The effects of a galectin-3 inhibitor on bladder pain syndrome in mice with cyclophosphamide-induced cystitis.

AIMS: To explore the effect of blocking galectin-3 in the bladder pain syndrome associated with interstitial cystitis. METHODS: A galectin-3 inhibitor was used to treat mice with cyclophosphamide-induced cystitis. The expression of galectin-3 in bladder tissues and urine was examined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Suprapubic-pelvic pain, bladder voiding, bladder pain-like nociceptive behavior, and referred hyperalgesia were assessed. The weights of the bladders were also measured, and inflammatory cell infiltration and inflammatory cytokine levels were examined by histopathological evaluation. The inflammatory cytokines interleukin 1ß (IL-1ß), nerve growth factor (NGF), IL-6, and tumor necrosis factor α (TNF-α) were measured by ELISA. RESULTS: Increases in galectin-3 levels, inflammation, bladder weight, and bladder pain-related symptoms were observed in bladders with cyclophosphamide-induced cystitis. Administration of the galectin-3 inhibitor significantly mitigated bladder pain-related symptoms and inflammatory response. In response to the 500 µM dose of the galectin-3 inhibitor, nociceptive behaviors, nociceptive score, and bladder-to-body weight ratios were reduced by 65.1%, 65.3%, and 40.3%, respectively, while 500 µM Gal-3 inhibitor increased pelvic pain threshold by 86.7%. Moreover, galectin-3 inhibitor treatment inhibited the inflammation. Compared to untreated CYP-induced mice, there were significant changes in the levels of IL-1ß (41.72 ± 2.05 vs. 18.91 ± 2.26 pg/mg tissues), NGF (9.64 ± 0.38 vs. 1.88 ± 0.05 pg/mg tissues), IL-6 (42.67 + 1.51 vs. 21.26 + 2.78 pg/mg tissues, and TNF-α (22.02 ± 1.08 vs. 10.70 ± 0.80 pg/mg tissues) in response to the highest dose of the Gal-3 inhibitor subgroup (500 µM), and 500 µM Gal-3 inhibitor reduced mast cell infiltration ratios by 71.8%. CONCLUSIONS: The galectin-3 inhibitor relieved pelvic pain, urinary symptoms, and bladder inflammation in mice with cyclophosphamide-induced cystitis. Thus, galectin-3 inhibitors may be novel agents in interstitial cystitis treatment.

Higenamine improves DSS-induced ulcerative colitis in mice through the Galectin-3/TLR4/NF-κB pathway.

Ulcerative colitis (UC) is an inflammatory disease of the colon and tends to relapse. Higenamine (HG) has anti-inflammatory, antioxidant and anti-apoptotic activities. This study aimed to investigate the role of HG in the treatment of UC as well as the underlying mechanism. In vivo and in vitro models of UC were respectively established in dextran sodium sulfate (DSS)-induced mice and DSS-induced NCM460 cells. The weight and disease performance and disease activity index (DAI) of mice were recorded every day. The colon length was measured and pathological changes of colon tissues were observed by HE staining. The apoptosis of colon cells in mice was detected by Tunel assay and FITC-dextran was used to detect intestinal permeability in mice. The MPO activity and expression of tight junction proteins and Galectin-3/TLR4/NF-κB pathway related proteins in colon tissues and cells were detected by MPO assay kit and western blot. The levels of TNF-α, IL-1ß, IL-6 and IL-10 in serum and cells, and levels of DAO and D-LA in serum were all detected by assay kits. The viability and apoptosis of NCM460 cells were analyzed by CCK-8 assay and flow cytometry analysis, and permeability of NCM460 monolayers was detected by TEER measurement. As a result, HG improved the weight, DAI, colon length and pathological changes of DSS-induced UC mice. HG alleviated DSS-induced colon inflammation, inhibited DSS-induced apoptosis of mouse colonic epithelial cells and restored the integrity of the mucosa barrier in mice. In addition, HG suppressed the Galectin-3/TLR4/NF-κB signaling pathway in DSS-induced UC mice. Similarly, HG improved viability and epithelial barrier function, and suppressed the apoptosis and inflammation of DSS-induced NCM460 cells by inhibiting the Galectin-3/TLR4/NF-κB signaling pathway. Galectin-3 overexpression could reverse the effect of HG on DSS-induced NCM460 cells. In conclusion, HG improved DSS-induced UC through the inactivation of Galectin-3/TLR4/NF-κB pathway in vivo and in vitro. AVAILABILITY OF DATA AND MATERIAL: The data are available from the corresponding author on reasonable request.

Role of galectin-3 in vascular calcification.

Vascular calcification is an abnormal process in which bone specific hydroxyapatite crystals are actively deposited on the vascular wall mediated by phenotypic differentiated smooth muscle cells and other mesenchymal cells under various pathological conditions. It is one of the important characteristics in the occurrence and development of atherosclerosis, prevalent in patients with type 2 diabetes and advanced chronic kidney disease, especially those requiring maintenance hemodialysis, with severely threatening human health. Previous studies have shown that the early diagnosis and control of vascular calcification is of great significance for cardiovascular risk stratification, prevention of acute cardiovascular events, which can greatly improve the prognosis and quality of life of patients. Galectins are a family of lectin superfamily. It is widely distributed in various animals and plays an important role in many physiological and pathological processes, such as cell adhesion, apoptosis, inflammatory response, tumor metastasis and so on. Many biomarker-and association-related studies and Preclinical-mechanistic studies have suggested that galactose-specific lectin-3 (galectin-3) plays an important role in vascular calcification and vascular intimal calcification (VIC) calcification induced by Wnt/ßcatenin signaling pathway, NF-κB signaling pathway and ERK1/2 signaling pathway. This paper mainly expounds the role and mechanism of galectin-3 in vascular calcification under different pathological conditions including atherosclerosis, diabetes and chronic kidney disease.

Trajectory modeling of endothelial-to-mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis.

The endothelial-to-mesenchymal transition (EndMT) is an important source of fibrotic cells in idiopathic pulmonary fibrosis (IPF). However, how endothelial cells (ECs) are activated and how EndMT impact IPF remain largely elusive. Here, we use unsupervised pseudotemporal analysis to recognize the heterogeneity of ECs and reconstruct EndMT trajectory of bleomycin (BLM)-treated Tie2creER/+;Rosa26tdTomato/+ IPF mice. Genes like C3ar1 and Lgals3 (protein name galectin-3) are highly correlated with the transitional pseudotime, whose expression is gradually upregulated during the fate switch of ECs from quiescence to activation in fibrosis. Inhibition of galectin-3 via siRNA or protein antagonists in mice could alleviate the pathogenesis of IPF and the transition of ECs. With the stimulation of human pulmonary microvascular endothelial cells (HPMECs) by recombinant proteins and/or siRNAs for galectin-3 in vitro, ß-catenin/GSK3ß signaling and its upstream regulator AKT are perturbed, which indicates they mediate the EndMT progress. These results suggest that EndMT is essential to IPF process and provide potential therapeutic targets for vascular remodeling.

LGALS3 Promotes Treatment Resistance in Glioblastoma and Is Associated with Tumor Risk and Prognosis.

BACKGROUND: LGALS3 promotes tumor progression in diverse cancers. However, the involvement of LGALS3 in glioblastoma has not yet been broadly illuminated. METHODS: Microarray was performed to detect the gene expression profiles of radioresistance in T98G cells and identified a universally upregulated gene, LGALS3. The impact of LGALS3 on the survival of glioblastoma cells facing ionizing irradiation or temozolomide was investigated by the Cell Counting Kit-8 (CCK-8). A total of 120 glioblastoma cases were collected to analyze the relationship between LGALS3 expression and patient prognosis. Another 961 patients with glioma and 1,351 healthy controls were recruited to study the association of SNPs across the LGALS3 gene with glioblastoma susceptibility. The functional SNP sites were also studied in cellular experiments. RESULTS: An effective protection of LGALS3 from ionizing irradiation or temozolomide-induced cell death in T98G and U251 cells was found. In addition, high expression of LGALS3 could work as an independent risk factor for survival of patients with glioblastoma. Two SNP sites (rs4644 and rs4652) across the LGALS3 gene were associated with increased risk for glioblastoma, and the C allele of rs4652 and the A allele of rs4644 could enhance glioblastoma resistance to radio-chemotherapy, but not cell proliferation. CONCLUSIONS: Our results suggest that LGALS3 is an important biomarker influencing glioblastoma risk and prognosis and a potential target for treating the malignancy, especially ones with resistance against the standard therapy. IMPACT: LGALS3 promotes glioblastoma cells' resistance to ionizing irradiation and temozolomide and predicts poor prognosis. Targeting LGALS3 may limit the therapeutic resistance in glioblastoma and increase patient survival.