Gal-3 Levels Research Articles

GALLANT-1: Galectin-3 (Gal-3) inhibitor GB1211 plus atezolizumab (atezo) in patients with non–small cell lung cancer (NSCLC)—A randomized, double-blind trial.

TPS9152 Background: Gal-3 is a protein that binds specifically to N-acetylglucosamine-expressing carbohydrates, which are upregulated on key tumorigenic cell surface proteins. Gal-3 is widely over-expressed in the tumor microenvironment and is generally linked to poor outcomes. Gal-3 regulates immune cell function of T cells and macrophages, and promotes neovascularization and fibrosis [Peng Cancer Res 2008; Markowska J Biol Chem 2011; Kouo Cancer Immunol Res 2015]. Gal-3 sequesters interferon gamma, reduces T-cell influx, and contributes to tumor cell evasion of the immune system via LAG-3 activation [Chen PNAS 2009; Gordon-Alonso Nat Commun 2017]. Gal-3 has been identified as a marker of resistance to checkpoint inhibitors (CPIs); patients with stage IV NSCLC with high Gal-3 levels (> 70% Gal-3 immunohistochemical staining) have been shown to be resistant to the CPI pembrolizumab [Capalbo Int J Mol Sci 2019]. Animal data indicate synergy between CPI therapy and Gal-3 inhibition [Vuong Cancer Res 2019; Zhang FEBS Open Bio 2021]. Thus, inhibiting Gal-3 together with CPI-based immunotherapy may enhance tumor-specific immune responses, and overcome CPI resistance. Methods: GALLANT-1 (NCT05240131) is a 3-part, placebo-controlled phase Ib/IIa trial that will investigate safety and efficacy of GB1211 (a Gal-3 inhibitor) + atezo vs placebo + atezo in patients with advanced NSCLC. Part A will include 8–12 patients and study safety and tolerability of 200 mg and 400 mg GB1211 twice-daily + atezo (open-label). Primary endpoint is number of adverse events (AEs) after 12 weeks’ treatment and will determine the dosage for Part B. Part B will include 75–94 patients, and is a randomized, double-blind study of GB1211 + atezo or placebo + atezo. Primary endpoints are safety (number of AEs) and efficacy (percentage change from baseline in the sum of longest diameter of target lesions after 12 weeks’ treatment). Part C is an expansion study including patients from Parts A and B, with safety and efficacy assessments. Eligibility criteria: advanced or metastatic stage IIIB or IV NSCLC adenocarcinoma; measurable disease per RECIST v1.1; expression of programmed death ligand-1 on ≥50% of tumor cells; eligible for 1200 mg atezo every 3 weeks. Exclusion criteria: symptomatic, untreated, or actively progressing central nervous system metastases; prior systemic chemotherapy for treatment of recurrent advanced or metastatic disease, except if part of neoadjuvant/adjuvant therapy; prior treatment with immune CPIs and/or GB1211; presence of EGFR mutation and ALK, ROS1, and RET alterations; treatment with antineoplastic or systemic immunotherapeutic agents prior to first GB1211 dose; severe infectious disease < 4 weeks prior to first GB1211 dose; active hepatitis B or C, HIV, or COVID-19. The study is being initiated; updated enrollment status will be presented at the meeting. Clinical trial information: NCT05240131.

Circulating Galectin-3 and Aldosterone for Predicting Atrial Fibrillation Recurrence after Radiofrequency Catheter Ablation.

Background Circulating galectin-3 (Gal-3) and aldosterone (ALD) are involved in fibrosis and inflammation. However, their potential value as predictors of atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA) is unknown or controversial. Therefore, the aim of this study was to assess the relationship between baseline Gal-3, ALD levels, and AF recurrence in patients performing RFCA. Methods 153 consecutive patients undergoing RFCA were included. Gal-3 and ALD were measured at baseline. Univariate and multivariate Cox regressions were performed to determine the predictors of AF recurrence. Receiver operating characteristic (ROC) curve and Kaplan-Meier (K-M) curve were used to assess the value of predictors. Results There were 35 (22.88%) cases of AF recurrence after RFCA. The recurrence group had significantly higher preoperative serum levels of Gal-3 and ALD than the nonrecurrence group. Univariate and multivariate analysis showed that Gal-3 (HR = 1.28, 95% CI: 1.04-1.56, p = 0.02) and ALD (OR = 1.02, 95% CI: 1.00-1.03, p < 0.03) were significantly associated with AF recurrence after RFCA. The area under the curve (AUC) of preoperative serum Gal-3, ALD, and 2 combined to predict the recurrence of AF patients after RFCA was 0.636, 0.798, and 0.893, respectively, while sensitivity was 65.32%, 71.69%, and 88.61%, respectively and specificity was 77.46%, 78.53%, and 86.0%, respectively. Patients with Gal-3 above the cutoff value of 14.57 pg/ml had higher frequent AF recurrence than the patients with Gal − 3 ≤ 14.57 pg/ml (35% vs. 12%, p < 0.001) during a follow-up. Meanwhile, patients with ALD above the cutoff value of 243.61 pg/ml also had a higher AF recurrence rate than those with ALD ≤ 243.61 pg/ml (37% vs. 11%, p < 0.001) during a follow-up. The recurrence rate in patients with Gal − 3 > 14.57 pg/ml + ALD > 243.61 pg/ml was higher than that in patients with baseline Gal − 3 > 14.57 pg/ml or ALD > 243.61 pg/ml and patients with Gal − 3 ≤ 14.57 pg/ml + ALD ≤ 243.61 pg/ml (57% vs. 14% vs. 9%, p < 0.01, respectively). Conclusion AF recurrence after RFCA had higher baseline Gal-3 and ALD levels, and higher preoperative circulating Gal-3 and ALD levels were independent predictors of AF recurrence for patients undergoing RFCA, while combination of preoperative Gal-3 and ALD levels has higher prediction accuracy.

Markers of Inflammation, Oxidative Stress, and Fibrosis in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. The pathogenesis of AF is linked to inflammatory reaction and oxidative stress, which leads to fibrosis of the atria and progression of the disease. The purpose of this study was to define the role of several biomarkers of inflammation, fibrosis, and oxidative stress (OxS). We included 75 patients with paroxysmal/persistent AF, who were admitted for electrical cardioversion or pulmonary vein isolation (PVI). High-sensitivity C-reactive protein (hsCRP), galectin-3 (Gal-3), myeloperoxidase (MPO), oxidized low-density lipoprotein (oxLDL), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured before the procedures. We compared the results with those of 75 healthy age-, sex-, and blood pressure-matched individuals. The patients were followed up for 1 year after the intervention to establish the recurrence of AF and its association with the measured markers. Patients with AF had higher MPO (52.6 vs. 36.2 ng/ml, p < 0.001) and NT-proBNP (209.0 vs. 28.0 pg/ml, p < 0.001) compared to healthy subjects. Also, they showed significantly higher levels of hsCRP (1.5 vs. 1.1 mg/l, p = 0.001) and Gal-3 (11.4 vs. 9.7 mg/l, p = 0.003), while there was no difference found in oxLDL (71.5 vs. 71.7 U/l, p = 0.449). MPO (OR = 1.012, p = 0.014), hsCRP (OR = 1.265, p = 0.026), and weight (OR = 1.029, p = 0.013) were independently associated with AF in a multivariable logistic regression analysis. Patients with successful maintenance of sinus rhythm (SR) for one year had lower baseline MPO (40.5 vs. 84.3 ng/ml, p = 0.005) and NT-proBNP (127.5 vs. 694.0 pg/ml, p < 0.001) compared to patients with recurrent AF episodes, but there was no difference in hsCRP, Gal-3, or oxLDL between them. MPO (OR = 0.985, p = 0.010) was independently associated with AF recurrence during the follow-up period when adjusted for cofounders. Patients with AF had increased markers of inflammation and fibrosis, while there was no increase detected in the OxS marker oxLDL. MPO was independently associated with AF in a multivariate model. Inflammatory and fibrotic mechanisms are important factors in electrical and structural remodelling progress in the atria of patients with AF.

Long-term Dexamethasone Treatment Increases Cardiac Galectin-3 Levels.

Glucocorticoids, which are widely prescribed around the world, cause cardiac remodeling in long-term treatment by triggering insulin resistance and increasing blood pressure. However, its role in cardiac remodeling remains unclear. Galectin-3 (gal-3) is a member of a beta-galactoside-binding animal lectins, upregulated as a result of insulin resistance and in the pressure-overloaded myocardium and regulate cardiac remodeling. We hypothesized that gal-3 may be upregulated in the myocardium with prolonged use of glucocorticoids and associated with cardiac hypertrophy. To examine the involvement of glucocorticoids in gal-3 levels in rat myocardium, sixteen female Wistar Albino rats were assigned to control (C; n = 8) and dexamethasone (Dex; n = 8) groups. Daily dexamethasone was injected subcutaneously for 28days at a dose of 1mg.kg-1. Control animals were injected with the same volume of saline. The body weight and heart weights were determined. Gal-3 levels in myocardium were determined by Western blot. Our data shows that dexamethasone administration resulted in significant increase in heart weight (p < 0.05) and HW/BW ratios (p < 0.001) and 28days of dexamethasone administration with the dose of 1mg.kg-1 caused a twofold increase in the gal-3 expression in the left ventricle (p < 0.001). The finding of the current study is the first to show that dexamethasone causes an increase in gal-3 levels in myocardium. Our study provides an important step in the development of possible therapeutics by determining that dexamethasone causes an increase in gal-3 levels in the myocardium and raises awareness about the follow-up of patients receiving long-term glucocorticoid therapy.

Galectin-3 as an early marker of diastolic dysfunction in children with end-stage renal disease on regular hemodialysis.

Diastolic dysfunction is a common finding in end-stage renal disease (ESRD) on regular hemodialysis (HD). Galectin-3 (Gal-3) has emerged as an early biomarker with diagnostic and prognostic values in cardiac dysfunction with reduced or preserved ejection fraction. We aimed to assess the correlation between Gal-3 levels and diastolic dysfunction in children with ESRD on regular HD. Gal-3 levels were assessed in 67 patients on regular HD and 67 healthy controls. Conventional echo-Doppler imaging and tissue-Doppler imaging were done to all patients and control groups. Patients were split into two categories: with or without diastolic dysfunction, based on the early diastolic transmitral velocity to early diastolic mitral annular velocity (E/E') whether more or less than 15, respectively. Plasma Gal-3 levels in ng/ml were 16.7 (12.0-22.0) in healthy controls, 15.7 (10.5-22.0) in patients on HD without diastolic dysfunction, and 23.4 (13.4-25.0) in patients on HD with diastolic dysfunction. Gal-3 levels were significantly higher in HD patients with left ventricular diastolic dysfunction (LVDD). Both uni- and multivariate logistic regression analyses revealed that low left ventricular Tei index, low early diastolic mitral annular velocity of lateral wall wave, low early diastolic mitral annular velocity of septal wall wave, high septal early diastolic transmitral velocity to early diastolic mitral annular velocity of lateral wall (E/E') ratio, and high Gal-3 are significant predictors for LVDD in the whole study group. Furthermore, there was a significant positive correlation between the Gal-3 and the grade of diastolic dysfunction. The cut of point of diagnostic accuracy of serum Gal-3 in diastolic dysfunction in HD children was 20.12 with a sensitivity of 93.3 and a specificity 78.4. Gal-3 is a potential early biomarker that can be used in early diagnosis and grading of diastolic dysfunction in ESRD children on regular HD.

Anti-Inflammatory and Pro-Regenerative Effects of Hyaluronan-Chitlac Mixture in Human Dermal Fibroblasts: A Skin Ageing Perspective.

Inflammation and the accumulation of reactive oxygen species (ROS) play an important role in the structural and functional modifications leading to skin ageing. The reduction of inflammation, cellular oxidation and dermal extracellular matrix (ECM) alterations may prevent the ageing process. The aim of this study is to investigate the expression of pro-inflammatory markers and ECM molecules in human dermal fibroblasts derived from young and middle-aged women and the effects of lactose-modified chitosan (Chitlac®, CTL), alone or in combination with mid-MW hyaluronan (HA), using an in vitro model of inflammation. To assess the response of macrophage-induced inflamed dermal fibroblasts to HA and CTL, changes in cell viability, pro-inflammatory mediators, MMPs and ECM molecules expression and intracellular ROS generation are analysed at gene and protein levels. The expression of pro-inflammatory markers, galectins, MMP-3 and ECM molecules is age-related. CTL, HA and their combination counteracted the oxidative damage, stimulating the expression of ECM molecules, and, when added to inflamed cells, restored the baseline levels of IL-1β, TNF-α, GAL-1, GAL-3 and MMP-3. In conclusion, HA and CTL mixture attenuated the macrophage-induced inflammation, inhibited the MMP-3 expression, exhibited the anti-oxidative effects and exerted a pro-regenerative effect on ECM.

Impact of moderately reduced renal function on the diagnostic and prognostic value of galectin-3 in patients with exertional dyspnea.

Blood concentration of galectin-3 (Gal-3) - a biomarker of fibrosis useful in diagnostics and prognostication in heart failure (HF) - is known to be elevated in patients with renal impairment, a condition which often accompanies cardiac insufficiency. To investigate the effect of moderately reduced renal function (estimated glomerular filtration rate (eGFR) 30-60 mL/min/1.73 m2) on the diagnostic and prognostic utility of circulating Gal-3 in patients with HF with preserved ejection fraction (HFpEF). Clinical, biochemical and echocardiographic variables were collected at baseline in 154 patients with HFpEF: 101 with normal and 53 with moderately reduced renal function, who were followed up for 48 (24-60) months for HF hospitalization and cardiovascular (CV) death (composite endpoint). Patients with moderately impaired renal function were characterized by higher age, Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, Gal-3, B-type natriuretic peptide (BNP) and New York Heart Association (NYHA) class, lower hemoglobin, and more advanced left ventricular diastolic dysfunction. Older age, female sex and deeper impairment of renal performance were determinants of higher Gal-3 blood concentrations. Lower exercise capacity (lower peak VO2) was associated with higher Gal-3 level and more pronounced renal impairment. Multivariable regression analysis demonstrated the significance of renal dysfunction as a determinant of lower exercise capacity and revealed a significant interaction between Gal-3 and eGFR with respect to peak VO2. The addition of Gal-3 to the prognostic models based on clinical data improved their predictive power for the study endpoint. The Kaplan-Meier analysis revealed that the presence of moderately reduced renal function with eGFR 30-60 mL/min/1.73 m2 did not enhance the increased risk of adverse outcome associated with Gal-3 above the median. In patients with HFpEF, the coexistence of moderate renal dysfunction does not deteriorate the prognostic usefulness of circulating Gal-3. However, renal impairment modifies the association between Gal-3 and exercise capacity, which supports the need to adjust for kidney function when interpreting the contribution of Gal-3 to exercise intolerance in this population.

Renal Function Impact in the Prognostic Value of Galectin-3 in Acute Heart Failure.

IntroductionGalectin-3 (Gal-3) is an inflammatory marker associated with the development and progression of heart failure (HF). A close relationship between Gal-3 levels and renal function has been observed, but data on their interaction in patients with acute HF (AHF) are scarce. We aim to assess the prognostic relationship between renal function and Gal-3 during an AHF episode.Materials and MethodsThis is an observational, prospective, multicenter registry of patients hospitalized for AHF. Patients were divided into two groups according to estimated glomerular filtration rate (eGFR): preserved renal function (eGFR ≥ 60 mL/min/1.73 m2) and renal dysfunction (eGFR <60 mL/min/1.73 m2). Cox regression analysis was performed to evaluate the association between Gal-3 and 12-month mortality.ResultsWe included 1,201 patients in whom Gal-3 values were assessed at admission. The median value of Gal-3 in our population was 23.2 ng/mL (17.3–32.1). Gal-3 showed a negative correlation with eGFR (rho = −0.51; p < 0.001). Gal-3 concentrations were associated with higher mortality risk in the multivariate analysis after adjusting for eGFR and other prognostic variables [HR = 1.010 (95%-CI: 1.001–1.018); p = 0.038]. However, the prognostic value of Gal-3 was restricted to patients with renal dysfunction [HR = 1.010 (95%-CI: 1.001–1.019), p = 0.033] with optimal cutoff point of 31.5 ng/mL, with no prognostic value in the group with preserved renal function [HR = 0.990 (95%-CI: 0.964–1.017); p = 0.472].ConclusionsGal-3 is a marker of high mortality in patients with acute HF and renal dysfunction. Renal function influences the prognostic value of Gal-3 levels, which should be adjusted by eGFR for a correct interpretation.

431 Galectin-3 as a Biomarker and Potential Therapeutic Target in Biliary Atresia

OBJECTIVES/GOALS: Biliary atresia (BA) is a progressive congenital disease that is characterized by periductular inflammation and fibrosis that leads to bile duct destruction and cholestasis in neonates. Galectin-3 (Gal3) plays a key role in inflammation and fibrosis. The aim of this study was to evaluate plasma Gal3 levels in early and late BA. METHODS/STUDY POPULATION: Samples from our institutional Pediatric Liver Biobank were used for this study. Patients were categorized as early BA (at diagnosis), late BA (at liver transplant), early other cholestatic liver disease (CLD), late other CLD, or controls without cholestasis or structural liver disease. Plasma Gal3 levels were measured by standard ELISA. Inflammatory cytokines were measured in a subset of samples using MSD Proinflammatory Panel 1 multiplex ELISA. Liver fibrosis was categorized as none (Ishak or METAVIR 0), mild (Ishak 1-2 or METAVIR 1), moderate (Ishak 3-4 or METAVIR 2-3), and severe (Ishak 5-6 or METAVIR 4) based on histology. Data are presented as median (IQR) and compared using Kruskal-Wallis test. Spearmans correlation was used to assess the relationship between Gal3 and clinical and inflammatory markers. RESULTS/ANTICIPATED RESULTS: Samples from 10 controls, 26 early BA, 24 late BA, 13 early other CLD, and 8 late other CLD patients were used for this study. Gal3 levels in late BA (20.8 [12.4-30.5] ng/mL) and late other CLD (21.8 [16.9 – 27.2] ng/mL) were significantly higher than in controls (10.2 [7.6 – 14.5] ng/mL, p &lt; 0.02) and early BA (11.3 [8.7 – 16.8] ng/mL, p &lt; 0.01), but not significantly different from early other CLD (15.7 [11.9 – 21.4] ng/mL, p &gt; 0.05). Gal3 positively correlated with fibrosis score (rho 0.3, p = 0.01), total bilirubin (rho 0.3, p = 0.002), ALT (rho 0.3, p = 0.01), AST (rho 0.3, p = 0.005), and APRI score (rho 0.3, p = 0.009), and negatively correlated with albumin (rho -0.3, p = 0.01). Out of the 10 cytokine proinflammatory panel, Gal3 was significantly correlated with IL-6 (rho 0.3, p = 0.006). DISCUSSION/SIGNIFICANCE: Gal3 is elevated in late BA and other CLD at time of transplant and correlated with degree of fibrosis, suggesting it may play a role in disease progression to cirrhosis. If targeted in the early disease stage, blocking Gal3 in pediatric cholestatic liver diseases may help delay the progression to cirrhosis and need for transplant.

Proposal of a prediction model for prognosis of patients with acute myocardial infarction after percutaneous coronary intervention based on galectin-3 and soluble growth stimulating expressed gene 2 levels

Abstract Background: To study the correlations of serum galectin-3 (Gal-3) and soluble growth stimulating expressed gene 2 (sST2) levels with prognosis of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Methods: A total of 112 patients diagnosed from August 2015 to October 2017 were selected. They were followed up for 3 years. Based on major adverse cardiovascular events (MACEs) during follow-up, they were divided into MACE and non-MACE groups. Multivariate logistic regression analysis was performed to explore the independent risk factors for MACEs. A nomogram model was established using the factors and validated. The optimal cut-off values of Gal-3 and sST2 levels were determined by receiver operating characteristic curves. Kaplan-Meier method was used for survival analysis. Results: MACEs occurred in 78 patients during follow-up. Patients in the MACE group were more often hypertensive, had higher total cholesterol, uric acid, sST2 and Gal-3, and lower left ventricular ejection fraction (LVEF) (P&lt;0.05). CK-MB, sST2, Gal-3 and LVEF were the independent risk factors for MACEs (P&lt;0.05). The nomogram model established with these factors had high accuracy for predicting overall survival, and its concordance index (C-index) was 0.768 (95% confidence interval: 0.692-0.865). The prognosis of the patients with Gal-3 ≥12.57 μg/ mL and sST2 ≥18.56 ng/mL was poorer 3 years after PCI. Conclusions: The levels of serum Gal-3 and sST2 are the independent risk factors for MACEs in AMI patients following PCI, with high prognostic value.

CLINICAL VALUE OF GALECTIN-3 IN DIFFERENTIATING PAPILLARY THYROID CANCER FROM NODULAR GOITER

"Introduction: Thyroid cancer in one of the most common cancers worldwide, with an increasing incidence over the last decades. Serum Galectin-3 (Gal-3) is used as biomarker in different types of cancer (gastric, hepatic), but its utility in papillary thyroid cancer differential diagnostic in still inconclusive. Objectives: The present study aims to evaluate the diagnostic value of preoperative serum Galectin-3 levels in differentiating between papillary thyroid cancer and nodular goiter. Methods: 277 of serum samples from patients with thyroid lesions were divided into two subgroups: nodular goiter (NG; n = 121) and papillary thyroid carcinoma (PTC; n = 136). Serum Gal-3 levels were measured before surgery for the entire group, and for 62 patients (33 NG, 29 PTC) it was measured a month post-surgery. Gal-3 was measured by ELISA, using Human Galectin-3 Quantikinine ELISA kit (R&amp;D Systems) and statistical analysis were performed using MedCalc Software. All paticipants signed the written informed consent and the study was approved by the Ethics Commitee of the C.I. Parhon National Institute of Endocrinology, Bucharest. Results: Circulating Gal-3 values show that this biomarker has a higher value in PTC patients compared with NG patients (7.17 ng/ml vs. 8.285 ng/ml, p = 0.0038), before thyroidectomy. There were not observed significant statistical correlations between serum Gal-3 values and histological subtype, focality, invasivity or dominant nodule dimension. Conclusion: Our results regarding Gal-3 values show that this biomarker has a higher value in PTC patients compared with NG patients, but its clinical value in preoperative diagnosis and evaluation of thyroid nodules needs further investigations. Keywords: thyroid cancer, papillary thyroid carcinoma, galectin-3"

Left Atrial Phasic Function in Older Adults Is Associated with Fibrotic and Low-Grade Inflammatory Pathways

Introduction: Concomitant risk factors challenge the mechanistic understanding of cardiac aging. We determined the degree to which the left atrial function could be distinguished by advanced cardiac magnetic resonance (CMR) imaging in older adults and assessed associations between the left atrial function and the plasma biomarkers related to biological aging and cardiovascular disease [serum monocyte chemoattractant protein-1 (MCP1), matrix metallopeptidase 9 (MMP-9), B-type natriuretic peptides (BNPs), galectin-3 (Gal-3), high-sensitivity cardiac troponin I (hsTn1), high-sensitivity C-reactive protein (hs-CRP), and soluble urokinase plasminogen activator receptor (sUPAR)]. Methods: Among a cross-sectional population-based cohort of older adults, longitudinal LA strain including reservoir strain (εs), conduit strain (εe), and booster strain (εa) as well as peak strain rates (SRs, SRe, SRa) were determined using CMR and studied in association with blood biomarkers. Results: We studied 243 community adults (42.8% female, mean age 70.3 ± 9.5 years). In bivariate analysis, εe and SRe were reduced in gradation with increasing risk factors (all p values <0.0001). Corresponding levels of sUPAR (ng/mL) were quantitatively higher in older adults with <2 risk factors (2.5 ± 1.6 vs. 1.7 ± 1.3, p = 0.0005), in those with ≥2 risk factors (3.3 ± 2.4 vs. 1.7 ± 1.3, p < 0.0001), compared to young adults; including between older adults with ≥2 risk factors and older adults with <2 risk factors (3.3 ± 2.4 vs. 2.5 ± 1.6, p = 0.017). Based on multivariate analysis, sUPAR was significantly associated with both εe (OR 1.52, p = 0.006) and SRe decline (OR 1.5, p = 0.019). The associations between Gal-3 and εe reduction (OR 1.2, p = 0.022) and between BNP and SRe decline were generally weaker (OR 1.03, p = 0.027). The addition of sUPAR to a model consisting of age, risk factors, Gal-3, and BNPs increased the area under the curve of εe from 0.72 to 0.77 (p = 0.015). Conclusion: By advanced CMR imaging, a panel of circulating biomarkers comprising galectin, MMP-9 and sUPAR were associated with left atrial dysfunction in older adults. Higher levels of Gal-3 and MMP-9 may be suggestive of fibrotic mechanisms in left atrial aging while impairments in left atrial strain seen in association with circulating sUPAR may be related to immune activation in the left atrium in response to left atrial remodeling and fibrotic processes.

Effects of liraglutide vs. lifestyle changes on soluble suppression of tumorigenesis-2 (sST2) and galectin-3 in obese subjects with prediabetes or type 2 diabetes after comparable weight loss

BackgroundSoluble suppression of tumorigenesis-2 (sST2) and galectin (Gal)-3 are two biomarkers related to inflammation, metabolic disturbances and to myocardial fibrosis that characterize several cardiac pathological conditions. Increased circulating levels of these molecules have been associated with risk of cardiovascular death. Treatment with liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We wanted to assess (I) potential differences between subjects with prediabetes or type 2 diabetes mellitus (T2DM) and healthy controls in sST2 and Gal-3 circulating levels, and their relationship with glycemic control and markers of beta cell function and myocardial injury; (II) whether liraglutide treatment modulates these markers in subjects with prediabetes or early T2DM independently of weight loss; (III) whether baseline levels of any of these two molecules may predict the response to liraglutide treatment.MethodsForty metformin-treated obese subjects (BMI ≥ 30) with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n = 23)] or newly diagnosed T2DM (n = 17), were randomized to liraglutide or lifestyle counseling until achieving a comparable weight loss (7% of initial body weight). Thirteen subjects were enrolled as healthy controls for baseline sST2 and Gal-3 levels.ResultsBaseline sST2 levels were comparable between controls and obese patients (p = 0.79) whereas Gal-3 levels were significantly higher in patients as compared to controls (p < 0.001). Liraglutide treatment, but not weight loss achieved by lifestyle counseling, decreased plasma sST2 levels (− 9%, beta = − 14.9, standard deviation 6.9, p = 0.037) while Gal-3 levels did not change. A reduction in serum hs-Troponin I was observed after intervention, due to a 19% (p = 0.29) increase in the lifestyle arm, and a 25% decrease (p = 0.033) in the liraglutide arm (between-group difference p = 0.083). Lower baseline Gal-3 levels predicted a better improvement in beta cell function after liraglutide treatment.ConclusionsLiraglutide-induced reduction in sST2 and possibly hs-TnI suggests that in obese patients with prediabetes or early T2DM this drug may have a positive effect on (cardiac) fibrosis, whereas plasma level of Gal-3 before liraglutide initiation may predict response to the drug in terms of beta cell function improvement.Trial registration Eudract: 2013-001356-36

Urinary Galectin-3 as a Novel Biomarker for the Prediction of Renal Fibrosis and Kidney Disease Progression.

Plasma galectin-3 (Gal-3) is associated with organ fibrosis, but whether urinary Gal-3 is a potential biomarker of kidney disease progression has never been explored. Between 2018 and 2021, we prospectively enrolled 280 patients who underwent renal biopsy and were divided into three groups based on their urinary Gal-3 levels (<354.6, 354.6–510.7, and ≥510.8 pg/mL) to assess kidney disease progression (defined as ≥40% decline in the estimated glomerular filtration rate or end-stage renal disease) and renal histology findings. Patients in the highest urinary Gal-3 tertile had the lowest eGFRs and highest proteinuria levels. In multivariate Cox regression models, patients in the highest tertile had the highest risk of kidney disease progression (adjusted hazard ratio, 4.60; 95% confidence interval, 2.85–7.71) compared to those in the lowest tertile. Higher urinary Gal-3 levels were associated with more severe renal fibrosis. Intrarenal mRNA expression of LGALS3 (Gal-3-encoded gene) was most correlated with the renal stress biomarkers (IGFBP7 and TIMB2), renal function biomarkers (PTGDS) and fibrosis-associated genes (TGFB1). The urinary Gal-3 level may be useful for the identification of patients at high risk of kidney disease progression and renal fibrosis, and for the early initiation of treatments for these patients.

Association Between Serum Galectin-3 Levels and Coronary Stenosis Severity in Patients With Coronary Artery Disease.

BackgroundThe relationship between galectin-3 (Gal-3) and coronary artery disease (CAD) has not been fully elucidated.AimThis study aimed to determine the relationship between the presence and severity of CAD and serum Gal-3 levels.Patients and MethodsThree-hundred thirty-one consecutive CAD patients were enrolled as the study group. An additional 62 patients without CAD were enrolled as the control group. Serum Gal-3 levels were separately compared between the non-CAD and CAD groups, among the stable CAD and Acute coronary syndrome (ACS) groups, and between CAD patients with low and high SYNTAX scores (SSs). The 1-year cumulative rate of major adverse cardiac events (MACEs) was also compared among ACS patients by Gal-3 levels.ResultsSerum Gal-3 was significantly higher in the CAD group than in the non-CAD group 3.89 (0.16–63.67) vs. 2.07 (0.23–9.38) ng/ml, P < 0.001. Furthermore, serum Gal-3 was significantly higher in the non-ST-segment elevation ACS (NSTE-ACS) group than that in the stable CAD group, 4.72 (1.0–16.14) vs. 2.23 (0.65–23.8) ng/ml, P = 0.04 and higher in the ST-segment elevation myocardial infarction (STEMI) group than that in the stable CAD group 7.87 (0.59–63.67) vs. 2.23 (0.65–23.8) ng/ml, P < 0.001. Serum Gal-3 level was an independent predictor of ACS compared with stable CAD group (OR = 1.131, 95% CI: 1.051–1.217, P = 0.001) as well as high SS (OR = 1.030, 95% CI: 1.021–1.047, P = 0.038) after adjust other confounding risk factors. Acute coronary syndrome patients with Gal-3 levels above the median (gal-3 = 4.78 ng/ml) showed a higher cumulative MACE rate than those with Gal-3 levels below the median. After adjusting other confounding risk factors, Gal-3 remained an independent risk factor for the cumulative rate of MACEs in ACS patients (6% higher rate of MACEs incidence per 1 ng/ml increment of Gal-3).ConclusionGalectin-3 correlated with the presence of CAD as well as coronary stability and complexity. Galectin-3 may be valuable in predicting mid-term prognosis in ACS patients.

A Novel Role of Galectin-3 and Thyroglobulin in Prognosis and Differentiation of Different Stages of Thyroid Cancer and Elucidation of the Potential Contribution of Bcl-2, IL-8 and TNF-α.

Thyroid cancer is among the most prevalent cancers with different types and stages. New markers are required for the prognosis and diagnosis of the disease. The present study aimed to detect the role of new markers, including galectin-3 (Gal-3) and thyroglobulin (TG), in the prognosis and staging of thyroid cancer. The study also investigated the potential apoptotic and inflammatory mechanisms involved in thyroid cancer through the determination of B-cell lymphoma 2 (Bcl-2), interleukin-8 (IL-8) and tumor necrosis factor α (TNFα) during the different stages of the cancer using a series of molecular methods. Histopathological and immunohistochemical examinations were also performed. A total of 300 subjects were classified into: 100 normal healthy subjects matched in age and sex, 100 patients with thyroid carcinoma stage I (T1N0M0) and 100 patients with thyroid carcinoma stage 2 (T2N1M1). Interestingly, the present study revealed a significant increase in the levels of TG and Gal-3 in thyroid cancer patients compared to the control group. Furthermore, the levels of Bcl-2, IL-8 and TNF-α significantly increased in the patient serum. The histopathological examination and immunohistochemical observations confirmed the molecular and hematological findings. Collectively, the present study concluded that serum TG and Gal-3 could be useful markers in the prognosis and staging of patients with thyroid cancer. Furthermore, the determination of Bax, Bcl-2, IL-8 and TNF-α levels constitute a major important marker for investigation of the mechanisms of apoptosis and inflammation in thyroid cancer. To our knowledge, this is the first study that used both galectin-3 and TG as tumor markers in the prognosis and differentiation between the different stages of cancer.

Gal3 Plays a Deleterious Role in a Mouse Model of Endotoxemia.

Lipopolysaccharide (LPS)-induced endotoxemia induces an acute systemic inflammatory response that mimics some important features of sepsis, the disease with the highest mortality rate worldwide. In this work, we have analyzed a murine model of endotoxemia based on a single intraperitoneal injection of 5 mg/kg of LPS. We took advantage of galectin-3 (Gal3) knockout mice and found that the absence of Gal3 decreased the mortality rate oflethal endotoxemia in the first 80 h after the administration of LPS, along with a reduction in the tissular damage in several organs measured by electron microscopy. Using flow cytometry, we demonstrated that, in control conditions, peripheral immune cells, especially monocytes, exhibited high levels of Gal3, which were early depleted in response to LPS injection, thus suggesting Gal3 release under endotoxemia conditions. However, serum levels of Gal3 early decreased in response to LPS challenge (1 h), an indication that Gal3 may be extravasated to peripheral organs. Indeed, analysis of Gal3 in peripheral organs revealed a robust up-regulation of Gal3 36 h after LPS injection. Taken together, these results demonstrate the important role that Gal3 could play in the development of systemic inflammation, a well-established feature of sepsis, thus opening new and promising therapeutic options for these harmful conditions.

Galectin-3 enhances atrial remodelling and arrhythmogenesis through CD98 signalling.

Galectin-3 (Gal-3) is a biomarker of atrial fibrillation (AF) that mediates atrial inflammation. CD98 is the membrane surface receptor for Gal-3. Nevertheless, the role of the Gal-3/CD98 axis in atrial arrhythmogenesis is unclear. In this study, we investigated the effects of Gal-3/CD98 signalling on atrial pathogenesis. Whole cell patch clamp and western blotting were used to analyse calcium/potassium homeostasis and calcium-related signalling in Gal-3-administrated HL-1 atrial cardiomyocytes with/without CD98 neutralized antibodies. Telemetry electrocardiographic recording, Masson's trichrome staining and immunohistochemistry staining of atrium were obtained from mice having received tail-vein injections with Gal-3. Gal-3-treated HL-1 myocytes had a shorter action potential duration, smaller L-type calcium current, increased sarcoplasmic reticulum (SR) calcium content, Na+ /Ca2+ exchanger (NCX) current, transient outward potassium current, and ultrarapid delayed rectifier potassium current than control cells had. Gal-3-treated HL-1 myocytes had greater levels of SR Ca2+ ATPase, NCX, Nav1.5, and NLR family pyrin domain containing 3 (NLRP3) expression and increased calcium/calmodulin-dependent protein kinase II (CaMKII), ryanodine receptor 2 (RyR2), and nuclear factor kappa B (NF-κB) phosphorylation than control cells had. Gal-3-mediated activation of CaMKII/RyR2 pathway was diminished in the cotreatment of anti-CD98 antibodies. Mice that were injected with Gal-3 had more atrial ectopic beats, increased atrial fibrosis, and activated NF-κB/NLRP3 signalling than did control mice (nonspecific immunoglobulin) or mice treated with Gal-3 and anti-CD98 antibodies. Gal-3 recombinant protein administration increases atrial fibrosis and arrhythmogenesis through CD98 signalling. Targeting Gal-3/CD98 axis might be a novel therapeutic strategy for patients with AF and high Gal-3 levels.

Increased synovial galectin-3 induce inflammatory fibroblast activation and osteoclastogenesis in patients with rheumatoid arthritis

Objective Galectin-3 (Gal-3) has been suggested as a proinflammatory mediator in rheumatoid arthritis (RA). We aimed to study clinical and pathogenic aspects of Gal-3 in RA. Method Plasma samples from healthy controls (n = 48) and patients with newly diagnosed, early RA were assayed for soluble Gal-3. In patients with chronic RA (n = 18), Gal-3 was measured in both plasma and synovial fluid. Synovial fluid mononuclear cells were used to purify fibroblast-like synoviocytes (FLSs) and osteoclasts. Monocultures of FLSs and autologous co-cultures of FLSs and peripheral blood mononuclear cells were established and co-incubated with a Gal-3 inhibitor. Results Patients with early and chronic RA had persistently increased plasma levels of Gal-3 compared with controls. However, changes in plasma Gal-3 at the level of individuals were associated with long-term disease activity. In seropositive early RA patients, all patients with decreasing plasma Gal-3 from 0 to 3 months had low disease activity after 2 years (p < 0.05). Gal-3 levels in synovial fluid were markedly elevated. In vitro, co-incubation with a Gal-3 inhibitor (GB1107, 10 µM) led to a significant reduction in both interleukin-1β and tumour necrosis factor-α secretion from FLS monocultures (both p < 0.05) and decreased monocyte-derived osteoclastogenesis compared with controls (both p < 0.05). Conclusions Our findings underscore the role of Gal-3 regarding disease activity and tissue destruction in RA. An initial decrease in plasma Gal-3 levels predicted decreased long-term disease activity. Correspondingly, a Gal-3 inhibitor decreased the activity of inflammatory FLSs and osteoclastogenesis in patients with RA.

Expression Pattern and Immunoregulatory Roles of Galectin-1 and Galectin-3 in Atopic Dermatitis and Psoriasis.

The pathogenesis of atopic dermatitis (AD) and psoriasis (Ps) overlaps, particularly the activation of the immune response and tissue damage. Here, we evaluated galectin (Gal)-1 and Gal-3 levels, which are beta-galactoside-binding proteins with immunomodulatory functions and examined their effects on human keratinocytes stimulated with either interleukin (IL)-4 or IL-17A. Skin biopsies from AD, Ps, and control patients were evaluated using histological and immunohistochemical analyses. Six studies containing publicly available transcriptome data were individually analyzed using the GEO2R tool to detect Gal-1 and Gal-3 mRNA levels. In vitro, IL-4- or IL-17A-stimulated keratinocytes were treated with or without Gal-1 or Gal-3 to evaluate cytokine release and migration. Our findings showed different patterns of expression for Gal-1 and Gal-3 in AD and Ps skins. Densitometric analysis in skin samples showed a marked increase in the protein Gal-1 levels in Ps epidermis and in both AD and Ps dermis compared to controls. Protein and mRNA Gal-3 levels were downregulated in AD and Ps lesional skin compared with the control samples. In vitro, both galectins addition abrogated the release of IL-8 and RANTES in IL-17-stimulated keratinocytes after 24h, whereas IL-6 release was downregulated by Gal-3 and Gal-1 in IL-4- and IL-17-stimulated cells, respectively. Administration of both galectins also increased the rate of keratinocyte migration under IL-4 or IL-17 stimulation conditions compared with untreated cells. Altogether, the immunoregulatory and migration effects of Gal-1 and Gal-3 on keratinocytes under inflammatory microenvironment make them interesting targets for future therapies in cutaneous diseases.