The Wnt signaling pathway in major depressive disorder: A systematic review of human studies.

Despite uncertainty about the specific molecular mechanisms driving major depressive disorder (MDD), the Wnt signaling pathway stands out as a potentially influential factor in the pathogenesis of MDD. Known for its role in intercellular communication, cell proliferation, and fate, Wnt signaling has been implicated in diverse biological phenomena associated with MDD, spanning neurodevelopmental to neurodegenerative processes. In this systematic review, we summarize the functional differences in protein and gene expression of the Wnt signaling pathway, and targeted genetic association studies, to provide an integrated synthesis of available human data examining Wnt signaling in MDD. Thirty-three studies evaluating protein expression (n = 15), gene expression (n = 9), or genetic associations (n = 9) were included. Only fifteen demonstrated a consistently low overall risk of bias in selection, comparability, and exposure. We found conflicting observations of limited and distinct Wnt signaling components across diverse tissue sources. These data do not demonstrate involvement of Wnt signaling dysregulation in MDD. Given the well-established role of Wnt signaling in antidepressant response, we propose that a more targeted and functional assessment of Wnt signaling is needed to understand its role in depression pathophysiology. Future studies should include more components, assess multiple tissues concurrently, and follow a standardized approach.

Mitochondrial unfolded protein response (UPRmt): what we know thus far.

Mitochondria are key organelles for the optimal function of the cell. Among their many functions, they maintain protein homeostasis through their own proteostatic machinery, which involves proteases and chaperones that regulate protein import and folding inside mitochondria. In the early 2000s, the mitochondrial unfolded protein response (UPRmt) was first described in mammalian cells. This stress response is activated by the accumulation of unfolded/misfolded proteins within the mitochondrial matrix, which results in the transmission of a signal to the nucleus to increase the expression of proteases and chaperones to address the abnormal mitochondrial protein load. After its discovery, this retrograde signaling pathway has also been described in other organisms of different complexities, suggesting that it is a conserved stress response. Although there are some specific differences among organisms, the mechanism of this stress response is mostly similar and involves the transmission of a signal from mitochondria to the nucleus that induces chromatin remodeling to allow the binding of specific transcription factors to the promoters of chaperones and proteases. In the last decade, proteins and signaling pathways that could be involved in the regulation of the UPRmt, including the Wnt signaling pathway, have been described. This minireview aims to summarize what is known about the mechanism of the UPRmt and its regulation, specifically in mammals and C. elegans.

Síndrome de Robinow autosómico recesivo en una familia con dos hermanos afectados. Reporte de caso / Autosomal recessive Robinow syndrome in a family with two affected siblings: a case report

El síndrome de Robinow es una enfermedad rara, de origen genético causada por mutaciones en diversos genes de la vía de señalización Wnt, entre ellos: WNT5A, DVL1, DVL3, ROR2, NXN y FZ2. El síndrome se caracteriza por anomalías craneofaciales, malformaciones en extremidades y alteraciones genitourinarias. Se presentan dos hermanos nacidos de padres sanos con manifestaciones típicas del Síndrome de Robinow, el estudio de la genealogía sugiere un mecanismo de herencia autosómico recesivo. El síndrome de Robinow ha sido reportado en muy pocas ocasiones en la literatura científica internacional, por este motivo, reportes como el del presente artículo son un aporte importante al conocimiento de las características clínicas y el mecanismo de transmisión del síndrome. Nuestro artículo se constituye en el primer reporte boliviano del síndrome y uno de los pocos que reporta dos hermanos afectados.

Robinow syndrome is a rare genetic disorder caused by mutations in various genes within the Wnt signaling pathway, including WNT5A, DVL1, DVL3, ROR2, NXN, and FZ2. The syndrome is characterized by craniofacial anomalies, limb malformations, and genitourinary disorders. Two siblings born to healthy parents present typical manifestations of Robinow syndrome. Genealogical analysis suggests an autosomal recessive inheritance mechanism. Although Robinow syndrome has been rarely reported in the international scientific literature, articles like the present contribute significantly to understanding the clinical features and transmission mechanism of the syndrome. Our article represents the first Bolivian report on this syndrome and is one of the few that describes two affected siblings.

Planar Cell Polarity Signaling: Coordinated Crosstalk for Cell Orientation.

The planar cell polarity (PCP) system is essential for positioning cells in 3D networks to establish the proper morphogenesis, structure, and function of organs during embryonic development. The PCP system uses inter- and intracellular feedback interactions between components of the core PCP, characterized by coordinated planar polarization and asymmetric distribution of cell populations inside the cells. PCP signaling connects the anterior-posterior to left-right embryonic plane polarity through the polarization of cilia in the Kupffer's vesicle/node in vertebrates. Experimental investigations on various genetic ablation-based models demonstrated the functions of PCP in planar polarization and associated genetic disorders. This review paper aims to provide a comprehensive overview of PCP signaling history, core components of the PCP signaling pathway, molecular mechanisms underlying PCP signaling, interactions with other signaling pathways, and the role of PCP in organ and embryonic development. Moreover, we will delve into the negative feedback regulation of PCP to maintain polarity, human genetic disorders associated with PCP defects, as well as challenges associated with PCP.

Polysacharide of Agaricus blazei gel mitigates bone necrosis in model of the jaws related to bisphosphonate via Wnt signaling.

To investigate de effect of PAb gel on the bone tissue of rats submitted to Bisphosphonate-related osteonecrosis of the jaws (BRONJ). Initially, 54 animals were submitted to BRONJ model by Zoledronic Acid (ZA) (0.1 mg/kg 3x/wk for 9 wk, ip), followed by the 1st upper left molar extraction at the 8th wk. After tooth removal, the animals were divided into 3 groups, ZA that received placebo gel or PAb gel that received 1% PAb gel, inside the dental alveolus. The control Group (CONTROL) received 0.1 mg/kg of 0.9% saline and then placebo gel. Three weeks after tooth extraction, the animals were euthanized, and maxillae were colleted for macroscopic, radiographic, histological and Raman spectomery assays. Additionally, GSK3b, beta-catenin, and Runx2 mRNA expressions were determined. Blood samples were collected for the analysis of Bone-specific alkaline phosphatase (BALP) levels. PAb gel improved mucosal healing, increased the number of viable osteocytes, while it reduced the number of empty lacunae, as well as the amount of bone sequestration. Furthermore, PAb gel positively influenced the number and functionality of osteoblasts by stimulating Wnt signaling, thereby inducing bone remodeling. Additionally, PAb gel contributed to improved bone quality, as evidenced by an increase in bone mineral content, a decrease in bone solubility, and an enhancement in the quality of collagen, particularly type I collagen. PAb gel mitigated bone necrosis by stimulating of bone remodeling through Wnt signaling and concurrently improved bone quality. PAb gel emerges as a promising pharmacological tool for aiding in BRONJ therapy or potentially preventing the development of BRONJ.

Eucommia granules activate Wnt/ß-catenin pathway, and improve oxidative stress, inflammation, and endothelial injury in preeclampsia rats

Purpose: Pre-eclampsia (PE) is a pregnancy-related complication. Eucommia is effective in the treatment of hypertensive disorders in pregnancy, but the specific effects and possible mechanisms of Eucommia granules (EG) in PE remain unknown. The aim of this study was to investigate the effects and possible mechanisms of EG in PE rats. Methods: Pregnant Sprague Dawley rats were divided into five groups (n = 6): the control group, the model group, the low-dose group, the medium-dose group, and the high-dose group of EG. The PE model was established by subcutaneous injection of levonitroarginine methyl ester. Saline was given to the blank and model groups, and the Eucommia granules were given by gavage to the remaining groups. Blood pressure and urinary protein were detected. The body length and weight of the pups and the weight of the placenta were recorded. Superoxide dismutase (SOD) activity and levels of malondialdehyde (MDA), placental growth factor (PIGF), and soluble vascular endothelial growth factor receptor-1 (sFIt-1) were measured in the placenta. Pathological changes were observed by hematoxylin-eosin staining. Wnt/ß-catenin pathway-related protein expression was detected using Western blot. Results: Compared with the model group, the PE rats treated with EG had lower blood pressure and urinary protein. The length and weight of the pups and placental weight were increased. Inflammation and necrosis in the placental tissue was improved. SOD level increased, MDA content and sFIt-1/PIGF ratio decreased, and Wnt/ß-catenin pathway-related protein expression level increased. Moreover, the results of EG on PE rats increased with higher doses of EG. Conclusions: EG may activate the Wnt/ß-catenin pathway and inhibit oxidative stress, inflammation, and vascular endothelial injury in PE rats, thereby improving the perinatal prognosis of preeclamptic rats. EG may inhibit oxidative stress, inflammation, and vascular endothelial injury through activation of the Wnt/ß-catenin pathway in preeclampsia rats, thereby improving perinatal outcomes in PE rats.

Mutant p53 gain-of-function stimulates canonical Wnt signaling via PI3K/AKT pathway in colon cancer.

Aberrant canonical Wnt signaling is a hallmark of colon cancer. The TP53 tumor suppressor gene is altered in many solid tumors, including colorectal cancer, resulting in mutant versions of p53 (mut-p53) that lose their tumor suppressor capacities and acquire new-oncogenic functions (GOFs) critical for disease progression. Although the mechanisms related to mut-p53 GOF have been explored extensively, the relevance of mut-p53 in the canonical Wnt pathway is not well defined. This work investigated the influence of mut-p53 compared to wt-p53 in ß-catenin-dependent Wnt signaling. Using the TCGA public data from Pan-Cancer and the GEPIA2 platform, an in silico analysis of wt-p53 versus mut-p53 genotyped colorectal cancer patients showed that TP53 (p53) and CTNNB1 (ß-catenin) are significantly overexpressed in colorectal cancer, compared with normal tissue. Using p53 overexpression or p53 knockdown assays of wt-p53 or mut-p53, we found that while wt-p53 antagonizes canonical Wnt signaling, mut-p53 induces the opposite effect, improving the ß-catenin-dependent transcriptional activity and colony formation ability of colon cancer cells, which were both decreased by mut-p53 knockdown expression. The mechanism involved in mut-p53-induced activation of canonical Wnt appears to be via AKT-mediated phosphorylation of Ser 552 of ß-catenin, which is known to stabilize and enhance its transcriptional activity. We also found that while wt-p53 expression contributes to 5-FU sensitivity in colon cancer cells, the RITA p53 reactivating molecule counteracted the resistance against 5-FU in cells expressing mut-p53. Our results indicate that mut-p53 GOF acts as a positive regulator of canonical Wnt signaling and participates in the induction of resistance to 5-FU in colon cancer cells.

Disheveled-1 Interacts with Claudin-5 and Contributes to Norrin-Induced Endothelial Barrier Restoration.

Previous studies have revealed that norrin can reverse vascular endothelial-growth-factor (VEGF)-induced permeability in a ß-catenin-dependent pathway. Here, we have explored the contribution of disheveled-1 (DVL1) in norrin-induced blood-retinal barrier (BRB) restoration. We provide evidence that in addition to canonical signaling, DVL1 promotes tight junction (TJ) stabilization through a novel, non-canonical signaling pathway involving direct claudin-5 (CLDN5) binding. Immunofluorescence staining of rat retinal cross-sections showed enriched expression of DVL1 and 3 at endothelial capillaries and co-localization with CLDN5 and ZO-1 at the TJ complex in primary bovine retinal endothelial cells (BRECs). Barrier properties of BRECs were determined via measurements of trans-endothelial electrical resistance (TEER) or permeability to 70 kDa RITC-dextran. These studies demonstrated that norrin restoration of barrier properties after VEGF treatment required DVL1 as an siRNA knockdown of Dvl1 but not Dvl2 or Dvl3, reduced basal barrier properties and ablated norrin-induced barrier restoration. However, loss of Dvl1 did not decrease ß-catenin signaling activity as measured by Axin2 mRNA expression, suggesting the contribution of a non-canonical pathway. DVL and TJ protein interactions were analyzed via co-immunoprecipitation of endogenous protein in BRECs, which demonstrated that DVL1 interacts with both CLDN5 and ZO-1, while DVL3 interacts only with ZO-1. These interactions were most abundant after inducing BRB restoration by treating BRECs with VEGF and norrin. DVL has previously been shown to form intramolecular bindings between the C-terminal PDZ-binding motif (PDZ-BM) with an internal PDZ domain. Co-transfection of HEK293 cells with DVL1 and CLDN5 or relevant mutants revealed that DVL1 interacts with CLDN5 through the DVL PDZ domain binding, CLDN5 PDZ-BM, in competition with DVL1 PDZ-BM, since DVL/CLDN5 interaction increases with deletion of the DVL1 PDZ-BM and decreases by co-expressing the C-terminal fragment of DVL1 containing the PDZ-BM or through deletion of CLDN5 PDZ-BM. In BREC cells, transfection of the C-terminal fragment of DVL1 downregulates the expression of CLDN5 but does not affect the expression of other proteins of the TJs, including ZO-1, occludin, CLDN1 or VE-cadherin. Blocking DVL1/CLDN5 interaction increased basal permeability and prevented norrin induction of barrier properties after VEGF. Combined with previous data, these results demonstrate that norrin signals through both a canonical ß-catenin pathway and a non-canonical signaling pathway by which DVL1 directly binds to CLDN5 to promote barrier properties.

Role of Hippocampal Wnt Signaling Pathways on Contextual Fear Memory Reconsolidation.

Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/ß-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/ß-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca2+ signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/ß-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca2+ signaling pathway is not involved in this process and, that there is a link between Wnt/ß-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders.

Pterostilbene and Probiotic Complex in Chemoprevention of Putative Precursor Lesions for Colorectal Cancer in an Experimental Model of Intestinal Carcinogenesis with 1,2-Dimethylhydrazine.

Dietary supplementation with pterostilbene (PS) and/or a probiotic (PRO) may ameliorate the intestinal microbiota in disease conditions. This study aims to evaluate PS and PRO for the chemoprevention of putative precursor lesions for colorectal cancer (CRC) in an experimental model of intestinal carcinogenesis with 1,2-dimethylhydrazine (1,2-DMH). Sixty male Wistar rats were equally divided into five groups: Sham, 1,2-DMH, 1,2-DMH + PS, 1,2-DMH + PRO, and 1,2-DMH + PS + PRO. PRO (5 × 107/mL) was offered in water, and PS (300 ppm) was provided in the diet ad libitum. 1,2-DMH (20 mg/kg/week) was administered for 15 consecutive weeks. In the 25th week, proctocolectomy was conducted. PRO alone and PRO combined with PS were the best intervention strategies to improve experimental 1,2-DMH-induced CRC regarding several parameters of carcinogenesis. Our findings may contribute to the development of novel preventive strategies for CRC and may help to identify novel modulators of colon carcinogenesis.

Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids.

The presence of cancer stem cells (CSCs) has been associated with the induction of drug resistance and disease recurrence after therapy. 5-Fluorouracil (5FU) is widely used as the first-line treatment of colorectal cancer (CRC). However, its effectiveness may be limited by the induction of drug resistance in tumor cells. The Wnt pathway plays a key role in the development and CRC progression, but it is not clearly established how it is involved in CSCs resistance to treatment. This work aimed to investigate the role played by the canonical Wnt/ß-catenin pathway in CSCs resistance to 5FU treatment. Using tumor spheroids as a model of CSCs enrichment of CRC cell lines with different Wnt/ß-catenin contexts, we found that 5FU induces in all CRC spheroids tested cell death, DNA damage, and quiescence, but in different proportions for each one: RKO spheroids were very sensitive to 5FU, while SW480 were less susceptible, and the SW620 spheroids, the metastatic derivative of SW480 cells, displayed the highest resistance to death, high clonogenic capacity, and the highest ability for regrowth after 5FU treatment. Activating the canonical Wnt pathway with Wnt3a in RKO spheroids decreased the 5FU-induced cell death. But the Wnt/ß-catenin pathway inhibition with Adavivint alone or in combination with 5FU in spheroids with aberrant activation of this pathway produced a severe cytostatic effect compromising their clonogenic capacity and diminishing the stem cell markers expression. Remarkably, this combined treatment also induced the survival of a small cell subpopulation that could exit the arrest, recover SOX2 levels, and re-grow after treatment.

Temporomandibular joint arthritis increases canonical Wnt pathway expression in the articular cartilage and trigeminal ganglion in rats.

The canonical Wnt pathway participates in inflammatory diseases and it is involved in neuropathic pain. This study evaluated the immunoexpression of the canonical Wnt signaling pathway in the articular cartilage of the temporomandibular joint (TMJ) and along the nociceptive trigeminal pathway in arthritic rats. For this, male Wistar rats were divided into Control (C) and Arthritic (RA) groups. Arthritis induction was performed through subcutaneous injection of methylated bovine serum albumin (mBSA) and complete Freund Adjuvant (CFA)/ Incomplete Freund Adjuvant (IFA) on the first 14 days (once a week), followed by 3 weekly intra-articular injections of mBSA (10 µl/joint; left TMJ). The following parameters were evaluated: nociceptive threshold, inflammatory infiltrate, type I and III collagen birefringence, immunohistochemistry for IL-1ß, TNF-α, IL-6, Wnt10b, ß-catenin, cyclin-D1 in articular cartilage, c-Myc in synovial membrane, and immunofluorescence analysis for c-Fos, Wnt-10b and ß-catenin in the trigeminal ganglion and the trigeminal subnucleus caudalis. The RA group showed intense articular cartilage damage with proliferation of type III collagen, increased immunoexpression of proinflammatory cytokines and Wnt-10b, ß-catenin and cyclin-D1 in the articular cartilage and c-Myc in the synovial membrane. In the RA group, a reduction in the nociceptive threshold was observed, followed by a significant increase in the expression of Wnt-10b in neurons and ß-catenin in satellite cells of the trigeminal ganglion. c-Fos immunoexpression was observed in neurons, peripherally and centrally, in arthritic rats. Our data demonstrated that TMJ arthritis in rats causes articular cartilage damage and nociceptive behavior, with increased immunoexpression of canonical Wnt pathway in the articular cartilage and trigeminal ganglion.

SMEK1 promotes lung adenocarcinoma proliferation and invasion by activating Wnt/ß-catenin signaling pathway.

PURPOSE: SMEK1, also known as PP4R3α, the regulatory subunit 3α of serine and threonine phosphatase PP4, participates in diversely critical biological processes such as the integration of centromere, deacetylation of histones, asymmetric divisions of neuroblast, and other crucial cellular activities. SMEK1 was formerly reported to play a part in carcinogenesis. This study aims to reveal the role of SMEK1 in lung adenocarcinoma and the underlying molecular mechanism. METHODS: Using immunohistochemical (IHC) staining, the protein level of SMEK1 in lung adenocarcinoma and adjacent non-tumor tissue was detected. The functional role of SMEK1 in cell proliferation and invasion was explored using cell counting kit-8 and Transwell assay, respectively. Xenograft tumor experiment was used to investigate the effect of SMEK1 on tumor growth in vivo. The alteration of Wnt/ß-catenin signaling pathway was detected by Western blotting, quantitative PCR, and dual-luciferase reporter assays. RESULTS: SMEK1 was highly expressed at the protein level in lung adenocarcinoma compared to the adjacent non-tumor tissue. In vitro, suppression of SMEK1 significantly decreased the proliferation, migration, and invasion of lung adenocarcinoma cell lines, while overexpression of SMEK1 enhanced above abilities. The xenograft model demonstrated that down-regulation of SMEK1 significantly inhibited tumor growth in vivo. In addition, we found that SMEK1 could positively regulate Wnt/ß-catenin signaling in lung adenocarcinoma cell lines. CONCLUSIONS: SMEK1 exerts a cancer-promoting effect in lung adenocarcinoma by activating Wnt/ß-catenin signaling.

Relationship between villous atrophy and Wnt pathway gene expressions in pediatric celiac patients

SUMMARY OBJECTIVE: Celiac disease is an autoimmune disease characterized by an abnormal immune response occurring in the small intestine linked to consumption of food containing gluten in individuals with a genetic predisposition. Dysregulation of Wnt signal transduction plays a role in the pathogenesis of many diseases including autoimmune diseases like celiac disease. In this study, the correlation of Wnt pathway gene expressions with each other and the correlation with clinical data were researched in pediatric celiac disease cases grouped according to the Marsh classification. METHODS: Gene expression levels of FZD8, DVL2, LRP5, RHOA, CCND2, CXADR, and NFATC1, which are involved in the Wnt pathway, were determined using quantitative real-time polymerase chain reaction in 40 celiac disease and 30 healthy individuals. RESULTS: All cases with the short height symptom were observed to be in Marsh 3b/3c groups (p=0.03). The gene expressions of DVL2, CCND2, and NFATC1 were high in the Marsh 3b group, and these genes showed positive correlation with each other (p=0.002). LRP5 and CXADR gene expressions were lower in the Marsh 3b group compared to other Marsh groups, and these genes showed a positive correlation with each other (p=0.003). CCND2 gene expression was associated with Marsh 3b group, diarrhea, and vomiting symptoms. DVL2 gene expression was correlated with Marsh 2 group and constipation symptom (p<0.05). CONCLUSION: Wnt signaling in the early stages of the disease of Marsh 1-2 involves high expression of LRP5 and CXADR genes, while expression of these two genes reduces, and DVL2, CCND2, and NFATC1 gene expressions clearly increase with a transduction variation observed from Marsh 3a stage when villous atrophy begins to form. It appears that the Wnt pathway may contribute to disease progression through expression changes.

Glycogen synthase kinase 3 inhibition enhances mineral nodule formation by cementoblasts in vitro

Abstract This study aimed to investigate whether GSK-3 inhibition (CHIR99021) effectively promoted mineralization by cementoblasts (OCCM-30). OCCM-30 cells were used and treated with different concentrations of CHIR99021 (2.5, 5, and 10 mM). Experiments included proliferation and viability, cellular metabolic activity, gene expression, and mineral nodule formation by Xylene Orange at the experimental time points. In general, CHIR99021 did not significantly affect OCCM-30 viability and cell metabolism (MTT assay) (p > 0.05), but increased OCCM-30 proliferation at 2.5 mM on days 2 and 4 (p < 0.05). Data analysis further showed that inhibition of GSK-3 resulted in increased transcript levels of Axin2 in OCCM-30 cells starting as early as 4 h, and regulated the expression of key bone markers including alkaline phosphatase (Alp), runt-related transcription factor 2 (Runx-2), osteocalcin (Ocn), and osterix (Osx). In addition, CHIR99021 led to an enhanced mineral nodule formation in vitro under both osteogenic and non-osteogenic conditions as early as 5 days after treatment. Altogether, the results of the current study suggest that inhibition of GSK-3 has the potential to promote cementoblast differentiation leading to increased mineral deposition in vitro.

Higher immunoexpression of CK14 from the Wnt-1/β-catenin pathway in the development of odontomas

Abstract Tooth development depends on a series of reciprocal signaling interactions between the oral epithelium and ectomesenchyme. This study aimed to investigate the role of CK14, a protein involved in Wnt-1/β-catenin signaling, in odontogenesis and the development of odontomas. This cross-sectional, retrospective, immunohistochemical study analyzed 30 compound odontomas, 30 complex odontomas, and 17 tooth germs. Higher immunoexpression of CK14 was observed in odontogenic epithelial cells of tooth germs (p < 0.001) and odontogenic epithelial cells of odontomas (p < 0.001). There was higher immunoexpression of Wnt-1 and β-catenin proteins in epithelial cells of tooth germs (p = 0.002 and p < 0.001, respectively), as well as in the ectomesenchyme of odontomas (p = 0.003 and p < 0.001, respectively). β-Catenin was moderately and significantly correlated with CK14 in the membrane of reduced enamel epithelial cells in odontomas (p = 0.007). Higher immunoexpression of CK14 was observed in the odontogenic epithelium during the bud and cap stages and lower immunoexpression in the internal enamel epithelium during the bell stage. In odontomas, lower expression of Wnt-1/β-catenin and higher immunoexpression of CK14 were found in odontogenic epithelial cells, especially adjacent to the mineralized material resembling the tooth formed in these lesions.

Resumo O desenvolvimento dentário depende de uma série de interações de sinalização recíproca entre o epitélio oral e o ectomesênquima. O objetivo deste estudo foi investigar o papel da CK14 das vias WNT-1/β-catenina na odontogênese e no desenvolvimento de odontomas. Este estudo transversal, retrospectivo, imuno-histoquímico analisou 30 odontomas compostos, 30 odontomas complexos e 17 germes dentários. A CK14 apresentou maior imunoexpressão em células epiteliais odontogênicas de germes dentários (p<0,001) e em células epiteliais odontogênicas de odontomas (p<0,001). A Wnt-1 e a β-catenina apresentaram maior imunoexpressão de proteínas nas células epiteliais dos germes dentários (p = 0,002 e p<0,001, respectivamente), bem como no ectomesênquima dos odontomas (p = 0,003 e p < 0,001, respectivamente). A β-catenina correlacionou-se moderada e significativamente com a CK14 na membrana de células epiteliais reduzidas do esmalte em odontomas (p = 0,007). Maior imunoexpressão da CK14 foi observada no epitélio odontogênico nos estágios de botão e capuz com menor imunoexpressão no epitélio interno do órgão do esmalte no estágio de sino. Nos odontomas, foi observado menor expressão de Wnt-1/β-catenina e maior imunoexpressão da CK14 presente nas células epiteliais odontogênicas, especialmente, vizinhas ao material mineralizado semelhante ao dente formado nessas lesões.

miR-29c-3p represses the angiogenesis of esophageal squamous cell carcinoma by targeting SERPINH1 to regulate the Wnt signaling pathway

Purpose: Esophageal squamous cell carcinoma (ESCC) is characterized by early metastasis and late diagnosis. miR-29c-3p is confirmed to repress angiogenesis in multiple tumor types. Yet, the functions of miR-29c-3p in the mechanism of ESCC angiogenesis, which were not sufficiently explored previously, were exactly what we investigated here at the molecular level. Methods: The mRNA level of miR-29c-3p and Serpin peptidase inhibitor clade H member 1 (SERPINH1) in ESCC tissues were assessed via bioinformatics analysis. Thereafter, miR-29c-3p and SERPINH1 (HSP47) mRNA level in ESCC cell lines was evaluated via quantitative real-time polymerase chain reaction. The effects of abnormal miR-29c-3p and SERPINH1 expression on ESCC cell viability, proliferation, migration, invasion, and HUVEC angiogenesis were examined via CCK8, colony formation, transwell, and angiogenesis assays, respectively. The protein levels of SERPINH1, vascular endothelial growth factor-A (VEGFA), Wnt-1, ?-catenin, and p-?-catenin were evaluated via Western blot. Expression of VEGFA secreted by ESCC cells was measured via enzyme-linked immunosorbent assay. Treatment with the Wnt activator BML-284 further revealed the way miR-29c-3p mediated the Wnt signaling pathway and its effects on angiogenesis. Results: Herein, we revealed a decrease of miR-29c-3p expression in ESCC tissues and cells, while the overexpressed miR-29c-3p could remarkably suppress ESCC cell progression, as well as HUVEC angiogenesis. Meanwhile, overexpressed miR-29c-3p notably downregulated VEGFA and repressed the Wnt signaling pathway. Treatment with the Wnt activator BML-284 could reverse the inhibition of HUVEC angiogenesis caused by miR-29c-3p. SERPINH1 was a downstream target of miR-29c-3p. SERPINH1 knockdown suppressed the malignant phenotypes of ESCC cells and impeded the Wnt signaling activation, while such suppression was reversed through miR-29c-3p inhibitor. Conclusions: We confirmed the mechanism that miR-29c-3p targeted SERPINH1, thus regulating angiogenesis in ESCC through the Wnt signaling pathway. It improves the understanding of angiogenesis in ESCC and offers new ideas for the research of ESCC treatment strategies in the future.

Modeling extracellular matrix through histo-molecular gradient in NSCLC for clinical decisions.

Lung cancer still represents a global health problem, being the main type of tumor responsible for cancer deaths. In this context, the tumor microenvironment, and the extracellular matrix (ECM) pose as extremely relevant. Thus, this study aimed to explore the prognostic value of epithelial-to-mesenchymal transition (EMT), Wnt signaling, and ECM proteins expression in patients with non-small-cell lung carcinoma (NSCLC) with clinical stages I-IIIA. For that, we used 120 tissue sections from patients and evaluated the immunohistochemical, immunofluorescence, and transmission electron microscopy (TEM) to each of these markers. We also used in silico analysis to validate our data. We found a strong expression of E-cadherin and ß-catenin, which reflects the differential ECM invasion process. Therefore, we also noticed a strong expression of chondroitin sulfate (CS) and collagens III and V. This suggests that, after EMT, the basal membrane (BM) enhanced the motility of invasive cells. EMT proteins were directly associated with WNT5A, and collagens III and V, which suggests that the WNT pathway drives them. On the other hand, heparan sulfate (HS) was associated with WNT3A and SPARC, while WNT1 was associated with CS. Interestingly, the association between WNT1 and Col IV suggested negative feedback of WNT1 along the BM. In our cohort, WNT3A, WNT5A, heparan sulfate and SPARC played an important role in the Cox regression model, influencing the overall survival (OS) of patients, be it directly or indirectly, with the SPARC expression stratifying the OS into two groups: 97 months for high expression; and 65 for low expression. In conclusion, the present study identified a set of proteins that may play a significant role in predicting the prognosis of NSCLC patients with clinical stages I-IIIA.

Menopause and development of Alzheimer's disease: Roles of neural glucose metabolism and Wnt signaling.

Late onset Alzheimer´s disease (AD) is a neurodegenerative disease with gender differences in its onset and progression, being the prevalence predominant in women and at an earlier age than in men. The pathophysiology of the menopausal condition has been associated to this dementia, playing major roles regarding both endocrine and glucose metabolism changes, amongst other mechanisms. In the current review we address the role of estrogen deficiency in the processes involved in the development of AD, including amyloid precursor protein (APP) processing to form senile plaques, Tau phosphorylation forming neurofibrillary tangles, Wnt signaling and AD neuropathology, the role of glucose brain metabolism, Wnt signaling and glucose transport in the brain, and our research contribution to these topics.

Wnt-5a induces the conversion of silent to functional synapses in the hippocampus.

Synapse unsilencing is an essential mechanism for experience-dependent plasticity. Here, we showed that the application of the ligand Wnt-5a converts glutamatergic silent synapses into functional ones by increasing both α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) currents (IAMPA and INMDA, respectively). These effects were mimicked by the hexapeptide Foxy-5 and inhibited by secreted frizzled-related protein sFRP-2. INMDA potentiation was produced by increased synaptic potency, followed by an increase in the probability of release (Pr), even in the presence of 7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile (CNQX). At a longer time of Wnt-5a exposure, the Pr increments were higher in INMDA than in IAMPA. In the presence of NMDAR inhibitors, Wnt-5a-induced conversion was fully inhibited in 69.0% of silent synapses, whereas in the remaining synapses were converted into functional one. Our study findings showed that the Wnt-5a-activated pathway triggers AMPAR insertion into mammalian glutamatergic synapses, unsilencing non-functional synapses and promoting the formation of nascent synapses during the early postnatal development of the brain circuits.