INTRODUCTION: The immunosuppressive roles of galectin-3 (Gal-3) in carcinogenesis make this lectin an attractive target for pharmacological inhibition in immunotherapy. Although current clinical immunotherapies appear promising in the treatment of solid tumors, their efficacy is significantly weakened by the hostile immunosuppressive tumor microenvironment (TME). Gal-3, a prominent TME modulator, efficiently subverts the elimination of cancer, either directly by inducing apoptosis of immune cells or indirectly by binding essential effector molecules, such as interferon-gamma (IFNγ). METHODS: N-(2-Hydroxypropyl)methacrylamide (HPMA)-based glycopolymers bearing poly-N-acetyllactosamine-derived tetrasaccharide ligands of Gal-3 were designed, synthesized, and characterized using high-performance liquid chromatography, dynamic light scattering, UV-Vis spectrophotometry, gel permeation chromatography, nuclear magnetic resonance, high-resolution mass spectrometry and CCK-8 assay for evaluation of glycopolymer non-toxicity. Pro-immunogenic effects of purified glycopolymers were tested by apoptotic assay using flow cytometry, competitive ELISA, and in vitro cell-free INFγ-based assay. RESULTS: All tested glycopolymers completely inhibited Gal-3-induced apoptosis of monocytes/macrophages, of which the M1 subtype is responsible for eliminating cancer cells during immunotherapy. Moreover, the glycopolymers suppressed Gal-3-induced capture of glycosylated IFNγ by competitive inhibition to Gal-3 carbohydrate recognition domain (CRD), which enables further inherent biological activities of this effector, such as differentiation of monocytes into M1 macrophages and repolarization of M2-macrophages to the M1 state. CONCLUSION: The prepared glycopolymers are promising inhibitors of Gal-3 and may serve as important supportive anti-cancer nanosystems enabling the infiltration of proinflammatory macrophages and the reprogramming of unwanted M2 macrophages into the M1 subtype.
- MeSH
- akrylamidy chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- galektin 3 * antagonisté a inhibitory MeSH
- galektiny MeSH
- interferon gama * metabolismus MeSH
- krevní proteiny MeSH
- lidé MeSH
- makrofágy účinky léků MeSH
- monocyty * účinky léků MeSH
- nádorové mikroprostředí účinky léků MeSH
- polymery * chemie farmakologie MeSH
- protinádorové látky * farmakologie chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Pulmonary hypertension is a cardiovascular disease with a low survival rate. The protein galectin-3 (Gal-3) binding β-galactosides of cellular glycoproteins plays an important role in the onset and development of this disease. Carbohydrate-based drugs that target Gal-3 represent a new therapeutic strategy in the treatment of pulmonary hypertension. Here, we present the synthesis of novel hydrophilic glycopolymer inhibitors of Gal-3 based on a polyoxazoline chain decorated with carbohydrate ligands. Biolayer interferometry revealed a high binding affinity of these glycopolymers to Gal-3 in the subnanomolar range. In the cell cultures of cardiac fibroblasts and pulmonary artery smooth muscle cells, the most potent glycopolymer 18 (Lac-high) caused a decrease in the expression of markers of tissue remodeling in pulmonary hypertension. The glycopolymers were shown to penetrate into the cells. In a biodistribution and pharmacokinetics study in rats, the glycopolymers accumulated in heart and lung tissues, which are most affected by pulmonary hypertension.
- MeSH
- arteria pulmonalis účinky léků metabolismus MeSH
- biologické markery MeSH
- fibroblasty účinky léků metabolismus MeSH
- galektin 3 * antagonisté a inhibitory metabolismus MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- lidé MeSH
- plicní hypertenze * farmakoterapie metabolismus MeSH
- polymery chemie farmakologie MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Elevated levels of galectin-3 are associated with tumorigenesis. Its inhibition with high-affinity carbohydrate ligands opens new therapeutic routes. Targeting of intracellular galectin-3 is challenging for polar inhibitors like carbohydrates. We demonstrate the potential of novel biomedical research tools, glycocalix[4]arenes, to enter epithelial cells, which may allow their interaction with galectin-3.
- MeSH
- buněčná membrána MeSH
- galektin 3 * MeSH
- galektiny MeSH
- glykokalyx * MeSH
- sacharidy farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- biologické markery * analýza MeSH
- galektin 3 analýza metabolismus normy MeSH
- lidé MeSH
- natriuretické peptidy analýza metabolismus MeSH
- růstový diferenciační faktor 15 analýza metabolismus normy MeSH
- srdeční selhání * diagnóza MeSH
- troponin analýza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
During innate immune responses, myeloid differentiation primary response 88 (MyD88) functions as a critical signaling adaptor protein integrating stimuli from toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family and translates them into specific cellular outcomes. In B cells, somatic mutations in MyD88 trigger oncogenic NF-κB signaling independent of receptor stimulation, which leads to the development of B-cell malignancies. However, the exact molecular mechanisms and downstream signaling targets remain unresolved. We established an inducible system to introduce MyD88 to lymphoma cell lines and performed transcriptomic analysis (RNA-seq) to identify genes differentially expressed by MyD88 bearing the L265P oncogenic mutation. We show that MyD88L265P activates NF-κB signaling and upregulates genes that might contribute to lymphomagenesis, including CD44, LGALS3 (coding Galectin-3), NFKBIZ (coding IkBƺ), and BATF. Moreover, we demonstrate that CD44 can serve as a marker of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and that CD44 expression is correlated with overall survival in DLBCL patients. Our results shed new light on the downstream outcomes of MyD88L265P oncogenic signaling that might be involved in cellular transformation and provide novel therapeutical targets.
- MeSH
- adaptorové proteiny signální transdukční metabolismus MeSH
- antigeny CD44 genetika metabolismus MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- galektin 3 metabolismus MeSH
- lidé MeSH
- mutace MeSH
- myeloidní diferenciační faktor 88 genetika metabolismus MeSH
- NF-kappa B * genetika metabolismus MeSH
- stanovení celkové genové exprese MeSH
- transkripční faktory bZIP genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Galektin-3, člen rodiny solubilních neglykosylovaných lektinů, patří mezi novější biomarkery s prognostickou rolí u onemocnění srdce, ale také plic, ledvin, jater a dalších orgánů. Má prozánětlivé a profibrotické účinky, podílí se na patofyziologii rozvoje srdečního selhání. Existuje automatizovaná analytická metoda stanovení galektinu-3 s robustními analytickými znaky. Jsou známá referenční rozmezí i rozhodovací limity; v kardiologické literatuře panuje shoda o zvýšeném riziku horší prognózy podmíněné fibrózou a zánětem při koncentracích galektinu-3 nad 18 μg/L. Je známá biologická variabilita u zdravých osob i u pacientů, hodnoty koncentrací galektinu-3 jsou v čase stabilní. Nejvíce dat o galektinu-3 se týká kardiologické diagnostiky, patří mezi biomarkery s možným využitím u srdečního selhání, infarktu myokardu, transplantace srdce a dalších kardiologických jednotek, má také roli u dalších onemocnění. Vzhledem k připravované úhradě podle Seznamu výkonů a jeho diagnostickému a prognostickému potenciálu jde o biomarker vhodný pro použití v běžné klinické praxi.
Galectin-3, a member of the family of soluble non-glycosylated lectins, is a newer biomarker with a prognostic role in heart, lung, kidney, liver, and other organ diseases. Galectin-3 has proinflammatory and profibrotic effects and is involved in the pathophysiology of the development of heart failure. An automated analytical method with robust analytical characteristics is available, and reference intervals and decision limits are known. There is a consensus in the cardiology literature for an increased risk of worse prognosis due to fibrosis and inflammation at galectin-3 concentrations above 18 μg/L. Biological variation is known both in healthy subjects and patients with heart diseases and galectin-3 concentrations are stable over time. Most data on galectin-3 available in the literature relate to cardiac disease diagnostics - it belongs among the biomarkers with possible use mainly in heart failure, myocardial infarction, and heart transplantation. Due to the planned reimbursement by health insurance companies and its diagnostic and prognostic potential, galectin-3 seems to be a biomarker suitable for use in routine clinical practice.
- Klíčová slova
- biologická variabilita, rozhodovací meze, analytické znaky,
- MeSH
- biologické markery * MeSH
- galektin 3 * analýza MeSH
- lidé MeSH
- referenční hodnoty MeSH
- srdeční selhání diagnóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Galektin-3 se v kardiologii používá především jako prognostický biomarker, jehož patofyziologické efekty souvisejí s rizikem fibrotizace a remodelace myokardu. Zvýšené koncentrace galektinu-3 v plazmě (obvykle nad rozhodovací mez 18 μg/L) znamenají riziko vyšší kardiovaskulární i celkové mortality především u pacientů se srdečním selháním, u pacientů po infarktu myokardu, po transplantaci srdce a u dalších kardiologických onemocnění. Výpovědní hodnota galektinu-3 se zvyšuje při kombinaci s natriuretickými peptidy. Galektin-3 v kardiologii představuje kandidátní molekulu pro odhad prognózy pacientů.
Galectin-3 is mainly used in cardiology as a prognostic marker. Its pathophysiological effects correlate with the risk of cardiac fibrosis and remodelation. Elevated concentrations of galectin-3 in plasma (above the decision limit of 18 μg/L) increase the risk of cardiovascular morbidity and overall mortality, especially in patients with heart failure, myocardial infarction, heart transplantation and other cardiac diseases. The predictive value of galectin-3 increases when combined with natriuretic peptides. In cardiology, galectin-3 is recognized as a candidate molecule for prognostication.
- MeSH
- biologické markery MeSH
- galektin 3 * analýza krev MeSH
- infarkt myokardu diagnóza MeSH
- kardiovaskulární nemoci diagnóza MeSH
- lidé MeSH
- srdeční selhání diagnóza MeSH
- transplantace srdce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Galectin-3 (Gal-3) participates in many cancer-related metabolic processes. The inhibition of overexpressed Gal-3 by, e.g., β-galactoside-derived inhibitors is hence promising for cancer treatment. The multivalent presentation of such inhibitors on a suitable biocompatible carrier can enhance the overall affinity to Gal-3 and favorably modify the interaction with Gal-3-overexpressing cells. We synthesized a library of C-3 aryl-substituted thiodigalactoside inhibitors and their multivalent N-(2-hydroxypropyl)methacrylamide (HPMA)-based counterparts with two different glycomimetic contents. Glycopolymers with a higher content of glycomimetic exhibited a higher affinity to Gal-3 as assessed by ELISA and biolayer interferometry. Among them, four candidates (with 4-acetophenyl, 4-cyanophenyl, 4-fluorophenyl, and thiophen-3-yl substitution) were selected for further evaluation in cancer-related experiments in cell cultures. These glycopolymers inhibited Gal-3-induced processes in cancer cells. The cyanophenyl-substituted glycopolymer exhibited the strongest antiproliferative, antimigratory, antiangiogenic, and immunoprotective properties. The prepared glycopolymers appear to be prospective modulators of the tumor microenvironment applicable in the therapy of Gal-3-associated cancers.
BACKGROUND: Galectin-3 (GAL3) is linked to the prognosis of patients with heart failure and after heart transplantation (HTx). We assessed the prognostic role of GAL3 in a long-term follow-up after HTx. METHODS: HTx patients (N = 121) were evaluated in a single-center, noninterventional, prospective, observational study. The median follow-up was 96 months (2942 days, interquartile range (IQR) 2408-3264 days), and 40 patients died. GAL3 was measured before HTx, +10 days after HTx, and during the first posttransplant year. Survival analysis (all-cause mortality) was performed with adjustments for clinical and laboratory variables. RESULTS: The median pretransplant GAL3 level was 18.0 μg/L (IQR 14.0-25.9), and higher values were associated with older age, worse kidney function, left ventricular assist device use before HTx, a higher IMPACT score, and mortality. Increased pretransplant GAL3 predicted shorter survival time (HR 2.05, 95% CI 1.09-3.85, p < .05). Similar prognostic power had GAL3 on the 10th posttransplant day (HR 2.03, 95% CI 1.08-3.82, p < .05). GAL3 was an independent predictor of death after adjustment for clinical variables (age, infection, diabetes, smoking, IMPACT score, and troponin). CONCLUSIONS: GAL3 was significantly associated with all-cause mortality after adjusting for clinical and laboratory variables and may serve as an additional prognostic biomarker.
The differential diagnosis of well-differentiated tumors of follicular cell origin remains the most problematic task in thyroid pathology. Specific morphologic criteria (capsular and/or vascular invasion, nuclear characteristics) are crucial in the diagnosis of these neoplasms. However, the assessment of malignant features is inconclusive in some cases. Moreover, oncocytic thyroid tumors remain controversial in a respect to their pathobiology, behavior and management. Therefore, the useful diagnostic/prognostic thyroid markers are awaited. The aim of our study was to evaluate the expression of galectin-3 and thyroid peroxidase (TPO) in benign and malignant thyroid tumors of follicular cell origin. A total of 186 archival thyroid samples including 38 non-oncocytic follicular adenomas, 53 oncocytic (Hürthle cell) adenomas, 6 non-oncocytic follicular carcinomas, 23 oncocytic (Hürthle cell) carcinomas, 43 non-oncocytic papillary carcinomas, and 23 oncocytic papillary carcinomas were analyzed for galectin-3 and TPO expression by immunohistochemistry. Both types of papillary carcinomas showed significant upregulation of galectin-3 in comparison with the other tumor types, likewise, significant differences in galectin-3 expression were discovered between non-oncocytic and oncocytic variants of studied tumors excluding follicular carcinoma. Significant lowering of TPO was revealed in oncocytic adenomas and papillary carcinomas. In conclusion, the combined use of galectin-3 and TPO markers could help to improve the differential diagnosis of thyroid tumors. Differences in the galectin-3 and TPO expression between some oncocytic and non-oncocytic tumors support their separation in the latest WHO classification of thyroid tumors.
- MeSH
- autoantigeny genetika MeSH
- diferenciální diagnóza MeSH
- galektin 3 genetika MeSH
- jodidperoxidasa genetika MeSH
- lidé MeSH
- nádorové biomarkery genetika MeSH
- nádory štítné žlázy klasifikace diagnóza MeSH
- proteiny vázající železo genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
