Animal galectins Galectins are water-soluble, non-glycosylated globular proteins that cannot covalently attach to carbohydrates. A collection of evolutionary-moderate, non-glycosylated globule proteins. Galectin-3 (Gal-3) is a galectin lectin and an in general human body -galactoside-binding lectin. Gal-3 is a galectin. Today we count 15 galectins in mammals. They share the same CRD and participate in cell growth, differentiation, apoptosis, cell adherence, immune response and signalling. We increasingly learn that galectin-3 is involved in the onset and progression of lung diseases such as idiopathic pulmonary fibrosis, lung cancer, pulmonary hypertension and bronchial asthma.
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Structure of Galectin-3
If a polyvalent contact with carbohydrate at the cell surface leads Gal-3 to self-oligomerize into pentamers or other structures by CRD-CRD linkage or NH2-NH2 linkage into an adhesion network. Each Gal-3 chain has at least one function: the NH2-end has a serine phosphorylation site and that's how its nuclear export is controlled; the proline-rich collagen-like domain can be cleaved by MMPs, and that cleavage can be used as a tissue-specific proxy diagnostic marker for MMP-2 and MMP-9; the COOH-terminus contains one CRD, the NWGR anti-death motif, and a signalling location to regulate its nuclear export.
Fig. 1 Structure of galectin-3 (Si, R., et al. 2020).
Expression and Localization of Galectin-3
Gal-3 is an endemic protein in the hematopoietic tissues, thymus, lymph nodes, skin, respiratory system, digestive system, genital system and urinary system, in adults, and varies with tissue type and tissue growth. Gal-3 expression is cell-specific too. It turns out that Gal-3 is highly expressed in tumor cells, macrophages, epithelial cells, fibroblasts, and activated T cells. And even in the same tissue, cells of different cell types encode Gal-3. For instance, in hematopoietic tissue Gal-3 is present in monocytes, but more significantly in macrophages. Gal-3 is formed in the cytoplasm, functions in the nucleus and cytoplasm is excreted into the cell wall and extracellular matrix and is present in the blood.
Gal-3 Gene and Post-transcriptional Modification
LGALS3 is a single Gal-3 gene in the human genome that is found between q21-22 of chromosome 14; it contains 6 exons and 5 introns, covering about 17,000 bases. The LGALS3 promoter methylation status, the promoter's CRE motif, the NF-B-like structure, and the GC box control Gal-3 expression.
Function of Gal-3
Gal-3 is not just a cell in the body but it is outside as well. It is a shuttle protein, and it can do a host of physiological or pathophysiological activities by binding to multiple ligands. Gal-3 has extracellular functions as a lectin and as a recognition of cell surface and extracellular matrix polysaccharides. Extracellular Gal-3 ligands are mainly -galactoside derivatives like lactose and N-acetylacetone, which do not covalently attach to the CRD of the Gal-3 structure. Gal-3 is also affine to sugars with different sugar sequences, linkage types, linear or branched structures and carbohydrate size.
Galectin-3-related Respiratory Diseases
Idiopathic Pulmonary Fibrosis
IPF is a unrelated pulmonary fibrosis (CF) in the adult with histopathological general interstitial pneumonia. IPF is the most common idiopathic interstitial pneumonia. The best-known form of interstitial lung disease of them has gained a lot of publicity as it is poorly understood and ineffective with traditional therapy. Pathological evolution of IPF is multifactorial and the pathogenesis of the disease is multi-functional in physiological and pathological aspects. Gal-3 may even be involved in IPF pathogenesis by regulating epithelial-mesenchymal transition or triggering fibroblasts.
Lung Cancer
Lung cancer is one of the most common malignant tumours on Earth. Lung cancer is a multifactorial disease and the research data behind Gal-3's effect are abundant.Gal-3 also induces TLR4/NFB signals by activating the expression of lncRNA-NEAT1, which fuels lung adenocarcinoma cells. A tumor cell's Gal-3 level is an indicator of recurrence, but a serum Gal-3 value does not indicate NSCLC recurrence. Gal-3, for instance, would be an attractive drug target for lung cancer (NSCLC particularly), and should be investigated.
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a progressive disease that results from pulmonary artery stenosis that causes high pulmonary vascular pressure and eventually right ventricular failure. A very debilitating and mortal illness also called cardiovascular cancer. Gal-3 modulates PAH pathogenesis by modulating the growth, differentiation and extracellular matrix production of pulmonary adventitial fibroblasts. If we can silence Gal-3 gene expression with Gal-3 knockout animals or a small interfering RNA in vitro experiments, the PAH levels decrease and so Gal-3 inhibitors could be potential new targets for the treatment of PAH.
Conclusion
In idiopathic pulmonary fibrosis, lung cancer, pulmonary hypertension and bronchial asthma, advances in Gal-3 research promise to give us something new to treat these conditions in clinical medicine. Also expressed in IPF is Gal-3, a process that causes fibrosis by multiple pathological mechanisms, such as epithelial-mesenchymal transition and fibroblast activation, and thus Gal-3 is an important target for IPF therapy. Gal-3 is found mostly in NSCLC in lung cancer. Applied either by itself or together with other tumor markers as a biomarker of prognosis, metastasis, responsiveness to anticancer medications, and recurrence in NSCLC. Gal-3, in pulmonary hypertension, informs disease pathobiology and clinical presentation of PAH, is a powerful marker of PAH mortality, and also an independent and powerful prognostic factor. Gal-3 inhibitors specifically have been effective against these disorders, so Gal-3 inhibitors have good therapeutic potential in disease and may represent an option for a target for the treatment of respiratory disorders.
References
- Si, R., et al. Research progress on galectin-3 as a potential therapeutic target for respiratory diseases. Acta Pharmaceutica Sinica. 2020, 55(7): 1401-1409.
- Jin, M., et al. Research progress on the relationship between galectin-3 and ventricular remodeling in heart failure. Journal of Clinical Cardiology. 2016, 32(5): 441-445.
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