ≥ 1.02 m for men and ≥ 0.88 m for women. Results: Two hundred and ninety two patients participated (men 56%, aged 18-59 years, alexithymia prevalence 15%). Patients with alexithymia had higher prevalence of depression (34 vs. 6%, p < 0.001), anxiety (61 vs. 30%, p < 0.001), high Gal3BP levels (39 vs. 17%, p = 0.004), high HbA1c levels (46 vs. 24%, p = 0.006), and abdominal obesity (29 vs. 15%, p = 0.045). Depression [adjusted odds ratio (AOR) 6.5, p < 0.001], high Gal3BP levels (AOR 2.4, p = 0.035), and age (AOR 0.96, p = 0.027) were independently associated with alexithymia. Abdominal obesity (AOR 4.0, p < 0.001), high Gal3BP levels (AOR 2.8, p = 0.002), and depression (AOR 2.9, p = 0.014) were associated with high HbA1c. Abdominal obesity and anxiety were associated [Crude odds ratio (COR) 2.4, p = 0.006]. Conclusions: T1D patients with alexithymia had higher prevalence of high Gal3BP levels, depression, impaired glycemic control, anxiety, and abdominal obesity, which are known risk factors for cardiovascular disease. Only high Gal3BP levels, depression, and younger age were independently associated with alexithymia in adult patients with T1D.

Elevated serum levels of galectin-3 binding protein are associated with insulin resistance in non-diabetic women after menopause.

OBJECTIVE: Galectin-3 binding protein (Gal-3BP) is one of the major fucosylated glycoprotein family members and has recently been implicated in non-alcoholic fatty liver disease, hyperlipaemia and coronary artery disease. Here, we analysed the serum concentrations of Gal-3BP in menopausal women to evaluate the association of circulating Gal-3BP and insulin resistance in females after menopause. MATERIALS AND METHODS: We evaluated serum levels of Gal-3BP in sixty-two non-diabetic women with menopausal status for at least one year. The clinical features, biochemical profiles and homeostasis model assessment of insulin resistance (HOMA-IR) indices were obtained routinely. RESULTS: Gal-3BP levels increased in women with higher HOMA-IR indices and were positively correlated with HOMA-IR indices. The Gal-3BP level was also an independent risk factor for a high HOMA-IR index and showed the most influence on the HOMA-IR index compared to fasting plasma glucose, triglyceride, age and body mass index. The cut-off value of the serum Gal-3BP level was 2234.32 ng/ml, with areas under the ROC curve (AUCs) of 0.68 (HOMA-IR index 1.5), 0.81 (HOMA-IR index 2.0) and 0.93 (HOMA-IR index 2.5). CONCLUSION: Serum levels of Gal-3BP are associated with impaired insulin sensitivity in non-diabetic menopausal women.

Galectin 3-binding protein suppresses amyloid-ß production by modulating ß-cleavage of amyloid precursor protein.

Alzheimer's disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of ß-amyloid (Aß) peptides. Aß is produced from amyloid precursor protein (APP) that is sequentially cleaved by ß- and γ-secretases. Therefore, APP processing has been a target in therapeutic strategies for managing AD; however, no effective treatment of AD patients is currently available. Here, to identify endogenous factors that modulate Aß production, we performed a gene microarray-based transcriptome analysis of neuronal cells derived from human induced pluripotent stem cells, because Aß production in these cells changes during neuronal differentiation. We found that expression of the glycophosphatidylinositol-specific phospholipase D1 (GPLD1) gene is associated with these changes in Aß production. GPLD1 overexpression in HEK293 cells increased the secretion of galectin 3-binding protein (GAL3BP), which suppressed Aß production in an AD model, neuroglioma H4 cells. Mechanistically, GAL3BP suppressed Aß production by directly interacting with APP and thereby inhibiting APP processing by ß-secretase. Furthermore, we show that cells take up extracellularly added GAL3BP via endocytosis and that GAL3BP is localized in close proximity to APP in endosomes where amyloidogenic APP processing takes place. Taken together, our results indicate that GAL3BP may be a suitable target of AD-modifying drugs in future therapeutic strategies for managing AD.

Female sex, high soluble CD163, and low HDL-cholesterol were associated with high galectin-3 binding protein in type 1 diabetes.

BACKGROUND: Galectin-3 binding protein (Gal3BP), sCD163, galectin-3, and depression have been linked to cardiovascular disease and mortality. In patients with type 1 diabetes, female sex has also been linked to cardiovascular disease and mortality. The aim was to explore whether female sex, sCD163, galectin-3, and depression were associated with Gal3BP in patients with type 1 diabetes. We adjusted for metabolic variables, creatinine, smoking, physical inactivity, and cardiovascular disease. METHODS: Cross-sectional design. Patients with type 1 diabetes (n = 285, women 44%, age18-59 years, diabetes duration 1-55 years) were consecutively recruited from one diabetes outpatient clinic. Blood samples, anthropometrics, and blood pressure were collected, supplemented with data from electronic medical records. High Gal3BP was defined as ≥3.3 mg/l (≥80th percentile). Depression was assessed by a self-report instrument. Linear and logistic regression models were elaborated for the associations and calibrated and validated for goodness of fit with the data variables. RESULTS: Median (q1, q3) Gal3BP was 2.3 (1.8, 3.1) mg/l. The prevalence of high Gal3BP for women was 30% and 14% for men (p = 0.001). Female sex (adjusted odds ratio (AOR) 3.0), sCD163 (per µg/l) (AOR 6.6), and total cholesterol (per mmol/l) (AOR 1.6) were positively associated with high Gal3BP, and HDL-cholesterol (per mmol/l) (AOR 0.2) was negatively associated with high Gal3BP. CONCLUSIONS: High Gal3BP levels were associated with female sex, increasing sCD163 and total cholesterol levels, and decreasing HDL-cholesterol levels in patients with type 1 diabetes. The prevalence of high Gal3BP was more than twice as high in the women as in the men.