Pectin: Health-promoting properties as a natural galectin-3 inhibitor.

Galectin-3 has a variety of important pathophysiological significance in the human body. Much evidence shows that the abnormal expression of galectin-3 is related to the formation and development of many diseases. Pectin is mostly obtained from processed citrus fruits and apples and is a known natural inhibitor of galactin-3. A large number of peels produced each year are discarded, and it is necessary to recycle some of the economically valuable active compounds in these by-products to reduce resource waste and environmental pollution. By binding with galectin-3, pectin can directly reduce the expression level of galectin-3 on the one hand, and regulate the expression level of cytokines by regulating certain signaling pathways on the other hand, to achieve the effect of treating diseases. This paper begins by presenting an overview of the basic structure of pectin, subsequently followed by a description of the structure of galectin-3 and its detrimental impact on human health when expressed abnormally. The health effects of pectin as a galectin-3 inhibitor were then summarized from the perspectives of anticancer, anti-inflammatory, ameliorating fibrotic diseases, and anti-diabetes. Finally, the challenges and prospects of future research on pectin are presented, which provide important references for expanding the application of pectin in the pharmaceutical industry or developing functional dietary supplements.

Effect of modified citrus pectin on galectin-3 inhibition in cisplatin-induced cardiac and renal toxicity.

This study evaluated the effect of pharmacological inhibition of galectin 3 (Gal-3) with modified citrus pectin (MCP) on the heart and kidney in a model of cisplatin-induced acute toxicity. Male Wistar rats were divided into four groups (n = 6/group): SHAM, which received sterile saline intraperitoneally (i.p.) for three days; CIS, which received cisplatin i.p. (10 mg/kg/day) for three days; MCP, which received MCP orally (100 mg/kg/day) for seven days, followed by sterile saline i.p. for three days; MCP+CIS, which received MCP orally for seven days followed by cisplatin i.p. for three days. The blood, heart, and kidneys were collected six hours after the last treatment. MCP treatment did not change Gal-3 protein levels in the blood and heart, but it did reduce them in the kidneys of the MCP groups compared to the SHAM group. While no morphological changes were evident in the cardiac tissue, increased malondialdehyde (MDA) levels and deregulation of the mitochondrial oxidative phosphorylation system were observed in the heart homogenates of the MCP+CIS group. Cisplatin administration caused acute tubular degeneration in the kidneys; the MCP+CIS group also showed increased MDA levels. In conclusion, MCP therapy in the acute model of cisplatin-induced toxicity increases oxidative stress in cardiac and renal tissues. Further investigations are needed to determine the beneficial and harmful roles of Gal-3 in the cardiorenal system since it can act differently in acute and chronic diseases/conditions.

Identification of benzothiazole derived monosaccharides as potent, selective, and orally bioavailable inhibitors of human and mouse galectin-3; a rare example of using a S···O binding interaction for drug design.

As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.

Saturation Transfer Difference NMR and Molecular Docking Interaction Study of Aralkyl-Thiodigalactosides as Potential Inhibitors of the Human-Galectin-3 Protein.

Human Galectin-3 (hGal-3) is a protein that selectively binds to ß-galactosides and holds diverse roles in both normal and pathological circumstances. Therefore, targeting hGal-3 has become a vibrant area of research in the pharmaceutical chemistry. As a step towards the development of novel hGal-3 inhibitors, we synthesized and investigated derivatives of thiodigalactoside (TDG) modified with different aromatic substituents. Specifically, we describe a high-yielding synthetic route of thiodigalactoside (TDG); an optimized procedure for the synthesis of the novel 3,3'-di-O-(quinoline-2-yl)methyl)-TDG and three other known, symmetric 3,3'-di-O-TDG derivatives ((naphthalene-2yl)methyl, benzyl, (7-methoxy-2H-1-benzopyran-2-on-4-yl)methyl). In the present study, using competition Saturation Transfer Difference (STD) NMR spectroscopy, we determined the dissociation constant (Kd) of the former three TDG derivatives produced to characterize the strength of the interaction with the target protein (hGal-3). Based on the Kd values determined, the (naphthalen-2-yl)methyl, the (quinolin-2-yl)methyl and the benzyl derivatives bind to hGal-3 94, 30 and 24 times more strongly than TDG. Then, we studied the binding modes of the derivatives in silico by molecular docking calculations. Docking poses similar to the canonical binding modes of well-known hGal-3 inhibitors have been found. However, additional binding forces, cation-π interactions between the arginine residues in the binding pocket of the protein and the aromatic groups of the ligands, have been established as significant features. Our results offer a molecular-level understanding of the varying affinities observed among the synthesized thiodigalactoside derivatives, which can be a key aspect in the future development of more effective ligands of hGal-3.

Inhibition of galectin-3 post-infarction impedes progressive fibrosis by regulating inflammatory profibrotic cascades.

AIMS: Acute myocardial infarction (MI) causes inflammation, collagen deposition, and reparative fibrosis in response to myocyte death and, subsequently, a pathological myocardial remodelling process characterized by excessive interstitial fibrosis, driving heart failure (HF). Nonetheless, how or when to limit excessive fibrosis for therapeutic purposes remains uncertain. Galectin-3, a major mediator of organ fibrosis, promotes cardiac fibrosis and remodelling. We performed a preclinical assessment of a protein inhibitor of galectin-3 (its C-terminal domain, Gal-3C) to limit excessive fibrosis resulting from MI and prevent ventricular enlargement and HF. METHODS AND RESULTS: Gal-3C was produced by enzymatic cleavage of full-length galectin-3 or by direct expression of the truncated form in Escherichia coli. Gal-3C was intravenously administered for 7 days in acute MI models of young and aged rats, starting either pre-MI or 4 days post-MI. Echocardiography, haemodynamics, histology, and molecular and cellular analyses were performed to assess post-MI cardiac functionality and pathological fibrotic progression. Gal-3C profoundly benefitted left ventricular ejection fraction, end-systolic and end-diastolic volumes, haemodynamic parameters, infarct scar size, and interstitial fibrosis, with better therapeutic efficacy than losartan and spironolactone monotherapies over the 56-day study. Gal-3C therapy in post-MI aged rats substantially improved pump function and attenuated ventricular dilation, preventing progressive HF. Gal-3C in vitro treatment of M2-polarized macrophage-like cells reduced their M2-phenotypic expression of arginase-1 and interleukin-10. Gal-3C inhibited M2 polarization of cardiac macrophages during reparative response post-MI. Gal-3C impeded progressive fibrosis post-MI by down-regulating galectin-3-mediated profibrotic signalling cascades including a reduction in endogenous arginase-1 and inducible nitric oxide synthase (iNOS). CONCLUSION: Gal-3C treatment improved long-term cardiac function post-MI by reduction in the wound-healing response, and inhibition of inflammatory fibrogenic signalling to avert an augmentation of fibrosis in the periinfarct region. Thus, Gal-3C treatment prevented the infarcted heart from extensive fibrosis that accelerates the development of HF, providing a potential targeted therapy.

Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants.

PURPOSE: Galectin-3, a ß-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1211 in healthy participants. METHODS: This phase 1, double-blind, placebo-controlled, first-in-human study (NCT03809052) included a single ascending-dose phase (with a food-effect cohort) where participants across seven sequential cohorts were randomized 3:1 to receive oral GB1211 (5, 20, 50, 100, 200 or 400 mg) or placebo. In the multiple ascending-dose phase, participants received 50 or 100 mg GB1211 or placebo twice daily for 10 days. All doses were administered in the fasted state except in the food-effect cohort where doses were given 30 min after a high-fat meal. RESULTS: All 78 participants received at least one GB1211 dose (n = 58) or placebo (n = 20) and completed the study. No safety concerns were identified. Following single and multiple oral doses under fasted conditions, maximum GB1211 plasma concentrations were reached at 1.75-4 h (median) post-dose; mean half-life was 11-16 h. There was a ~ twofold GB1211 accumulation in plasma with multiple dosing, with steady-state reached within 3 days; 30% of the administered dose was excreted in urine as unchanged drug. Absorption in the fed state was delayed by 2 h but systemic exposure was unaffected. CONCLUSION: GB1211 was well tolerated, rapidly absorbed, and displayed favorable PK, indicating a potential to treat multiple disease types. These findings support further clinical development of GB1211. CLINICAL TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifier: NCT03809052).

Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration.

BACKGROUND: Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a ß-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. METHODS: Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and Cx3cr1GFP/+ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and Cx3cr1GFP/+ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. RESULTS: We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. CONCLUSION: This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies.

Novel Selective Galectin-3 Antagonists Are Cytotoxic to Acute Lymphoblastic Leukemia.

Galectin-3 is a ß-galactoside-specific, carbohydrate-recognizing protein (lectin) that is strongly implicated in cancer development, metastasis, and drug resistance. Galectin-3 promotes migration and ability to withstand drug treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. Due to high amino acid conservation among galectins and the shallow nature of their glycan-binding site, the design of selective potent antagonists targeting galectin-3 is challenging. Herein, we report the design and synthesis of novel taloside-based antagonists of galectin-3 with enhanced affinity and selectivity. The molecules were optimized by in silico docking, selectivity was established against four galectins, and the binding modes were confirmed by elucidation of X-ray crystal structures. Critically, the specific inhibition of galectin-3-induced BCP-ALL cell agglutination was demonstrated. The compounds decreased the viability of ALL cells even when grown in the presence of protective stromal cells. We conclude that these compounds are promising leads for therapeutics, targeting the tumor-supportive activities of galectin-3 in cancer.

Pectic polysaccharide from Smilax china L. ameliorated ulcerative colitis by inhibiting the galectin-3/NLRP3 inflammasome pathway.

Ulcerative colitis (UC) is an inflammatory bowel disease that affects the colon and rectum. Although galectin-3 (Gal-3) has been reported to play a proinflammatory role in UC, it is unknown whether pectic polysaccharide, a Gal-3 inhibitor in tumor metastasis, can alleviate UC by inhibiting Gal-3. The aim of this study was to investigate the anti-inflammatory effects and underlying mechanisms of SCLP, a pectic polysaccharide purified from Smilax china L. in our previous work, on dextran sulfate sodium-induced UC in BALB/c mice. The results showed that SCLP could significantly improve symptoms, alleviate histopathological damage and reduce the secretion of inflammatory mediators in mice with UC. Analysis of the anti-colitis mechanisms indicated that SCLP could inhibit the Gal-3/NLRP3 inflammasome/IL-1ß pathway by suppressing the expression of Gal-3 and the interaction of Gal-3 and NLRP3. Our results suggested that SCLP could be a promising candidate for prevention and treatment of UC.

Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia.

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.

Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors.

Galectin-3 is a member of a family of ß-galactoside-binding proteins. A substantial body of literature reports that galectin-3 plays important roles in cancer, inflammation, and fibrosis. Small-molecule galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent galectin-3 inhibitors. Compounds 36, 40, and 45 were selected for further in vivo evaluation. The synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based galectin-3 inhibitors are described.

Galectin­3 facilitates the proliferation and migration of nasopharyngeal carcinoma cells via activation of the ERK1/2 and Akt signaling pathways, and is positively correlated with the inflammatory state of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial carcinoma originating from the nasopharyngeal mucosal tissue and is highly prevalent in southeast Asia. Galectin­3 (gal­3) serves crucial roles in many cancers but its role in NPC remains to be elucidated. The aim of the present study was to investigate the role of gal­3 in NPC. Immunohistochemistry and ELISA were used to determine the expression level of gal­3 in patients with NPC or chronic rhinitis (CR). Gal­3 short hairpin (sh)RNA was established to knockdown gal­3 in 5­8F and 6­10B cells, allowing for the evaluation of the roles of gal­3 in proliferation, migration and apoptosis in NPC cell lines. Immunohistochemistry staining of IL­6 and IL­8 was applied to access the inflammatory state of tumor tissues, and the correlation between the inflammatory state and gal­3 was analyzed. The results demonstrated that gal­3 was upregulated in patients with NPC compared with patients with CR. Knockdown of gal­3 inhibited proliferation and migration in 5­8F and 6­10B cells, as well as promoted apoptosis in these cells. The expression levels of MMP­9 and IL­8 were also decreased in 5­8F and 6­10B cells after transfection with gal­3 shRNA. A positive correlation was identified between the expression level of gal­3 and the inflammatory state of NPC. The phosphorylation levels of ERK1/2 and Akt were downregulated after knockdown of gal­3 in 5­8F and 6­10B cells. In conclusion, the expression level of gal­3 was upregulated in patients with NPC and was positively correlated with the inflammatory state of NPC. The results suggested that gal­3 promoted the proliferation and migration of 5­8F and 6­10B cells, while inhibiting the apoptosis of these cells. Moreover, activation of ERK1/2 and Akt may be the underlying mechanism of the effects of gal­3 on NPC.

Galectin-3 in T cell-mediated immunopathology and autoimmunity.

Galectin-3 (Gal-3) is the only member of galectin family able to form pentamers and heterodimers with chemokines. Its presence in various cells and tissues suggests variety of regulatory functions in physiological conditions, but increasing body of evidence indicates involvement of Gal-3 in pathological cascades of many diseases. Gal-3 exerts different, sometimes opposite, effects in various disorders or in different phases of the same disease. These differences in action of Gal-3 are related to the localization of Gal-3 in the cell, types of receptors through which it acts, or the types of cells that secrete it. As a regulator of immune response and T-cell activity, Gal-3 appears to have important role in development of autoimmunity mediated by T cells. Absence of Gal-3 in C57Bl6 mice favors Th2 mediated inflammatory myocarditis but attenuate fibrosis. Recent data also indicate Gal-3 involvement in development atherosclerosis. In pathogenesis of diabetes type 1 and autoimmune components of diabetes type 2 Gal-3 may have detrimental or protective role depending on its intracellular or extracellular localization. Gal-3 mediates autoimmune hepatic damage through activation of T-cells or natural killer T cells. Gal-3 is an important mediator in neurodevelopment, neuropathology and behavior due to its expression both in neurons and glial cells. All together, assessing the role of Gal-3 in immunopathology and autoimmunity it could be concluded that it is an important participant in pathogenesis, as well as promising monitoring marker and therapeutic target.

Inhibition of galectin-3 augments the antitumor efficacy of PD-L1 blockade in non-small-cell lung cancer.

Multiple clinical trials have shown that monoclonal antibodies (mAbs) against programmed death-ligand 1 (PD-1/PD-L1) can benefit patients with lung cancer by increasing their progression-free survival and overall survival. However, a significant proportion of patients do not respond to anti-PD-1/PD-L1 mAbs. In the present study, we investigated whether galectin (Gal)-3 inhibitors can enhance the antitumor effect of PD-L1 blockade. Using the NSCLC-derived cell line A549, we examined the expression of Gal-3 in lung cancer cells under hypoxic conditions and investigated the regulatory effect of Gal-3 on PD-L1 expression, which is mediated by the STAT3 pathway. We also explored whether Gal-3 inhibition can facilitate the cytotoxic effect of T cells induced by PD-L1 blockade. The effects of combined use of a Gal-3 inhibitor and PD-L1 blockade on tumor growth and T-cell function were also investigated, and we found that hypoxia increased the expression and secretion of Gal-3 by lung cancer cells. Gal-3 increased PD-L1 expression via the upregulation of STAT3 phosphorylation, and administration of a Gal-3 inhibitor enhanced the effect of PD-L1 blockade on the cytotoxic activity of T cells against cancer cells in vitro. In a mouse xenograft model, the combination of a Gal-3 inhibitor and PD-L1 blockade synergistically suppressed tumor growth. Furthermore, the administration of a Gal-3 inhibitor enhanced T-cell infiltration and granzyme B release in tumors. Collectively, our results show that Gal-3 increases PD-L1 expression in lung cancer cells and that the administration of a Gal-3 inhibitor as an adjuvant enhanced the antitumor activity of PD-L1 blockade.

Galectin-3 mediates cardiac remodeling caused by impaired glucose and lipid metabolism through inhibiting two pathways of activating Akt.

Pathological cardiac remodeling is a leading cause of mortality in patients with diabetes. Given the glucose and lipid metabolism disorders (GLDs) in patients with diabetes, it is urgent to conduct a comprehensive study of the myocardial damage under GLDs and find key mechanisms. Apolipoprotein E knockout (ApoE-/-) mice, low-density lipoprotein receptor heterozygote (Ldlr+/-) Syrian golden hamsters, or H9C2 cells were used to construct GLDs models. GLDs significantly promoted cardiomyocyte fibrosis, apoptosis, and hypertrophy in vivo and in vitro, but inhibition of galectin-3 (Gal-3) could significantly reverse this process. Then, the signal transmission pathways were determined. It was found that GLDs considerably inhibited the phosphorylation of Akt at Thr308/Ser473, whereas the silencing of Gal-3 could reverse the inhibition of Akt activity through phosphoinositide 3-kinase-AktThr308 (PI3K-AktThr308) and AMP-activated protein kinase-mammalian target of rapamycin complex 2-AktSer473 (AMPK-mTOR2-AktSer473) pathways. Finally, the PI3K, mTOR, AMPK inhibitor, and Akt activator were used to investigate the role of pathways in regulating cardiac remodeling. Phospho-AktThr308 could mediate myocardial fibrosis, whereas myocardial apoptosis and hypertrophy were regulated by both phospho-AktThr308 and phospho-AktSer473. In conclusion, Gal-3 was an important regulatory factor in GLDs-induced cardiac remodeling, and Gal-3 could suppress the phosphorylation of Akt at different sites in mediating cardiomyocyte fibrosis, apoptosis, and hypertrophy.NEW & NOTEWORTHY Studies on the pathogenesis of diabetic cardiac remodeling are highly desired. Glucose and lipid metabolism are both disordered in diabetes. Glucose and lipid metabolism disturbances promote myocardial fibrosis, apoptosis, and hypertrophy through galectin-3. Galectin-3 promotes cardiac remodeling by inhibiting phosphorylation of AktThr308 or AktSer473. The present study finds that glucose and lipid metabolism disorders are important causes for myocardial damage and provides novel ideas for the prevention and treatment of diabetic cardiac remodeling.

Combining inhibition of galectin-3 with and before a therapeutic vaccination is critical for the prostate-tumor-free outcome.

BACKGROUND: Prostate cancer (PCa) is a major health problem worldwide. Taxol derivatives-based chemotherapies or immunotherapies are usually proposed depending on the symptomatic status of the patient. In the case of immunotherapy, tumors develop robust immune escape mechanisms that abolish any protective response, and to date why prostate cancer is one of the most resistant diseases remains unresolved. METHODS: By using a combination of clinical data to study the transcriptome of metastasis samples from patients with castration-refractory prostate cancer, and state of the art cellular and molecular biology assays in samples from tumor-bearing mice that have been submitted to surgical resection of the tumor before receiving a vaccination, we answered several essential questions in the field of immunotherapy for prostate cancer. We also used two different methods to inhibit the expression of galectin-3 (Gal-3) in tumor cells: a stable RNA interference method to control the expression of this galectin efficiently only in tumor cells, and low and non-cytotoxic doses of docetaxel to easily transfer our findings to clinical settings. RESULTS: Herein, we show for the first time that Gal-3 expressed by prostate tumor cells is the main immune checkpoint responsible for the failure of vaccine-based immunotherapy. Our results show that low and non-cytotoxic doses of docetaxel lead to the inhibition of Gal-3 expression in PCa cells as well as in clinical samples of patients with metastatic and castration-resistant PCa promoting a Th1 response. We thus optimized a prostate cancer animal model that undergoes surgical resection of the tumor to mimic prostatectomy usually performed in patients. Importantly, using Gal-3-knocked down-PCa cells or low and non-cytotoxic doses of taxane before vaccination, we were able to highly control tumor recurrence through a direct impact on the proliferation and infiltration of CD8+ cytotoxic T. CONCLUSIONS: Thus, Gal-3 expression by PCa cells is a crucial inhibitor for the success of immunotherapy, and low doses of docetaxel with non-cytotoxic effect on leukocyte survival could be used before immunotherapy for all patients with PCa to reduce the expression of this critical negative immune checkpoint, pre-conditioning the tumor-microenvironment to activate an antitumor immune response and promote tumor-free outcome.

The purification of pectin from commercial fruit flours results in a jaboticaba fraction that inhibits galectin-3 and colon cancer cell growth.

Fruits are a prime source of nutrients, bioactive compounds, and dietary fibers. Some products available on the Brazilian market use fruit by-products and claim to have useful effects on human health due to their dietary fiber content. The study aimed to extract and purify the total (28-47 w/w yield) and soluble dietary fiber (4-7 w/w yield) from jaboticaba, papaya, and plum commercial flours sold in Brazil and to study the in vitro biological effects of the fractions. The purified water-soluble fractions consisted mainly of pectin-derived oligosaccharides (5-15 KDa molecular weight) with a negligible content of polyphenols, protein, ashes, and starch. Jaboticaba sample was 95% galacturonic acid while plum and papaya samples were 40% galacturonic acid and 40% galactose (mol%), approximately. The samples were tested for recombinant human galectin-3 inhibition and changes in the cell viability of human colorectal cancer cells. Only the jaboticaba sample inhibited galectin-3 and decreased HCT116 cell viability after 48 h of treatment (p ≤ 0.01) while the plum sample decreased the cell viability after 24 h treatment (p ≤ 0.05). The results obtained in this study demonstrate the relationship between the structure of the soluble fibers extracted from jaboticaba flour and the possible beneficial effects of their consumption.

Roles of galectin­3 in the tumor microenvironment and tumor metabolism (Review).

Galectin­3 is expressed in various tissues and plays an important role in the tumor microenvironment (TME). Galectin­3 has been found to be overexpressed in a variety of cancers and is associated with tumor progression and metastasis. Over the past decades, emerging evidence has suggested that the TME may induce galectin­3 expression to maintain cellular homeostasis and promote cell survival. Furthermore, galectin­3 regulates immune cell function to promote tumor­driven immunosuppression through several mechanisms. In the TME, intracellular and extracellular galectin­3 has different functions. In addition, it has been reported that galectin­3 is associated with glycolysis and mitochondrial metabolism in tumors, and it is involved in the regulation of relevant signaling pathways, thus promoting cancer cell survival via adapting to the TME. The aim of the present review was to summarize the current knowledge on galectin­3 production and its function in the TME, its effect on TME immunosuppression, its association with tumor metabolism and relevant signaling pathways, and to report common types of cancer in which galectin­3 is highly expressed, in order to ensure a comprehensive understanding of the critical effects of galectin­3 on tumor progression and metastasis.

Hyperinflammation and Fibrosis in Severe COVID-19 Patients: Galectin-3, a Target Molecule to Consider.

COVID-19 disease have become so far the most important sanitary crisis in the XXI century. In light of the events, any clinical resource should be considered to alleviate this crisis. Severe COVID-19 cases present a so-called cytokine storm as the most life-threatening symptom accompanied by lung fibrosis. Galectin-3 has been widely described as regulator of both processes. Hereby, we present compelling evidences on the potential role of galectin-3 in COVID-19 in the regulation of the inflammatory response, fibrosis and infection progression. Moreover, we provide a strong rationale of the utility of measuring plasma galectin-3 as a prognosis biomarker for COVID-19 patients and propose that inhibition of galectin-3 represents a feasible and promising new therapeutical approach.

Secretory galectin-3 induced by glucocorticoid stress triggers stemness exhaustion of hepatic progenitor cells.

Adult progenitor cell populations typically exist in a quiescent state within a controlled niche environment. However, various stresses or forms of damage can disrupt this state, which often leads to dysfunction and aging. We built a glucocorticoid (GC)-induced liver damage model of mice, found that GC stress induced liver damage, leading to consequences for progenitor cells expansion. However, the mechanisms by which niche factors cause progenitor cells proliferation are largely unknown. We demonstrate that, within the liver progenitor cells niche, Galectin-3 (Gal-3) is responsible for driving a subset of progenitor cells to break quiescence. We show that GC stress causes aging of the niche, which induces the up-regulation of Gal-3. The increased Gal-3 population increasingly interacts with the progenitor cell marker CD133, which triggers focal adhesion kinase (FAK)/AMP-activated kinase (AMPK) signaling. This results in the loss of quiescence and leads to the eventual stemness exhaustion of progenitor cells. Conversely, blocking Gal-3 with the inhibitor TD139 prevents the loss of stemness and improves liver function. These experiments identify a stress-dependent change in progenitor cell niche that directly influence liver progenitor cell quiescence and function.