Search

Galectins are widely distributed throughout the animal kingdom, from marine sponges to mammals. Galectins are a family of soluble lectins that specifically recognize β-galactoside-containing glycans and are categorized into three subgroups based on the number and function of their carbohydrate recognition domains (CRDs). The interaction of galectins with specific ligands mediates a wide range of biological activities, depending on the cell type, tissue context, expression levels of individual galectin, and receptor involvement. Galectins affect various immune cell processes through both intracellular and extracellular mechanisms and play roles in processes, such as apoptosis, angiogenesis, and fibrosis. Their importance has increased in recent years because they are recognized as biomarkers, therapeutic agents, and drug targets, with many other applications in conditions such as cardiovascular diseases and cancer. However, little is known about the involvement of galectins in liver diseases. Here, we review the functions of various galectins and evaluate their roles in liver diseases. [ABSTRACT FROM AUTHOR]

Cellular mesenchymal-epithelial transition factor (c-MET), also known as hepatocyte growth factor receptor (HGFR), is a crucial receptor tyrosine kinase implicated in various solid tumors, including lung, breast, and liver cancers. The concomitant expression of c-MET and PD-L1 in tumors, such as hepatocellular carcinoma, highlights their prognostic significance and connection to therapeutic resistance. Cancer-associated fibroblasts and mesenchymal stromal cells produce hepatocyte growth factor (HGF), activating c-MET signaling in tumor cells and myeloid-derived suppressor cells (MDSC). This activation leads to metabolic reprogramming and increased activity of enzymes like glutaminase (GLS), indoleamine 2,3-dioxygenase (IDO), and arginase 1 (ARG1), depleting essential amino acids in the tumor microenvironment that are vital for effector immune cell function. This review highlights the interplay between tumor cells and myeloid-derived suppressor cells (MDSCs) that create an immunosuppressive environment while providing targets for c-MET-focused immunotherapy. It emphasizes the clinical implications of c-MET inhibition on the behavior of immune cells such as neutrophils, macrophages, T cells, and NK cells. It explores the potential of c-MET antagonism combined with immunotherapeutic strategies to enhance cancer treatment paradigms. This review also discusses the innovative cancer immunotherapies targeting c-MET, including chimeric antigen receptor (CAR) therapies, monoclonal antibodies, and antibody-drug conjugates, while encouraging the development of a comprehensive strategy that simultaneously tackles immune evasion and enhances anti-tumor efficacy further to improve the clinical prognoses for patients with c-MET-positive malignancies. Despite the challenges and variability in efficacy across different cancer subtypes, continued research into the molecular mechanisms and the development of innovative therapeutic strategies will be crucial. [ABSTRACT FROM AUTHOR]

Abstract New insights into cellular interactions and key biomolecules involved in lung cancer (LC) bone metastasis could offer remarkable therapeutic benefits. Using a panel of four LC cells, we investigated LC-bone interaction by exposing differentiating osteoclasts (OCs) to LC cells (LC-OC interaction) directly in a co-culture setting or indirectly via treatment with LC secretomes (conditioned media or exosomes). LC-OC interaction facilitated the production of large-sized OCs (nuclei > 10) coupled with extensive bone resorption pits. Proteomic analysis of LC exosomes identified galectin-3-binding protein (Gal3bp) as a potential biomarker which was released primarily by most of LC-derived exosomes. The facilitation of OC differentiation and function by LC-exosomal Gal3bp was supported by the application of recombinant Gal3bp and anti-Gal3bp in OC treatment. Further, our results exhibited a dysregulation of crucial OC markers (TRAF6, p-SAPK/JNK, p-44/42 MAPK, NFAT2 and CD9) during LC-OC interaction that possibly contributed to the facilitation of osteoclastogenesis. Simulation of bone metastasis via intratibial injection of LC cells revealed Gal3bp’s possible roles in enhancing OC activation leading to osseous tissue resorption. Overall, this work implicated LC-exosomal Gal3bp in osteolytic metastasis of LC which warrants further studies to assess its potential prognostic and therapeutic relevance.

Autophagy is a crucial immune defense mechanism that controls the survival and pathogenesis of M. tb by maintaining cell physiology during stress and pathogen attack. The E3-Ub ligases (PRKN, SMURF1, and NEDD4) and autophagy receptors (SQSTM1, TAX1BP1, CALCOCO2, OPTN, and NBR1) play key roles in this process. Galectins (LGALSs), which bind to sugars and are involved in identifying damaged cell membranes caused by intracellular pathogens such as M. tb, are essential. These include LGALS3, LGALS8, and LGALS9, which respond to endomembrane damage and regulate endomembrane damage caused by toxic chemicals, protein aggregates, and intracellular pathogens, including M. tb. They also activate selective autophagy and de novo endolysosome biogenesis. LGALS3, LGALS9, and LGALS8 interact with various components to activate autophagy and repair damage, while CGAS-STING1 plays a critical role in providing immunity against M. tb by activating selective autophagy and producing type I IFNs with antimycobacterial functions. STING1 activates cGAMP-dependent autophagy which provides immunity against various pathogens. Additionally, cytoplasmic surveillance pathways activated by ds-DNA, such as inflammasomes mediated by NLRP3 and AIM2 complexes, control M. tb. Modulation of E3-Ub ligases with small regulatory molecules of LGALSs and TRIM proteins could be a novel host-based therapeutic approach for controlling TB. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide and is a leading cause of cancer-related mortality. Since many colon cancers present no significant clinical symptoms, identifying new biomarkers or a set of biological indicators significant for clinical trials is crucial for the early detection of CRC. This advancement also aids in establishing new objectives for interventional therapeutic strategies against the disease. Currently, research is exploring various proteins, glycoproteins, and cellular and humoral substances involved in cellular homeostasis mechanisms as potential cancer markers. This review examines the potential utility of fucosylation and sialylation processes, as well as sex hormones, as biomarkers in the diagnosis and prognosis of CRC. A comprehensive search was conducted in PUBMED, MEDLINE, and Google Scholar, supplemented by a manual search of relevant journals. The keywords were L-fucose, sialic acid, fucosyltransferase-4, galectin-3, and steroid hormones in CRCs.

Abstract Background Premature rupture of the membranes (PROM) is a key cause of preterm birth and represents a major cause of neonatal mortality and morbidity. Natural products N-acetyl-d-galactosamine (GalNAc), which are basic building blocks of important polysaccharides in biological cells or tissues, such as chitin, glycoproteins, and glycolipids, may improve possible effects of wound healing. Methods An in vitro inflammation and oxidative stress model was constructed using tumor necrosis-α (TNF-α) and lipopolysaccharide (LPS) action on WISH cells. Human amniotic epithelial cells (hAECs) were primarily cultured by digestion to construct a wound model. The effects of GalNAc on anti-inflammatory and anti-oxidative stress, migration and proliferation, epithelial-mesenchymal transition (EMT), glycosaminoglycan (GAG)/hyaluronic acid (HA) production, and protein kinase B (Akt) pathway in hAECs and WISH cells were analyzed using the DCFH-DA fluorescent probe, ELISA, CCK-8, scratch, transwell migration, and western blot to determine the mechanism by which GalNAc promotes amniotic wound healing. Results GalNAc decreased IL-6 expression in TNF-α-stimulated WISH cells and ROS expression in LPS-stimulated WISH cells (P 0.05). GalNAc upregulated the expression of sGAG in WISH cells (P 0.05). Conclusions GalNAc might be a potential target for the prevention and treatment of PROM through the galectin pathway, including (i) inflammation; (ii) epithelial-mesenchymal transition; (iii) proliferation and migration; and (iv) regression, remodeling, and healing.

Galectin recognizes β-galactosides through its carbohydrate recognition domains (CRDs). This study aimed to determine the biological features of a novel Trichinella spiralis galectin (galactoside-binding lectin family protein, TsGLFP) and its role in driving macrophage M1 polarization and enhancing ADCC killing of larvae. TsGLFP belongs to the galectin family and has two CRDs. The complete TsGLFP cDNA sequence was cloned and then expressed in Escherichia coli BL21. The results of qPCR, Western blot, and indirect immunofluorescence tests (IIFTs) revealed that TsGLFP was expressed in various stages of T. spiralis worms and principally localized at the cuticle and around the female embryos of the nematode. rTsGLFP had the function of agglutinating mouse erythrocytes, and this agglutination activity could be inhibited by lactose. After the mouse macrophage RAW264.7 was incubated with rTsGLFP, the expression level of the M1 genes (iNOS, IL-6, and TNF-α) and NO production were obviously increased. After incubating macrophages with rTsGLFP, there was a noticeable rise in the expression levels of p-IκB-α and p-NF-κB p65. Additionally, rTsGLFP enhanced the macrophage's ability to kill newborn larvae by ADCC cytotoxicity. When the macrophages were pretreated with the specific p-NF-κB p65 inhibitor PDTC, and then stimulated with rTsGLFP, the expression levels of iNOS, NO, and p-NF-κB p65 and the macrophages' ADCC cytotoxicity were distinctly decreased. These findings indicated that rTsGLFP enhanced the macrophage ADCC killing of larvae by driving M1 polarization through activating the NF-κB pathway. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide and is a leading cause of cancer-related mortality. Since many colon cancers present no significant clinical symptoms, identifying new biomarkers or a set of biological indicators significant for clinical trials is crucial for the early detection of CRC. This advancement also aids in establishing new objectives for interventional therapeutic strategies against the disease. Currently, research is exploring various proteins, glycoproteins, and cellular and humoral substances involved in cellular homeostasis mechanisms as potential cancer markers. This review examines the potential utility of fucosylation and sialylation processes, as well as sex hormones, as biomarkers in the diagnosis and prognosis of CRC. A comprehensive search was conducted in PUBMED, MEDLINE, and Google Scholar, supplemented by a manual search of relevant journals. The keywords were L-fucose, sialic acid, fucosyltransferase-4, galectin-3, and steroid hormones in CRCs. [ABSTRACT FROM AUTHOR]

We here report the purification of a novel member of the galectin family, the β-galactoside-binding lectin hRTL, from the marine sponge Chondrilla australiensis. The hRTL lectin is a tetrameric proto-type galectin with a subunit molecular weight of 15.5 kDa, consisting of 141 amino acids and sharing 92% primary sequence identity with the galectin CCL from the congeneric species C. caribensis. Transcriptome analysis allowed for the identification of additional sequences belonging to the same family, bringing the total number of hRTLs to six. Unlike most other galectins, hRTLs display a 23 amino acid-long signal peptide that, according to Erdman degradation, is post-translationally cleaved, leaving an N-terminal end devoid of acetylated modifications, unlike most other galectins. Moreover, two hRTLs display an internal insertion, which determines the presence of an unusual loop region that may have important functional implications. The characterization of the glycan-binding properties of hRTL revealed that it had high affinity towards TF-antigen, sialyl TF, and type-1 N-acetyl lactosamine with a Galβ1-3 structure. When administered to DLD-1 cells, a colorectal carcinoma cell line expressing mucin-associated TF-antigen, hRTL could induce glycan-dependent cytotoxicity. [ABSTRACT FROM AUTHOR]

Introduction: Galectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human KD = 25 nM; rabbit KD = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH). Methods: Male New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson's trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression. Results: Steatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease. Discussion: Selvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dosedependent manner. These data support the human selvigaltin dose of 100 mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis. [ABSTRACT FROM AUTHOR]

Sialic acid is a unique sugar moiety that resides in the distal and most accessible position of the glycans on mammalian cell surface and extracellular glycoproteins and glycolipids. The potential for sialic acid to obscure underlying structures has long been postulated, but the means by which such structural changes directly affect biological processes continues to be elucidated. Here, we appraise the growing body of literature detailing the importance of sialic acid for the generation, differentiation, function and death of haematopoietic cells. We conclude that sialylation is a critical post‐translational modification utilized in haematopoiesis to meet the dynamic needs of the organism by enforcing rapid changes in availability of lineage‐specific cell types. Though long thought to be generated only cell‐autonomously within the intracellular ER‐Golgi secretory apparatus, emerging data also demonstrate previously unexpected diversity in the mechanisms of sialylation. Emphasis is afforded to the mechanism of extrinsic sialylation, whereby extracellular enzymes remodel cell surface and extracellular glycans, supported by charged sugar donor molecules from activated platelets. [ABSTRACT FROM AUTHOR]

BACKGROUND: Galectins (GALs) are a family of mammalian sugar‐binding proteins specific for β‐galactosides. Our previous studies have shown that the larval development of the diamondback moth (Plutella xylostella) is significantly disturbed when fed with recombinant mammalian galectin 1 (GAL1) derived from Escherichia coli. To further explore its applicability, two GAL1‐overexpressed Arabidopsis [GAL1‐Arabidopsis (whole plant) and GAL1‐Arabidopsis‐vas (vascular bundle‐specific)] lines were established for insecticidal activity and mechanism studies. RESULTS: The expression level of GAL1 in transgenic Arabidopsis is 1–0.5% (GAL1‐Arabidopsis) and 0.08–0.01% (GAL1‐Arabidopsis‐vas) of total leaf soluble protein. Survival, body weight, and food consumption significantly decreased in a time‐dependent manner in P. xylostella larvae (with chewing mouthparts) fed on GAL1‐Arabidopsis. The mortality of Kolla paulula (with piercing‐sucking mouthparts and xylem feeder) fed on GAL1‐Arabidopsis‐vas was also significantly higher than that fed on wild‐type Arabidopsis (WT‐Arabidopsis), but was lower than that fed on GAL1‐Arabidopsis. The histochemical structure and results of immunostaining suggested that the binding of GAL1 to the midgut epithelium of P. xylostella fed on GAL1‐Arabidopsis was dose‐ and time‐dependent. Ultrastructural studies further showed the disruption of microvilli, abnormalities in epithelial cells, and fragments of the peritrophic membrane (PM) in P. xylostella larvae fed on GAL1‐Arabidopsis. CONCLUSION: The insecticidal mechanism of GAL1 involves interference with PM integrity and suggests that GAL1 is a potential candidate for bioinsecticide development. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: Galectin-3 has been proposed as a candidate marker for cardiovascular risk stratification, although its role in kidney failure is unclear. The aim of this systematic review was to assess the association of serum galectin-3 levels with overall survival and cardiovascular outcomes among hemodialysis patients. Methods: Medline, Scopus, Web of Science and CENTRAL were systematically searched from inception till Aug 20, 2023. Observational studies evaluating the association of serum galectin-3 with mortality, cardiovascular disease and arterial stiffness in hemodialysis patients were included. The exposure–response relationship between galectin-3 and mortality was explored by dose–response meta-analysis using restricted cubic splines in a one-stage approach. Results: Overall, 13 studies were included (9 cohort and 4 cross-sectional), comprising 6025 hemodialysis individuals. Increasing galectin-3 values were associated with greater all-cause mortality risk (χ2: 18.71, p-value < 0.001) and an insignificant trend toward higher cardiovascular mortality risk (χ2: 5.06, p-value: 0.079). Compared to a reference galectin-3 value of 10 ng/ml, all-cause mortality risk was significantly higher with levels of 20 ng/ml (Hazard ratio–HR: 2.62, 95% confidence intervals-CI: 1.66–4.15), 30 ng/ml (HR: 3.78, 95% CI: 2.05–6.97) and 40 ng/ml (HR: 4.01, 95% CI: 2.14–7.52). Qualitative synthesis of evidence indicated that serum galectin-3 may be linked to abdominal aortic calcification severity and progression, as well as to left ventricular systolic and diastolic dysfunction. Conclusions: This study suggests that high serum galectin-3 levels are associated with greater all-cause mortality risk among patients on maintenance hemodialysis. Preliminary cross-sectional evidence indicates that serum galectin-3 may be associated with arterial stiffness and left ventricular dysfunction. [ABSTRACT FROM AUTHOR]

Obesity has reached epidemic proportions in the United States, emerging as a risk factor for the onset of breast cancer and a harbinger of unfavorable outcomes [1–3]. Despite limited understanding of the precise mechanisms, both obesity and breast cancer are associated with extracellular matrix (ECM) rewiring [4–6]. Utilizing total breast tissue proteomics, we analyzed normal-weight (18.5 to

Cellular mesenchymal-epithelial transition factor (c-MET), also known as hepatocyte growth factor receptor (HGFR), is a crucial receptor tyrosine kinase implicated in various solid tumors, including lung, breast, and liver cancers. The concomitant expression of c-MET and PD-L1 in tumors, such as hepatocellular carcinoma, highlights their prognostic significance and connection to therapeutic resistance. Cancer-associated fibroblasts and mesenchymal stromal cells produce hepatocyte growth factor (HGF), activating c-MET signaling in tumor cells and myeloid-derived suppressor cells (MDSC). This activation leads to metabolic reprogramming and increased activity of enzymes like glutaminase (GLS), indoleamine 2,3-dioxygenase (IDO), and arginase 1 (ARG1), depleting essential amino acids in the tumor microenvironment that are vital for effector immune cell function. This review highlights the interplay between tumor cells and myeloid-derived suppressor cells (MDSCs) that create an immunosuppressive environment while providing targets for c-MET-focused immunotherapy. It emphasizes the clinical implications of c-MET inhibition on the behavior of immune cells such as neutrophils, macrophages, T cells, and NK cells. It explores the potential of c-MET antagonism combined with immunotherapeutic strategies to enhance cancer treatment paradigms. This review also discusses the innovative cancer immunotherapies targeting c-MET, including chimeric antigen receptor (CAR) therapies, monoclonal antibodies, and antibody-drug conjugates, while encouraging the development of a comprehensive strategy that simultaneously tackles immune evasion and enhances anti-tumor efficacy further to improve the clinical prognoses for patients with c-MET-positive malignancies. Despite the challenges and variability in efficacy across different cancer subtypes, continued research into the molecular mechanisms and the development of innovative therapeutic strategies will be crucial.

Abstract Background Centella Asiatica has been shown to have beneficial value for the treatment of tumors. However, its active ingredients and molecular mechanisms of action have not been fully elucidated. Pectic polysaccharides are the primary active components from medicinal plants. Moreover, these polysaccharides are regarded as potential inhibitors of galectins, such as galectin-1, -3, -7, that generally promote tumor growth. Nevertheless, detailed structural analysis of pectic polysaccharides from Centella Asiatica is sorely lacking, as is knowledge of their interactions with galectins. Methods Water-soluble pectic polysaccharides (WCAP) isolated from Centella Asiatica were purified into two homogeneous fractions (WCAP-A2b and WCAP-A5b) by a combination of anion-exchange and gel-permeation chromatography. Monosaccharide composition, FT-IR, NMR and enzymatic analyses were used to characterize their structural features. Furthermore, the interactions between galectin-1, -3, -7 and a series of these polysaccharides, including two pectin fractions and their structural domains produced by enzymatic hydrolysis, were evaluated by using hemagglutination and biolayer interferometry. Results WCAP-A2b and WCAP-A5b have weight averaged molecular weights of 30.0 kDa and 34.0 kDa, respectively, and both polysaccharides consist of rhamnogalacturonan I (RG-I), rhamnogalacturonan II (RG-II) and homogalacturonan (HG) domains, with mass ratios of 1.3: 1.0: 1.4 and 1.1: 1.0: 2.4, respectively. Their RG-I domains contain arabinan, galactan, and/or arabinogalactan, along with neutral sugar side chains that are more prevalent in WCAP-A2b than in WCAP-A5b. Hemagglutination and biolayer interferometry binding assays indicate that galectin-3 vis-à-vis galectin-1 and -7, binds strongly to the RG-I domain (likely via its neutral side chains) in WCAP-A5b, thereby inhibiting galectin-3-mediated cell–cell interactions. Conclusions Our study provides structural information on pectin polysaccharides from Centella Asiatica. Results suggest that RG-I domains from WCAP-A5b and WCAP-A2b may be developed as potential inhibitors of galectin-3-mediated cell–cell adhesion and tumor growth. Graphical Abstract

Galectins are a group of β-galactoside-binding proteins with several roles in immune response, cellular adhesion, and inflammation development. Current evidence suggest that these proteins could play a crucial role in many respiratory diseases such as pulmonary fibrosis, lung cancer, and respiratory infections. From this standpoint, an increasing body of evidence have recognized galectins as potential biomarkers involved in several aspects of asthma pathophysiology. Among them, galectin-3 (Gal-3), galectin-9 (Gal-9), and galectin-10 (Gal-10) are the most extensively studied in human and animal asthma models. These galectins can affect T helper 2 (Th2) and non-Th2 inflammation, mucus production, airway responsiveness, and bronchial remodeling. Nevertheless, while higher Gal-3 and Gal-9 concentrations are associated with a stronger degree of Th-2 phlogosis, Gal-10, which forms Charcot–Leyden Crystals (CLCs), correlates with sputum eosinophilic count, interleukin-5 (IL-5) production, and immunoglobulin E (IgE) secretion. Finally, several galectins have shown potential in clinical response monitoring after inhaled corticosteroids (ICS) and biologic therapies, confirming their potential role as reliable biomarkers in patients with asthma.

Background: Centella Asiatica has been shown to have beneficial value for the treatment of tumors. However, its active ingredients and molecular mechanisms of action have not been fully elucidated. Pectic polysaccharides are the primary active components from medicinal plants. Moreover, these polysaccharides are regarded as potential inhibitors of galectins, such as galectin-1, -3, -7, that generally promote tumor growth. Nevertheless, detailed structural analysis of pectic polysaccharides from Centella Asiatica is sorely lacking, as is knowledge of their interactions with galectins. Methods: Water-soluble pectic polysaccharides (WCAP) isolated from Centella Asiatica were purified into two homogeneous fractions (WCAP-A2b and WCAP-A5b) by a combination of anion-exchange and gel-permeation chromatography. Monosaccharide composition, FT-IR, NMR and enzymatic analyses were used to characterize their structural features. Furthermore, the interactions between galectin-1, -3, -7 and a series of these polysaccharides, including two pectin fractions and their structural domains produced by enzymatic hydrolysis, were evaluated by using hemagglutination and biolayer interferometry. Results: WCAP-A2b and WCAP-A5b have weight averaged molecular weights of 30.0 kDa and 34.0 kDa, respectively, and both polysaccharides consist of rhamnogalacturonan I (RG-I), rhamnogalacturonan II (RG-II) and homogalacturonan (HG) domains, with mass ratios of 1.3: 1.0: 1.4 and 1.1: 1.0: 2.4, respectively. Their RG-I domains contain arabinan, galactan, and/or arabinogalactan, along with neutral sugar side chains that are more prevalent in WCAP-A2b than in WCAP-A5b. Hemagglutination and biolayer interferometry binding assays indicate that galectin-3 vis-à-vis galectin-1 and -7, binds strongly to the RG-I domain (likely via its neutral side chains) in WCAP-A5b, thereby inhibiting galectin-3-mediated cell–cell interactions. Conclusions: Our study provides structural information on pectin polysaccharides from Centella Asiatica. Results suggest that RG-I domains from WCAP-A5b and WCAP-A2b may be developed as potential inhibitors of galectin-3-mediated cell–cell adhesion and tumor growth. [ABSTRACT FROM AUTHOR]

Placental protein 13 (PP13) exhibits a plasma concentration that increases gradually during normal gestation, a process that is disrupted in preeclampsia, which is characterized by elevated vascular resistance, reduced utero-placental blood flow, and intrauterine growth restriction. This study investigated PP13's role in vascular tone regulation and its molecular mechanisms. Uterine and subcutaneous arteries, isolated from both pregnant and non-pregnant women, were precontracted with the thromboxane analogue U46619 and exposed to PP13 using pressurized myography. The molecular mechanisms were further investigated, using specific inhibitors for nitric oxide synthase (L-NAME+LNNA at 10−4 M) and guanylate cyclase (ODQ at 10−5 M). The results showed that PP13 induced vasodilation in uterine arteries, but not in subcutaneous arteries. Additionally, PP13 counteracted U46619-induced vasoconstriction, which is particularly pronounced in pregnancy. Further investigation revealed that PP13's mechanism of action is dependent on the activation of the nitric oxide–cGMP pathway. This study provides novel insights into the vasomodulatory effects of PP13 on human uterine arteries, underscoring its potential role in regulating utero-placental blood flow. These findings suggest that PP13 may be a promising candidate for improving utero-placental blood flow in conditions such as preeclampsia. Further research and clinical studies are warranted to validate PP13's efficacy and safety as a therapeutic agent for managing preeclampsia. [ABSTRACT FROM AUTHOR]

In the galectin family, a group of lectins is united by their evolutionarily conserved carbohydrate recognition domains. These polypeptides play a role in various cellular processes and are implicated in disease mechanisms such as cancer, fibrosis, infection, and inflammation. Following synthesis in the cytosol, manifold interactions of galectins have been described both extracellularly and intracellularly. Extracellular galectins frequently engage with glycoproteins or glycolipids in a carbohydrate-dependent manner. Intracellularly, galectins bind to non-glycosylated proteins situated in distinct cellular compartments, each with multiple cellular functions. This diversity complicates attempts to form a comprehensive understanding of the role of galectin molecules within the cell. This review enumerates intracellular galectin interaction partners and outlines their involvement in cellular processes. The intricate connections between galectin functions and pathomechanisms are illustrated through discussions of intracellular galectin assemblies in immune and cancer cells. This underscores the imperative need to fully comprehend the interplay of galectins with the cellular machinery and to devise therapeutic strategies aimed at counteracting the establishment of galectin-based disease mechanisms. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to explore the effect of nonsurgical periodontal treatment on Galectin-1 and -3 GCF levels in gingivitis and periodontitis stage III compared to periodontally healthy individuals, to determine whether they could serve as diagnostic markers / therapeutic targets for periodontitis and revealing their possible role in periodontal disease. Materials and methods: Forty-five systemically healthy participants were included and equally subdivided into three groups: gingivitis, periodontitis (stage III), and a periodontally healthy control group. The clinical parameters were recorded. Galectin-1 and -3 GCF levels were evaluated (before and after non-surgical treatment for periodontitis) using an enzyme linked immune-sorbent assay (ELISA) kit. Receiver operating characteristic (ROC) curve was performed to reveal sensitivity, specificity, predictive value, and diagnostic accuracy of both markers. Results: The study showed statistical significance between different groups regarding Galectin-3 with higher values in periodontitis and the lowest values in healthy control. Also, Galectin-1 was significantly higher in the periodontitis/gingivitis groups than in the control group. Moreover, non-surgical periodontal treatment in periodontitis patients caused a statistical reduction in clinical parameters and biomarkers. ROC analysis revealed excellent diagnostic ability of both biomarkers in discriminating periodontitis/gingivitis against healthy individuals (100% diagnostic accuracy for Galectin-1 and 93% for Galectin-3, AUC > 0.9) and acceptable diagnostic ability between periodontitis participants against gingivitis (73% diagnostic accuracy for Gal-1 and 80% for Gal-3, AUC > 0.7). Conclusions: Both Galectin-1 and Galectin-3 seem to have outstanding diagnostic accuracy for the identification of periodontal disease, an acceptable ability to measure periodontal disease activity and the severity of inflammatory status. Additionally, they could serve as therapeutic targets to monitor treatment efficiency. Clinicaltrial.gov registration number: (NCT06038812). [ABSTRACT FROM AUTHOR]

N-acetylgalactosaminyltransferases (GALNTs) are a polypeptide responsible for aberrant glycosylation in breast cancer (BC), but the mechanism is unclear. In this study, expression levels of GALNT6, GALNT14, and Gal-3 were assessed in BC, and their association with GDF-15, β-catenin, stemness (SOX2 and OCT4), and drug resistance marker (ABCC5) was evaluated. Gene expression of GALNT6, GALNT14, Gal-3, GDF-15, OCT4, SOX2, ABCC5, and β-catenin in tumor and adjacent non-tumor tissues (n = 30) was determined. The same was compared with GEO-microarray datasets. A significant increase in the expression of candidate genes was observed in BC tumor compared to adjacent non-tumor tissue; and in pre-therapeutic patients compared to post-therapeutic. GALNT6, GALNT14, Gal-3, and GDF-15 showed positive association with β-catenin, SOX2, OCT4, and ABCC5 and were significantly associated with poor Overall Survival. Our findings were also validated via in silico analysis. Our study suggests that GALNT6, GALNT14, and Gal-3 in association with GDF-15 promote stemness and intrinsic drug resistance in BC, possibly by β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Galectins are soluble glycan-binding proteins that interact with a wide range of glycoproteins and glycolipids and modulate a broad spectrum of physiological and pathological processes. The expression and subcellular localization of different galectins vary among tissues and cell types and change during processes of tissue repair, fibrosis and cancer where epithelial cells loss differentiation while acquiring migratory mesenchymal phenotypes. The epithelial-mesenchymal transition (EMT) that occurs in the context of these processes can include modifications of glycosylation patterns of glycolipids and glycoproteins affecting their interactions with galectins. Moreover, overexpression of certain galectins has been involved in the development and different outcomes of EMT. This review focuses on the roles and mechanisms of Galectin-1 (Gal-1), Gal-3, Gal-4, Gal-7 and Gal-8, which have been involved in physiologic and pathogenic EMT contexts.

Galectins are soluble glycan-binding proteins that interact with a wide range of glycoproteins and glycolipids and modulate a broad spectrum of physiological and pathological processes. The expression and subcellular localization of different galectins vary among tissues and cell types and change during processes of tissue repair, fibrosis and cancer where epithelial cells loss differentiation while acquiring migratory mesenchymal phenotypes. The epithelial-mesenchymal transition (EMT) that occurs in the context of these processes can include modifications of glycosylation patterns of glycolipids and glycoproteins affecting their interactions with galectins. Moreover, overexpression of certain galectins has been involved in the development and different outcomes of EMT. This review focuses on the roles and mechanisms of Galectin-1 (Gal-1), Gal-3, Gal-4, Gal-7 and Gal-8, which have been involved in physiologic and pathogenic EMT contexts. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease associated with increased cardiovascular (CV) burden. Besides increased arterial stiffness and subclinical atherosclerosis, microvascular dysfunction is considered an important component in the pathophysiology of CV disease. However, there is a lack of data regarding the effect of multiple target organ damage (TOD) on CV health. Objectives: This study aimed to evaluate (i) the presence of microvascular changes in SLE in various vascular beds, (ii) the possible associations between the accumulation of microvascular TOD and CV risk and (iii) whether Galectin-3 represents a predictor of combined microvascular TOD. Methods: Participants underwent (i) evaluation of skin microvascular perfusion (laser speckle contrast analysis), (ii) fundoscopy (non-mydriatic fundus camera), (iii) indirect assessment of myocardial perfusion (subendocardial viability ratio) and (iv) determination of urine albumin-to-creatinine ratio (UACR). CV risk was calculated using the QResearch Risk Estimator version 3 (QRISK3). Serum Galectin-3 levels were determined. Results: Forty-seven SLE patients and fifty controls were studied. SLE patients demonstrated impaired skin microvascular reactivity (160.2 ± 41.0 vs. 203.6 ± 40.1%), retinal arteriolar narrowing (88.1 ± 11.1 vs. 94.6 ± 13.5 μm) and higher UACR levels compared to controls. Furthermore, SLE individuals had significantly higher Galectin-3 levels [21.5(6.1) vs. 6.6(6.6) ng/dL], QRISK3 scores [7.0(8.6) vs. 1.3(3.6)%] and a greater chance for microvascular dysfunction. In the SLE group, patients with multiple TOD exhibited higher QRISK3. In the multivariate analysis, the accumulation of TOD correlated with disease activity and Galectin-3 (p < 0.05). Conclusions: Our study showed for the first time that SLE patients exhibit a greater number of cases of TOD. The accumulation of TOD was associated with increased CV risk. Clinicians dealing with SLE should be aware and seek microvascular alterations. [ABSTRACT FROM AUTHOR]

Following invasion of the host cell, pore-forming toxins secreted by pathogens compromise vacuole integrity and expose the microbe to diverse intracellular defence mechanisms. However, the quantitative correlation between toxin expression levels and consequent pore dynamics, fostering the intracellular life of pathogens, remains largely unexplored. In this study, using Streptococcus pneumoniae and its secreted pore-forming toxin pneumolysin (Ply) as a model system, we explored various facets of host-pathogen interactions in the host cytosol. Using time-lapse fluorescence imaging, we monitored pore formation dynamics and lifespans of different pneumococcal subpopulations inside host cells. Based on experimental histograms of various event timescales such as pore formation time, vacuolar death or cytosolic escape time and total degradation time, we developed a mathematical model based on first-passage processes that could correlate the event timescales to intravacuolar toxin accumulation. This allowed us to estimate Ply production rate, burst size and threshold Ply quantities that trigger these outcomes. Collectively, we present a general method that illustrates a correlation between toxin expression levels and pore dynamics, dictating intracellular lifespans of pathogens. [ABSTRACT FROM AUTHOR]

IntroductionGalectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human KD = 25 nM; rabbit KD = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH).MethodsMale New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson’s trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression.ResultsSteatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease.DiscussionSelvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dose-dependent manner. These data support the human selvigaltin dose of 100 mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis.

Abstract Previous studies showed that Trichinella spiralis galectin (Tsgal) facilitates larval invasion of intestinal epithelium cells (IECs). However, IEC proteins binding with Tsgal were not identified, and the mechanism by which Tsgal promotes larval invasion is not clear. Toll-like receptors (TLRs) are protein receptors responsible for recognition of pathogens. The aim of this study was to investigate whether recombinant Tsgal (rTsgal) binds to TLR-4, activates inflammatory pathway in gut epithelium and mediates T. spiralis invasion. Indirect immunofluorescence (IIF), GST pull-down and co-immunoprecipitation (Co-IP) assays confirmed specific binding between rTsgal and TLR-4 in Caco-2 cells. qPCR and Western blotting showed that binding of rTsgal with TLR-4 up-regulated the TLR-4 transcription and expression in Caco-2 cells, and activated p-NF-κB p65 and p-ERK1/2. Activation of inflammatory pathway TLR-4/MAPK-NF-κB by rTsgal up-regulated pro-inflammatory cytokines (IL-1β and IL-6) and down-regulated anti-inflammatory cytokine TGF-β in Caco-2 cells, and induced intestinal inflammation. TAK-242 (TLR-4 inhibitor) and PDTC (NF-κB inhibitor) significantly inhibited the activation of TLR-4 and MAPK-NF-κB pathway. Moreover, the two inhibitors also inhibited IL-1β and IL-6 expression, and increased TGF-β expression in Caco-2 cells. In T. spiralis infected mice, the two inhibitors also inhibited the activation of TLR-4/MAPK-NF-κB pathway, ameliorated intestinal inflammation, impeded larval invasion of gut mucosa and reduced intestinal adult burdens. The results showed that rTsgal binding to TLR-4 in gut epithelium activated MAPK-NF-κB signaling pathway, induced the expression of TLR-4 and pro-inflammatory cytokines, and mediated larval invasion. Tsgal might be regarded as a candidate molecular target of vaccine against T. spiralis enteral invasive stage.

We here report the purification of a novel member of the galectin family, the β-galactoside-binding lectin hRTL, from the marine sponge Chondrilla australiensis. The hRTL lectin is a tetrameric proto-type galectin with a subunit molecular weight of 15.5 kDa, consisting of 141 amino acids and sharing 92% primary sequence identity with the galectin CCL from the congeneric species C. caribensis. Transcriptome analysis allowed for the identification of additional sequences belonging to the same family, bringing the total number of hRTLs to six. Unlike most other galectins, hRTLs display a 23 amino acid-long signal peptide that, according to Erdman degradation, is post-translationally cleaved, leaving an N-terminal end devoid of acetylated modifications, unlike most other galectins. Moreover, two hRTLs display an internal insertion, which determines the presence of an unusual loop region that may have important functional implications. The characterization of the glycan-binding properties of hRTL revealed that it had high affinity towards TF-antigen, sialyl TF, and type-1 N-acetyl lactosamine with a Galβ1-3 structure. When administered to DLD-1 cells, a colorectal carcinoma cell line expressing mucin-associated TF-antigen, hRTL could induce glycan-dependent cytotoxicity.

Abstract Objective Galectins are sugar-binding proteins that participate in many biological processes, such as immunity, by regulating host immune cells and their direct interaction with pathogens. They are involved in mediating infection by Schistosoma mansoni, a parasitic trematode that causes schistosomiasis. However, their direct effects on schistosomes have not been investigated. Results We found that galectin-2 recognizes S. mansoni glycoconjugates and investigated whether galectin-1, 2, and 3 can directly affect S. mansoni in vitro. Adult S. mansoni were treated with recombinant galectin-1, 2, and 3 proteins or praziquantel, a positive control. Treatment with galectin-1, 2, and 3 had no significant effect on S. mansoni motility, and no other differences were observed under a stereoscopic microscope. Hence, galectin-1, 2, and 3 may have a little direct effect on S. mansoni. However, they might play a role in the infection in vivo via the modulation of the host immune response or secretory molecules from S. mansoni. To the best of our knowledge, this is the first study to investigate the direct effect of galectins on S. mansoni and helps in understanding the roles of galectins in S. mansoni infection in vivo.

Non-DNA-binding Stabilin-2/HARE receptors expressed on liver sinusoidal endothelial cells specifically bind to and internalize several classes of phosphorothioate antisense oligonucleotides (PS-ASOs). After Stabilin-mediated uptake, PS-ASOs are trafficked within endosomes (>97%–99%), ultimately resulting in destruction in the lysosome. The ASO entrapment in endosomes lowers therapeutic efficacy, thereby increasing the overall dose for patients. Here, we use confocal microscopy to characterize the intracellular route transverse by PS-ASOs after Stabilin receptor-mediated uptake in stable recombinant Stabilin-1 and -2 cell lines. We found that PS-ASOs as well as the Stabilin-2 receptor transverse the classic path: clathrin-coated vesicle-early endosome-late endosome-lysosome. Chloroquine exposure facilitated endosomal escape of PS-ASOs leading to target knockdown by more than 50% as compared to untreated cells, resulting in increased PS-ASO efficacy. We also characterize cytosolic galectins as novel contributor for PS-ASO escape. Galectins knockdown enhances ASO efficacy by more than 60% by modulating EEA1, Rab5C, and Rab7A mRNA expression, leading to a delay in the endosomal vesicle maturation process. Collectively, our results provide additional insight for increasing PS-ASO efficacy by enhancing endosomal escape, which can further be utilized for other nucleic acid-based modalities.

Galectin (Gal) is considered a promising immune checkpoint molecule. More and more studies have shown that high expression levels of galectins in hematologic cancer are positively correlated with poor clinical prognosis. However, the exact prognostic significance of galectins remains unclear. PubMed, Embase, Web of Science, and Cochrane Library were searched for studies addressing the correlation of galectin expression levels with prognosis of hematologic cancers. Stata software was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Hematologic cancer patients with high galectin expression levels showed poor overall survival (OS, HR = 2.43, 95% CI: 1.95, 3.04), disease-free survival (DFS, HR = 3.29, 95% CI: 1.61, 6.71), and event-free survival (EFS, HR = 2.20, 95% CI: 1.47, 3.29) outcomes. Subgroup analysis revealed that high expression levels of galectins pointed to relatively poor OS in MDS (HR = 5.44, 95% CI: 2.09, 14.18), as compared to AML, CHL and CLL. No correlation was found between galectins and OS in NHL and MM. Among the three galectins, Gal-9 (HR = 3.60, 95% CI: 2.03, 6.38) showed higher correlation with poor prognosis than Gal-1 and Gal-3. In addition, use of peripheral blood (HR = 2.96, 95% CI: 2.07, 4.22) samples and qRT-PCR (HR = 2.80, 95% CI: 1.96, 4.01) method for galectin detection were shown to improve its prognostic correlation in hematologic cancers. Meta-analysis revealed high expression of galectins was associated with poor prognosis in hematologic cancer patients and galectins can be considered a promising prognostic predictive marker. [ABSTRACT FROM AUTHOR]

Previous studies showed that Trichinella spiralis galectin (Tsgal) facilitates larval invasion of intestinal epithelium cells (IECs). However, IEC proteins binding with Tsgal were not identified, and the mechanism by which Tsgal promotes larval invasion is not clear. Toll-like receptors (TLRs) are protein receptors responsible for recognition of pathogens. The aim of this study was to investigate whether recombinant Tsgal (rTsgal) binds to TLR-4, activates inflammatory pathway in gut epithelium and mediates T. spiralis invasion. Indirect immunofluorescence (IIF), GST pull-down and co-immunoprecipitation (Co-IP) assays confirmed specific binding between rTsgal and TLR-4 in Caco-2 cells. qPCR and Western blotting showed that binding of rTsgal with TLR-4 up-regulated the TLR-4 transcription and expression in Caco-2 cells, and activated p-NF-κB p65 and p-ERK1/2. Activation of inflammatory pathway TLR-4/MAPK-NF-κB by rTsgal up-regulated pro-inflammatory cytokines (IL-1β and IL-6) and down-regulated anti-inflammatory cytokine TGF-β in Caco-2 cells, and induced intestinal inflammation. TAK-242 (TLR-4 inhibitor) and PDTC (NF-κB inhibitor) significantly inhibited the activation of TLR-4 and MAPK-NF-κB pathway. Moreover, the two inhibitors also inhibited IL-1β and IL-6 expression, and increased TGF-β expression in Caco-2 cells. In T. spiralis infected mice, the two inhibitors also inhibited the activation of TLR-4/MAPK-NF-κB pathway, ameliorated intestinal inflammation, impeded larval invasion of gut mucosa and reduced intestinal adult burdens. The results showed that rTsgal binding to TLR-4 in gut epithelium activated MAPK-NF-κB signaling pathway, induced the expression of TLR-4 and pro-inflammatory cytokines, and mediated larval invasion. Tsgal might be regarded as a candidate molecular target of vaccine against T. spiralis enteral invasive stage. [ABSTRACT FROM AUTHOR]

Lectins presents the ability to interact with glycans and trigger varied responses, including the inhibition of the development of various pathogens. Structural studies of these proteins are essential to better understand their functions. In marine sponges, so far only a few lectins have their primary structures completely determined. Thus, the objective of this work was to structurally characterize and evaluate antibacterial potential, in association with different antibiotics, of the lectin isolated from the marine sponge Aplysina lactuta (ALL). ALL is a homotetramer of 60 kDa formed by four 15 kDa-subunits. The lectin showed affinity only for the glycoproteins fetuin, asialofetuin, mucin type III, and bovine submaxillary mucin type I. The complete amino acid sequences of two isoforms of ALL, named ALL-a and ALL-b, were determined by a combination of Edman degradation and overlapped peptides sequenced by tandem mass spectrometry. ALL-a and ALL-b have 144 amino acids with molecular masses of 15,736 Da and 15,985 Da, respectively. Both structures contain conserved residues typical of the galectin family. ALL is a protein with antibacterial potential, when in association with ampicillin and oxacillin the lectin potentiates its antibiotic effect, included Methicillin-resistant Staphylococcus strains. Thus, ALL shows to be a molecule with potential for the development of new antibacterial drugs. • ALL conserves structural motifs and carbohydrate-binding residues of galectins. • The predicted 3-D structure of ALL is a typical galectin β-sandwich. • ALL in association with ampicillin potentiates the effect of the antibiotic. • ALL in association with tetracycline confers an additive effect to the antibiotic. [ABSTRACT FROM AUTHOR]

Cell surface glycans play essential roles in diverse physiological and pathological processes and their assessment has important implications in biomedicine and biotechnology. Here we present a rapid, versatile, and single-step multicolor flow cytometry method for evaluation of cell surface glycan signatures using a panel of selected fluorochrome-conjugated lectins. This procedure allows simultaneous detection of cell surface glycans with a 10-fold reduction in the number of cells required compared with traditional multistep lectin staining methods. Interestingly, we used this one-step lectin array coupled with dimension reduction algorithms in a proof-of-concept application for discrimination among different tumor and immune cell populations. Moreover, this procedure was also able to unveil T-, B-, and myeloid cell subclusters exhibiting differential glycophenotypes. Thus, we report a rapid and versatile lectin cytometry method to simultaneously detect a particular repertoire of surface glycans on living cells that can be easily implemented in different laboratories and core facilities. [ABSTRACT FROM AUTHOR]

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.

Carbohydrate-protein conjugates have diverse applications. They have been used clinically as vaccines against bacterial infection and have been developed for high-throughput assays to elucidate the ligand specificities of glycan-binding proteins (GBPs) and antibodies. Here, we report an effective process that combines highly efficient chemoenzymatic synthesis of carbohydrates, production of carbohydrate-bovine serum albumin (glycan-BSA) conjugates using a squarate linker, and convenient immobilization of the resulting neoglycoproteins on carboxylate-coated fluorescent magnetic beads for the development of a suspension multiplex array platform. A glycan-BSA-bead array containing BSA and 50 glycan-BSA conjugates with tuned glycan valency was generated. The binding profiles of six plant lectins with binding preference towards Gal and/or GalNAc, as well as human galectin-3 and galectin-8, were readily obtained. Our results provide useful information to understand the multivalent glycan-binding properties of human galectins. The neoglycoprotein-immobilized fluorescent magnetic bead suspension multiplex array is a robust and flexible platform for rapid analysis of glycan and GBP interactions and will find broad applications.

Objective: Galectins are sugar-binding proteins that participate in many biological processes, such as immunity, by regulating host immune cells and their direct interaction with pathogens. They are involved in mediating infection by Schistosoma mansoni, a parasitic trematode that causes schistosomiasis. However, their direct effects on schistosomes have not been investigated. Results: We found that galectin-2 recognizes S. mansoni glycoconjugates and investigated whether galectin-1, 2, and 3 can directly affect S. mansoni in vitro. Adult S. mansoni were treated with recombinant galectin-1, 2, and 3 proteins or praziquantel, a positive control. Treatment with galectin-1, 2, and 3 had no significant effect on S. mansoni motility, and no other differences were observed under a stereoscopic microscope. Hence, galectin-1, 2, and 3 may have a little direct effect on S. mansoni. However, they might play a role in the infection in vivo via the modulation of the host immune response or secretory molecules from S. mansoni. To the best of our knowledge, this is the first study to investigate the direct effect of galectins on S. mansoni and helps in understanding the roles of galectins in S. mansoni infection in vivo. [ABSTRACT FROM AUTHOR]

Psoriasis is a complex disease that nowadays is considered not only a dermatosis but a kind of systemic disorder associated with many accompanying diseases. Metabolic complications leading to cardiovascular incidences are the cause of increased mortality in psoriatic patients. Galectins (gal) are beta-galactoside-binding lectins that exert different functions, including engagement in metabolic processes. Our aim was to assess the concentrations of gal-1, 2 and 12 in psoriatics, to establish their potential clinical implications, including in metabolic complications. Plasma galectins were assessed by ELISA in 60 psoriatic patients and 30 controls without dermatoses and a negative family history of psoriasis. Plasma concentrations of all galectins were significantly higher in patients than controls (gal-1 with p < 0.001, gal-2 and 12 with p < 0.05). There were no correlations between galectins concentrations and psoriasis severity in PASI or disease duration (p > 0.05). Gal-1 and 12 were significantly negatively correlated with GFR (p < 0.05, p < 0.01, respectively) and gal-2 with HDL (p < 0.05). Gal-2 was significantly positively correlated with CRP (p < 0.05) and gal-12 with fasting glucose (p < 0.01). Based on the results and given the reported role of galectins in metabolic disorders we may conclude that gal-1, 2 and 12 could be potentially engaged in metabolic complications in psoriatics, most probably in atherosclerosis. Gal-2 could be perhaps further investigated as a marker of metabolically induced inflammation in psoriasis, gal-1 and gal-12 as predictors of renal impairment in psoriatics due to metabolic disorders. Potentially, gal-12 could be considered in the future as a marker of carbohydrate metabolism disorders in psoriatics. [ABSTRACT FROM AUTHOR]

Objective: Despite being highly genetic, the etiology of autism spectrum disorder (ASD), has not yet been clarified. Recent research has focused on the role of neuroinflammation and immune system dysfunction in the pathophysiology of neurodevelopmental disorders including ASD. Galectin-1 and galactin-3 are considered among the biomarkers of neuroinflammation and there has been recent reports on the potential role of galectins in the etiology of neurodevelopmental disorders. However, there has been no study examining the relationship between ASD and galectin levels. Methods: Current study aimed to investigate galectin-1 and galectin-3 serum levels in young subjects with ASD comparing with their unaffected siblings and healthy controls. Results: We found significantly higher levels of galectin-1 in case group compared to both unaffected siblings and healthy controls, and higher levels of galectin-3 in case group compared to healthy controls. However, there was no significant association between galectin-1 and galectin-3 levels with the severity of ASD. Conclusion: Findings of our study may support neuroinflammation hypothesis in the etiology of ASD and the potential role of galectin-1 and galectin-3 as biomarkers. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether galectin-9 gene (LGALS9) expression is correlated with cervical cancer progression, clinicopathological characteristics, and overall survival. To determine the biological processes and the abundance of tumour infiltrating immune cells related to the expression of LGALS9.Patients and Methods: The study was conducted in two phases: 1) The expression level of LGALS9 was determined using the data of 193 squamous cell carcinoma (SCC) samples from The Cancer Genome Atlas (TCGA) database. Biological processes and tumour infiltrating cells associated to LGALS9 expression were evaluated using gene set enrichment analysis (GSEA) and tumour immune estimation resource (TIMER). 2) Independently, galectin-9 was identified in 40 SCC samples by immunohistochemistry and optical density quantified using ImagePro® software.Results: The LGALS9 gene showed increased expression in cervical cancer samples. A higher expression level in SCC was related to better overall survival and to early clinical stages. GSEA showed that tumours with higher expression of LGALS9 were enriched in immune pathways such as interferon_alpha_response, and complement, the analysis of TIMER database showed a positive correlation between the expression level of LGALS9 and the abundance of tumour infiltrating immune cells. In addition, higher expression of galectin-9 was found in biopsies of SCC patients at early clinical stages, showing a trend of better survival.Conclusion: Higher expression levels of LGALS9 and galectin-9 in SCC were related to early clinical stages and better prognosis. GSEA and TIMER analysis suggested that galectin-9 could play an antitumor role in cervical SCC. [ABSTRACT FROM AUTHOR]

Although considerable attention has been paid to the role of extracellular galectins in modulating, positively or negatively, tumor growth and metastasis, we have witnessed a growing interest in the role of intracellular galectins in response to their environment. This is not surprising as many galectins preferentially exist in cytosolic and nuclear compartments, which is consistent with the fact that they are exported outside the cells via a yet undefined nonclassical mechanism. This review summarizes our most recent knowledge of their intracellular functions in cancer cells and provides some directions for future strategies to inhibit their role in cancer progression. [ABSTRACT FROM AUTHOR]

Extra- and intra-cellular activity occurs under the direction of numerous inter-molecular interactions, and in any tissue or cell, molecules are densely packed, thus promoting those molecular interactions. Galectins and chemokines, the focus of this review, are small, protein effector molecules that mediate various cellular functions—in particular, cell adhesion and migration—as well as cell signaling/activation. In the past, researchers have reported that combinations of these (and other) effector molecules act separately, yet sometimes in concert, but nevertheless physically apart and via their individual cell receptors. This view that each effector molecule functions independently of the other limits our thinking about functional versatility and cooperation, and, in turn, ignores the prospect of physiologically important inter-molecular interactions, especially when both molecules are present or co-expressed in the same cellular environment. This review is focused on such protein-protein interactions with chemokines and galectins, the homo- and hetero-oligomeric structures that they can form, and the functional consequences of those paired interactions. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims to understand the role of galectins by breast cancer subtype and their change in response to cancer treatment. Galectins are proteins involved in cancer growth, metastasis, immune evasion, and cell division. Galectin-1, -3, and -9 levels were measured in breast cancer patients using a technique called ELISA and analyzed for their relationship with tumor characteristics such as stage, subtype, and receptor expression. The study found that galectin-9 levels were significantly increased in HER2-enriched tumors but reduced in hormone-receptor-positive tumors, while galectin-1 levels were higher in patients who underwent systemic cancer therapy. These findings provide valuable insights into galectin changes during cancer progression, treatment response, and tumor biology. They have implications for future research on therapeutic targets using galectin inhibitors and the use of galectin biomarkers for diagnosing and monitoring breast cancer. Galectins have been shown to have roles in cancer progression via their contributions to angiogenesis, metastasis, cell division, and the evasion of immune destruction. This study analyzes galectin-1, -3, and -9 serum concentrations in breast cancer patients through enzyme-linked immunosorbent assay (ELISA) against the characteristics of the patient and the tumor such as stage, molecular subtype, and receptor expression. Galectin-9 was found to be statistically significantly increased in HER2-enriched tumors and reduced in patients with hormone-receptor-positive tumors. Galectin-1 was found to be statistically significantly increased in the serum of patients who had undergone hormonal, immunotherapy, or chemotherapy. These findings provide insight into the changes in galectin levels during the progress of cancer, the response to treatment, and the molecular phenotype. These findings are valuable in the further understanding of the relationships between galectin and tumor biology and can inform future research on therapeutic targets for galectin inhibitors and the utility of galectin biomarkers. [ABSTRACT FROM AUTHOR]

Abstract Galectins are animal lectins with specific affinity for galactosides via the conserved carbohydrate recognition domains. Increasing studies recently have identified critical roles of galectin family members in tumor progression. Abnormal expression of galectins contributes to the proliferation, metastasis, epithelial-mesenchymal transformation (EMT), immunosuppression, radio-resistance and chemoresistance in various cancers, which has attracted cumulative clinical interest in galectin-based cancer treatment. Galectin family members have been reported to participate in autophagy regulation under physiological conditions and in non-tumoral diseases, and implication of galectins in multiple processes of carcinogenesis also involves regulation of autophagy, however, the relationship between galectins, autophagy and cancer remains largely unclear. In this review, we introduce the structure and function of galectins at the molecular level, summarize their engagements in autophagy and cancer progression, and also highlight the regulation of autophagy by galectins in cancer as well as the therapeutic potentials of galectin and autophagy-based strategies. Elaborating on the mechanism of galectin-regulated autophagy in cancers will accelerate the exploitation of galectins-autophagy targeted therapies in treatment for cancer.