Gal-1-mediated cytochrome p450 activation promotes fibroblast into myofibroblast differentiation in pulmonary fibrosis.

Pulmonary fibrosis (PF) results from excessive extracellular matrix (ECM) deposition and tissue remodeling after activation of fibroblasts into myofibroblasts. Abnormally deposited fibrotic ECM, in turn, promotes fibroblast activation and accelerates loss of lung structure and function. However, the molecular mediators and exact mechanisms by which fibrotic ECM promotes fibroblast activation are unclear. In a bleomycin-induced PF mouse model, we found Galectin-1 (Gal-1) expression was significantly increased in lung tissue, and overexpression of Gal-1 plasmid-transfected fibroblasts were activated into myofibroblasts. Using the decellularization technique to prepare decellularized fibrotic ECM and constructing a 3D in vitro co-culture system with fibroblasts, we found that decellularized fibrotic ECM induced a high expression of Gal-1 and promoted the activation of fibroblasts into myofibroblasts. Therefore, Gal-1 has been identified as a pivotal mediator in PF. Further, we found that decellularized fibrotic ECM delivered mechanical signals to cells through the Gal-1-mediated FAK-Src-P130Cas mechanical signalling pathway, while the CYP450 enzymes (mainly involved in CYP1A1, CYP24A1, CYP3A4, and CYP2D6 isoforms) acted as a chemical signalling pathway to receive mechanical signals transmitted from upstream Gal-1, thereby promoting fibroblast activation. The Gal-1 inhibitor OTX008 or the CYP1A1 inhibitor 7-Hydroxyflavone prevented PF in mice and inhibited the role of fibrotic ECM in promoting fibroblast activation into myofibroblasts, preventing PF. These results reveal novel molecular mechanisms of lung fibrosis formation and identify Gal-1 and its downstream CYP1A1 as potential therapeutic targets for PF disease treatmnts.

Galectin-1-producing mesenchymal stem cells restrain the proliferation of T lymphocytes from patients with systemic lupus erythematosus.

INTRODUCTION: Bone marrow mesenchymal stem cell (BMMSC) transplantation is beneficial in treating Systemic lupus erythematosus (SLE); however, the underlying mechanism remains elusive. This study investigates the role of BMMSCs in regulating lymphocyte proliferation and cell cycle progression during SLE and delves into the contribution of BMMSC-produced galectin-1. METHODS: BMMSCs were co-cultured with T lymphocytes to assess their impact on suppressing CD4+ T cells in SLE patients. Proliferation and cell cycle distribution of CD4+ T cells were analyzed using flow cytometry. The expression of cell cycle-related proteins, including p21, p27, and cyclin-dependent kinase 2 (CDK2), was investigated through western blotting. Extracellular and intracellular galectin-1 levels were determined via ELISA and flow cytometry. The role of galectin-1 in CD4+ T cell proliferation and cell cycle was evaluated through RNAi-mediated galectin-1 expression disruption in BMMSCs. RESULTS AND DISCUSSION: BMMSCs effectively inhibited CD4+ T cell proliferation and impeded their cell cycle progression in SLE patients, concurrently resulting in a reduction in CDK2 levels and an increase in p21 and p27 expression. Moreover, BMMSCs expressed a high level of galectin-1 in the co-culture system. Galectin-1 was found to be critical in maintaining the suppressive activity of BMMSCs and restoring the cell cycle of CD4+ T cells. CONCLUSION: This study demonstrates that BMMSCs suppress the proliferation and influence the cell cycle of CD4+ T cells in SLE patients, an effect mediated by the upregulation of galectin-1 in BMMSCs.

Ganoderic acid T, a Ganoderma triterpenoid, modulates the tumor microenvironment and enhances the chemotherapy and immunotherapy efficacy through downregulating galectin-1 levels.

Ganoderic acid T (GAT), a triterpenoid molecule of Ganoderma lucidum, exhibits anti-cancer activity; however, the underlying mechanisms remain unclear. Therefore, in this study, we aimed to investigate the anti-cancer molecular mechanisms of GAT and explore its therapeutic applications for cancer treatment. GAT exhibited potent anti-cancer activity in an ES-2 orthotopic ovarian cancer model in a humanized mouse model, leading to significant alterations in the tumor microenvironment (TME). Specifically, GAT reduced the proportion of α-SMA+ cells and enhanced the infiltration of tumor-infiltrating lymphocytes (TILs) in tumor tissues. After conducting proteomic analysis, it was revealed that GAT downregulates galectin-1 (Gal-1), a key molecule in the TME. This downregulation has been confirmed in multiple cancer cell lines and xenograft tumors. Molecular docking suggested a theoretical direct interaction between GAT and Gal-1. Further research revealed that GAT induces ubiquitination of Gal-1. Moreover, GAT significantly augmented the anti-cancer effects of paclitaxel, thereby increasing intratumoral drug concentrations and reducing tumor size. Combined with immunotherapy, GAT enhanced the tumor-suppressive effects of the anti-programmed death-ligand 1 antibody and increased the proportion of CD8+ cells in the EMT6 syngeneic mammary cancer model. In conclusion, GAT inhibited tumor growth, downregulated Gal-1, modulated the TME, and promoted chemotherapy and immunotherapy efficacy. Our findings highlight the potential of GAT as an effective therapeutic agent for cancer.

Prognostic Influence of Galectin-1 in Gastric Adenocarcinoma.

Galectin-1 (Gal-1), a member of the human lectin family, has garnered attention for its association with aggressive behavior in human tumors, prompting research into the development of targeted drugs. This study aims to assess the staining pattern and prognostic significance of Gal-1 immunohistochemical expression in a homogeneous cohort of Western patients with gastric cancer (GC). A total of 149 cases were included and tissue microarrays were constructed. Stromal Gal-1 expression was observed to some extent in most tumors, displaying a cytoplasmic pattern. Cases with stromal Gal-1 overexpression showed significantly more necrosis, lymphovascular invasion, advanced pTNM stages, recurrences, and cancer-related deaths. Epithelial Gal-1 expression was present in 63.8% of the cases, primarily exhibiting a cytoplasmic pattern, and its overexpression was significantly associated with lymphovascular invasion, peritumoral lymphocytic infiltration, and tumor-related death. Kaplan/Meier curves for cancer-specific survival (CSS) revealed a significantly worse prognosis for patients with tumors exhibiting stromal or epithelial Gal-1 overexpression. Furthermore, stromal Gal-1 expression stratified stage III patients into distinct prognostic subgroups. In a multivariable analysis, increased stromal Gal-1 expression emerged as an independent prognostic factor for CSS. These findings underscore the prognostic relevance of Gal-1 and suggest its potential as a target for drug development in Western patients with GC.

Improving cancer immunotherapy in prostate cancer by modulating T cell function through targeting the galectin-1.

Our study aimed to elucidate the role of Galectin-1 (Gal-1) role in the immunosuppressive tumor microenvironment (TME) of prostate cancer (PCa). Our previous findings demonstrated a correlation between elevated Gal-1 expression and advanced PCa stages. In this study, we also observed that Gal-1 is expressed around the tumor stroma and its expression level is associated with PCa progression. We identified that Gal-1 could be secreted by PCa cells, and secreted Gal-1 has the potential to induce T cell apoptosis. Gal-1 knockdown or inhibition of Gal-1 function by LLS30 suppresses T cell apoptosis resulting in increased intratumoral T cell infiltration. Importantly, LLS30 treatment significantly improved the antitumor efficacy of anti-PD-1 in vivo. Mechanistically, LLS30 binds to the carbohydrate recognition domain (CRD) of Gal-1, disrupting its binding to CD45 leading to the suppression of T cell apoptosis. In addition, RNA-seq analysis revealed a novel mechanism of action for LLS30, linking its tumor-intrinsic oncogenic effects to anti-tumor immunity. These findings suggested that tumor-derived Gal-1 contributes to the immunosuppressive TME in PCa by inducing apoptosis in effector T cells. Targeting Gal-1 with LLS30 may offer a strategy to enhance anti-tumor immunity and improve immunotherapy.

Galectin-1 Promotes Gastric Carcinoma Progression and Cisplatin Resistance Through the NRP-1/c-JUN/Wee1 Pathway.

PURPOSE: Gastric cancer (GC) is among the deadliest malignancies and the third leading cause of cancer-related deaths worldwide. Galectin-1 (Gal-1) is a primary protein secreted by cancer-associated fibroblasts (CAFs); however, its role and mechanisms of action of Gal-1 in GC remain unclear. In this study, we stimulated GC cells with exogenous human recombinant galectin-1 protein (rhGal-1) to investigate its effects on the proliferation, migration, and resistance to cisplatin. MATERIALS AND METHODS: We used simulated rhGal-1 protein as a paracrine factor produced by CAFs to induce GC cells and investigated its promotional effects and mechanisms in GC progression and cisplatin resistance. Immunohistochemical (IHC) assay confirmed that Gal-1 expression was associated with clinicopathological parameters and correlated with the expression of neuropilin-1 (NRP-1), c-JUN, and Wee1. RESULTS: Our study reveals Gal-1 expression was significantly associated with poor outcomes. Gal-1 boosts the proliferation and metastasis of GC cells by activating the NRP-1/C-JUN/Wee1 pathway. Gal-1 notably increases GC cell resistance to cisplatin The NRP-1 inhibitor, EG00229, effectively counteracts these effects. CONCLUSIONS: These findings revealed a potential mechanism by which Gal-1 promotes GC growth and contributes to chemoresistance, offering new therapeutic targets for the treatment of GC.

"Inhibitory immune checkpoints predict 7-day, in-hospital and 1-year mortality of internal medicine patients admitted with bacterial sepsis".

BACKGROUND: Sepsis is a life-threatening syndrome with complex pathophysiology and great clinical heterogeneity which complicates the delivery of personalized therapies. Our goals were to demonstrate that some biomarkers identified as regulatory immune checkpoints in preclinical studies could 1)improve sepsis prognostication based on clinical variables and 2)guide the stratification of septic patients in subgroups with shared characteristics of immune response or survival outcomes. METHODS: We assayed the soluble counterparts of 12 biomarkers of immune response in 113 internal medicine patients with bacterial sepsis. RESULTS: IL-1 receptor-associated kinase M (IRAK-M) exhibited the highest hazard ratios (HRs) for increased 7-day (1.94 [1.17-3.20]) and 30-day mortality (1.61 [1.14-2.28]). HRs of IRAK-M and Galectin-1 for predicting 1-year mortality were 1.52 (1.20-1.92) and 1.64 (1.13-2.36), respectively. A prognostic model including IRAK-M, Galectin-1, and clinical variables (Charlson Comorbidty Index, multiple source of sepsis, and SOFA score) had high discrimination for death at 7 days and 30 days (area under the curve 0.90 [0.82-0.99]) and 0.86 [0.79-0.94], respectively). Patients with elevated serum levels of IRAK-M and Galectin-1 had clinical traits of immune suppression and low survival rates. None of the 12 biomarkers were independent predictors of 2-year mortality. CONCLUSIONS: Two inhibitory immune checkpoint biomarkers (IRAK-M and Galectin-1) helped identify 3 distinct sepsis phenotypes with distinct prognoses. These biomarkers shed light on the interplay between immune dysfunction and prognosis in patients with bacterial sepsis and may prove to be useful prognostic markers, therapeutic targets, and biochemical markers for targeted enrollment in targeted therapeutic trials.

Determining the Affinity and Kinetics of Small Molecule Inhibitors of Galectin-1 Using Surface Plasmon Resonance.

The beta-galactoside-binding mammalian lectin galectin-1 can bind, via its carbohydrate recognition domain (CRD), to various cell surface glycoproteins and has been implicated in a range of cancers. As a consequence of binding to sugar residues on cell surface receptors, it has been shown to have a pleiotropic effect across many cell types and mechanisms, resulting in immune system modulation and cancer progression. As a result, it has started to become a therapeutic target for both small and large molecules. In previous studies, we used fluorescence polarization (FP) assays to determine KD values to screen and triage small molecule glycomimetics that bind to the galectin-1 CRD. In this study, surface plasmon resonance (SPR) was used to compare human and mouse galectin-1 affinity measures with FP, as SPR has not been applied for compound screening against this galectin. Binding affinities for a selection of mono- and di-saccharides covering a 1000-fold range correlated well between FP and SPR assay formats for both human and mouse galectin-1. It was shown that slower dissociation drove the increased affinity at human galectin-1, whilst faster association was responsible for the effects in mouse galectin-1. This study demonstrates that SPR is a sound alternative to FP for early drug discovery screening and determining affinity estimates. Consequently, it also allows association and dissociation constants to be measured in a high-throughput manner for small molecule galectin-1 inhibitors.

A Quantitative Human Red Blood Cell Agglutination Assay for Characterisation of Galectin Inhibitors.

Galectins are a family of beta-galactoside-binding proteins that are characterised by their carbohydrate recognition domain (CRD) and include galectin-1 and galectin-3. These galectins have been implicated in numerous diseases due to their pleiotropic nature, including cancer and fibrosis, with therapeutic inhibitors being clinically developed to block the CRD. One of the early methods developed to characterise these galectins was the hemagglutination of red blood cells. Although it is insightful, this approach has been hampered by a lack of sensitivity and accurate quantification of the agglutination observed. In this study, we aimed to validate a more precise and quantitative method to enable the further investigation of differences between galectins in respect to agglutination induction in different blood groups, as well as the characterisation of small molecule inhibitors. Quantification of hemagglutination was shown to be optimal using U-bottom plates imaged and analysed with FIJI ImageJ rather than flat-bottom plates read for absorbance on an optical density plate reader. Galectin-3-induced red blood cell agglutination efficacy increased significantly from blood group O to A to B. However, for both the galectin-1 monomer and concatemer, a more comparable effect was observed between blood group B and O, but with more potent effects than in blood group A. Inhibition assays for both galectin-3 and galectin-1 induced-hemagglutination were able to demonstrate clear concentration responses and expected selectivity profiles for a set of small-molecule glycomimetics, confirming the historical profiles obtained in biochemical binding and functional cellular assays.

A C-type lectin from Bothrops jararacussu venom reprograms endothelial cell biology.

Snake venoms are intricate mixtures of enzymes and bioactive factors that induce a range of detrimental effects in afflicted hosts. Certain Viperids, including Bothrops jararacussu, harbor C-type lectins (CTLs) known for their modulation of a variety of host cellular responses. In this study, we isolated and purified BjcuL, a CTL from B. jararacussu venom and investigated its impact on endothelial cell behavior, contrasting it with human galectin-1 (Gal-1), a prototype member of the galectin family with shared ß-galactoside-binding activity. We found that BjcuL binds to human dermal microvascular endothelial cells (HMECs) in a concentration- and carbohydrate-dependent fashion and reprograms the function of these cells, favoring a pro-inflammatory and pro-coagulant endothelial phenotype. In light of the quest for universal antagonists capable of mitigating the harmful consequences of snake venoms, BjcuL emerges as a promising target to be blocked in order to regulate pathological endothelial cell responses.

Investigating the Effects of HMGB1 Overexpression on Colorectal Cancer Cell Migration via Oncolytic Herpes simplex Virus Type 1 (oHSV-1).

Background: Colorectal Cancer (CRC) represents a significant global health challenge, and its progression, resistance to therapy, and metastasis are strongly influenced by the tumor microenvironment, including factors like hypoxia. This study explores the impact of High Mobility Group Box 1 (HMGB1) overexpression on CRC cell migration, while identifying potential genes associated with this process. Methods: To explore this, we developed oncolytic virotherapy, resulting in HSVHMGB1, an oncolytic Herpes simplex virus that expresses HMGB1. HMGB1 is known its role in cancer progression, particularly in the context of cancer cell migration. Results: Contrary to expectations, our scratch assays indicated that HSV-HMGB1 did not significantly induce migration in CRC cells, suggesting that HMGB1 might not directly contribute to this process. Employing microarray analysis, we investigated gene expression changes linked to CRC cell migration, leading to construction of a Protein-Protein Interaction (PPI) network. This network revealed the presence of hub proteins, including as NDRG1, LGALS1, and ANGPTL4, which are recognized for their roles in cancer cell migration. The differential expression of these genes under hypoxic conditions was further validated using quantitative RT-PCR, aligning with the findings from our microarray data. Conclusion: Our findings emphasize the complex regulation of CRC cell migration, and provides valuable insights into potential molecular mechanisms and pathways. These findings have implications for further research into cancer progression and the development of therapeutic strategies.

Design and synthesis of novel coumarin-benzimidazole hybrids as human galectin-1 inhibitors.

Aim: To develop novel non-carbohydrate inhibitors of human galectin-1 (GAL-1), we have designed a series of coumarin-benzimidazole hybrids. Methods: We synthesized and characterized the coumarin-benzimidazole hybrids and further evaluated them using an in vitro GAL-1 enzyme-linked immunosorbent assay and in silico methods. Results: Among all, the compounds 6p and 6q were found to be potent, with GAL-1 inhibition of 37.61 and 36.92%, respectively, at 10 µM in GAL-1-expressed cell culture supernatant of MCF-7 cells. These two compounds are feasible for fluorine-18 radiolabeling to develop GAL-1 selective PET radiotracers. Computational studies revealed strong binding interactions of GAL-1 with these novel coumarin-benzimidazole hybrids. Conclusion: Coumarin-benzimidazole hybrids can serve as potential leads to develop selective non-carbohydrate GAL-1 inhibitors for cancer therapy.

[Box: see text].

Spectroscopic Assessment of Doxorubicin (DOX)-Gemcitabine (GEM) Gold Complex Nanovector as Diagnostic Tool of Galectin-1 Biomarker.

Introduction: The aim of this study is focused on the development of theranostic hybrid nanovectors based on gold-doxorubicin (DOX)-gemcitabine (GEM) complexes and their active targeting with Galectin-1 (Gal-1) as a promising therapeutic and prognostic marker in cancer. Methods: For this purpose, a gold salt (HAuCl4) interacts with antitumor drugs (DOX; GEM) by chelation and then stabilizes with dicarboxylic acid-terminated polyethylene glycol (PEG) as a biocompatible surfactant. The proposed methodology is fast and reproducible, and leads to the formation of a hybrid nanovector named GEM@DOX IN PEG-AuNPs, in which the chemo-biological stability was improved. All synthetic chemical products were evaluated using various spectroscopic techniques (Raman and UV-Vis spectroscopy) and transmission electron microscopy (TEM). Results: To conceive a therapeutic application, our hybrid nanovector (GEM@DOX IN PEG-AuNPs) was conjugated with the Galectin-1 protein (Gal-1) at different concentrations to predict and specifically recognize cancer cells. Gal-1 interacts with GEM@DOX in PEG-AuNPs, as shown by SPR and Raman measurements. We observed both dynamic variation in the plasmon position (SPR) and Raman band with Gal-1 concentration. Discussion: We identified that GEM grafted electrostatically onto DOX IN PEG-AuNPs assumes a better chemical conformation, in which the amino group (NH3+) reacts with the carboxylic (COO-) group of PEG diacide, whereas the ciclopenthanol group at position C-5' reacts with NH3+ of DOX. Conclusion: This study opens further way in order to built "smart nanomedical devices" that could have a dual application as therapeutic and diagnostic in the field of nanomedicine and preclinical studies associated.

Noninvasively Deciphering the Immunosuppressive Tumor Microenvironment Using Galectin-1 PET to Inform Immunotherapy Responses.

Immune checkpoint blockade (ICB) has achieved groundbreaking results in clinical cancer therapy; however, only a subset of patients experience durable benefits. The aim of this study was to explore strategies for predicting tumor responses to optimize the intervention approach using ICB therapy. Methods: We used a bilateral mouse model for proteomics analysis to identify new imaging biomarkers for tumor responses to ICB therapy. A PET radiotracer was synthesized by radiolabeling the identified biomarker-targeting antibody with 124I. The radiotracer was then tested for PET prediction of tumor responses to ICB therapy. Results: We identified galectin-1 (Gal-1), a member of the carbohydrate-binding lectin family, as a potential negative biomarker for ICB efficacy. We established that Gal-1 inhibition promotes a sensitive immune phenotype within the tumor microenvironment (TME) for ICB therapy. To assess the pre-ICB treatment status of the TME, a Gal-1-targeted PET radiotracer, 124I-αGal-1, was developed. PET imaging with 124I-αGal-1 showed the pretreatment immunosuppressive status of the TME before the initiation of therapy, thus enabling the prediction of ICB resistance in advance. Moreover, the use of hydrogel scaffolds loaded with a Gal-1 inhibitor, thiodigalactoside, demonstrated that a single dose of thiodigalactoside-hydrogel significantly potentiated ICB and adoptive cell transfer immunotherapies by remodeling the immunosuppressive TME. Conclusion: Our study underscores the potential of Gal-1-targeted PET imaging as a valuable strategy for early-stage monitoring of tumor responses to ICB therapy. Additionally, Gal-1 inhibition effectively counteracts the immunosuppressive TME, resulting in enhanced immunotherapy efficacy.

Regulation of Nrf2/Keap1 signaling pathway in cancer drug resistance by galectin-1: cellular and molecular implications.

Oxidative stress is characterized by the deregulation of the redox state in the cells, which plays a role in the initiation of various types of cancers. The activity of galectin-1 (Gal-1) depends on the cell redox state and the redox state of the microenvironment. Gal-1 expression has been related to many different tumor types, as it plays important roles in several processes involved in cancer progression, such as apoptosis, cell migration, adhesion, and immune response. The erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is a crucial mechanism involved in both cell survival and cell defense against oxidative stress. In this review, we delve into the cellular and molecular roles played by Gal-1 in the context of oxidative stress onset in cancer cells, particularly focusing on its involvement in activating the Nrf2/Keap1 signaling pathway. The emerging evidence concerning the anti-apoptotic effect of Gal-1, together with its ability to sustain the activation of the Nrf2 pathway in counteracting oxidative stress, supports the role of Gal-1 in the promotion of tumor cells proliferation, immuno-suppression, and anti-tumor drug resistance, thus highlighting that the inhibition of Gal-1 emerges as a potential strategy for the restraint and regression of tumor progression. Overall, a deeper understanding of the multi-functionality and disease-specific expression profiling of Gal-1 will be crucial for the design and development of novel Gal-1 inhibitors as anticancer agents. Excitingly, although it is still understudied, the ever-growing knowledge of the sophisticated interplay between Gal-1 and Nrf2/Keap1 will enable researchers to gain valuable insights into the underlying causes of carcinogenesis and metastasis.

Neuroprotective effects of galectin­1 on cerebral ischemia/reperfusion injury by regulating oxidative stress.

Oxidative stress contributes to the pathology of cerebral ischemia/reperfusion (I/R) injury. Galectin-1 has shown an anti-oxidative stress effect. The present study investigated whether this anti-oxidative stress effect can account for the neuroprotective actions of galectin-1 induced by cerebral I/R injury. A cerebral I/R injury model was created in C57Bl/6 mice by transient occlusion of the middle cerebral artery, after which the mice were treated with galectin-1 for 3 days. Infarct volumes were measured. A rotarod test and neurological deficit score assessment was performed to evaluate the neurological deficits. Oxidative stress was evaluated by measuring the levels of reactive oxygen species (ROS) and lipid peroxidation malondialdehyde (MDA), while the anti-oxidative stress status was assessed by measuring molecules such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidation enzyme (GSH-Px) in the ischemic cerebral hemisphere of mice. The inflammatory cytokines, including Interleukin 1 (IL-1), IL-6 and tumor necrosis factor alpha (TNF-α) were measured, and the expression of microglia was evaluated by immunohistochemistry in the ischemic cerebral hemisphere of mice. Galectin-1 treatment ameliorated neurological deficits and reduced infarct volumes in the mice model with cerebral I/R injury. Moreover, it was demonstrated that galectin-1 can significantly alleviate cerebral I/R injury in the ischemic cerebral hemisphere by decreasing the production of ROS and MDA, but increasing the production of CAT, SOD and GSH-Px. Galectin-1 treatment decreased microglia expression, and IL-1, IL-6 and TNF-α levels in the ischemic cerebral hemisphere of mice. Galectin-1 could improve the outcome of cerebral I/R injury by alleviating oxidative stress. Moreover, the neuroprotective effect of galectin-1 in cerebral ischemia could be related to its anti-oxidative stress effect.

Baseline levels of circulating galectin-1 associated with radiographic hand but not radiographic knee osteoarthritis at a two-year follow-up.

Objective: We tested the potential of circulating galectin-1, interleukin (IL)-1 beta, IL-6, and tumour necrosis factor alpha (TNF alpha) levels at baseline in individuals with knee pain as biomarkers for development of radiographic knee and/or hand osteoarthritis (OA). Design: This study comprised 212 individuals with knee pain from the Halland osteoarthritis cohort (HALLOA). Clinical characteristics and serum/plasma levels of galectin-1, IL-1 beta, IL-6, and TNF alpha were measured at baseline, and knee and hand radiographs were obtained at a two-year follow-up. The predictive value of circulating inflammatory markers and clinical variables at baseline was assessed using multinominal logistic regression for those who developed radiographic OA in knees only (n â€‹= â€‹25), in hands only (n â€‹= â€‹40), and in both knees and hands (n â€‹= â€‹43); the group who did not develop OA (n â€‹= â€‹104) was used as reference. Correlations were assessed using Spearman's correlation coefficients. Results: As expected, age was identified as a risk factor for having radiographic knee and/or hand OA at the two-year follow-up. Baseline circulating galectin-1 levels did not associate with developing radiographic knee OA but associated with developing radiographic hand OA (odds ratio (OR) for a 20% increased risk: 1.14, 95% confidence interval (CI) 1.01-1.29) and both radiographic knee and hand OA (OR for a 20% increased risk: 1.18, 95% CI 1.05-1.30). However, baseline IL-1 beta, IL-6, and TNF alpha did not associate with developing radiographic knee and/or hand OA. Conclusion: Non-age adjusted circulating galectin-1 is superior to IL-6, IL-1 beta, and TNF alpha in predicting radiographic hand but not knee OA.

Effect of galectin-1 on prognosis and responsiveness of immune checkpoint plus tyrosine kinase inhibition in renal cell carcinoma.

BACKGROUND: In renal cell carcinoma (RCC), no clinically available biomarker has been utilized for checkpoint inhibitor immunotherapy (IO) + tyrosine kinase inhibitor (TKI) combinations. Galectin-1 overexpression is found in tumors, with potential immune-regulating roles. METHODS: RNA-sequencing was performed in two cohorts of RCC treated with IO/TKI combination therapy (ZS-MRCC, JAVELIN-101). Immunohistochemistry and flow cytometry were performed to investigate immune cell infiltration and function in the tumor microenvironment of RCC. The RECIST criteria were used to define response and progression-free survival (PFS). RESULTS: Galectin-1 expression was elevated in RCC with higher stage (p < 0.001) and grade (p < 0.001). Galectin-1 expression was also elevated in non-responders of IO/TKI therapy (p = 0.047). High galectin-1 was related with shorter PFS in both ZS-MRCC cohort (p = 0.036) and JAVELIN-101 cohort (p = 0.005). Multivariate Cox analysis defined galectin-1 as an independent factor for PFS (HR 2.505; 95% CI 1.116-5.622; p = 0.026). In the tumor microenvironment, high galectin-1 was related with decreased GZMB+CD8+ T cells (Speraman's ρ = -0.31, p = 0.05), and increased PD1 + CD8+ T cells (Speraman's ρ = 0.40, p = 0.01). Besides, elevated number of regulatory T cells (p = 0.039) and fibroblasts (p = 0.011) was also found in high galectin-1 tumors. Finally, a random-forest score (RFscore) was built for predicting IO/TKI benefit. IO/TKI therapy showed benefit only in low-RFscore patients (HR 0.489, 95% CI 0.358-0.669, p < 0.001), rather than high-RFscore patients (HR 0.875, 95% CI 0.658-1.163, p = 0.357). CONCLUSIONS: High galectin-1 indicated therapeutic resistance and shorter PFS of IO/TKI therapy. High galectin-1 also indicated CD8+ T cell dysfunction. High galectin-1 could be applied for patient selection of IO/TKI therapy in RCC.

Galectin inhibitors and nanoparticles as a novel therapeutic strategy for glioblastoma multiforme.

Over the past two decades, the gold standard of glioblastoma multiforme (GBM) treatment is unchanged and adjunctive therapy has offered little to prolong both quality and quantity of life. To improve pharmacotherapy for GBM, galectins are being studied provided their positive correlation with the malignancy and disease severity. Despite the use of galectin inhibitors and literature displaying the ability of the lectin proteins to decrease tumor burden and decrease mortality within various malignancies, galectin inhibitors have not been studied for GBM therapy. Interestingly, anti-galectin siRNA delivered in nanoparticle capsules, assisting in blood brain barrier penetrance, is well studied for GBM, and has demonstrated a remarkable ability to attenuate both galectin and tumor count. Provided that the two therapies have an analogous anti-galectin effect, it is hypothesized that galectin inhibitors encapsuled within nanoparticles will likely have a similar anti-galectin effect in GBM cells and further correlate to a repressed tumor burden.

Serum Galectin-1, Galectin-9, and YKL-40 levels in bipolar disorder and their relationship with cognitive functions.

PURPOSE: The number of studies conducted on the role of neuroinflammation in the etiopathogenesis of bipolar disorder has been increasing in recent years. The role of Galectin-1, Galectin-9, and YKL-40, which are considered to play roles in neuroinflammation and the etiopathogenesis of bipolar disorder, and the relationship of these parameters with cognitive functions were investigated in the present study. METHOD: Serum Galectin-1, Galectin-9, and YKL-40 levels were measured with the ELISA Method in 64 bipolar euthymic patients and 64 healthy controls. The Stroop and trail-making tests were administered to assess cognitive functions in all participants. RESULTS: Serum Galectin-1, Galectin-9, and YKL-40 levels were statistically and significantly lower in the patient group when compared to the healthy control group. The scores of the Stroop test and trail-making tests were statistically higher in the patient group than in the healthy control group. There was a weak and positive correlation between serum Galectin-1, Galectin-9, and YKL-40 levels and cognitive performance in all participants. DISCUSSION AND CONCLUSION: Statistically significant low levels of serum Galectin-1, Galectin-9, and YKL-40 detected in the patient group suggest that these parameters have important roles in neuroinflammation. The statistically higher Stroop and trail-making test scores of the patient group compared to the control group indicates that the cognitive performance of the patient group was weaker. Also, the positive correlation between Galectin-1, Galectin-9, and YKL-40 levels and cognitive performance suggests that these molecules may have a neuroprotective role. We think that the present study will contribute to this field where there is very limited data in the literature.