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Journal ArticleDOI

The Role of Galectins as Modulators of Metabolism and Inflammation.

21 May 2018-Mediators of Inflammation (Hindawi Publishing Corporation)-Vol. 2018, pp 9186940-9186940
TL;DR: Information on galectin-1, -2, -3, -4, -7, -8, -9, and -12 can all induce T-cell apoptosis and modulate inflammation and the potential to target galectins for therapeutic purposes is presented.
Abstract: Galectins are β-galcotosid-binding lectins. The function of galectins varies with their tissue-specific and subcellular location, and their binding to carbohydrates makes them key players in several intra- and extracellular processes where they bind to glycosylated proteins and lipids. In humans, there are 12 identified galectins, some with tissue-specific distribution. Galectins are found inside cells and in the nucleus, cytosol, and organelles, as well as extracellularly. Galectin-1, -2, -3, -4, -7, -8, -9, and -12 can all induce T-cell apoptosis and modulate inflammation. In the context of metabolic control and loss of the same in, for example, diabetes, galectin-1, -2, -3, -9, and -12 are especially interesting. This review presents information on galectins relevant to the control of inflammation and metabolism and the potential to target galectins for therapeutic purposes.

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Citations
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Journal ArticleDOI
TL;DR: A platform for ultra-high throughput serum and plasma proteomics that builds on ISO13485 standardisation and high-flow liquid chromatography to facilitate implementation in clinical laboratories and identifies 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19.
Abstract: The COVID-19 pandemic is an unprecedented global challenge, and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that builds on ISO13485 standardization to facilitate simple implementation in regulated clinical laboratories. Our low-cost workflow handles up to 180 samples per day, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. We use our platform on samples collected from a cohort of early hospitalized cases of the SARS-CoV-2 pandemic and identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory factors upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. In total, this work supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets.

407 citations


Cites background from "The Role of Galectins as Modulators..."

  • ...Of note, Galectin-3 has long been considered an attractive drug target in combating various forms of TGF-b-mediated fibrosis and pathological inflammatory conditions (Brinchmann et al., 2018; Mackinnon et al., 2012; Shen et al., 2018; Yu et al., 2013)....

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Journal ArticleDOI
TL;DR: 3D models of the interacting complexes have been proposed based on the findings of the deeply analysed and characterized glycan structures of the receptor binding domain of the SARS‐CoV2 spike glycoprotein studied by using NMR.
Abstract: The glycan structures of the receptor binding domain of the SARS-CoV2 spike glycoprotein expressed in human HEK293F cells have been studied by using NMR. The different possible interacting epitopes have been deeply analysed and characterized, providing evidence of the presence of glycan structures not found in previous MS-based analyses. The interaction of the RBD 13 C-labelled glycans with different human lectins, which are expressed in different organs and tissues that may be affected during the infection process, has also been evaluated by NMR. In particular, 15 N-labelled galectins (galectins-3, -7 and -8 N-terminal), Siglecs (Siglec-8, Siglec-10), and C-type lectins (DC-SIGN, MGL) have been employed. Complementary experiments from the glycoprotein perspective or from the lectin's point of view have permitted to disentangle the specific interacting epitopes in each case. Based on these findings, 3D models of the interacting complexes have been proposed.

66 citations

Journal ArticleDOI
TL;DR: Experimental data and description of a novel chronic granulomatous disease subtype imply that ROS generated in intracellular compartments are key for NETosis and for controlling inflammatory signaling.
Abstract: The phagocyte NADPH oxidase is responsible for the neutrophil's great capacity to produce reactive oxygen species (ROS). The NADPH oxidase can be assembled in the plasma membrane, as well as in membranes of intracellular vesicles, giving neutrophils the ability to direct ROS production to distinct subcellular sites. Neutrophil ROS contribute to microbial killing, trigger formation of neutrophil extracellular traps and appear to partake in inflammation control. Consequently, function-disrupting mutations in the NADPH oxidase lead to chronic granulomatous disease, characterized by severe infections and inflammatory disorders. Recent experimental data and description of a novel chronic granulomatous disease subtype (p40phox-deficiency) imply that ROS generated in intracellular compartments are key for NETosis and for controlling inflammatory signaling. We foresee boosted interest in intracellular ROS production. To fully understand where and how such ROS function, however, limitations of assay systems to measure ROS need to be appreciated, and the development of novel techniques/reagents would be highly useful.

58 citations


Cites background from "The Role of Galectins as Modulators..."

  • ...Galectins are present in a variety of inflammatory exudates and have many different effects on immune regulation (17, 18)....

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Journal ArticleDOI
05 Dec 2018-PLOS ONE
TL;DR: It is revealed that presence of molecular perturbations involving the vasculature, extracellular matrix and metabolism are pertinent to the onset and early pathogenesis of WBD in commercial meat-type chickens.
Abstract: Wooden Breast Disease (WBD), a myopathy in commercial broiler chickens characterized by abnormally firm consistency of the pectoral muscle, impacts the poultry industry negatively due to severe reduction in meat quality traits. To unravel the molecular profile associated with the onset and early development of WBD in broiler chickens, we compared time-series gene expression profiles of Pectoralis (P.) major muscles between unaffected and affected birds from a high-breast-muscle-yield, purebred broiler line. P. major biopsy samples were collected from the cranial and caudal aspects of the muscle belly in birds that were raised up to 7 weeks of age (i.e. market age). Three subsets of biopsy samples comprising 6 unaffected (U) and 10 affected (A) from week 2 (cranial) and 4 (caudal), and 4U and 11A from week 3 (cranial) were processed for RNA-sequencing analysis. Sequence reads generated were processed using a suite of bioinformatics programs producing differentially expressed (DE) genes for each dataset at fold-change (A/U or U/A) >1.3 and False Discovery Ratio (FDR) <0.05 (week 2: 41 genes; week 3: 618 genes and week 4: 39 genes). Functional analysis of DE genes using literature mining, BioDBnet and IPA revealed several biological processes and pathways associated with onset and progress of WBD. Top among them were dysregulation of energy metabolism, response to inflammation, vascular disease and remodeling of extracellular matrix. This study reveals that presence of molecular perturbations involving the vasculature, extracellular matrix and metabolism are pertinent to the onset and early pathogenesis of WBD in commercial meat-type chickens.

57 citations

Journal ArticleDOI
TL;DR: In conclusion, EVs sustain an intricate crosstalk between graft tissue and innate/adaptive immune systems and are promising as biomarkers and therapeutic tools in KT.
Abstract: Immune cell-derived extracellular vesicles (EVs) are known immune-modulators and exert a critical role in kidney transplantation (KTx). EV bioactive cargo includes graft antigens, costimulatory/inhibitory molecules, cytokines, growth factors and functional microRNAs (miRNAs) that modulate expression of recipient cell target genes. At cellular level, neutrophil- and macrophage-derived EVs exert respectively immunosuppressive and immune-stimulating effects on dendritic cells. Dendritic cell-derived EVs mediate alloantigen spreading among them and modulate antigen-presentation to T lymphocytes. At systemic level, EVs exert pleiotropic effects on complement and coagulation. Depending on their biogenesis, they can amplify complement activation, or shed complement-inhibitors and prevent cell lysis. Likewise, endothelial and platelet-derived EVs can exert pro-coagulant/pro-thrombotic effects but also promote endothelial survival and angiogenesis after ischemic injury. Kidney endothelial and tubular-derived EVs play a key-role in ischemia-reperfusion injury and, during the healing process, can trigger rejection by inducing both allo- and autoimmune responses. Endothelial EVs have pro-coagulant/pro-inflammatory effects and can release sequestered self-antigens, triggering a tissue-specific autoimmunity. Renal tubule-derived EVs shuttle pro-fibrotic mediators (TGFβ, miR21) to interstitial fibroblasts and modulate neutrophil and T-lymphocyte influx. These processes can lead to peritubular capillary rarefaction and interstitial fibrosis-tubular atrophy. Different EVs, including those from mesenchymal stromal cells, have been employed as therapeutic tool in experimental models of rejection and ischemia-reperfusion injury. These particles protect tubular and endothelial cells (by inhibition of apoptosis and inflammation-fibrogenesis and autophagy induction) and stimulate tissue regeneration (by triggering angiogenesis, cell proliferation and migration). Finally, urinary and serum EVs represent potential biomarkers for delayed graft function and acute rejection. In conclusion, EVs sustain an intricate cross talk between graft tissue and innate/adaptive immune systems. EVs play a major role in allorecognition, ischemia-reperfusion injury, auto- and alloimmunity, and are promising as biomarkers and therapeutic tools in KTx.

51 citations

References
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Journal ArticleDOI
TL;DR: It is proposed that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue, and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance.
Abstract: Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance However, the underlying molecular pathways are largely unknown In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO) The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue

6,165 citations

Journal ArticleDOI
14 Dec 1995-Nature
TL;DR: Galectin-1 induced apoptosis of activated human T cells and human T leukaemia cell lines and represents a new mechanism for regulating the immune response.
Abstract: Galectin-1, a member of the family of beta-galactoside binding proteins, has growth regulatory and immunomodulatory activities. We report here that galectin-1, expressed by stromal cells in human thymus and lymph nodes, is present at sites of cell death by apoptosis during normal T-cell development and maturation. Galectin-1 induced apoptosis of activated human T cells and human T leukaemia cell lines. Resting T cells also bound galectin-1, but did not undergo apoptosis. Human endothelial cells that expressed galectin-1 induced apoptosis of bound T cells. Galectin-1-induced apoptosis required expression of CD45, and was decreased when N-glycan elongation was blocked by treatment of the cells by swainsonine, whereas inhibition of O-glycan elongation potentiated the apoptotic effect of galectin-1. Induction of apoptosis by an endogenous mammalian lectin represents a new mechanism for regulating the immune response.

1,028 citations

Journal ArticleDOI
TL;DR: Through specific interactions with a variety of intra- and extracellular proteins galectin-3 affects numerous biological processes and seems to be involved in different physiological and pathophysiological conditions, such as development, immune reactions, and neoplastic transformation and metastasis.

1,003 citations

Journal ArticleDOI
TL;DR: Natural killer cells constitute 50–90% of lymphocytes in human uterine decidua in early pregnancy and are compared with the CD56bright and CD56dim peripheral NK cell subsets by microarray analysis, with verification of results by flow cytometry and RT-PCR.
Abstract: Natural killer cells constitute 50–90% of lymphocytes in human uterine decidua in early pregnancy. Here, CD56bright uterine decidual NK (dNK) cells were compared with the CD56bright and CD56dim peripheral NK cell subsets by microarray analysis, with verification of results by flow cytometry and RT-PCR. Among the ∼10,000 genes studied, 278 genes showed at least a threefold change with P ≤ 0.001 when comparing the dNK and peripheral NK cell subsets, most displaying increased expression in dNK cells. The largest number of these encoded surface proteins, including the unusual lectinlike receptors NKG2E and Ly-49L, several killer cell Ig-like receptors, the integrin subunits αD, αX, β1, and β5, and multiple tetraspanins (CD9, CD151, CD53, CD63, and TSPAN-5). Additionally, two secreted proteins, galectin-1 and progestagen-associated protein 14, known to have immunomodulatory functions, were selectively expressed in dNK cells.

804 citations


"The Role of Galectins as Modulators..." refers background in this paper

  • ...These decidual NK cells are CD56-positive and CD16-negative cells that are important in immunomodulation in implantation and pregnancy [76]....

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Journal ArticleDOI
TL;DR: A new class of agents, exemplified by 4,5-dimethyl-3-phenacylthiazolium chloride (DPTC), which can chemically break already-formed AGE protein-protein crosslinks, are developed, based on a new theory of AGE crosslinking that postulates that alpha-dicarbonyl structures are present in AGEprotein- protein crosslinks.
Abstract: Biological amines react with reducing sugars to form a complex family of rearranged and dehydrated covalent adducts that are often yellow-brown and/or fluorescent and include many cross-linked structures. Food chemists have long studied this process as a source of flavor, color, and texture changes in cooked, processed, and stored foods. During the 1970s and 1980s, it was realized that this process, called the Maillard reaction or advanced glycation, also occurs slowly in vivo. Advanced glycation endproducts (AGEs) that form are implicated, causing the complications of diabetes and aging, primarily via adventitious and crosslinking of proteins. Long-lived proteins such as structural collagen and lens crystallins particularly are implicated as pathogenic targets of AGE processes. AGE formation in vascular wall collagen appears to be an especially deleterious event, causing crosslinking of collagen molecules to each other and to circulating proteins. This leads to plaque formation, basement membrane thickening, and loss of vascular elasticity. The chemistry of these later-stage, glycation-derived crosslinks is still incompletely understood but, based on the hypothesis that AGE formation involves reactive carbonyl groups, the authors introduced the carbonyl reagent aminoguanidine hydrochloride as an inhibitor of AGE formation in vivo in the mid 1980s. Subsequent studies by many researchers have shown the effectiveness of aminoguanidine in slowing or preventing a wide range of complications of diabetes and aging in animals and, recently, in humans. Since, the authors have developed a new class of agents, exemplified by 4,5-dimethyl-3-phenacylthiazolium chloride (DPTC), which can chemically break already-formed AGE protein-protein crosslinks. These agents are based on a new theory of AGE crosslinking that postulates that alpha-dicarbonyl structures are present in AGE protein-protein crosslinks. In studies in aged animals, DPTC has been shown to be capable of reverting indices of vascular compliance to levels seen in younger animals. Human clinical trials are underway.

803 citations


"The Role of Galectins as Modulators..." refers background in this paper

  • ...In diabetes mellitus, a long-standing hyperglycemic state can give production of advanced glycation end products (AGEs) that bind to organic molecules and cause complications [10]....

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