Galectin-7 promotes cisplatin efficacy by facilitating apoptosis and G3BP1 degradation in cervical cancer.

The emergence of chemoresistance in cervical cancer is extremely challenging in chemotherapy. Oxidative stress has emerged as the regulatory factor in drug resistance, but the detailed mechanism is still unknown. Stress granules, are membrane-less ribonucleoprotein-based condensates, could enhance chemoresistance by sequestering proapoptotic proteins inhibition of cell death upon exposure to drug-induced oxidative stress. Galectin-7, a member of galectin family, exerts varied roles in tumor repression or progression in different cancers. However, its role in cervical cancer has not been sufficiently studied. Here, we found that galectin-7 promotes cisplatin (CDDP) induced apoptosis and associates with stress granule-nucleating protein G3BP1 degradation. With the treatment of cisplatin, galectin-7 could enhance apoptosis by upregulating cleaved-PARP1 and the generation of reactive oxygen species (ROS), promoting mitochondrial fission, and reducing mitochondrial membrane potential (MMP). Furthermore, galectin-7 also reduces resistance by facilitating cisplatin-induced stress granules clearance through galectin-7/RACK1/G3BP1 axis. All these data suggested that galectin-7 promotes cisplatin sensitivity, and it would be potential target for potentiating efficacy in cervical cancer chemotherapy.

In vitro evaluation of the effect of galectins on Schistosoma mansoni motility.

OBJECTIVE: Galectins are sugar-binding proteins that participate in many biological processes, such as immunity, by regulating host immune cells and their direct interaction with pathogens. They are involved in mediating infection by Schistosoma mansoni, a parasitic trematode that causes schistosomiasis. However, their direct effects on schistosomes have not been investigated. RESULTS: We found that galectin-2 recognizes S. mansoni glycoconjugates and investigated whether galectin-1, 2, and 3 can directly affect S. mansoni in vitro. Adult S. mansoni were treated with recombinant galectin-1, 2, and 3 proteins or praziquantel, a positive control. Treatment with galectin-1, 2, and 3 had no significant effect on S. mansoni motility, and no other differences were observed under a stereoscopic microscope. Hence, galectin-1, 2, and 3 may have a little direct effect on S. mansoni. However, they might play a role in the infection in vivo via the modulation of the host immune response or secretory molecules from S. mansoni. To the best of our knowledge, this is the first study to investigate the direct effect of galectins on S. mansoni and helps in understanding the roles of galectins in S. mansoni infection in vivo.

Antitumor Effect of Galectin-9 on Cell Proliferation and Tumor Growth of Human Duodenal Adenocarcinoma Cells.

BACKGROUND/AIM: Galectin-9 (Gal-9) induces tumor cell apoptosis in lymphoma and other malignant cell types. Duodenal adenocarcinoma is a rare malignancy, and there are insufficient data to determine a standard therapeutic approach. Here, we investigated the antitumor effect of Gal-9 in HuTu-80 duodenal adenocarcinoma cells. MATERIALS AND METHODS: Cell proliferation was examined in HuTu-80 cells using a Cell Counting Kit-8 assay. Cell cycle analysis, apoptosis array, and microRNA expression analysis were performed to identify the effect of Gal-9 on HuTu-80 cells. The antitumor effect of Gal-9 was also examined using xenograft mouse models. RESULTS: Gal-9 suppressed the proliferation of HuTu-80 via blockade of the G0 to G1 cell cycle transition. This blockade was accompanied by a strong decrease in cyclin D1 and phosphorylated Rb, suggesting a G1 arrest. Additionally, Gal-9 induced apoptosis, and the expression of cleaved caspase-3 was increased in Gal-9-treated HuTu-80 cells according to the apoptosis array. MiRNA microarrays revealed that Gal-9 altered the expression of miRNAs in HuTu-80 cells. CONCLUSION: These data demonstrate the therapeutic potential of Gal-9 and provide molecular mechanistic insights into its antitumor effect in HuTu-80 cells.

Immune checkpoint molecule Tim-3 promotes NKT cell apoptosis and predicts poorer prognosis in Sepsis.

BACKGROUND: Sepsis is a leading cause of death among critically ill patients, which is defined as life-threatening organ dysfunction caused by a deregulated host immune response to infection. Immune checkpoint molecule Tim-3 plays important and complex roles in regulating immune responses and in inducing immune tolerance. Although immune checkpoint blockade would be expected as a promising therapeutic strategy for sepsis, but the underlying mechanism remain unknown, especially under clinical conditions. METHODS: Tim-3 expression and apoptosis in NKT cells were compared in septic patients (27 patients with sepsis and 28 patients with septic shock). Phenotypic and functional characterization of Tim-3+ NKT cells were analysed, and then the relationship between Tim-3 + NKT cells and clinical prognosis were investigated in septic patients. α-lactose (Tim-3/Galectin-9 signalling inhibitor) and Tim-3 mutant mice (targeting mutation of the Tim-3 cytoplasmic domain) were utilized to evaluate the protective effect of Tim-3 signalling blockade following septic challenge. RESULTS: There is a close correlation between Tim-3 expression and the functional status of NKT cells in septic patients, Upregulated Tim-3 expression promoted NKT cell activation and apoptosis during the early stage of sepsis, and it was associated with worse disease severity and poorer prognosis in septic patients. Blockade of the Tim-3/Galectin-9 signal axis using α-lactose inhibited in vitro apoptosis of NKT cells isolated from septic patients. Impaired activity of Tim-3 protected mice following septic challenge. CONCLUSIONS: Overall, these findings demonstrated that immune checkpoint molecule Tim-3 in NKT cells plays a critical role in the immunopathogenesis of septic patients. Blockade of immune checkpoint molecule Tim-3 may be a promising immunomodulatory strategy in future clinical practice for the management of sepsis.

Galectin-8 involves in arthritic condylar bone loss via podoplanin/AKT/ERK axis-mediated inflammatory lymphangiogenesis.

OBJECTIVE: The lymphatic system plays a crucial role in the maintenance of tissue fluid homeostasis and the immunological response to inflammation. Galectin-8 (Gal-8) regulates pathological lymphangiogenesis but the effects of which on inflammation-related condylar bone loss in temporomandibular joint (TMJ) have not been well studied. DESIGN: We used TNFα-transgenic (TNFTG) mice and their wildtype (WT) littermates to compare their inflammatory phenotype in TMJs. Next, lymphatic endothelial cells (LECs) were used to examine the effects of which on osteoclast formation, pro-inflammatory factor expression, and inflammatory lymphangiogenesis with or without thiodigalactoside (TDG, a Gal-8 inhibitor) treatment. At last, two murine models (TNFTG arthritic model and forced mouth opening model) were used to explore TDG as a potential drug for the treatment of inflammation-related condylar bone loss. RESULTS: In comparison to WT mice, lymphatic areas of lymphatic vessel endothelial receptor 1 (LYVE1)+/podoplanin (PDPN)+ and Gal-8+/PDPN+, TRAP-positive osteoclast number, and condylar bone loss are increased in TNFTG mice. Inhibition of Gal-8 in LECs by TDG, reduces TNFα-induced osteoclast formation, pro-inflammatory factor expression, and inflammatory lymphangiogenesis. In addition, Gal-8 promotes TNFα-activated AKT/ERK/NF-κB pathways by binding to PDPN. Finally, the administration of TDG attenuates inflammatory lymphangiogenesis, inhibits osteoclast activity, and reduces condylar bone loss in TNFTG arthritic mice and forced mouth opening mice. CONCLUSIONS: Our findings reveal the important role of Gal-8-promoted pathological lymphangiogenesis in inflammation-related condylar bone loss.

Regulation of wound healing and fibrosis by galectins.

Galectins are a family of proteins with at least one carbohydrate-recognition domain. Galectins are present in various tissues and organs and participate in different physiological and pathological molecular reactions in vivo. Wound healing is the basic process of traumatic disease recovery. Wound healing involves three overlapping stages: inflammation, proliferation, and remodelling. Furthermore, a comparison of wound healing with the tumour microenvironment revealed that galectin plays a key role in the wound healing process. The current review describes the role of galectin in inflammation, angiogenesis, re-epithelialisation, and fibrous scar formation and evaluates its potential as a therapeutic drug for wounds.

Modulation of the Epithelial-Immune Cell Crosstalk and Related Galectin Secretion by DP3-5 Galacto-Oligosaccharides and ß-3'Galactosyllactose.

Prebiotic galacto-oligosaccharides (GOS) were shown to support mucosal immune development by enhancing regulatory-type Th1 immune polarization induced by synthetic CpG oligodeoxynucleotides (TLR9 agonist mimicking a bacterial DNA trigger). Epithelial-derived galectin-9 was associated with these immunomodulatory effects. We aimed to identify the most active fractions within GOS based on the degree of polymerization (DP), and to study the immunomodulatory capacities of DP3-sized ß-3'galactosyllactose (ß-3'GL) using a transwell co-culture model of human intestinal epithelial cells (IEC) and activated peripheral blood mononuclear cells (PBMC). IEC were apically exposed to different DP fractions of GOS or ß-3'GL in the presence of CpG, and basolaterally co-cultured with αCD3/CD28-activated PBMC, washed, and incubated in fresh medium for IEC-derived galectin analysis. Only DP3-5 in the presence of CpG enhanced galectin-9 secretion. DP3-sized ß-3'GL promoted a regulatory-type Th1 response by increasing IFNγ and IL-10 or galectin-9 concentrations as compared to CpG alone. In addition, IEC-derived galectin-3, -4, and -9 secretion was increased by ß-3'GL when combined with CpG. Therefore, the GOS DP3-5 and most effectively DP3-sized ß-3'GL supported the immunomodulatory properties induced by CpG by enhancing epithelial-derived galectin secretion, which, in turn, could support mucosal immunity.

Detection of Reactive Oxygen Species in Human Neutrophils Under Various Conditions of Exposure to Galectin.

Reactive oxygen species (ROS) have been extensively studied in biology in the past years. This class of molecules can be derived from endogenous sources (e.g., phagocytic cells as neutrophils, eosinophils, monocytes, macrophages, and organelles as mitochondria and peroxisomes) and participate in physiological and pathological conditions. The beneficial and harmful effects of ROS depend on redox regulation, which establishes the balance between their production and the activity of antioxidant systems to prevent oxidative stress in vivo. Neutrophils are the immune effectors most well depicted with an intense oxidative burst in response to tissue inflammation. Several proteins and members of the galectin family are involved in this fine modulation of ROS production by neutrophils. Interestingly, studies have indicated that Galectin-1 (Gal-1) can up- or downregulate ROS production by neutrophils even when exposed to N-formyl-Met-Leu-Phe (fMLP) or Phorbol Myristate Acetate (PMA), both of which are potent neutrophil stimulants that trigger high levels of ROS production. Similarly, Galectin-3 (Gal-3) induces ROS in neutrophils from a sterile or nonsterile inflammatory environment, possibly creating a negative loop that could control ROS production. Besides, superoxide production is also induced by Galectin-8 (Gal-8) and Galectin-9 (Gal-9) in neutrophils but in a different manner. We describe herein the luminol and lucigenin-dependent chemiluminescence technique by using a luminometer as a method of assessment to measure ROS production by human neutrophils isolated and exposed to purified human recombinant Gal-1. The protocol described herein could be applied for the investigation of the role of other galectins in the modulation of ROS production by neutrophils.

Methods for Assessing the Effects of Galectins on Leukocyte Trafficking and Clearance.

Numerous protocols exist for investigating leukocyte recruitment and clearance both in vitro and in vivo. Here we describe an in vitro flow chamber assay typically used for studying the mechanisms underpinning leukocyte movement through the endothelium and zymosan-induced peritonitis, an acute in vivo model of inflammation that enables both leukocyte trafficking and clearance to be monitored. Insight is given as to how these models can be used to study the actions of galectins on the inflammatory process.

Galectin-9 restricts hepatitis B virus replication via p62/SQSTM1-mediated selective autophagy of viral core proteins.

Autophagy has been linked to a wide range of functions, including a degradative process that defends host cells against pathogens. Although the involvement of autophagy in HBV infection has become apparent, it remains unknown whether selective autophagy plays a critical role in HBV restriction. Here, we report that a member of the galectin family, GAL9, directs the autophagic degradation of HBV HBc. BRET screening revealed that GAL9 interacts with HBc in living cells. Ectopic expression of GAL9 induces the formation of HBc-containing cytoplasmic puncta through interaction with another antiviral factor viperin, which co-localized with the autophagosome marker LC3. Mechanistically, GAL9 associates with HBc via viperin at the cytoplasmic puncta and enhanced the auto-ubiquitination of RNF13, resulting in p62 recruitment to form LC3-positive autophagosomes. Notably, both GAL9 and viperin are type I IFN-stimulated genes that act synergistically for the IFN-dependent proteolysis of HBc in HBV-infected hepatocytes. Collectively, these results reveal a previously undescribed antiviral mechanism against HBV in infected cells and a form of crosstalk between the innate immune system and selective autophagy in viral infection.

Coprinopsis cinerea Galectin CGL1 Induces Apoptosis and Inhibits Tumor Growth in Colorectal Cancer Cells.

Mushroom galectins are promising anticancer agents for their low IC50 values against cancer cells in vitro. In this study, two Coprinopsis cinerea galectins, CGL1 and CGL2, were heterologously expressed, and their biochemistry properties and anticancer effects were evaluated. The purified galectins were thermostable at neutral pH conditions. They both existed as tetramers and shared a high affinity towards lactose. CGL1 and CGL2 strongly inhibited the cell viability of many cancer cell lines, including three colorectal cancer cells, in a dose-dependent manner by inducing mitochondria-mediated caspase-dependent apoptosis. Furthermore, CGL1 exhibited higher apoptosis-inducing ability and cytotoxicity than CGL2. In vivo cell viability experiments based on two xenograft mouse models showed that CGL1 had a more substantial inhibitory effect than CGL2 on HCT116 tumor growth (p < 0.0001), whereas only CGL1 inhibited DLD1 tumor growth (p < 0.01). This is the first study to evaluate the anti-colorectal cancer effect of mushroom lectins in vivo, and our results showed that CGL1 is a potent agent for colorectal cancer treatment.

Cytotoxicity of Frutalin on Distinct Cancer Cells Is Independent of Its Glycosylation.

Frutalin is a plant lectin with beneficial immunobiological action, although the access to its active form is still restricted. Moreover, there is a knowledge gap on isoform activity and glycosylation impact on its bioactivity, and recombinant production protocols were seen as ineffective. Here, a simpler and faster production and purification protocol was developed, attaining a yield of purified frutalin 3.3-fold higher than that obtained previously. Hemagglutination assays confirmed that this frutalin isoform could not agglutinate rabbit erythrocytes, while maintaining the native tetrameric structure, as indicated by DLS analysis, and strong interaction with methyl-alpha-galactose, in fluorescence spectroscopy studies. The cytotoxicity of the recombinant frutalin isoform was shown in a broad panel of human cancer cells: colon (HCT116), melanoma (A375), triple-negative breast cancer (MDA-MB-231), and ovarian (IGROV-1). Treatment with 8.5-11.8 µM TrxFTL reduced proliferation of all cancer cells to half in 48 h. This anti-proliferative effect encompasses the p53 pathway since it was significantly reduced in p53-null colon cancer cells (HCT116 p53-/-; GI50 of 25.0 ± 3.0 µM), when compared to the isogenic p53-positive cells (HCT116 p53+/+; GI50 of 8.7 ± 1.8 µM; p < 0.002). This recombinantly produced frutalin isoform has relevant cytotoxic effect and its biological activity is not dependent on glycosylation. The developed E. coli production and purification protocol generates high yield of non-glycosylated frutalin isoform with potent cytotoxic activity, enabling the development of novel anticancer p53-targeting therapies.

Regulatory roles of galectins on influenza A virus and their potential as a therapeutic strategy.

Galectins, are ß-galactoside binding lectins expressed in numerous cells and are known to regulate various immune responses and cellular physiological functions. Galectins have been reported to participate in the regulation of several viral infections via carbohydrate­dependent/independent manner. Galectins have displayed various regulatory functions on viral infection, however, the detailed mechanism remains unclear. More recently, some members of galectins have been reported to regulate influenza A virus (IAV) infection. In this review, we aim to analyze and summarize current findings regarding the role of galectins in IAV infection and their antiviral potential therapeutic application in the treatment of IAVs. The eligible articles were selected according to the PRISMA guidelines. Results indicate that Galectin-1(Gal-1), Galectin-3(Gal-3) and Galectin-9 (Gal-9) were found as the predominant galectins reported to participate in the regulation of IAVs infection. The inhibitory regulation of IAVs by these galectins occurred mainly through extracellular binding to glycosylated envelope proteins, further blocking the interaction between influenza envelope and sialic acid receptor, interacting with ligands or receptors on immune cells to trigger immunol or cellular response against IAVs, and endogenously interacting cellular components in the cytoplasm to activate inflammasome and autophagy. This study offers information regarding the multiple roles of galectins observed in IAVs infection and suggest that galectins has the potential to be used as therapeutic agents for IAVs.

Isolation, characterization of galactose-specific lectin from Odoiporus longicollis and its antibacterial and anticancer activities.

Lectins are renowned hemagglutinins and multivalent proteins with a well known quality for sugar-binding specificity that participate significantly in invertebrate defense functions. Studies on biological activity of lectin from coleopteran insect are very scarce. In this study, lectin from the hemolymph in the grub of banana pest, Odoiporus longicollis was subjected to purification, biochemical and functional characterizations. The lectin was purified by PEG precipitation and ion-exchange chromatography using Q-Sepharose as a matrix. The purified lectin showed hemagglutination activity against rat erythrocytes, heat-labile, cation independent and insensitive to EDTA. Further, the carbohydrate affinity of this lectin was found with mannitol, adonitol, L-arabinose, L-rhamnose, D-galactose and sorbitol. The native form of purified lectin was calculated as 360 kDa by FPLC system. Denatured gel electrophoresis of the purified lectin consisted of five distinct polypeptides with molecular weights approximately 160, 60, 52, 40 and 38 kDa, respectively. The amino acid sequences obtained through peptide mass fingerprinting analysis exhibited homologies to the known conserved regions of galactose binding lectins. Further, the purified lectin exhibited bacterial inhibition with LPS from Serratia marcescens. In addition, isolated lectin also exerted bacterial agglutination, antibacterial and anti-proliferative activity against Mycobacterium smegmatis, Bacillus pumilus and Neuro 2a cell line, respectively.

[Cell Function Research of ß-Trefoil Lectins from Mytilidae].

Two novel ß-trefoil lectins, MytiLec-1 and SeviL were found from mussels in the coast of Yokohama and Nagasaki. MytiLec-1 was purified from gill and mantle of Mytilus galloprovincialis. It was consisted of 149 amino acid residues and there was no similarity with any other proteins when it was discovered. We advocate for this "Mytilectin" as a new protein family because of their novelty of its primary structure and homologues were also found in other mussels. Glycan array analysis revealed that MytiLec-1 specifically bound to the Gb3 and Gb4 glycan which contained the α-galactoside. MytiLec-1 caused the apoptosis against the Burkitt's lymphoma cells through the interaction of Gb3 express in their cell surface. On the other hand, SeviL obtained from gill and mantle of Mytilisepta virgata showed the specific binding against GM1b, asialo GM1 and SSEA-4 which are known as glycosphingolipid glycan including the ß-galactoside. In addition, SeviL was identified as R type lectin by confirmation of QXW motif within its primary structure. Messenger RNA of SeviL like R type lectins was also found among the musssels including Mytilus galloprovincialis. SeviL also showed the apoptosis against asialo GM1 expressing cells. To apply the anticancer lectin as a novel molecular target drug, primary structure of MytiLec-1 was analyzed to enhance the stabilization of confirmation by computational design technique. It was succeeded to produce a monomeric artificial ß-trefoil lectin, Mitsuba-1 without losing the Gb3 binding ability. Comparison of biological function between Mitsuba-1 and MytiLec-1 is also described in this study.

Galectin­9 suppresses the tumor growth of colon cancer in vitro and in vivo.

Colon cancer is the second leading cause of cancer­related mortality worldwide, and the prognosis of advanced colon cancer has remained poor in recent years. Galectin­9 (Gal­9) is a tandem­repeat type galectin that has recently been shown to exert antiproliferative effects on various types of cancer cells. The present study aimed to assess the effects of Gal­9 on human colon and colorectal cancer cells in vitro and in vivo, as well as to evaluate the microRNAs (miRNAs/miRs) associated with the antitumor effects of Gal­9. We examined the ability of Gal­9 to inhibit cell proliferation via apoptosis, and the effects of Gal­9 on cell cycle­related molecules in various human colon and colorectal cancer cell lines. In addition, Gal­9­mediated changes in activated tyrosine kinase receptors and angiogenic molecules were assessed using protein array chips in colon and colorectal cancer cells. Moreover, miRNA array analysis was performed to examine Gal­9­induced miRNA expression profiles. We also elucidated if Gal­9 inhibited tumor growth in a murine in vivo model. We found that Gal­9 suppressed the cell proliferation of colon cancer cell lines in vitro and in vivo. Our data further revealed that Gal­9 increased caspase­cleaved keratin 18 levels in Gal­9­treated colon cancer cells. In addition, Gal­9 enhanced the phosphorylation of ALK, DDR1, and EphA10 proteins. Furthermore, the miRNA expression levels, such as miR­1246, miR­15b­5p, and miR­1237, were markedly altered by Gal­9 treatment in vitro and in vivo. In conclusion, Gal­9 suppresses the cell proliferation of human colon cancer by inducing apoptosis, and these findings suggest that Gal­9 can be a potential therapeutic target in the treatment of colon cancer.

Pronociceptive Roles of Schwann Cell-Derived Galectin-3 in Taxane-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of taxanes such as paclitaxel and docetaxel. Despite the high medical needs, insufficient understanding of the complex mechanism underlying CIPN pathogenesis precludes any endorsed causal therapy to prevent or relieve CIPN. In this study, we report that elevation of plasma galectin-3 level is a pathologic change common to both patients with taxane-treated breast cancer with CIPN and a mouse model of taxane-related CIPN. Following multiple intraperitoneal injections of paclitaxel in mice, galectin-3 levels were elevated in Schwann cells within the sciatic nerve but not in other peripheral organs or cells expressing galectin-3. Consistent with this, paclitaxel treatment of primary cultures of rat Schwann cells induced upregulation and secretion of galectin-3. In vitro migration assays revealed that recombinant galectin-3 induced a chemotactic response of the murine macrophage cell line RAW 264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. By contrast, chemical depletion of macrophages by clodronate liposomes suppressed paclitaxel-induced mechanical hypersensitivity despite the higher level of plasma galectin-3. Deficiency (Galectin-3 -/- mice) or pharmacologic inhibition of galectin-3 inhibited paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. In conclusion, we propose that Schwann cell-derived galectin-3 plays a pronociceptive role via macrophage infiltration in the pathogenesis of taxane-induced peripheral neuropathy. Therapies targeting this phenomenon, which is common to patients with CIPN and mouse models, represent a novel approach to suppress taxane-related CIPN. SIGNIFICANCE: These findings demonstrate that the elevation of plasma galectin-3 is a CIPN-related pathologic change common to humans and mice, and that targeting galectin-3 is a therapeutic option to delay CIPN progression.

COVID-19: disease, or no disease? - that is the question. It's the dose stupid!

The COVID-19 pandemic has raised many issues not the least of which is the reason for its high variability in consequences to the infected person. In this opinion letter, we advocate that the dose and presentation of the infecting virus is a major factor that affects whether the outcome is subclinical, tissue damaging or even lethal following infection. We briefly describe the known effects of virus dose on the course COVID-19 and discuss practical maneuvers as well as largely untested procedures that can raise the threshold dose needed to break through barriers of resistance.

Binding of a Soluble meso-Tetraarylporphyrin to Human Galectin-7 Induces Oligomerization and Modulates Its Pro-Apoptotic Activity.

The selective targeting of protein-protein interactions remains a significant determinant for the proper modulation and regulation of cell apoptosis. Prototypic galectins such as human galectin-7 (GAL-7) are characterized by their ability to form homodimers that control the molecular fate of a cell by mediating subtle yet critical glycan-dependent interactions between pro- and anti-apoptotic molecular partners. Altering the structural architecture of GAL-7 can therefore result in resistance to apoptosis in various human cancer cells, further illustrating its importance in cell survival. In this study, we used a combination of biophysical and cellular assays to illustrate that binding of a water-soluble meso-tetraarylporphyrin molecule to GAL-7 induces protein oligomerization and modulation of GAL-7-induced apoptosis in human Jurkat T cells. Our results suggest that the integrity of the GAL-7 homodimer architecture is essential for its molecular function, in addition to providing an interesting porphyrin binding modulator for controlling apoptosis in mammalian cells.

Galectin-7 Impairs Placentation and Causes Preeclampsia Features in Mice.

Preeclampsia is a serious pregnancy-induced disorder unique to humans. The etiology of preeclampsia is poorly understood; however, poor placental formation is thought causal. Galectin-7 is produced by trophoblast and is elevated in first-trimester serum of women who subsequently develop preeclampsia. We hypothesized that elevated placental galectin-7 may be causative of preeclampsia. Here, we demonstrated increased galectin-7 production in chorionic villous samples from women who subsequently develop preterm preeclampsia compared with uncomplicated pregnancies. In vitro, galectin-7 impaired human first-trimester trophoblast outgrowth, increased placental production of the antiangiogenic sFlt-1 splice variant, sFlt-1-e15a, and reduced placental production and secretion of ADAM12 (a disintegrin and metalloproteinase12) and angiotensinogen. In vivo, galectin-7 administration (E8-E12) to pregnant mice caused elevated systolic blood pressure, albuminuria, impaired placentation (reduced labyrinth vascular branching, impaired decidual spiral artery remodeling, and a proinflammatory placental state demonstrated by elevated IL1ß, IL6 and reduced IL10), and dysregulated expression of renin-angiotensin system components in the placenta, decidua, and kidney, including angiotensinogen, prorenin, and the angiotensin II type 1 receptor. Collectively, this study demonstrates that elevated galectin-7 during placental formation contributes to abnormal placentation and suggests that it leads to the development of preeclampsia via altering placental production of sFlt-1 and renin-angiotensin system components. Targeting galectin-7 may be a new treatment option for preeclampsia.