Wingless Research Articles

Relationship of Dickkopf-1 With Atherosclerosis and Arterial Stiffness in Renal Transplant Recipients

IntroductionDickkopf wingless (Wnt) signaling pathway inhibitor-1 (DKK-1) is a potent antagonist of the WNT canonical signaling pathway. DKK-1 is a substance that exerts anabolic effects on bone and is also involved in vascular cell regulation. The study aimed to determine the relationship of DKK-1 with atherosclerosis as determined by carotid artery intima-media thickness (CA-IMT) and arterial stiffness (AS) as determined by brachial-ankle pulse wave velocity (baPWV) in renal transplant recipients (RTRs). MethodsA total of 62 (62%) male and 38 (438%) female RTRs with a mean age of 44.22 ± 10.88 years were included in the study. RTRs were compared with 65 healthy individuals. CA-IMT measurement with ultrasonography was used as a marker of atherosclerosis. The presence of AS was detected with the baPWV device. ResultsCreatinine, CA-IMT, and baPWV were higher in the RTRs compared to the healthy subjects. No difference was determined between the two groups regarding log10 DKK-1. No difference was noted in the levels of CA-IMT and baPWV in patients with log10 DKK-1 > 3.83 pg/mL compared to patients with ≤3.83 pg/mL. Correlation and multivariate analyses showed no correlation between log10 DKK-1 and CA-IMT and baPWV. DiscussionIn RTRs, an increased development of atherosclerosis and AS was observed compared to healthy individuals. There was no difference in DKK-1 between the groups based on improved renal function. DKK-1 was not correlated with atherosclerosis and AS.

High sugar diet promotes tumor progression paradoxically through aberrant upregulation of pepck1

High dietary sugar (HDS), a contemporary dietary concern due to excessive intake of added sugars and carbohydrates, escalates the risk of metabolic disorders and concomitant cancers. However, the molecular mechanisms underlying HDS-induced cancer progression are not completely understood. We found that phosphoenolpyruvate carboxykinase 1 (PEPCK1), a pivotal enzyme in gluconeogenesis, is paradoxically upregulated in tumors by HDS, but not by normal dietary sugar (NDS), during tumor progression. Targeted knockdown of pepck1, but not pepck2, specifically in tumor tissue in Drosophila in vivo, not only attenuates HDS-induced tumor growth but also significantly improves the survival of Ras/Src tumor-bearing animals fed HDS. Interestingly, HP1a-mediated heterochromatin interacts directly with the pepck1 gene and downregulates pepck1 gene expression in wild-type Drosophila. Mechanistically, we demonstrated that, under HDS conditions, pepck1 knockdown reduces both wingless and TOR signaling, decreases evasion of apoptosis, reduces genome instability, and suppresses glucose uptake and trehalose levels in tumor cells in vivo. Moreover, rational pharmacological inhibition of PEPCK1, using hydrazinium sulfate, greatly improves the survival of tumor-bearing animals with pepck1 knockdown under HDS. This study is the first to show that elevated levels of dietary sugar induce aberrant upregulation of PEPCK1, which promotes tumor progression through altered cell signaling, evasion of apoptosis, genome instability, and reprogramming of carbohydrate metabolism. These findings contribute to our understanding of the complex relationship between diet and cancer at the molecular, cellular, and organismal levels and reveal PEPCK1 as a potential target for the prevention and treatment of cancers associated with metabolic disorders.

Lysosomes accumulate at the perinuclear region of muscle cells during chick myogenesis.

Lysosomes are involved in a myriad of cellular functions, such as degradation of macromolecules, endocytosis and exocytosis, modulation of several signaling pathways, and regulation of cell metabolism. To fulfill these diverse functions, lysosomes can undergo several dynamic changes in their content, size, pH, and location within cells. Here, we studied some of these parameters during embryonic chick skeletal muscle cells. We used an anti-lysosome-associated membrane protein 2 (LAMP2) antibody to specifically determine the intracellular localization of lysosomes in these cells. Our data shows that lysosomes are highly enriched in the perinuclear region of chick embryonic muscle cells. We also showed that the wingless signaling pathway (Wnt)/β-catenin signaling pathway can modulate the location of LAMP2 in chick myogenic cells. Our results highlight the role of lysosomes during muscle differentiation and particularly the presence of a subcellular population of lysosomes that are concentrated in the perinuclear region of muscle cells.

Carboxypeptidase inhibitor Latexin (LXN) regulates intestinal organogenesis and intestinal remodeling involved in intestinal injury repair in mice

The self-renewal and regeneration of intestinal epithelium are mainly driven by intestinal stem cells resided in crypts, which are crucial for rapid recovery intestinal tissue following injury. Latexin (LXN) is a highly expressed stem cell proliferation and differentiation related gene in intestinal tissue. However, it is still ambiguous whether LXN participates in intestine regeneration by regulating intestinal stem cells (ISCs). Here, we report that LXN colocalizes with Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) in intestinal crypts, and deletion of LXN upregulates the expression of Lgr5 in intestinal crypts. LXN deficiency promotes the proliferation of ISCs, thereby enhances the development of intestinal organoids. Mechanically, we show that LXN deficiency enhances the expression of Lgr5 in ISCs by activating the Yes-associated protein (YAP) and wingless (Wnt) signal pathways, thus accelerating intestinal normal growth and regeneration post-injury. In summary, these findings uncover a novel function of LXN in intestinal regeneration post-injury and intestinal organogenesis, suggesting the potential role of LXN in the treatment of inflammatory bowel diseases.

E3 ubiquitin ligase Deltex facilitates the expansion of Wingless gradient and antagonizes Wingless signaling through a conserved mechanism of transcriptional effector Armadillo/β-catenin degradation.

The Wnt/Wg pathway controls myriads of biological phenomena throughout the development and adult life of all organisms across the phyla. Thus, an aberrant Wnt signaling is associated with a wide range of pathologies in humans. Tight regulation of Wnt/Wg signaling is required to maintain proper cellular homeostasis. Here, we report a novel role of E3 ubiquitin ligase Deltex in Wg signaling regulation. Drosophila dx genetically interacts with wg and its pathway components. Furthermore, Dx LOF results in a reduced spreading of Wg while its over-expression expands the diffusion gradient of the morphogen. We attribute this change in Wg gradient to the endocytosis of Wg through Dx which directly affects the short- and long-range Wg targets. We also demonstrate the role of Dx in regulating Wg effector Armadillo where Dx down-regulates Arm through proteasomal degradation. We also showed the conservation of Dx function in the mammalian system where DTX1 is shown to bind with β-catenin and facilitates its proteolytic degradation, spotlighting a novel step that potentially modulates Wnt/Wg signaling cascade.

CP-04. UNVEILING THE MYSTERIES OF PEDIATRIC ADAMANTINOMATOUS CRANIOPHARYNGIOMA - INSIGHTS FROM DIAGNOSIS TO ADVANCED THERAPEUTICS

Abstract BACKGROUND Adamantinomatous Craniopharyngiomas (ACPs) are rare tumors arising from the remnants of the craniopharyngeal duct epithelium. Their diagnosis poses unique challenges, often resulting in delayed identification due to their slow growth and nonspecific symptoms. Additionally, the prolonged overall survival (OS) is overshadowed by a substantial recurrence rate and late consequences, posing significant challenges, and impairing the patient’s quality of life (QoL). Recent advancements in understanding ACP’s genomic, transcriptomic, and proteomic aspects underscore the need for innovative treatments to mitigate these long-term consequences. METHODS We conducted an in-depth literature review, focusing on large clinical trials and major publications in ACP to provide a comprehensive perspective on the challenges in the diagnosis, treatment, and molecular aspects of pediatric ACP. RESULTS ACP’s clinical presentation involves increased intracranial pressure, endocrine abnormalities, and visual impairments. Despite their low-grade classification, ACPs exhibit aggressive clinical behavior, often invading or adhering to adjacent tissues, particularly critical neurovascular structures. Imaging techniques, including CT and MRI with a focus on hypothalamic involvement, play a crucial role in diagnosis, pre-operative evaluation, and surgical planning. Multidisciplinary approaches are essential for developing tailored treatment strategies. Neurosurgical management and radiotherapy, particularly proton therapy, are the primary therapeutic modalities. The molecular landscape reveals intricate and complex mechanisms and include the upregulation of the Wingless (WNT) signaling pathway driven by CTNNB1 mutations, along with involvement of inflammatory, programmed cell death, and the MAPK/ERK pathways. Ongoing trials exploring targeted therapies may play a pivotal role in refining treatment strategies and improving outcomes. CONCLUSIONS Navigating the complexities of ACP requires a multidisciplinary approach. Advances in diagnostics, surgical strategies, and targeted therapies, informed by molecular insights, offer promising avenues for improving outcomes and QoL. Ongoing collaborative efforts and participation in clinical trials are vital for refining treatment strategies and advancing the understanding of this challenging condition.

Serum sclerostin as a biomarker of disease activity in ankylosing spondylitis in correlation with radiographic imaging

BackgroundThe wingless signaling pathway of bone development is inhibited by sclerostin, which may contribute to the etiology of ankylosing spondylitis.AimThe study aimed to evaluate serum sclerostin levels in ankylosing spondylitis patients and investigate how it correlated with radiographic damage using the Spondylo-arthritis Research Consortium of Canada index (SPARCC), disease activity, and functional impairment.ResultsThis cross-sectional case–control study revealed a significantly lower mean serum sclerostin (11.28 ng/ml) in AS patients compared with controls (101.25 ng/ml). Serum sclerostin levels showed a significant negative correlation with each of Bath Ankylosing Spondylitis Metrology Index (BASMI) (p = 0.043), sacroiliac joints SPARCC, spine SPARCC, and overall SPARCC scores (p = 0.012, p = 0.036, and p = 0.007). The detection of AS, serum sclerostin levels ≤ 20 ng/ml showed 100% sensitivity and specificity.ConclusionSerum sclerostin had good discriminating power between ankylosing spondylitis cases and healthy control individuals and was correlated with subclinical activity status on magnetic resonance imaging.

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway

Background5-Fluorouracil (5FU) is a primary chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC). However, the development of drug resistance has significantly limited its clinical application. Therefore, there is an urgent need to determine the mechanisms underlying drug resistance and identify effective targets. In recent years, the Wingless and Int-1 (WNT) signaling pathway has been increasingly studied in cancer drug resistance; however, the role of WNT3, a ligand of the canonical WNT signaling pathway, in OSCC 5FU-resistance is not clear. This study delved into this potential connection.Methods5FU-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells underwent RNA sequencing analysis, which was then substantiated via Real-time quantitative PCR (RT-qPCR) and western blot tests. The influence of the WNT signaling on OSCC chemoresistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor methyl 3-benzoate (MSAB) was probed for its capacity to boost 5FU efficacy.ResultsIn this study, the WNT/β-catenin signaling pathway was notably activated in 5FU-resistant OSCC cell lines, which was confirmed through transcriptome sequencing analysis, RT-qPCR, and western blot verification. Additionally, the key ligand responsible for pathway activation, WNT3, was identified. By knocking down WNT3 in resistant cells or overexpressing WNT3 in parental cells, we found that WNT3 promoted 5FU-resistance in OSCC. In addition, the WNT inhibitor MSAB reversed 5FU-resistance in OSCC cells.ConclusionsThese data underscored the activation of the WNT/β-catenin signaling pathway in resistant cells and identified the promoting effect of WNT3 upregulation on 5FU-resistance in oral squamous carcinoma. This may provide a new therapeutic strategy for reversing 5FU-resistance in OSCC cells.

Ionizing radiation induces cells with past caspase activity that contribute to the adult organ in Drosophila and show reduced Loss of Heterozygosity

There is increasing recognition that cells may activate apoptotic caspases but not die, instead displaying various physiologically relevant consequences. Mechanisms that underlie the life-or-death decision in a cell that has activated apoptotic caspases, however, are incompletely understood. By optimizing a published reporter for past caspase activity, we were able to visualize cells that survived caspase activation specifically after exposure to ionizing radiation in Drosophila larval wing discs. We found that cells with X-ray-induced past active caspases (XPAC) did not arise at random but were born at specific locations within the developing wing imaginal discs of Drosophila larvae. Inhibiting key components of the apoptotic pathway decreased XPAC number, suggesting that apoptotic signaling is needed to induce XPAC cells. Yet, XPAC cells appeared in stereotypical patterns that did not follow the pattern of IR-induced apoptosis, suggesting additional controls at play. Functional testing identified the contribution of wingless (Drosophila Wnt1) and Ras signaling to the prevalence of XPAC cells. Furthermore, by following irradiated larvae into adulthood, we found that XPAC cells contribute to the adult wing. To address the relationship between XPAC and genome stability, we combined a reporter for past caspase activity with mwh, an adult marker for Loss of Heterozygosity (LOH). We found a lower incidence of LOH among XPAC compared to cells that did not activate the reporter for past caspase activity. In addition, at time points when wing disc cells are finishing DNA repair, XPAC cells show an anti-correlation with cells with unrepaired IR-induced double-stranded breaks. Our data suggest that non-lethal caspase activity safeguards the genome by facilitating DNA repair and reducing LOH after transient exposure to X-rays. These results identify a physiological role for non-lethal caspase activity during recovery from radiation damage.

Role for ubiquitin-specific protease 7 (USP7) in the treatment and the immune response to hepatocellular carcinoma: potential mechanisms.

Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme that can affect or regulate a variety of cellular activities. The purpose of this study was to investigate therapeutic and immunologic effects of USP7 in hepatocellular carcinoma (HCC), and as well to evaluate potential mechanisms of action. USP7-related gene expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) dataset, International Cancer Genome Consortium (ICGC) dataset, and Gene Expression Omnibus (GEO) dataset. Pathways associated with USP7 were determined by gene set enrichment analysis (GSEA). The relationships among USP7, immunity, and drug therapy were also investigated and potential mechanisms of action were explored. TCGA database results demonstrated USP7 mRNA expression levels to be upregulated in HCC tissues. Results were validated with UALCAN, ICGC, and GSE10143 datasets, as well as immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) experiments and were consistent with TCGA database findings (all P<0.05). GSEA analysis demonstrated increased USP7 levels to be associated with CHEMOKINE, Janus kinase/signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase (MAPK), P53, vascular endothelial growth factor (VEGF), and wingless (WNT) signaling pathways. Based on immune correlation analysis, USP7 was dramatically associated with immune cells and immune checkpoint molecules. In terms of drug therapy, USP7 expression levels were significantly related to HCC sensitivity to ciclosporin, talazoparib, dabrafenib, trametinib, paclitaxel, sorafenib, bortezomib, sunitinib, and crizotinib. Based on these results, we mechanistically propose an association between USP7 and these four drug targets: B-Raf proto-oncogene serine/threonine protein kinase (BRAF), mitogen-activated extracellular signal-regulated kinase (MEK), DNA topoisomerase I (TOPOI), and poly ADP-ribose polymerase (PARP). USP7 plays a therapeutic and immunological role in HCC. The four drug targets BRAF, MEK, TOPOI, and PARP are implicated in the USP7 mechanism of action.

The Wnt/β-catenin signaling pathway inhibits osteoporosis by regulating the expression of TERT: an in vivo and in vitro study.

Our study was performed to investigate whether the Wingless and int-1 (Wnt) signaling pathway promotes osteogenic differentiation and inhibits apoptosis in bone marrow mesenchymal stem cells (BMSCs) by regulating telomerase reverse transcriptase (TERT) expression. An in vivo model of osteoporosis (OP) in C57BL/6J mice by bilateral ovariectomy (OVX) and an in vitro model of H2O2-induced BMSCs were established separately. Western blotting was used to detect the expression of the pathway-related proteins TERT, β-catenin, and phosphorylated-glycogen synthase kinase-3beta (p-GSK3β)/GSK3β, the osteogenic-related markers osteopontin (OPN), bone morphogenetic protein 2 (BMP2), and runt-related transcription factor 2 (Runx2), and the apoptosis-related indicators B-cell lymphoma-2 (Bcl-2) and BAX. Osteoblastic phenotypes were also evaluated by alkaline phosphatase (ALP) staining and serum ALP activity assays. Osteogenic differentiation phenotypes in mice were verified by H&E staining, micro-CT, and parameter analysis of the femur. Western blotting results showed that the expression of the pathway-related proteins TERT, β-catenin, p-GSK3β/GSK3β was reduced in OVX mice and H2O2-induced BMSCs, accompanied by downregulated protein expression of osteogenic-related markers and antiapoptotic indicators and upregulated protein expression of apoptotic proteins compared to those in the control group. Mechanistic studies showed that the activation of Wnt signaling pathway in BMSCs promoted β-catenin translocation to the nucleus, as verified by immunofluorescence and facilitated colocalization between β-catenin and TERT, as verified by double-labeling immunofluorescence, thereby promoting osteogenic differentiation and reducing apoptosis. In summary, our experiments confirmed that the GSK3β/β-catenin/TERT pathway could regulate the osteogenic differentiation and apoptosis of BMSCs and that TERT might be a promising target for the future treatment of osteoporosis.

Natural Compounds for Carcinoma Therapy by Wingless Signaling Pathway Down-regulation

Abstract: Cancer is a prominent cause of death that places a significant financial strain on the healthcare system. Because of its prevalence, there is unquestionably unmet need for new chemotherapeutics. Atypical activation and deregulation of the wingless (Wnt) signaling pathway are considered one of the major causes of various types of carcinomas. This receptor activation is directly correlated with the activation of β -catenin and β -catenin-dependent transcription. In the modern era of drug development, natural compounds have shown to be an unrivaled source of anticancer medications. Herbal compounds have been identified as potent β-catenin signaling inhibitors, mainly by their downregulation, modulating its phosphorylation, increasing ubiquitination and proteasomal destruction, blocking nuclear translocation, or other molecular mechanisms. In vitro and in vivo studies have revealed that these natural product inhibitors can prevent and treat cancer in a variety of cancer models. Natural products have the potential to be promising novel molecules for cancer treatment, making them an essential topic of study. The importance of natural products in blocking the numerous signaling pathways that promote carcinogenesis is explored in this review, paving the way for developing and discovering anticancer medicines.

Loss of the extracellular matrix protein Perlecan disrupts axonal and synaptic stability during Drosophila development.

Heparan sulfate proteoglycans (HSPGs) form essential components of the extracellular matrix (ECM) and basement membrane (BM) and have both structural and signaling roles. Perlecan is a secreted ECM-localized HSPG that contributes to tissue integrity and cell-cell communication. Although a core component of the ECM, the role of Perlecan in neuronal structure and function is less understood. Here, we identify a role for Drosophila Perlecan in the maintenance of larval motoneuron axonal and synaptic stability. Loss of Perlecan causes alterations in the axonal cytoskeleton, followed by axonal breakage and synaptic retraction of neuromuscular junctions. These phenotypes are not prevented by blocking Wallerian degeneration and are independent of Perlecan's role in Wingless signaling. Expression of Perlecan solely in motoneurons cannot rescue synaptic retraction phenotypes. Similarly, removing Perlecan specifically from neurons, glia, or muscle does not cause synaptic retraction, indicating the protein is secreted from multiple cell types and functions non-cell autonomously. Within the peripheral nervous system, Perlecan predominantly localizes to the neural lamella, a specialized ECM surrounding nerve bundles. Indeed, the neural lamella is disrupted in the absence of Perlecan, with axons occasionally exiting their usual boundary in the nerve bundle. In addition, entire nerve bundles degenerate in a temporally coordinated manner across individual hemi-segments throughout larval development. These observations indicate disruption of neural lamella ECM function triggers axonal destabilization and synaptic retraction of motoneurons, revealing a role for Perlecan in axonal and synaptic integrity during nervous system development.

Loss of the extracellular matrix protein Perlecan disrupts axonal and synaptic stability during Drosophila development

Heparan sulfate proteoglycans (HSPGs) form essential components of the extracellular matrix (ECM) and basement membrane (BM) and have both structural and signaling roles. Perlecan is a secreted ECM-localized HSPG that contributes to tissue integrity and cell-cell communication. Although a core component of the ECM, the role of Perlecan in neuronal structure and function is less understood. Here, we identify a role for Drosophila Perlecan in the maintenance of larval motoneuron axonal and synaptic stability. Loss of Perlecan causes alterations in the axonal cytoskeleton, followed by axonal breakage and synaptic retraction of neuromuscular junctions. These phenotypes are not prevented by blocking Wallerian degeneration and are independent of Perlecan’s role in Wingless signaling. Expression of Perlecan solely in motoneurons cannot rescue synaptic retraction phenotypes. Similarly, removing Perlecan specifically from neurons, glia, or muscle does not cause synaptic retraction, indicating the protein is secreted from multiple cell types and functions non-cell autonomously. Within the peripheral nervous system, Perlecan predominantly localizes to the neural lamella, a specialized ECM surrounding nerve bundles. Indeed, the neural lamella is disrupted in the absence of Perlecan, with axons occasionally exiting their usual boundary in the nerve bundle. In addition, entire nerve bundles degenerate in a temporally coordinated manner across individual hemi-segments throughout larval development. These observations indicate disruption of neural lamella ECM function triggers axonal destabilization and synaptic retraction of motoneurons, revealing a role for Perlecan in axonal and synaptic integrity during nervous system development.

O-282 Role of extra-cellular vesicles in reproduction

Abstract Extracellular vesicles (EVs) are bilayer-membrane-bound vesicles isolated from biofluids and tissues. Recently, these organelles have been recognized as a novel mode for inter and intra-cellular communication. The three critical subtypes of EVs include exosomes, microvesicles, and apoptotic bodies. They can be discriminated according to their size, cargo, biogenesis, release pathways, and functions. These organelles serve as vehicles for transferring bioactive molecules as lipids, proteins, cytokines, and regulatory molecules as RNAs, locally and remotely. A wide range of cell types releases EVs, and their cargo differs under normal and pathological conditions. These facts make them possible biomarkers for diagnosing and treating different medical conditions. Isolation of EVs from various female and male reproductive tissues such as prostate, epididymis, seminal fluid, fallopian tube, cumulus, and mural granulosa cells, oocytes, embryos at various developmental stages, endometrium, and decidua has been described. Oogenesis, sperm maturation, fertilization, embryo development, and implantation are composite processes highly reliant on the interaction between tissues and cells. Existing data show that miRNAs and proteins in epididymal fluid associated with testicular maturation are transferred to the sperm by EVs Ovarian follicular growth is a synchronized process comprising bidirectional communication between the oocyte, cumulus, and mural granulosa cells. Some studies have identified EVs from several species' follicular fluid (FF), including bovine, equine, and human. To date, data linking EVs with oogenesis are primarily descriptive. EV micro-RNA (EV-miRNA) isolated from FF target pathways as mitogen-activated protein kinase (MAPK), wingless signaling pathway (WNT), epidermal growth factor receptor (ErbB), and transforming growth factor beta (TGFß). These pathways are related to folliculogenesis, meiotic resumption, and ovulation. EV-miRNAs isolated from follicles that contained mature oocytes were associated with fertilization potential and embryo quality. In addition, EVs derived from microvillous-rich oolemma may neutralize acrosome reaction and prevent polyspermy. Animal and human studies have confirmed that embryos at various developmental stages secrete EVs into the extracellular medium, and embryos internalize EVs. The number, miRNA profile, and size of EVs secreted vary across the cycle and according to embryos’ developmental potential. Endometrial EVs release miRNAs essential for the blastocyst's adhesion. In ovine, EVs were identified from the uterine lumen and uterine flushing during implantation. Uterine lumen flush EVs were internalized by the trophectoderm cells in the conceptus, reducing trophectoderm cell proliferation. The study of EVs in reproduction has increased exponentially in the last few years. Evidence support that these organelles contribute to oogenesis, fertilization, embryo development, and implantation. Further research in EVs will help us expand noninvasive methods and identify new biomarkers in the reproductive field.

Implication of Wnt/GSK-3β/β-Catenin Signaling in the Pathogenesis of Mood Disturbances Associated with Hyperthyroidism in Rats: Potential Therapeutic Effect of Naringin.

Patients with hyperthyroidism are commonly diagnosed with mood disorders. Naringin, (4',5,7-trihydrocyflavanone-7-O-rhamnoglucoside), a natural bioflavonoid, has many neurobehavioral activities including anxiolytic and antidepressant properties. The role of Wingless (Wnt) signaling in psychiatric disorders is considered substantial but debatable. Recently, regulation of Wnt signaling by naringin has been reported in different disorders. Therefore, the present study aimed to investigate the possible role of Wnt/GSK-3β/β-catenin signaling in hyperthyroidism-induced mood disturbances and explore the therapeutic effects of naringin. Hyperthyroidism was induced in rats by intraperitoneal injection of 0.3 mg/kg levothyroxine for 2 weeks. Naringin was orally administered to rats with hyperthyroidism at a dose of 50 or 100 mg/kg for 2 weeks. Hyperthyroidism induced mood alterations as revealed by behavioral tests and histopathological changes including marked necrosis and vacuolation of neurons in the hippocampus and cerebellum. Intriguingly, hyperthyroidism activated Wnt/p-GSK-3β/β-catenin/DICER1/miR-124 signaling pathway in the hippocampus along with an elevation in serotonin, dopamine, and noradrenaline contents and a reduction in brain-derived neurotrophic factor (BDNF) content. Additionally, hyperthyroidism induced upregulation of cyclin D-1 expression, malondialdehyde (MDA) elevation, and glutathione (GSH) reduction. Naringin treatment alleviated behavioral and histopathological alterations and reversed hyperthyroidism-induced biochemical changes. In conclusion, this study revealed, for the first time, that hyperthyroidism could affect mental status by stimulating Wnt/p-GSK-3β/β-catenin signaling in the hippocampus. The observed beneficial effects of naringin could be attributed to increasing hippocampal BDNF, controlling the expression of Wnt/p-GSK-3β/β-catenin signaling as well as its antioxidant properties.

Assessing the relationship between single nucleotide polymorphisms in Wingless signaling pathway genes and sella turcica morphology.

Sella turcica development involves molecular factors and genes responsible for ossification. It is possible that single nucleotide polymorphisms (SNPs) in key genes are involved in morphological variation of sella turcica. Genes belonging to the WNT signaling pathway are involved in the ossification process and are candidates of sella turcica morphology. This study aimed to evaluate if SNPs in WNT6 (rs6754599) and WNT10A (rs10177996 and rs3806557) genes are associated with the calcification and patterns of the sella turcica. Nonsyndromic individuals were included in the research. Cephalometric radiographs were examined and the sella calcification was evaluated and classified according to the calcification of the interclinoid ligament (no calcification, partial calcification, and incomplete calcification) and sella turcica pattern (normal sella turcica, bridge type A-ribbon-like fusion, bridge type B-extension of the clinoid processes, incomplete bridge, hypertrophic posterior clinoid process, hypotrophic posterior clinoid process, irregularity in the posterior part, pyramidal shape of the dorsum, double contour of the floor, oblique anterior wall, and oblique contour of the floor). DNA samples were used to evaluate SNPs in the WNT genes (rs6754599, rs10177996, and rs3806557) using real-time PCR. Chi-square test or Fisher's exact test were used to compare the allele and genotype distributions according to sella turcica phenotypes. The alpha was set as 5% for all comparisons. A total of 169 individuals were included, 133 (78.7%) present sella turcica partially or completely calcified. Sella turcica anomalies were found in 131 individuals (77.5%). Sella turcica bridge type A (27.8%), posterior hypertrophic clinoid process (17.1%), and sella turcica bridge type B (11.2%) were the most prevalent morphological patterns observed. Individuals carrying the TT genotype in rs10177996 (TT vs. CT + CC) had higher chance to present a partially calcified sella turcica (p=0.047; Odds ratio=2.27, Confidence Interval 95% 1.01-5.13). In conclusion, the SNP in WNT10A is associated with the calcification phenotype of the sella turcica, the pleiotropic effect of this gene should be taken into consideration in future studies.

Cellular compartmentalisation and receptor promiscuity as a strategy for accurate and robust inference of position during morphogenesis.

Precise spatial patterning of cell fate during morphogenesis requires accurate inference of cellular position. In making such inferences from morphogen profiles, cells must contend with inherent stochasticity in morphogen production, transport, sensing and signalling. Motivated by the multitude of signalling mechanisms in various developmental contexts, we show how cells may utilise multiple tiers of processing (compartmentalisation) and parallel branches (multiple receptor types), together with feedback control, to bring about fidelity in morphogenetic decoding of their positions within a developing tissue. By simultaneously deploying specific and nonspecific receptors, cells achieve a more accurate and robust inference. We explore these ideas in the patterning of Drosophila melanogaster wing imaginal disc by Wingless morphogen signalling, where multiple endocytic pathways participate in decoding the morphogen gradient. The geometry of the inference landscape in the high dimensional space of parameters provides a measure for robustness and delineates stiff and sloppy directions. This distributed information processing at the scale of the cell highlights how local cell autonomous control facilitates global tissue scale design.

Identification and validation of the pyroptosis-related long noncoding rna signature to predict the prognosis of patients with bladder cancer.

Bladder cancer ranked the second most frequent tumor among urological malignancies. This work investigated bladder cancer prognosis, including the relevance of pyroptosis-related long noncoding RNA (lncRNA) in it and its potential roles. The Cancer Genome Atlas database offered statistics on lncRNAs and clinical data from 411 bladder cancer patients. Pearson correlation analysis was used to evaluate pyroptosis-related lncRNAs. To explore prognosis-associated lncRNAs, we performed univariate Cox regression, least absolute shrinkage and selection operator regression analyses, as well as the Kaplan-Meier method. Multivariate Cox analysis was leveraged to establish the risk score model. Afterward, a nomogram was constructed according to the risk score and clinical variables. Finally, to investigate the potential functions of pyroptosis-related lncRNAs, gene set enrichment analysis was employed. Eleven pyroptosis-related lncRNAs were screened to be closely associated with patients prognosis. On this foundation, a risk score model was created to classify patients into high and low risk groups. The signature was shown to be an independent prognostic factor (P < .001) with an area under the curve of 0.730. Then a nomogram was established including risk scores and clinical characteristics. The nomogram prediction effect is excellent, with a concordance index of 0.86. The 11-lncRNAs signature was associated with the supervision of oxidative stress, epithelial-mesenchymal transition, cell adhesion, TGF-β, and Wingless and INT-1 signaling pathway, according to the gene set enrichment analysis. Our findings indicate that pyroptosis-related lncRNAs, which may affect tumor pathogenesis in many ways, might be exploited to assess the prognosis of bladder cancer patients.

Clinicomorphological and molecular analysis of medulloblastoma and association with survival: A single tertiary care center experience.

Medulloblastoma (MB) is a heterogeneous disease, displaying distinct genetic profiles, with specific molecular subgroups. Various clinical, pathological and molecular variables have been associated with disease outcome and therefore utilised in risk stratification of patients. To perform molecular classification of medulloblastoma using surrogate immunohistochemistry (IHC) and associate molecular subgroups, histopathological types, and available clinicopathological parameters with overall survival (OS) of MB patients. This study included 65 medulloblastoma patients. Immunohistochemical staining, using β-catenin YAP1 and GRB2-Associated Binding Protein 1 (GAB1) antibodies was used to classify MB cases into wingless signalling (WNT) activated, sonic hedgehog (SHH) activated, and non-WNT/non-SHH molecular subgroups. The relevant statistical analysis was done using GraphPad Prism version 9.3.0. Histological patterns included classic (40 cases, 62%), desmoplastic nodular (D/N) (14 cases, 22%), large cell/anaplastic (LC/A) (9 cases, 13%), medulloblastoma with extensive nodularity (MBEN) (1 case, 1.5%) and one special subtype, i.e., medulloblastoma with myogenic and melanotic differentiation. Molecular subgroups included WNT (4 cases, 6%), SHH (34 cases, 52%), and non-WNT/non-SHH (27 cases, 42%) subgroups. Histopathological types differed significantly according to tumor location, degree of anaplasia and molecular subgroups. Molecular subgroups differed significantly in age distribution and tumor location. The probability of survival was 78% and 68% after 1 and 2 years, respectively. Infants (<3 years of age), LC/A pattern, and TP53-mutant status among SHH subgroup conferred poor prognosis in our study. At the end of the study (at 65 months of maximum follow-up period) probability of survival was 51%. Immunohistochemical analysis helps in molecular classification of medulloblastoma in majority of the cases as well as helps in predicting prognosis and treatment response.