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15 pages, 1965 KiB

Open AccessArticle

Plasma Levels of a Cleaved Form of Galectin-9 Are the Most Sensitive Biomarkers of Acquired Immune Deficiency Syndrome and Tuberculosis Coinfection

by Shirley T. Padilla, Toshiro Niki, Daisuke Furushima, Gaowa Bai, Haorile Chagan-Yasutan, Elizabeth Freda Telan, Rosario Jessica Tactacan-Abrenica, Yosuke Maeda, Rontgene Solante and Toshio Hattori

Biomolecules 2020, 10(11), 1495; https://doi.org/10.3390/biom10111495 - 30 Oct 2020

Cited by 11 | Viewed by 3063

Abstract

Acquired immunodeficiency syndrome (AIDS) complicated with tuberculosis (TB) is a global public issue. Due to the paucity of bacteria in AIDS/TB, blood-based biomarkers that reflect disease severity are desired. Plasma levels of matricellular proteins, such as osteopontin (OPN) and galectin-9 (Gal-9), are known [...] Read more.

Acquired immunodeficiency syndrome (AIDS) complicated with tuberculosis (TB) is a global public issue. Due to the paucity of bacteria in AIDS/TB, blood-based biomarkers that reflect disease severity are desired. Plasma levels of matricellular proteins, such as osteopontin (OPN) and galectin-9 (Gal-9), are known to be elevated in AIDS and TB. Therefore, full-length (FL)-Gal9 and FL-OPN, and their truncated forms (Tr-Gal9, Ud-OPN), and 38 cytokines/chemokines were measured in the plasma of 24 AIDS (other than TB), 49 TB, and 33 AIDS/TB patients. Receiver-operating characteristic analysis was used to screen molecules that could distinguish either between disease and normal group, among each disease group, or between deceased patients and survivors. Selected molecules were further analyzed for significant differences. Tr-Gal9 had the highest ability to differentiate TB from AIDS or AIDS/TB, while Ud-OPN distinguished multidrug resistance (MDR)-TB from non-MDR TB, and extra-pulmonary TB from pulmonary TB. Molecules significantly elevated in deceased patients included; FL-Gal9, Tr-Gal9, interleukin (IL)-1 receptor antagonist, IL-17A and transforming growth factor-α in AIDS; IL-6, granulocyte colony-stimulating factor and monocyte chemotactic protein-1 in TB; and macrophage inflammatory protein-1β in AIDS/TB. From the sensitivity, specificity, and significant elevation, Tr-Gal9 is the best biomarker of inflammation and severity in AIDS and AIDS/TB. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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15 pages, 3729 KiB

Open AccessArticle

Galectin-3 Stimulates Tyro3 Receptor Tyrosine Kinase and Erk Signalling, Cell Survival and Migration in Human Cancer Cells

by Nour Al Kafri and Sassan Hafizi

Biomolecules 2020, 10(7), 1035; https://doi.org/10.3390/biom10071035 - 11 Jul 2020

Cited by 15 | Viewed by 4670

Abstract

The TAM (Tyro3, Axl, MerTK) subfamily of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and protein S (ProS1), are implicated in tumorigenesis and chemoresistance in various cancers. The β-galactoside binding protein galectin-3 (Gal-3), which is also implicated in oncogenesis, has previously been [...] Read more.

The TAM (Tyro3, Axl, MerTK) subfamily of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and protein S (ProS1), are implicated in tumorigenesis and chemoresistance in various cancers. The β-galactoside binding protein galectin-3 (Gal-3), which is also implicated in oncogenesis, has previously been shown to be a ligand for MerTK. However, the selectivity of Gal-3 for the other TAM receptors, and its TAM-mediated signalling and functional properties in cancer cells, remain to be explored. The present study was aimed at determining these, including through direct comparison of Gal-3 with the two canonical TAM ligands. Exogenous Gal-3 rapidly stimulated Tyro3 receptor phosphorylation to the same extent as the Tyro3 ligand ProS1, but not Axl, in the cultured human cancer cell lines SCC-25 (express both Tyro3 and Axl) and MGH-U3 (express Tyro3 only). Gal-3 also activated intracellular Erk and Akt kinases in both cell lines and furthermore protected cells from acute apoptosis induced by staurosporine but not from serum-starvation induced apoptosis. In addition, Gal-3 significantly stimulated cancer cell migration rate in the presence of the Axl blocker BGB324. Therefore, these results have shown Gal-3 to be a novel agonist for Tyro3 RTK, activating a Tyro3-Erk signalling axis, as well as Akt signalling, in cancer cells that promotes cell survival, cell cycle progression and cell migration. These data therefore reveal a novel mechanism of Tyro3 RTK activation through the action of Gal-3 that contrasts with those of the known TAM ligands Gas6 and ProS1. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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16 pages, 13115 KiB

Open AccessArticle

Exposure of Intestinal Epithelial Cells to 2′-Fucosyllactose and CpG Enhances Galectin Release and Instructs Dendritic Cells to Drive Th1 and Regulatory-Type Immune Development

by Veronica Ayechu-Muruzabal, Saskia A. Overbeek, Atanaska I. Kostadinova, Bernd Stahl, Johan Garssen, Belinda van’t Land and Linette E.M. Willemsen

Biomolecules 2020, 10(5), 784; https://doi.org/10.3390/biom10050784 - 19 May 2020

Cited by 28 | Viewed by 4179

Abstract

Intestinal epithelial cells (IEC) release immunomodulatory galectins upon exposure to CpG DNA (mimicking bacterial triggers) and short-chain galacto- and long-chain fructo-oligosaccharides (GF). This study aims to investigate the immunomodulatory properties of 2′-fucosyllactose (2′-FL), a non-digestible oligosaccharide (NDO) abundantly present in human milk, using [...] Read more.

Intestinal epithelial cells (IEC) release immunomodulatory galectins upon exposure to CpG DNA (mimicking bacterial triggers) and short-chain galacto- and long-chain fructo-oligosaccharides (GF). This study aims to investigate the immunomodulatory properties of 2′-fucosyllactose (2′-FL), a non-digestible oligosaccharide (NDO) abundantly present in human milk, using a co-culture model developed to study the crosstalk between IEC and innate and adaptive immune cells. IECs, co-cultured with αCD3/CD28-activated peripheral blood mononuclear cells (PBMC), were apically exposed to NDOs and CpG, washed and co-cultured with immature monocyte-derived dendritic cells (moDC). Subsequently, moDC were co-cultured with naïve CD4+ T-cells. In the presence of CpG, both 2′-FL or GF-exposed IEC enhanced Th1-type IFNγ and regulatory IL-10 secretion of PBMCs, compared to CpG alone, while Th2-type IL-13 was reduced. Both NDOs increased IEC-derived galectin-3, -4, -9 and TGF-β1 of CpG-exposed IEC. Only galectin-9 correlated with all modified immune parameters and TGF-β1 secretion. MoDCs exposed to 2′-FL and CpG-conditioned IEC instructed IFNγ and IL-10 secretion by CD4+ T-cells, suggesting the development of a regulatory Th1 response. These results reveal that 2′-FL and GF could contribute to the mucosal immune development by supporting the effect of microbial CpG DNA associated with the modulation of epithelial galectin and TGF-β1 secretion. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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13 pages, 2928 KiB

Open AccessArticle

Oral Administration of Fucoidan Can Exert Anti-Allergic Activity after Allergen Sensitization by Enhancement of Galectin-9 Secretion in Blood

by Masashi Mizuno, Kana Sakaguchi and Iwao Sakane

Biomolecules 2020, 10(2), 258; https://doi.org/10.3390/biom10020258 - 09 Feb 2020

Cited by 15 | Viewed by 3393

Abstract

A previous study revealed that fucoidan inhibited mast cell degranulation through the upregulation of galectin-9 in blood. The purpose of this study is to elucidate its mechanism using ovalbumin (OVA) induced anaphylaxis model mice (BALB/c, Female, 5-week-old) and mast cell line (RBL-2H3 cells). [...] Read more.

A previous study revealed that fucoidan inhibited mast cell degranulation through the upregulation of galectin-9 in blood. The purpose of this study is to elucidate its mechanism using ovalbumin (OVA) induced anaphylaxis model mice (BALB/c, Female, 5-week-old) and mast cell line (RBL-2H3 cells). Oral administration of fucoidan after sensitization with OVA/Al(OH)₃ inhibited reduction of rectal temperature induced by activation of mast cells. Fucoidan increased galectin-9 mRNA expression only in colonic epithelial cells. These results suggested that fucoidan could suppress the allergic symptoms in sensitized mice by inducing galectin-9 production from colonic epithelial cells. In addition, to check the influence of galectin 9 on the degranulation of mast cells, RBL-2H3 cell lines were treated directly with recombinant galectin-9. As expected, galectin-9 inhibited degranulation of RBL-2H3 cells pre-bound with IgE. Moreover, the residual amounts of IgE on RBL-2H3 cells were decreased by an addition of galectin-9. It was demonstrated that galectin-9 could remove IgE even if IgE was already bound to mast cells and suppress the mast cells degranulation induced by antigen. This study shows that fucoidan might become an effective therapeutic agent for patients already developed type I allergic diseases. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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20 pages, 4147 KiB

Open AccessArticle

Galectin Domain Containing Protein from Haemonchus contortus Modulates the Immune Functions of Goat PBMCs and Regulates CD4+ T-Helper Cells In Vitro

by Muhammad Ali-ul-Husnain Naqvi, Muhammad Ali Memon, Tahseen Jamil, Sana Zahra Naqvi, Kalibixiati Aimulajiang, Javaid Ali Gadahi, Lixin Xu, Xiaokai Song, Xiangrui Li and Ruofeng Yan

Biomolecules 2020, 10(1), 116; https://doi.org/10.3390/biom10010116 - 09 Jan 2020

Cited by 17 | Viewed by 3041

Abstract

Galectins are glycan-binding proteins that are widely expressed and distributed in mammalian tissues as well as cells of innate and adaptive immune responses. CD4+ T-helper cells differentiate into effector subsets in response to cytokines. T helper 9 cells are one of the recently [...] Read more.

Galectins are glycan-binding proteins that are widely expressed and distributed in mammalian tissues as well as cells of innate and adaptive immune responses. CD4+ T-helper cells differentiate into effector subsets in response to cytokines. T helper 9 cells are one of the recently described subsets of effector T cells that are relatively new and less studied. In this study, galectin domain containing protein from Haemonchus contortus (Hc-GDC) was cloned, expressed in pET32a, and immunoblotting was performed. Localization of recombinant (r)Hc-GDC on outer and inner surface of H. contortus worm and binding with goat Peripheral Blood Mononuclear cells (PBMCs) were performed using immunofluorescence assay. Moreover, effects of rHc-GDC on proliferation, apoptosis, cell migration, and the nitric oxide production in goat PBMCs were evaluated. Furthermore, modulatory effects of rHc-GDC on production of Th1, Th2, and Th9 cells were evaluated by flowcytometry and on interferon gamma, interleukin (IL)-4 and IL-9 were evaluated by quantitative real-time polymerase chain reaction. The results demonstrated that rHc-GDC was successfully cloned, expressed in expression vector as well as in the gut surface of adult H. contortus worm and successful binding with PBMCs surface were observed. Immunoblotting results revealed that rHc-GDC is an important active protein of H. contortus excretory and secretory products. Moreover, the interaction of rHc-GDC with host cells increased the production of Th2, Th9 cells, IL4, IL-9, PBMC proliferation, nitric oxide, and cell migration. No effects of rHc-GDC were observed on PMBC apoptosis, production of Th1 cells, and secretions of IFN-γ and IL-10 cytokines. These findings indicate that recombinant GDC protein from H. contortus modulates the immune functions of goat PBMCs and has the potential to enhance protective immunity by inducing T helper-9-derived IL-9 in vitro. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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Review

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21 pages, 2074 KiB

Open AccessReview

Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases

by Hiroko Iwasaki-Hozumi, Haorile Chagan-Yasutan, Yugo Ashino and Toshio Hattori

Biomolecules 2021, 11(3), 430; https://doi.org/10.3390/biom11030430 - 15 Mar 2021

Cited by 21 | Viewed by 3483

Abstract

Galectin-9 (Gal-9) is a β-galactoside-binding lectin capable of promoting or suppressing the progression of infectious diseases. This protein is susceptible to cleavage of its linker-peptides by several proteases, and the resulting cleaved forms, N-terminal carbohydrate recognition domain (CRD) and C-terminal CRD, bind to [...] Read more.

Galectin-9 (Gal-9) is a β-galactoside-binding lectin capable of promoting or suppressing the progression of infectious diseases. This protein is susceptible to cleavage of its linker-peptides by several proteases, and the resulting cleaved forms, N-terminal carbohydrate recognition domain (CRD) and C-terminal CRD, bind to various glycans. It has been suggested that full-length (FL)-Gal-9 and the truncated (Tr)-Gal-9s could exert different functions from one another via their different glycan-binding activities. We propose that FL-Gal-9 regulates the pathogenesis of infectious diseases, including human immunodeficiency virus (HIV) infection, HIV co-infected with opportunistic infection (HIV/OI), dengue, malaria, leptospirosis, and tuberculosis (TB). We also suggest that the blood levels of FL-Gal-9 reflect the severity of dengue, malaria, and HIV/OI, and those of Tr-Gal-9 markedly reflect the severity of HIV/OI. Recently, matrix metallopeptidase-9 (MMP-9) was suggested to be an indicator of respiratory failure from coronavirus disease 2019 (COVID-19) as well as useful for differentiating pulmonary from extrapulmonary TB. The protease cleavage of FL-Gal-9 may lead to uncontrolled hyper-immune activation, including a cytokine storm. In summary, Gal-9 has potential to reflect the disease severity for the acute and chronic infectious diseases. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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21 pages, 1665 KiB

Open AccessReview

Galectin-3: Roles in Neurodevelopment, Neuroinflammation, and Behavior

by Ivan Srejovic, Dragica Selakovic, Nemanja Jovicic, Vladimir Jakovljević, Miodrag L. Lukic and Gvozden Rosic

Biomolecules 2020, 10(5), 798; https://doi.org/10.3390/biom10050798 - 21 May 2020

Cited by 35 | Viewed by 8554

Abstract

There is a plethora of evidence to suggest that Galectin-3 plays an important role in normal functions of mammalian cells, as well as in different pathogenic conditions. This review highlights recent data published by researchers, including our own team, on roles of Galectin-3 [...] Read more.

There is a plethora of evidence to suggest that Galectin-3 plays an important role in normal functions of mammalian cells, as well as in different pathogenic conditions. This review highlights recent data published by researchers, including our own team, on roles of Galectin-3 in the nervous system. Here, we discuss the roles of Galectin-3 in brain development, its roles in glial cells, as well as the interactions of glial cells with other neural and invading cells in pathological conditions. Galectin-3 plays an important role in the pathogenesis of neuroinflammatory and neurodegenerative disorders, such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. On the other hand, there is also evidence of the protective role of Galectin-3 due to its anti-apoptotic effect in target cells. Interestingly, genetic deletion of Galectin-3 affects behavioral patterns in maturing and adult mice. The results reviewed in this paper and recent development of highly specific inhibitors suggests that Galectin-3 may be an important therapeutic target in pathological conditions including the disorders of the central nervous system. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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24 pages, 1616 KiB

Open AccessReview

Galectins as Checkpoints of the Immune System in Cancers, Their Clinical Relevance, and Implication in Clinical Trials

by Daniel Compagno, Carolina Tiraboschi, José Daniel Garcia, Yorfer Rondón, Enrique Corapi, Carla Velazquez and Diego José Laderach

Biomolecules 2020, 10(5), 750; https://doi.org/10.3390/biom10050750 - 12 May 2020

Cited by 36 | Viewed by 3783

Abstract

Galectins are small proteins with pleiotropic functions, which depend on both their lectin (glycan recognition) and non-lectin (recognition of other biomolecules besides glycans) interactions. Currently, 15 members of this family have been described in mammals, each with its structural and ligand recognition particularities. [...] Read more.

Galectins are small proteins with pleiotropic functions, which depend on both their lectin (glycan recognition) and non-lectin (recognition of other biomolecules besides glycans) interactions. Currently, 15 members of this family have been described in mammals, each with its structural and ligand recognition particularities. The galectin/ligand interaction translates into a plethora of biological functions that are particular for each cell/tissue type. In this sense, the cells of the immune system are highly sensitive to the action of these small and essential proteins. While galectins play central roles in tumor progression, they are also excellent negative regulators (checkpoints) of the immune cell functions, participating in the creation of a microenvironment that promotes tumor escape. This review aims to give an updated view on how galectins control the tumor’s immune attack depending on the tumor microenvironment, because determining which galectins are essential and the role they play will help to develop future clinical trials and benefit patients with incurable cancer. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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19 pages, 1517 KiB

Open AccessReview

Galectin-3 as a Next-Generation Biomarker for Detecting Early Stage of Various Diseases

by Akira Hara, Masayuki Niwa, Kei Noguchi, Tomohiro Kanayama, Ayumi Niwa, Mikiko Matsuo, Yuichiro Hatano and Hiroyuki Tomita

Biomolecules 2020, 10(3), 389; https://doi.org/10.3390/biom10030389 - 03 Mar 2020

Cited by 93 | Viewed by 8298

Abstract

Galectin-3 is a β-galactoside-binding lectin which is important in numerous biological activities in various organs, including cell proliferation, apoptotic regulation, inflammation, fibrosis, and host defense. Galectin-3 is predominantly located in the cytoplasm and expressed on the cell surface, and then often secreted into [...] Read more.

Galectin-3 is a β-galactoside-binding lectin which is important in numerous biological activities in various organs, including cell proliferation, apoptotic regulation, inflammation, fibrosis, and host defense. Galectin-3 is predominantly located in the cytoplasm and expressed on the cell surface, and then often secreted into biological fluids, like serum and urine. It is also released from injured cells and inflammatory cells under various pathological conditions. Many studies have revealed that galectin-3 plays an important role as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease, viral infection, autoimmune disease, neurodegenerative disorders, and tumor formation. In particular, it has been recognized that galectin-3 is extremely useful for detecting many of these diseases in their early stages. The purpose of this article is to review and summarize the recent literature focusing on the biomarker characteristics and long-term outcome predictions of galectin-3, in not only patients with various types of diseases, but associated animal models. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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12 pages, 661 KiB

Open AccessReview

Role of Human Galectins in Inflammation and Cancers Associated with Endometriosis

by Brooke V. Hisrich, R. Brant Young, Alison M. Sansone, Zachary Bowens, Lisa J. Green, Bruce A. Lessey and Anna V. Blenda

Biomolecules 2020, 10(2), 230; https://doi.org/10.3390/biom10020230 - 04 Feb 2020

Cited by 24 | Viewed by 5725

Abstract

Galectins are a family of β-galactoside-binding proteins that contribute to multiple cellular functions, including immune surveillance and apoptosis. Human galectins are also important regulators of inflammation, making them a research target for various inflammatory diseases and tumorigenesis associated with pro-inflammatory conditions. This review [...] Read more.

Galectins are a family of β-galactoside-binding proteins that contribute to multiple cellular functions, including immune surveillance and apoptosis. Human galectins are also important regulators of inflammation, making them a research target for various inflammatory diseases and tumorigenesis associated with pro-inflammatory conditions. This review focuses on the involvement of human galectins in modulation of inflammation and in the pathophysiology of endometriosis and endometriosis-associated neoplasms. Endometriosis is a chronic inflammatory disease with unknown etiology. Galectins-1, -3 and -9 were found to be overexpressed in ectopic and eutopic endometrium of females with endometriosis compared to those without endometriosis. These findings suggest galectins’ role in the progression on endometriotic lesions and their potential use as diagnostic biomarkers and/or targets for therapeutic approaches. Galectins-1, -3, and -9 have also been implicated in the development of endometriosis-associated neoplasms. Furthermore, galectin-3 has been shown to interact with KRAS protein and contribute to cellular growth, proliferation, inflammation, and the uptake of nutrients in endometriotic lesions and may be involved in the maintenance and propagation of endometriosis. These galectins have been shown to be upregulated in certain forms of cervical, ovarian, endometrial, and colon cancer associated with endometriosis and have become a potential target for anti-cancer therapies. Full article

(This article belongs to the Special Issue Galectins: their Network and Roles in Infection/Immunity/Tumor Growth Control)

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