Higher Galectin-3 Research Articles

Soluble CD163 was linked to galectin-3, diabetic retinopathy and antidepressants in type 1 diabetes

ObjectiveDepression has been associated with diabetic retinopathy and increased plasma levels of galectin-3, a lectin expressed in activated macrophages. Increased levels of sCD163, the soluble form of a macrophage expressed scavenger receptor involved in several inflammatory processes, have been demonstrated in the vitreous of the eye in type 1 diabetes (T1D) patients with severe diabetic retinopathy. The aim was to explore whether circulating sCD163 was associated with diabetic retinopathy, depression and/or galectin-3 in T1D patients, controlling for gender, metabolic factors, other diabetes complications, life style and medication.DesignCross sectional.MethodsTwo hundred eighty-seven T1D patients, men 56%, age 18–59 years, diabetes duration ≥1 year, were consecutively recruited from one specialist diabetes clinic. Depression was assessed by Hospital Anxiety and Depression Scale-Depression subscale. Blood samples, anthropometrics and blood pressure values were collected, supplemented with data from electronic medical records and the Swedish National Diabetes Registry. High plasma sCD163 was defined as ≥0.575 mg/L (corresponding to the 80th percentile) and high plasma galectin-3 as ≥4.659 µg/L (corresponding to the 95th percentile).ResultsThe prevalence of depression was 10%, antidepressant medication 8%, diabetic retinopathy 72%, high sCD163 20% and high galectin 3 5%. High galectin-3 (AOR 9.7), antidepressants (AOR 3.8), diabetic retinopathy (AOR 2.4) and systolic blood pressure (per mmHg) (AOR 1.03) were associated with high sCD163.ConclusionsThis is the first study to show that circulating sCD163 was independently associated with galectin-3, the use of antidepressants and diabetic retinopathy, in patients with T1D. Depression was not associated with sCD163.

Subclinical myocardial injury during vaso-occlusive crisis in pediatric sickle cell disease.

Acute painful crisis is the most frequent complication of sickle cell disease (SCD) in children. Recurrent vaso-occlusion may be associated with cardiac injury. The study aimed to assess silent myocardial injuries for sickle cell children during acute painful crisis by measuring serum level of troponin I and galectin-3. The study included 87 participates; study group (n = 44) sickle cell children presented at Jeddah hospitals in Saudi Arabia by painful crisis or acute illness as fever or cough (2017-2018). The controls were healthy children (n = 43). Demographic and history data were collected from the cases. Troponin I and galectin-3 were measured. Galectin-3 values were higher among cases with significant difference when compared to controls (7.5 ± 3.1 versus 3.2 ± 1.6, < 0.001). Galectin-3 at a cutoff > 5.1ng/ml, the sensitivity was 88.64 and specificity was 88.37. Galectin-3 levels were higher for the pain crisis subgroup in comparison to acute illness group with significant difference (r 0.551*, p < 0.001*). Galectin-3 values were higher among troponin-positive cases with significant difference (p = 0.046) to troponin-negative cases.Conclusion: Positive results of troponin I and high levels of galectin-3 in sickle cell children during acute painful crisis were potent indicators for subclinical myocardial injury. What is Known: • The hallmark of sickle cell disease is recurrent episodes of vaso-occlusive crisis which had deleterious effects on many organs. • Cardiac changes in pediatric sickle cell disease whether structural or functional are mainly attributed to chronic anemia and or pulmonary hypertension. What is New: • The observed positive results of cardiac troponin I and high values of galectin-3 in sickle cell children during vaso-occlusive crisis are strong indicator of myocardial ischemia and ongoing cardiac fibrosis respectively. • The observed correlation between biological markers (positive troponin and high galectin-3) could be an indication of subclinical cardiac injury.

Depression in type 1 diabetes was associated with high levels of circulating galectin-3.

ObjectiveNeuroinflammatory responses are implicated in depression. The aim was to explore whether depression in patients with type 1 diabetes (T1D) was associated with high circulating galectin-3, controlling for metabolic variables, s-creatinine, life style factors, medication and cardiovascular complications.DesignCross-sectional.MethodsParticipants were T1D patients (n = 283, 56% men, age 18–59 years, diabetes duration ≥1 year). Depression was assessed by Hospital Anxiety and Depression Scale-depression subscale. Blood samples, anthropometrics and blood pressure were collected, and supplemented with data from medical records and the Swedish National Diabetes Registry. Galectin-3 ≥2.562 µg/l, corresponding to the 85th percentile, was defined as high galectin-3.ResultsMedian (quartile1, quartile3) galectin-3 (µg/l) was 1.3 (0.8, 2.9) for the 30 depressed patients, and 0.9 (0.5, 1.6) for the 253 non-depressed, P = 0.009. Depression was associated with high galectin-3 in all the 283 patients (adjusted odds ratio (AOR) 3.5), in the 161 men (AOR 3.4), and in the 122 women (AOR 3.9). HbA1c, s-lipids, s-creatinine, blood pressure, obesity, smoking, physical inactivity, cardiovascular complications and drugs (antihypertensive, lipid lowering, oral antidiabetic drugs and antidepressants) were not associated with high galectin-3.ConclusionsThis is the first study to show an association between depression and galectin-3. Depression was the only explored parameter associated with high circulating galectin-3 levels in 283 T1D patients. High galectin-3 levels might contribute to the increased risk for Alzheimer’s disease, cardiovascular and all-cause mortality observed in persons with depression. Potentially, in the future, treatment targeting galactin-3 might improve the prognosis for patients with high galectin-3 levels.

Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity.

Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (Kd down to 1-2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (Kd 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry.

870P - Expression of Galectin-1 Determines Tumor Recurrence and Cancer-specific Survival in Patients with pT3 Upper Urinary Tract Urothelial Carcinoma

Background: Upper urinary tract urothelial carcinoma (UTUC) is an aggressive and lethal disease. For patients with locally advanced UTUC, recurrence of tumor is frequent, and lacks of predictive biologic markers limited the choice of postoperative treatment. Galectin-1 (GAL1) is a β-galactoside-binding protein, participating in many parts of tumorigenesis, including cell proliferation, invasiveness, metastasis, and angiogenesis. However, the role of GAL1 in UTUC has not been fully investigated. The aim of this study was to examine the prognostic impact of GAL1 in patients with UTUC. Methods: The study enrolled 86 UTUC patients who underwent radical nephroureterectomy and bladder cuff excision with final pathologically diagnosed as pT3N0 stage between January 2005 and December 2012. Perioperative characteristics and pathologic features were recorded. Immunohistochemical staining of tumor specimens using anti-GAL1 antibody were performed. UTUC cell line (BFTC-909) was used for in vitro study of tumor invasiveness and migration. Kaplan-Meier analyses and Cox proportional regression models were used for univariate and multivariate survival analyses. Results: Using 10% expression of GAL1 protein as a cuff-off point, the study population could be classified as GAL1-high (GAL1 > 10%, n = 35) or GAL1-low (GAL1 ≤ 10%; n = 51) group. Basic clinicopathologic characteristics were comparable between two groups. In univariate analysis, high GAL1 expression was significantly associated with a worse recurrence-free survival (RFS; p = 0.028) and cancer-specific survival (CSS; p = 0.025). Multivariate analysis showed GAL1-high is an independent factor for RFS (HR 2.43; 95% CI 1.17-5.05, p = 0.018) and CSS (HR 4.04; 95% CI 1.25-13.03, p = 0.019). In vitro study, we found that knockdown of GAL1 reduced UTUC cancer cell migration and invasion significantly. Conclusions: Galectin-1 expression is a reliable prognostic factor for locally advanced UTUC. GAL1 inhibition may serve as a potential therapeutic target for patients with UTUC. Legal entity responsible for the study: Yu-Li Su Funding: None Disclosure: All authors have declared no conflicts of interest.

Synergistic interaction between galectin-3 and carcinoembryonic antigen promotes colorectal cancer metastasis.

In this study, we investigated the role of galectin-3 and carcinoembryonic antigen (CEA) in metastasis and survival of colorectal cancer (CRC) patients. CEA interacted with galectin-3 at the cell surface and cytoplasm of Caco2 and DLD1 CRC cells. Knocking down galectin-3 did not affect CEA expression in CRC cells. However, there was a dose-dependent increase in CRC cell migration upon addition of small amounts of exogenous CEA (≤1ng/ml). Galectin-3 knockdown blocked induction of CRC cell migration by CEA, suggesting interaction between galectin-3 and CEA was necessary for CRC cell migration. Exogenous CEA and galectin-3 synergistically promoted migration of galectin-3 knockdown DLD1 cells. Immunohistochemical analysis showed that CEA co-localized with galectin-3 in CRC patient tissues. In additon, advanced stage CRC patients had higher serum galectin-3 and CEA levels than early stage CRC patients. High serum CEA and galectin-3 levels correlated with advanced N stage and poor survival in CRC patients. These findings suggest interaction between galectin-3 and CEA promotes CRC migration and metastasis, and correlates with poor survival of CRC patients. Thus combinatorial therapy targeting galectin-3 and CEA may improve outcomes for advanced stage CRC patients.

Intranuclear accumulation of galectin-3 is an independent prognostic factor for patients with distal cholangiocarcinoma.

Galectin-3 has been reported to be associated with the prognosis of patients with various malignancies; however, it has not yet been investigated in patients with extrahepatic cholangiocarcinoma (EHCC). Expression of galectin-3 was retrospectively examined in 58 patients with EHCC: 21 with perihilar cholangiocarcinoma and 37 with distal cholangiocarcinoma (DCC). The Cox proportional hazard model was used to identify independent prognostic factors. Intranuclear accumulation of galectin-3 (gal-3-INA) was associated with poorer overall survival (OS) in all patients (P=0.003), as well as in patients with DCC (P=0.004). Patients with gal-3-INA also exhibited a poorer disease-free survival (DFS) than those without gal-3-INA in all patients with EHCC (P<0.001), and in patients with DCC (P<0.001). Gal-3-INA was an independent prognostic factor of OS and DFS in all patients [OS: Hazard ratio (HR), 4.470; 95% confidence interval (CI), 1.759–11.357; P=0.002; and DFS: HR, 5.116; 95% CI, 2.025–12.925; P=0.001]. Gal-3-INA was also an independent prognostic factor in patients with DCC (OS: HR, 2.979; 95% CI, 1.035–8.570; P=0.043; and DFS: HR, 6.773; 95% CI, 1.558–29.439; P=0.011). In the analysis of patients with DCC, the number of patients with high galectin-3 expression (P=0.038), recurrence (P<0.001), distant metastases (P<0.001), R0 status (P=0.029) or microscopic vascular invasion (P=0.019) was significantly higher in the gal-3-INA-positive group than in the gal-3-INA-negative group. In conclusion, gal-3-INA was identified as a strong prognostic factor for OS and DFS in patients with DCC.

Galectin-3 as a marker for clinical prognosis and cardiac remodeling in acute heart failure.

Galectin-3 has been reported as a mediator of heart failure (HF) development and progression. Most studies, however, have been conducted on patients with chronic HF rather than acute HF (AHF). The aim of this study was to confirm galectin-3 as a prognostic marker in subjects with AHF and to investigate its possible relationship with left ventricular (LV) remodeling. A total of 69patients hospitalized with a primary diagnosis of AHF were followed up for 18months. Galectin-3 and echocardiographic parameters were measured at baseline and after 6months. Survival analysis and exploratory analysis of LV remodeling were performed. Patients with high baseline galectin-3 values (>16.5 ng/ml) had a significantly worse survival profile over the 18-month follow-up (log-rank test, p= 0.017), with Cox proportional hazards modeling showing a crude hazard ratio (HR) of 4.66 (95% CI= 1.16-18.67; likelihood-ratio test, p= 0.037) for all-cause mortality. Changes in galectin-3 levels (1SD increase over 6months) proved to be a significant explanatory factor for HF hospital re-admission in the short term when compared with quasi-stationary galectin-3 levels: worse Kaplan-Meier survival curves (log-rank test, p= 0.001) and acrude HR of 4.44 (95% CI= 1.76-11.18; likelihood-ratio test, p= 0.004). A significant association was found between the pathological evolution of relative wall thickness, LV end-diastolic diameter, LV end-diastolic volume, and increasing levels of galectin-3 in the short term (Cochran-Mantel-Haenszel test, p< 0.01). Galectin-3 can predict long-term mortality in patients with AHF. The results of our study suggest apossible relation between left ventricular remodeling and increasing galectin-3 levels.

Expression levels of β-catenin and galectin-3 in meningioma and their effect on brain invasion and recurrence: a tissue microarray study.

Objective:Meningiomas are neoplasms that arise from the meninges of the central nervous system (CNS). They constitute about 25.6% of CNS tumors diagnosed in Egypt. Some morphological variants of meningiomas display aggressive behavior, leading to brain-invasive growth pattern. Although meningiomas are usually treated by complete surgical excision, the risk of postoperative recurrence remains. Hence, additional biomarkers for predicting aggressive behavior must be discovered. This study aims to explore the clinical and biological relevance of the protein expression levels of β-catenin and galectine-3 in meningioma and to understand the pathobiology of this neoplasm.Methods:This retrospective study was carried out on 153 cases of meningioma by using tissue microarrays and immunohistochemistry for β-catenin and galectine-3.Results:High β-catenin expression was significantly associated with transitional and meningiotheliomatous meningiomas, low tumor grade, low recurrence rate, and low incidence of brain invasion. Meanwhile, high galectin-3 expression was associated with brain invasion, recurrence, high tumor grade, and tumor type. Logistic regression analysis indicated that among all variables included in the model, β-catenin and galactin-3 expression levels were significant predictors of tumor recurrence (P<0.001).Conclusions:Galectin-3 and β-catenin are involved in meningioma recurrencebut not in brain invasion. These molecules could be important potential therapeutic targets and predictors for meningiomas.

Evaluation of the association between serum uric acid level andthe predicted risk score of sudden cardiac death in five years in patients with hypertrophic cardiomyopathy.

The aim of this study was to determine the relationship between serum uric acid (UA) level and the predicted risk score for sudden cardiac death in 5 years (the HCM Risk-SCD), galectin-3 level, and positive fragmented QRS (fQRS) on electrocardiography (ECG) in patients with hypertrophic cardiomyopathy (HCM). This was a prospective, observational study. In all, 115 consecutive patients (age >17 years) with HCM and 80 healthy participants were included in the study. The HCM Risk-SCD score (%), galectin-3 level, and fQRS on ECG were evaluated in all patients. The serum UA, galectin-3 level, UA/Creatinine ratio, incidence of ventricular tachycardia (VT) and syncope, and some echocardiographic parameters were significantly higher in the patient group than in the control group (all p<0.05). The UA value was significantly higher in patients with a high score on the HCM Risk-SCD, a positive fQRS, a high galectin-3 level, VT incidence, and need for implantable cardioverter defibrillator (ICD) implantation or cardiopulmonary resuscitation (CPR) than in those without (HCM Risk-SCD >6%. Namely, HCM Risk-SCD >6%, UA: 6.71±1.29 mg/dL, HCM Risk-SCD ≤5.9%, UA: 5.84±1.39 mg/dL, p=0.001; fQRS(+), UA: 6.56±1.20 mg/dL, fQRS(-), UA: 5.63±1.49 mg/dL, p<0.001; galectin-3 >6.320 pg/mL, UA: 6.56±1.27 mg/dL, galectin-3 ≤6.310 pg/mL, p=0.016; left atrium anterior-posterior dimension (LAAPD) >36 mm, UA: 6.31±1.33 mg/dL, LAAPD <36 mm, UA: 5.20±1.60 mg/dL, p=0.005; VT(+), UA: 6.83±1.19 mg/dL, VT(-), UA: 5.97±1.42 mg/dL, p=0.008; ICD(+), UA: 7.08±0.88 mg/dL, ICD(-), UA: 6.06±1.42 mg/dL, p=0.022; CPR(+), UA: 7.03±0.96 mg/dL, CPR(-), UA: 6.04±1.42 mg/dL, p=0.018. A statistically significant correlation was observed between UA and HCM Risk-SCD, galectin-3 level, LAAPD, and left ventricular (LV) mass (LVM) (r and p values, respectively: 0.355, <0.001; 0.297, 0.002; 0.309, 0.001; 0.276, 0.003. The serum UA level was significantly higher in patients with HCM compared with the control group. A high UA level was associated with a higher HCM Risk-SCD score, positive fQRS, higher galectin-3 level, greater LAAPD, VT incidence, and the need for ICD implantation and CPR in patients with HCM.

Galectin-1 promotes tumor progression via NF-κB signaling pathway in epithelial ovarian cancer.

Purpose: We previously reported that Galectin-1 (Gal-1) played a role in epithelial ovarian cancer (EOC) progression. In this study, we aimed to further investigate the association between Gal-1 expression and prognosis in EOC patients and tried to reveal some novel potential mechanisms of Gal-1 in EOC invasion and migration.Materials and Methods: Gal-1 and nucleus NF-κBp65 expression in 109 human epithelial ovarian cancer tissue specimens were evaluated by immunohistochemistry. The Cox model and survival curves were used to investigate the effect of Gal-1 on EOC prognosis. Correlation between Gal-1 expression and NF-κB activation in EOC patients was also analyzed. In vitro experiments were further performed to reveal the function and mechanisms of Gal-1 in invasion and migration of EOC cells.Results: Expression level of Gal-1 in EOC tissue was an independent prognostic factor on overall survival (p<0.05) and progression-free survival (p<0.05). Patients with high Galectin-1 expression had shorter overall survival (OS, p<0.05)) and progression-free survival (PFS, p<0.05). Immunohistochemistry revealed that expression of Gal-1 was positively associated with activation of NF-κBp65 in EOC tissues (Kappa coefficient=0.458, p<0.001). Patients with tumors concomitantly co-over-expressing Gal-1 and NF-κBp65 had the worse OS (p<0.001) and PFS (p<0.001). The abilities of migration and invasion for EOC cells were significantly reduced after Gal-1 knocked-down in human EOC cell line HO8910, which was accompanied with the suppression of NF-κb pathway activation and with the matrix metalloproteinase-2 and matrix metalloproteinase-9 down-regulation.Conclusions: Our results suggest that Gal-1 is associated with poor outcome in EOC and Galectin-1 promotes tumor progression via NF-κB pathway activation in EOC.

Galectin-3 and Myocardial Fibrosis By Cardiac Magnetic Resonance in Thalassaemia Major

Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) technique is the only validated non-invasive approach used for detecting macroscopic myocardial fibrosis. Galectin-3 has been shown to participate in tissue fibrogenesis and was already associated with LGE-assessed myocardial replacement fibrosis in a cohort of patients with non-ischemic dilated cardiomyopathy (NICM).Our aim was to investigate the relationships between galectin-3 circulating level and myocardial fibrosis in patients with thalassemia major (TM) who underwent CMR technique during the Myocardial Iron Overload in Thalassemia (MIOT) project.All patients underwent also an extensive biohumoral characterization, including Troponin, NT Pro BnP, BNP, VES, PCR assay.At UOSD Malattie rare del globule Rosso of Cardarelli hospital (Naples, Italia), between January 2015 and March 2016, all patients who underwent contrast-enhanced CMR were progressively enrolled to test Galectin-3.Eighty-six patients were evaluated (males 43%; age 37, SD 8 years): six (7%) had diabetes mellitus (DM), 64 had anti-HCV antibodies and 28 (32%) were HCV RNA positive. Median galectin-3 value was 14.04ng/mL (5.26 ng/mL), and LGE was detected in 42 (49%) patients. Patients with LGE had higher galectin-3 than those without (14.48 ± 5.98, vs 13.63 ± 5.98), but without a statistically significant difference (p=0.109).Galectin-3 was significantly associated with age (R=0.34; p=0.001), but not with sex.Patients with DM, with anti-HCV antibodies and with HCV-RNA positivity, had significant higher level of Galectin 3 with respect to those without (22.5± 11.1 vs 13.4± 4, p=0.009; 14.9 ± 5.4 vs 11.5± 3.7, p=0.001; 16.2 ± 6.5 vs 13± 4.2, p=0.011, respectively).No correlation was found between Galectin 3 and other tested biochemical variables and iron overload and cardiac parameters.In conclusion, in our cohort of TM patients there was a great prevalence of myocardial fibrosis. In patients with myocardial fibrosis, the level of galectin-3 was higher and comparable to that found in a previous study performed in patients with NICM, but not significantly different with respect to those without fibrosis. The elevated prevalence of patients with previous exposure to HCV virus and/or DM and/or iron overload may significantly influence Galectin-3 level limiting the ability of the marker to identify patients without fibrosis. DisclosuresDe Franceschi:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding. Pepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.

Abstract 11614: The Clinical Significance and Novel Mechanism of Reactive Oxygen Species in Heart Failure With Preserved Left Ventricular Ejection Fraction

Introduction: By performing basic and clinical researches, we investigated the clinical significance of reactive oxygen species (ROS) biomarker and the mechanism of ROS production in heart failure with preserved left ventricular ejection fraction (HFpEF). Methods and Results: (1) We measured derivatives of reactive oxidative metabolites (DROM), new biomarker of ROS, in 287 HFpEF patients, and followed them. DROM was significantly higher in HFpEF patients compared to risk factor matched non-HF patients (p&lt;0.001), and was associated with the severity of HF (p&lt;0.001). Kaplan-Meier analysis demonstrated higher probability of cardiovascular events in high-DROM than low-DROM group (p=0.01). Multivariate Cox hazard analysis identified ln-DROM as independent predictor for cardiovascular events (p=0.04). (2) We examined the association of ROS with galectin-3, a predictor of cardiovascular events in HFpEF, by using angiotensin II (AII) receptor blocker (ARB) and galectin-3-inhibitor (Gal3-i) administrated Dahl salt-sensitive rats (DS rats), useful model of HFpEF. Increased left ventricular (LV) galectin-3 protein expressions by Western blotting in HFpEF DS rats were inhibited by ARB, indicating AII-induced galectin-3 expression in HFpEF. Furthermore, Gal3-i significantly reversed LV hypertrophy in DS rats suffered HFpEF (p=0.02), accompanied by the tendency of reduction in collagen-related mRNA gene expression (collagen-I, -III and MMP-2) by real-time RT-PCR. Serum DROM and LV mRNA gene expressions of subunits of ROS generative NADPH oxidase (p22 phox and NOX-2) were increased in HFpEF rats, and Gal3-i tended to downregulate them. These indicated AII induced galectin-3 is involved in LV fibrosis via ROS. (3) Galectin-3 at coronary sinus was higher than at aortic root in HFpEF patients, but not different in non-HF, indicating galectin-3 production in coronary circulation in HFpEF. Moreover, Kaplan-Meier analysis demonstrated higher probability of cardiovascular events in plasma high galectin-3 than in low galectin-3 group in HFpEF patients (p&lt;0.05), indicating clinical significance of galectin-3. Conclusions: These studies demonstrated clinical significance and novel mechanism of ROS in HFpEF.

Systems-level effects of ectopic galectin-7 reconstitution in cervical cancer and its microenvironment.

BackgroundGalectin-7 (Gal-7) is negatively regulated in cervical cancer, and appears to be a link between the apoptotic response triggered by cancer and the anti-tumoral activity of the immune system. Our understanding of how cervical cancer cells and their molecular networks adapt in response to the expression of Gal-7 remains limited.MethodsMeta-analysis of Gal-7 expression was conducted in three cervical cancer cohort studies and TCGA. In silico prediction and bisulfite sequencing were performed to inquire epigenetic alterations. To study the effect of Gal-7 on cervical cancer, we ectopically re-expressed it in the HeLa and SiHa cervical cancer cell lines, and analyzed their transcriptome and SILAC-based proteome. We also examined the tumor and microenvironment host cell transcriptomes after xenotransplantation into immunocompromised mice. Differences between samples were assessed with the Kruskall-Wallis, Dunn’s Multiple Comparison and T tests. Kaplan–Meier and log-rank tests were used to determine overall survival.ResultsGal-7 was constantly downregulated in our meta-analysis (p < 0.0001). Tumors with combined high Gal-7 and low galectin-1 expression (p = 0.0001) presented significantly better prognoses (p = 0.005). In silico and bisulfite sequencing assays showed de novo methylation in the Gal-7 promoter and first intron. Cells re-expressing Gal-7 showed a high apoptosis ratio (p < 0.05) and their xenografts displayed strong growth retardation (p < 0.001). Multiple gene modules and transcriptional regulators were modulated in response to Gal-7 reconstitution, both in cervical cancer cells and their microenvironments (FDR < 0.05 %). Most of these genes and modules were associated with tissue morphogenesis, metabolism, transport, chemokine activity, and immune response. These functional modules could exert the same effects in vitro and in vivo, even despite different compositions between HeLa and SiHa samples.ConclusionsGal-7 re-expression affects the regulation of molecular networks in cervical cancer that are involved in diverse cancer hallmarks, such as metabolism, growth control, invasion and evasion of apoptosis. The effect of Gal-7 extends to the microenvironment, where networks involved in its configuration and in immune surveillance are particularly affected.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2700-8) contains supplementary material, which is available to authorized users.

A Selective Galactose–Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model

Synthesis of doubly 3-O-coumarylmethyl-substituted thiodigalactosides from bis-3-O-propargyl-thiodigalactoside resulted in highly selective and high affinity galectin-3 inhibitors. Mutant studies, structural analysis, and molecular modeling revealed that the coumaryl substituents stack onto arginine side chains. One inhibitor displayed efficacy in a murine model of bleomycin-induced lung fibrosis similar to that of a known nonselective galectin-1/galectin-3 inhibitor, which strongly suggests that blocking galectin-3 glycan recognition is an important antifibrotic drug target.

MiRNA-22 inhibits oncogene galectin-1 in hepatocellular carcinoma.

Hepatic stellate cells (HSCs) induce immune privilege and promote hepatocellular carcinoma (HCC) by suppressing the immune system. On the other hand, galectin-1 and miRNA-22 (miR-22) are dysregulated in HCC and serve as prognostic indicators for patients. In this study, therefore, we measured galectin-1 and miR-22 expression in HSCs isolated from HCC tissues (Ca-HSCs), and in normal liver tissues (N-HSCs) as a control. We also investigated the apoptosis rate among T cells and the production of cytokines (IFN-η and IL-10) in HSCs co-cultured with T cells. And we used immunohistochemical staining to tested for correlation between galectin-1 expression, CD3 expression and clinicopathological features in 162 HCC patients. Our results showed that galectin-1 expression was much higher in Ca-HSCs than in N-HSCs. Overexpression of galectin-1 promoted HSC-induced T cell apoptosis and cytokine production (IFN-η and IL-10), while miR-22 expression inhibited it. Galectin-1 expression correlated negatively with miR-22 expression in HSCs. High galectin-1 and low CD3 expression levels were associated with poor prognosis in HCC patients. These results suggest that the immunosuppressive microenvironment promoted by HSC-derived galectin-1 in HCC can be inhibited by miR-22. Galectin-1 and miR-22 could potentially serve as prognostic markers and therapeutic targets in HCC.

Interaction of Galectin-3 Concentrations with the Treatment Effects of β-Blockers and RAS Blockade in Patients with Systolic Heart Failure: A Derivation-Validation Study from TIME-CHF and GISSI-HF.

Galectin-3 predicts prognosis in heart failure (HF) and may help to select HF patients in need of intensified therapy. This retrospective post hoc analysis included 219 patients from the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-HF) and 631 patients from Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) with HF who had reduced ejection fraction and available galectin-3 plasma concentrations. The interaction between galectin-3, β-blockers, renin-angiotensin system (RAS) blockade, and spironolactone on outcome was evaluated in TIME-CHF and validated in GISSI-HF. End points were all-cause mortality and the composite of mortality with HF hospitalization or any hospitalization. High galectin-3 concentrations were associated with adverse outcome in both cohorts and remained significantly associated with death after multivariate adjustment [hazard ratio 2.42 (95% CI 1.17-5.01), P = 0.02, in TIME-CHF; 1.47 (1.02-2.10), P = 0.04, in GISSI-HF). In TIME-CHF, patients with low galectin-3 plasma concentrations had a better prognosis when β-blockers were up-titrated, whereas patients with high galectin-3 plasma concentrations did not (interaction P < 0.05 for mortality and death with or without hospitalization). Opposite trends were seen for RAS blockade but were not statistically significant. Patients with high galectin-3 plasma concentrations had neutral prognosis when receiving spironolactone, whereas patients with low galectin-3 plasma concentrations had worse prognosis when receiving spironolactone (interaction P < 0.10 for death with or without hospitalization). In the GISSI-HF validation cohort, these interactions were confirmed for β-blockers (P < 0.05 for all end points) and consistent for RAS blockade (P < 0.10 for death with or without hospitalization), but inconsistent for spironolactone. Galectin-3 is a mediocre prognostic marker, and galectin-3 concentrations interact with the treatment effect of β-blockers and possibly RAS blockade in patients with systolic HF.

Regional circulatory distribution of novel cardiac bio-markers and their relationships with haemodynamic measurements

BackgroundRegional sampling may identify sites of production or removal of novel biomarkers in the circulation; their relationship to haemodynamic measurements may clarify their association with the pathophysiology of heart failure. MethodsSamples were obtained from up to eight circulatory sites from 22 patients with left ventricular dysfunction undergoing elective cardiac catheterisation. The plasma concentrations (PC) of six biomarkers [mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adreno-medullin (MR-proADM), high sensitivity pro-calcitonin (hsPCT), copeptin and galectin-3 (Gal-3)] were measured. ResultsPlasma concentrations of MR-proANP were highest in the pulmonary artery (PA) and left ventricle, suggesting myocardial production. Lower concentrations of copeptin, CT-proET-1, MR-proADM and hsPCT were found in the supra-renal inferior vena cava (SRIVC) sample suggesting renal extraction. Plasma concentrations of Galectin-3 varied little by sampling site. Plasma concentrations of MR-proANP (R=0.69, P=0.002), MR-proADM (R=0.51, P=0.03), CT-proET-1 (R=0.60, P=0.009) and Copeptin (R=0.47, P<0.05) measured from PA samples correlated with PA systolic pressure. There was no relation between any measured marker and cardiac index. ConclusionsRegional sampling shows variation in the plasma concentration of various novel peptides that provides clues to sites of net production and removal. Plasma concentrations of several biomarkers were positively correlated with pulmonary artery pressure.

High GAL-3 may be Associated with Higher Age and Low Levels of Chloride, RDW, and MCHC in Heart Failure

Introduction: Elevated galectin-3 (GAL-3) levels has been associated with decompensated heart failure (HF) which is a complex mechanical and neurohormonal syndrome. Many clinical and biochemical factors have been implicated in the pathophysiology of HF. In a group of patients who are referred to the emergency clinic for HF, GAL-3 levels and their association with various clinical and biochemical parameters were determined. GAL-3levels were measured with the VIDAS® automated enzyme-linked fluorescent assay (BioMerieux, France). Method: Our study group consists of 70 patients (33 women and 37 men) and 25 healthy controls. All 70 patients had at least Class II or higher levels of HF according to NYHA criteria. Results: GAL-3 was significantly higher in the patient's group (17.98 vs. 10.24 ng/mL; p

Clinical implication of the serum galectin-1 expression in epithelial ovarian cancer patients.

Backgroundgalectin-1 has been implicated in tumor invasion and metastasis and is frequently over-expressed in epithelial ovarian cancer (EOC), but its potential as a biomarker remains unclear. In this novel study, we have explored the possible use of galectin-1 as a biomarker for EOC.Methodsgalectin-1 in sera was evaluated by ELISA in a pilot panel of EOC patients, healthy volunteers, patients with benign gynecologic tumors or other gynecologic malignancies. We examined galectin-1 expression in EOC tumor samples by Western Blot, qRT-PCR and immunohistochemistry. In vitro experiments were conducted to elucidate the biologic role of galectin-1 in EOC progression using over-expression of galectin-1 in OVCAR-3 cells. We also looked for the association of galectin-1 expression with clinic pathological variables and survival outcomes in EOC.ResultsA significant difference was detected in serum galectin-1 between EOC patients with non-metastatic and those with metastatic disease, but not between EOC patients and healthy volunteers. It increased in recurrent cases and decreased after debulking surgery. Both of galectin-1 mRNA and protein levels were increased in 90 % of the examined EOC tissue samples, compared with a wedge resection of a normal ovary. High galectin-1 in peritumor stroma was primarily detected in advanced stages of EOC. Over expression of galectin-1 significantly increased the ability of OVCAR-3 cells’ migration and invasion.ConclusionsOur results suggest that galectin-1 might play a role in tumor progression and be associated with poor outcome in EOC. It could be a novel prognostic and progression biomarker in EOC patients.