The β-galactoside-binding protein galectin-3 is currently a hotly pursued therapeutic target in cancer, inflammation and fibrosis-associated diseases due to its multi-mode actions and broad impact on the pathogenesis and progress of the diseases. Various natures of galectin-3 inhibitors have been developed and investigated, and several have shown promising results in early-phase clinical trials. All these galectin-3 antagonists were designed to target the canonical carbohydrate-binding site, the S-face, of the galectin-3 carbohydrate recognition domain (CRD). This review discussed the current galectin-3 antagonists and explored their modes of actions, focusing particularly on their targeting regions on galectin-3. It discussed the tri-modular structure of galectin-3 and the roles of different segments in galectin-3 actions. It proposed that, in addition to the canonical carbohydrate-binding sites on the S-face, the non-canonical carbohydrate-binding interface, the F-face of the galectin-3 CRD as well as its flexible N-terminal domain are also targetable in the design of galectin-3-targeted therapeutics. Given the high degree of structural similarities of CRDs among galectin family members but unique nature of galectin-3 N-terminus, antagonists developed against the N-terminal domain of galectin-3 can potentially offer greater target specificity by avoiding cross-reactivity with other galectin members. Antagonists that can interact with more than one segment of galectin-3, or a combination of antagonists against different galectin-3 segments, may potentially provide improved efficacy and therapeutic effectiveness for treatment of galectin-3-mediated pathologies and diseases.

Chagas heart disease is a major public concern since 30% of infected patients develop cardiac alterations. The relationship between Trypanosoma cruzi discrete typing units (DTUs) and the biological properties exhibited by the parasite population has yet to be elucidated. In this study, we analysed the expression of α-smooth muscle actin (α-SMA) and galectin-3 (Gal-3) associated with cardiac extracellular matrix (ECM) remodelling a murine chronic cardiomyopathy induced by Tc I genotypes. We found the induction of myocarditis was associated with the upregulation of Col I, α-SMA, Gal-3, IFN-γ and IL-13, as analysed by q-PCR. In myocardial areas of fibrosis, the intensity of myocarditis and significant ECM remodelling correlated with the presence of Col I-, Gal-3- and α-SMA-positive cells. These results are promising for the further efforts to evaluate the relevance of Gal-3 in Chagas heart disease, since this galectin was proposed as a prognosis marker in heart failure patients.

Toxoplasma gondii stimulates a potent pro-inflammatory response and neutrophils are involved in early infection. Galectin-3 (Gal-3) is an endogenous modulator of inflammatory processes and anti-infective agents, but its interaction with neutrophils in T. gondii infection is still unclear. Here, we evaluated the role of Gal-3 in peritoneal inflammation, reactive oxygen species (ROS) production by neutrophils and survival, after in vivo T. gondii infection with virulent RH strain, using Gal-3 deficient and wild type mice. Animals were inoculated with thioglycollate or tachyzoites, and peritoneal cells were harvested for analysis of the influx of leukocytes. Neutrophils were isolated from peritoneal exudates from infected mice and stimulated with phorbol myristate acetate (PMA) to evaluate ROS production by luminol-dependent chemiluminescence assay. Our results showed that: (1) Gal-3 upregulates peritoneal inflammation, with enhanced recruitment of neutrophils and lymphocytes after thioglycollate stimulation, but does not influence the enhanced neutrophil influx after early T. gondii infection; (2) Gal-3 upregulates ROS generation by inflammatory peritoneal neutrophils from infected mice, but downregulates its production in non-infected mice and (3) Gal-3 does not influence the survival of mice after infection with the virulent T. gondii strain. In conclusion, Gal-3 is essential for ROS generation by neutrophils in the initial acute phase of T. gondii infection and this phenomenon may constitute an attempt to control parasite growth during in vivo infection with the T. gondii virulent strain.