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Introduction: Hair loss is one of the common clinical conditions in modern society. Although it is not a serious disease that threatens human life, it brings great mental stress and psychological burden to patients. This study investigated the role of dendrobium officinale polysaccharide (DOP) in hair follicle regeneration and hair growth and its related mechanisms. Methods: After in vitro culture of mouse antennal hair follicles and mouse dermal papilla cells (DPCs), and mouse vascular endothelial cells (MVECs), the effects of DOP upon hair follicles and cells were evaluated using multiple methods. DOP effects were evaluated by measuring tentacle growth, HE staining, immunofluorescence, Western blot, CCK-8, ALP staining, tube formation, scratch test, and Transwell. LDH levels, WNT signaling proteins, and therapeutic mechanisms were also analyzed. Results: DOP promoted tentacle hair follicle and DPCs growth in mice and the angiogenic, migratory and invasive capacities of MVECs. Meanwhile, DOP was also capable of enhancing angiogenesis and proliferation-related protein expression. Mechanistically, DOP activated the WNT signaling and promoted the expression level of β-catenin, a pivotal protein of the pathway, and the pathway target proteins Cyclin D1, C-Myc, and LDH activity. The promotional effects of DOP on the biological functions of DPCs and MVECs could be effectively reversed by the WNT signaling pathway inhibitor IWR-1. Conclusion: DOP advances hair follicle and hair growth via the activation of the WNT signaling. This finding provides a mechanistic reference and theoretical basis for the clinical use of DOP in treating hair loss.

The Frizzleds (FZDs) receptors on the cell surface belong to the class F of G protein-coupled receptors (GPCRs) which are the major receptors of WNT protein that mediates the classical WNT signaling pathway and other non-classical pathways. Besides, the FZDs also play a core role in tissue regeneration and tumor occurrence. With the structure and mechanism of FZDs activation becoming clearer, a series of FZDs modulators (inhibitors and agonists) have been developed, with the hope of bringing benefits to the treatment of cancer and degenerative diseases. Most of the FZDs inhibitors (small molecules, antibodies or designed protein inhibitors) block WNT signaling through binding to the cysteine-rich domain (CRD) of FZDs. Several small molecules impede FZDs activation by targeting to the third intracellular domain or the transmembrane domain of FZDs. However, three small molecules (FZM1.8, SAG1.3 and purmorphamine) activate the FZDs through direct interaction with the transmembrane domain. Another type of FZDs agonists are bivalent or tetravalent antibodies which activate the WNT signaling via inducing FZD-LRP5/6 heterodimerization. In this article, we reviewed the FZDs modulators reported in recent years, summarized the critical molecules’ discovery processes and the elucidated relevant structural and pharmacological mechanisms. We believe the summaried molecular mechanisms of the relevant modulators could provide important guidance and reference for the future development of FZD modulators.

Osteoporosis, characterized by compromised bone density and microarchitecture, represents a significant global health challenge, particularly in aging populations. This comprehensive review delves into the intricate signaling pathways implicated in the pathogenesis of osteoporosis, providing valuable insights into the pivotal role of signal transduction in maintaining bone homeostasis. The exploration encompasses cellular signaling pathways such as Wnt, Notch, JAK/STAT, NF-κB, and TGF-β, all of which play crucial roles in bone remodeling. The dysregulation of these pathways is a contributing factor to osteoporosis, necessitating a profound understanding of their complexities to unveil the molecular mechanisms underlying bone loss. The review highlights the pathological significance of disrupted signaling in osteoporosis, emphasizing how these deviations impact the functionality of osteoblasts and osteoclasts, ultimately resulting in heightened bone resorption and compromised bone formation. A nuanced analysis of the intricate crosstalk between these pathways is provided to underscore their relevance in the pathophysiology of osteoporosis. Furthermore, the study addresses some of the most crucial long non-coding RNAs (lncRNAs) associated with osteoporosis, adding an additional layer of academic depth to the exploration of immune system involvement in various types of osteoporosis. Finally, we propose that SKP1 can serve as a potential biomarker in osteoporosis.

Background: Diesel exhaust particles (DEPs), a predominant component of ambient particulate matter (PM), are classified as ultrafine particles with the capacity to penetrate the cerebral blood-brain barrier (BBB). This penetration is implicated in the pathogenesis of central nervous system (CNS) disorders. The integrity of the BBB is inextricably linked to cerebrovascular homeostasis and the development of neurodegenerative disease, highlighting the importance of studying the effects and mechanisms of DEPs on BBB function damage. Methods and results: Utilizing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we explored the detrimental effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an upregulation in the secretion of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, , and diminished tight junction (TJ) protein expression. Microarray analysis revealed that 23 miRNAs were upregulated and 11 were downregulated in response to a 50 μg/mL DEPs treatment, with miR-466d-3p being notably differentially expressed. Wnt3 was identified as a target of miR-466d-3p, with the Wnt signaling pathway being significantly enriched. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/β-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and β-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression. Conclusions: Our study further confirmed that DEPs can induce the disruption of BBB integrity through inflammatory processes. We identified alterations in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a key regulator of tight junction (TJ) proteins, essential for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ β-catenin and Wnt/PCP signaling pathway can be activated by DEPs and are regulated by miR-466d-3p. Under the combined effects of Wnt/PCP and inflammation, there is an ultimate increase in BBB hyperpermeability. Methods and results: Employing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we investigated the adverse effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an increase in the release of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, loss of intercellular junctional organization, and diminished tight junction (TJ) protein expression. Microarray analysis disclosed that 23 miRNAs were upregulated and 11 were downregulated in bEND.3 cells treated with 50 μg/mL DEPs compared to the controls. In particular, miR-466d-3p was identified as a significantly differentially expressed miRNA. Wnt3 was predicted to be a target of miR-466d-3p, and the Wnt signaling pathway was identified as one of the most significantly enriched pathways. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/β-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and β-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression. Conclusions: Our study further confirmed that DEPs can induce the disruption of BBB integrity by inflammation. We identified changes in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a regulator of tight junction (TJ) proteins, which are critical for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ β-catenin and Wnt/PCP signaling pathway can be activated by DEPs and is regulated by miR-466d-3p, and under the combined effects of Wnt/PCP and inflammation ultimately led to hyperpermeability BBB.

A type of colorectal cancer (CRC)，Colitis-associated colorectal cancer (CAC)， is closely associated with chronic inflammation and gut microbiota dysbiosis. Berberine (BBR) has a long history in the treatment of intestinal diseases, which has been reported to inhibit colitis and CRC. However, the mechanism of its action is still unclear. Here, this study aimed to explore the potential protective effects of BBR on azoxymethane (AOM)/dextransulfate sodium (DSS)-induced colitis and tumor mice, and to elucidate its potential molecular mechanisms by microbiota, genes and metabolic alterations. The results showed that BBR inhibited the gut inflammation and improved the function of mucosal barrier to ameliorate AOM/DSS-induced colitis. And BBR treatment significantly reduced intestinal tumor development and ki-67 expression of intestinal tissue along with promoted apoptosis. Through microbiota analysis based on the 16 S rRNA gene, we found that BBR treatment improved intestinal microbiota imbalance in AOM/DSS-induced colitis and tumor mice, which were characterized by an increase of beneficial bacteria, for instance Akkermanisa, Lactobacillus, Bacteroides uniformis and Bacteroides acidifaciens. In addition, transcriptome analysis showed that BBR regulated colonic epithelial signaling pathway in CAC mice particularly by tryptophan metabolism and Wnt signaling pathway. Notably, BBR treatment resulted in the enrichment of amino acids metabolism and microbiota-derived SCFA metabolites. In summary, our research findings suggest that the gut microbiota-amino acid metabolism-Wnt signaling pathway axis plays critical role in maintaining intestinal homeostasis, which may provide new insights into the inhibitory effects of BBR on colitis and colon cancer.

Globally cancer and Alzheimer's disease (AD) are two major diseases and still, there is no clearly defined molecular mechanism. There is an opposite relation between cancer and AD which are the proportion of emerging cancer was importantly slower in AD patients, whereas slow emerging AD in patients with cancer. In cancer, regulation of cell mechanisms is interrupted by an increase in cell survival and proliferation, while on the contrary, AD is related to augmented neuronal death, that may be either produced by or associated with amyloid-β (Aβ) and tau deposition. Stated that the probability that disruption of mechanisms takes part in the regulation of cell survival/death and might be implicated in both diseases. The mechanism of actions such as DNA-methylation, genetic polymorphisms, or another mechanism of actions that induce alteration in the action of drugs with significant roles in resolving the finding to repair and live or die might take part in the pathogenesis of these two ailments. The functions of miRNA, p53, Pin1, the Wnt signaling pathway, PI3 KINASE/Akt/mTOR signaling pathway GRK2 signaling pathway, and the pathophysiological role of oxidative stress are presented in this review as potential candidates which hypothetically describe inverse relations between cancer and AD. Innovative materials almost mutual mechanisms in the aetiology of cancer and AD advocates novel treatment approaches. Among these treatment strategies, the most promising use treatment such as tyrosine kinase inhibitor, nilotinib, protein kinase C, and bexarotene.

Background: Intestinal stem cells (ISCs) are the reservoir source of various types of intestinal cells, and the decline of stem cell function in the gut may be a potential factor for aging-related disease. The present study aimed to explore the regulatory mechanisms of Panax ginseng C.A.Meyer (Araliaceae, Panax genus) that could restore gut aging by enhancing intestinal function and regulating ISCs in aging mice based on the Wnt/β-catenin signaling pathway. Methods: A total of 60 ICR male mice were randomly divided into control, model, metformin, and ginseng water decoction (GWD) 3.6, 1.8, and 0.9 g/kg groups. The aging model was induced by 1 % D-galactose (s.c. 0.1 mL/10 g) for 28 days. Moreover, GWD was given to aging mice intragastrically (i.g.) once a day for 28 successive days. The learning memory ability, pathological status, and function in the ileum tissue, the activity of digestive enzymes, and short-chain fatty acid (SCFA) content in the colon were evaluated, and the related mechanism was investigated. Results: Ginseng can decrease the escape latency time and increase the swimming speed and the number of crossing platforms in aging mice. Moreover, the pathology of ileum tissue improved, the length of the intestinal villi increased, and the width of the villi and the depth of the crypts decreased. The activities of trypsin, α-amylase, and lipase increased in duodenal content and intestinal mucosa. In the colon, the content of SCFA, such as acetic acid, propionic acid and butyric acid, increased, indicating that ginseng significantly improves intestinal function impairment. The mRNA expressions and protein levels of β-catenin, C-myc, GSK-3β, Lgr5, and Olfm4 were upregulated in the ginseng group. Conclusions: Ginseng improves intestinal function and regulates the function of ISCs in order to protect intestinal health by activating the Wnt/β-catenin signaling pathway in aging mice.

Objective: Many factors during pregnancy can induce intrauterine growth restriction (IUGR), resulting in various adverse perinatal outcomes such as low birth weight and multiple organ disorders. Among these factors, prenatal smoke/nicotine exposure is a common cause of IUGR, often associated with altered fetal lung development. The classical Wnt signaling pathway plays a vital role in lung development, and its alterations are commonly associated with developmental lung pathologies. The purpose of this study was to determine whether electroacupuncture (EA) at ''Zusanli'' (ST 36) points protects perinatal nicotine exposure (PNE)-induced offspring lung dysplasia through Wnt/β-catenin signaling pathway and to identify specific Wnt signaling pathway targets of EA. Methods: Following a well-established protocol, nicotine (1 mg/kg/ body weight) was administered subcutaneously to pregnant Sprague Dawley rat dams from gestational day 6 to postnatal day 21. In the EA group, dams were treated with EA at both ST 36 acupoints, while in another experimental group, Wnt/β-catenin signaling pathway agonist was injected subcutaneously (2 mg/kg/ body weight). Offspring body weight (PND 1, 7, 14, and 21), lung weight, Wnt signaling markers, pulmonary function, and lung morphology were determined at sacrifice on PND 21. Specifically, Western blotting and Real-time PCR were used to detect the protein and mRNA levels of critical Wnt signaling markers Wnt2, Wnt7b, FZD4, FZD7, LRP5, and LRP6 in the offspring lung. The protein levels of β-catenin in lung tissue of offspring rats were detected by ELISA that of LEF-1 by Western blotting. Results: Compared to the control group, the body and lung weights of the offspring rats were significantly decreased in the nicotine-only exposed group. The pulmonary function determined as FVC, PEF, TV, and Cdyn was also significantly decreased, while PIF was significantly increased. The protein levels and mRNA expression of Wnt2, Wnt7b, FZD4, FZD7, LRP5, and LRP6 in the lung tissue of the PNE offspring rats were significantly increased. With EA administration at ST 36 acupoints concomitant with nicotine administration, the body and lung weights, pulmonary function (FVC, PEF, PIF, TV, and Cdyn), protein and mRNA levels Wnt signaling pathway markers (Wnt2, Wnt7b, FZD4, FZD7, LRP5, LRP6, β-catenin, and LEF-1) normalized and were not different from the control group. Notably, Wnt agonists agonist administration blocked the protective effects of EA against PNE-induced lung morphological, molecular, and function changes, highlighting the central significance of Wnt pathway signaling in PNE-induced offspring pulmonary pathology and its modulation by EA at ST 36 acupoints. Conclusion: Concomitant maternal EA at ST 36 acupoints from gestational day 6 to PND 21 protects against offspring PNE-induced lung phenotype. The protective effect is achieved by regulating the expression of Wnt ligand proteins (Wnt2 and Wnt7b) and receptor proteins (FZD4, FZD7, LRP5, and LRP6) upstream of the Wnt/β-catenin signaling pathway intermediates β-catenin, and LEF-1.

Phenylethanoid glycosides derived from Cistanche deserticola (PhGs) are plant-derived natural medicinal compounds that occur in many medicinal plants. This study aims to investigate whether PhGs treatment improves the stroke and its potential mechanisms. Adult male C57BL/6 J mice were administrated PhGs once daily for 7 days after MCAO surgery. The neurological score, and catwalk were evaluated on Day 1, 3 and 7 after ischemic stroke. Furthermore, triphenyl-2,3,5-tetrazoliumchloride (TTC) and hematoxylin-eosin (H&E) staining were used for evaluating the infarct volume and neuronal restoration. The effects of PhGs on NSCs proliferation were investigated in vitro and in vivo. Western blot was used to detect the proteins of Wnt/β-catenin signaling pathway. This study found that PhGs effectively improved the neurological functions in ischemic stroke mice. TTC and H&E staining demonstrated that PhGs not only reduced infarct volume, but also improved neuronal restoration. The immunohistochemistry and 5-Ethynyl-2-deoxyuridine (EdU) incorporation assays revealed that PhGs promoted the proliferation of neural stem cells (NSCs) in subventricular zone (SVZ). In addition, transcriptome analysis of NSCs showed that the Wnt/β-catenin signaling pathway was involved in the PhGs induced NSCs proliferation. Importantly, the related proteins in the Wnt/β-catenin signaling pathway were changed after PhGs treatment, including β-catenin, Wnt3a, GSK-3β, c-Myc. PhGs treatment improved the stroke through enhancing endogenous NSCs proliferation via activating Wnt/β-catenin signaling pathway. Due to its effect on the proliferation of NSCs, PhGs are a potential adjuvant therapeutic drug for post-stroke treatment.

Gold nanoparticle (AuNPs) influence the biomedical sciences owing to different potential characteristics and potential features. To date, the bioinspired fabrication of AuNPs is further recognized due to their safety and efficacy. In this study, we synthesized AuNPs using leaf extract of Citrus medica (C. medica) and well-characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and UV–visible analyses. Afterward the selective anticancer effects of biosynthesized AuNPs against HepG2 cells were evaluated by different techniques including MTT, oxidative markers, qPCR, and western blot assays.The results showed that the polyphenols of the C. medica leaf extract was responsible for the bioinspired reduction and stability of the AuNPs with a powder size in the range of 20–50 nm. Additionally, it was seen that biosynthesized AuNPs show selective inhibition on the proliferation of HepG2 (human liver cancer cell line) relative to THLE3 (normal adult liver epithelial cells) via generation of ROS and MDA, reduction of GSH level and SOD activity, and over expression of Bax/Bcl-2 and Caspase-3 mRNA. It was also shown that biosynthesized AuNPs regulate the Wnt signaling pathway through upregulation of phosphorylated GSK-3β known as the inactivated form of GSK-3β and downregulation of β-catenin and Cyclin-D1 at protein level. This study may hold great promise for development of NP-based anticancer agents, although it needs further investigations in vivo.

T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive hematologic malignancy. It progresses quickly and it is likely to be fatal within a few months without treatment. Despite the limitations of current clinical therapies, there is an urgent need for novel and targeted therapies. To explore potential targeted therapies, molecular genetic mechanisms of T-ALL metastasis must be uncovered. However, the genes and mechanisms that mediate T-ALL metastasis are largely unknown. Recent insights into T-ALL biology have identified several genes that can be grouped into several targetable signaling pathways. The Wnt/β-catenin signaling pathway is one of the most important pathways. Our work investigated the functions of TCF1 and LEF1 in cell growth and migration mediated by the Wnt signaling pathway. We found that TCF1 and LEF1 knockdown weakly repressed T-ALL cell proliferation but distinctly impaired cell migration. T-ALL metastasis is dependent on cell migration and invasion. Our results displayed that TCF1 and LEF1 regulated T-ALL cell migration by the Wnt-dependent chemokine and cytokine-induced inflammation and cadherin signaling pathways. By transcriptionally regulating these pathways-associated genes, TCF1 and LEF1 inhibited cell adhesion and promoted cell migration and invasion.

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-1β, TNF-α, IL-6, Wnt10b, β-catenin, cyclin-D1 in articular cartilage, c-Myc in synovial membrane, and immunofluorescence analysis for c-Fos, Wnt-10b and β-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, β-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 β-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.

Adriamycin (ADR), one of the most effective broad-spectrum antitumor chemotherapeutic agents in clinical practice, is used to treat solid tumors as well as hematological malignancies in adults and children. However, long-term ADR use causes several adverse reactions, including time- and dose-dependent cardiotoxicity, which limit its clinical application. In addition, the mechanism by which ADR induces cardiotoxicity remains unclear. Therefore, we used zebrafish as animal models to evaluate ADR toxicity during embryonic heart development owing to the similarity of this process in zebrafish to that in humans. Exposure of zebrafish embryos to 1.25, 2.5, and 5 mg/L ADR induced abnormal embryonic development, with the occurrence of cardiac malformations, pericardial edema, decreased movement speed and activity, and increased distance between the venous sinus and the arterial bulb (SV-BA). ADR exposure induced dysregulated cardiogenesis during the precardiac mesoderm formation period. We also observed irregular expression of cardiac-related genes, an upregulation of apoptotic gene expression, and a dose-dependent increase in oxidative stress levels. Furthermore, oxidative stress-induced apoptosis exerted deleterious effects on cardiac development in zebrafish embryos, and treatment with astaxanthin (ATX) alleviated these heart defects. ADR- and Wnt pathway-related genes exhibited good energy and spatial matching, and ADR upregulated the Wnt signaling pathway in zebrafish. Moreover, IWR-1 effectively alleviated ADR-induced heart defects. In conclusion, we demonstrated that the toxic effects of ADR on cardiac development in zebrafish embryos could provide a theoretical basis for explaining the pathogenesis of ADR-induced cardiotoxicity, which occurs through the upregulation of oxidative stress and Wnt signaling pathway, as well as its prevention and treatment in humans. These findings will help develop effective treatment strategies to combat ADR-induced cardiotoxicity and broaden the application of ADR for clinical practice.

The Wnt signaling pathway plays a critical role in almost all aspects of skeletal development and homeostasis. Many studies suggest the importance of this signaling pathway in connection with bone metabolism through many skeletal disorders caused by mutations in Wnt signaling genes. The knowledge gained through targeting this pathway is of great value for skeletal health and diseases, for example of increased bone mass in the case of osteoporosis. Our objective was to focus on the detection of single nucleotide polymorphisms and investigate the associations between possible polymorphisms in selected genes that are part of those signaling pathways and parameters of bones in hens of ISA Brown hybrids (bone breaking strength, length, width, and bone mass). Different regions of the GPR177, ESR1 and RUNX2 genes were studied, using PCR and sequencing, in a total of forty-eight samples for each marker. Thirteen polymorphisms have been discovered in selected regions of studied genes, whereas these polymorphisms were only within the GPR177 gene. Eight of these polymorphisms were synonymous and five were in the intron. The tested regions of the ESR1 and RUNX2 genes were monomorphic. The only statistically significant difference was found within the GPR177 gene (exon 2) and the bone length parameter, in the c.443 + 86G > A polymorphism. However, this polymorphism was found in the intron, and no other one was found within the selected regions to show associations with the observed bone parameters.

Background: Alveolar capillary endothelial cell (EC) injury has a pivotal role in driving acute respiratory distress syndrome (ARDS) progression and maintaining endothelial homeostasis. A previous ex vivo study revealed that overexpression of homeobox B4 (HOXB4) in bone marrow mesenchymal stem cells (BMSCs) enhanced protection against lipopolysaccharide (LPS)-induced EC injury by activating the Wnt/β-catenin pathway. This in vivo study was performed to verify whether BMSCs overexpressing HOXB4 exert similar protective effects on LPS-induced acute lung injury (ALI) in an animal model., Methods: The ALI rat model was established by intraperitoneal injection of LPS. Wildtype BMSCs or BMSCs overexpressing HOXB4 were then injected via the tail vein. The lung characteristics of rats were visualized by computed tomography. Lung histopathological characteristics and collagen deposition were assessed by hematoxylin-eosin and Masson's staining, respectively, which were combined with the lung wet/dry ratio and proinflammatory factor levels in bronchoalveolar lavage fluid to further evaluate therapeutic effects. Expression of β-catenin and VE-cadherin was assessed by western blotting and immunofluorescence., Results: Compared with wildtype BMSCs, overexpression of HOXB4 optimized the therapeutic effects of BMSCs, which manifested as improvements in lung exudation and histopathological features, reduced lung collagen deposition, amelioration of lung permeability, attenuation of lung inflammation, and enhanced expression of β-catenin and VE-cadherin proteins., Conclusions: HOXB4-overexpressing BMSCs optimized the protective effect against LPS-induced ALI by partially activating Wnt/β-catenin signaling., Competing Interests: Declaration of competing interest The author has no financial or other conflicts of interest to disclose., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: Diesel exhaust particles (DEPs), a predominant component of ambient particulate matter (PM), are classified as ultrafine particles with the capacity to penetrate the cerebral blood-brain barrier (BBB). This penetration is implicated in the pathogenesis of central nervous system (CNS) disorders. The integrity of the BBB is inextricably linked to cerebrovascular homeostasis and the development of neurodegenerative disease, highlighting the importance of studying the effects and mechanisms of DEPs on BBB function damage., Methods and Results: Utilizing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we explored the detrimental effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an upregulation in the secretion of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, , and diminished tight junction (TJ) protein expression. Microarray analysis revealed that 23 miRNAs were upregulated and 11 were downregulated in response to a 50 μg/mL DEPs treatment, with miR-466d-3p being notably differentially expressed. Wnt3 was identified as a target of miR-466d-3p, with the Wnt signaling pathway being significantly enriched. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/β-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and β-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression., Conclusions: Our study further confirmed that DEPs can induce the disruption of BBB integrity through inflammatory processes. We identified alterations in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a key regulator of tight junction (TJ) proteins, essential for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ β-catenin and Wnt/PCP signaling pathway can be activated by DEPs and are regulated by miR-466d-3p. Under the combined effects of Wnt/PCP and inflammation, there is an ultimate increase in BBB hyperpermeability., Methods and Results: Employing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we investigated the adverse effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an increase in the release of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, loss of intercellular junctional organization, and diminished tight junction (TJ) protein expression. Microarray analysis disclosed that 23 miRNAs were upregulated and 11 were downregulated in bEND.3 cells treated with 50 μg/mL DEPs compared to the controls. In particular, miR-466d-3p was identified as a significantly differentially expressed miRNA. Wnt3 was predicted to be a target of miR-466d-3p, and the Wnt signaling pathway was identified as one of the most significantly enriched pathways. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/β-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and β-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression., Conclusions: Our study further confirmed that DEPs can induce the disruption of BBB integrity by inflammation. We identified changes in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a regulator of tight junction (TJ) proteins, which are critical for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ β-catenin and Wnt/PCP signaling pathway can be activated by DEPs and is regulated by miR-466d-3p, and under the combined effects of Wnt/PCP and inflammation ultimately led to hyperpermeability BBB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Clarifying the cellular origin and regulatory mechanisms of intramuscular fat (IMF) deposition is crucial for improving beef quality. Here, we used single-nucleus RNA sequencing to analyze the structure and heterogeneity of skeletal muscle cell populations in different developmental stages of Yanbian cattle and identified eight cell types in two developmental stages of calves and adults. Among them, fibro/adipogenic progenitors (FAPs) expressing CD29 (ITGA7) pos and CD56 (NCAM1) neg surface markers were committed to IMF deposition in beef cattle and expressed major Wnt ligands and receptors. LY2090314/XAV-939 was used to activate/inhibit Wnt/β-catenin signal. The results showed that the blockade of Glycogen Synthase Kinase 3 (GSK3) by LY2090314 promoted the stabilization of β-catenin and reduced the expression of genes related adipogenic differentiation (e.g., PPARγ and C/EBPα) in bovine FAPs, confirming the anti-adipogenic effect of GSK3. XAV-939 inhibition of the Wnt/β-catenin pathway promoted the lipid accumulation capacity of FAPs. Furthermore, we found that blocking GSK3 enhanced the paracrine effects of FAPs-MuSCs and increased myotube formation in muscle satellite cells (MuSCs). Overall, our results outline a single-cell atlas of skeletal muscle development in Yanbian cattle, revealed the role of Wnt/GSK3/β-catenin signaling in FAPs adipogenesis, and provide a theoretical basis for further regulation of bovine IMF deposition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Serving as a part of intestinal innate immunity, Paneth cells play an important role in intestinal homeostasis maintenance via their multiple functions. However, the regulation of Paneth cells has been proven to be complex and diverse. Here, we identified nuclear receptor Nur77 as a novel regulator of Paneth cell differentiation and function. Nur77 deficiency led to the loss of Paneth cells in murine ileal crypts. Intestinal tissues or organoids with Nur77 deficiency exhibited the impaired intestinal stem cell niche and failed to enhance antimicrobial peptide expression after Paneth cell degranulation. The defects in Paneth cells and antimicrobial peptides in Nur7 -/- mice led to intestinal microbiota disorders. Nur77 deficiency rendered postnatal mice susceptible to necrotizing enterocolitis. Mechanistically, Nur77 transcriptionally inhibited Dact1 expression to activate Wnt signaling activity, thus promoting Paneth cell differentiation and function. Taken together, our data suggest the regulatory role of Nur77 in Paneth cell differentiation and function and reveal a novel Dact1-mediated Wnt inhibition mechanism in Paneth cell development., (Copyright © 2023. Published by Elsevier Inc.)

In the zebrafish lateral line, non-sensory supporting cells readily re-enter the cell cycle to generate new hair cells and supporting cells during homeostatic maintenance and following damage to hair cells. This contrasts with supporting cells from mammalian vestibular and auditory sensory epithelia which rarely re-enter the cell cycle, and hence loss of hair cells results in permanent sensory deficit. Lateral line supporting cells are derived from multipotent progenitor cells that migrate down the trunk midline as a primordium and are deposited to differentiate into a neuromast. We have found that we can revert zebrafish support cells back to a migratory progenitor state by pharmacologically altering the signaling environment to mimic that of the migratory primordium, with active Wnt signaling and repressed FGF signaling. The reverted supporting cells migrate anteriorly and posteriorly along the horizontal myoseptum and will re-epithelialize to form an increased number of neuromasts along the midline when the pharmacological agents are removed. These data demonstrate that supporting cells can be readily reprogrammed to a migratory multipotent progenitor state that can form new sensory neuromasts, which has important implications for our understanding of how the lateral line system matures and expands in fish and also suggest avenues for returning mammalian supporting cells back to a proliferative state., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Frizzleds (FZDs) receptors on the cell surface belong to the class F of G protein-coupled receptors (GPCRs) which are the major receptors of WNT protein that mediates the classical WNT signaling pathway and other non-classical pathways. Besides, the FZDs also play a core role in tissue regeneration and tumor occurrence. With the structure and mechanism of FZDs activation becoming clearer, a series of FZDs modulators (inhibitors and agonists) have been developed, with the hope of bringing benefits to the treatment of cancer and degenerative diseases. Most of the FZDs inhibitors (small molecules, antibodies or designed protein inhibitors) block WNT signaling through binding to the cysteine-rich domain (CRD) of FZDs. Several small molecules impede FZDs activation by targeting to the third intracellular domain or the transmembrane domain of FZDs. However, three small molecules (FZM1.8, SAG1.3 and purmorphamine) activate the FZDs through direct interaction with the transmembrane domain. Another type of FZDs agonists are bivalent or tetravalent antibodies which activate the WNT signaling via inducing FZD-LRP5/6 heterodimerization. In this article, we reviewed the FZDs modulators reported in recent years, summarized the critical molecules' discovery processes and the elucidated relevant structural and pharmacological mechanisms. We believe the summaried molecular mechanisms of the relevant modulators could provide important guidance and reference for the future development of FZD modulators., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Single-driver molecular events specific to the metabolic colorectal cancer (CRC) have not been clearly elucidated. Herein, we identified 12 functional miRNAs linked to activated metabolism by integrating multi-omics features in metabolic CRC. These miRNAs exhibited significantly enriched CRC driver miRNAs, significant impacts on CRC cell growth and significantly correlated metabolites. Importantly, miR-20a is minimally expressed in normal colorectal tissues but highly expressed in metabolic CRC, suggesting the potential therapeutic target. Bioinformatics analyses further revealed miR-20a as the most powerful determinant that regulates a cascade of dysregulated events, including Wnt signaling pathway, core enzymes involved in FA metabolism program and triacylglycerol abundances. In vitro assays demonstrated that elevated miR-20a up-regulated FA synthesis enzymes via Wnt/β-catenin signaling, and finally promoted proliferative and migration of metabolic CRC cells. Overall, our study revealed that miR-20a promoted progression of metabolic CRC by regulating FA metabolism and served as a potential target for preventing tumor metastasis.

Summary: β-Catenin is a central component in the Wnt signaling pathway; its degradation has been tightly connected to ubiquitylation, but it is rarely examined by loss-of-function assays. Here we observe that endogenous β-catenin is not stabilized upon ubiquitylation depletion by a ubiquitylation inhibitor, TAK-243. We demonstrate that N-terminal phosphorylated β-catenin is quickly and strongly stabilized by a specific neddylation inhibitor, MLN4924, in all examined cell types, and that β-catenin and TCF4 interaction is strongly enhanced by inhibition of neddylation but not ubiquitylation. We also confirm that the E3 ligase β-TrCP2, but not β-TrCP1, is associated with neddylation and destruction of β-catenin. GSK3β and adenomatous polyposis coli (APC) are not required for β-catenin neddylation but essential for its subsequent degradation. Our findings not only clarify the process of β-catenin modification and degradation in the Wnt signaling pathway but also highlight the importance of reassessing previously identified ubiquitylation substrates.

Glycogen synthase kinase-3 beta (GSK-3β) is a desired pharmacological target for cancer treatment. Despite its role in the development of various cancers, any target directing GSK-3 inhibitors have not been authorized for cancer treatment. The therapeutic importance of this enzyme is reflected in its monitoring character in autophagy, genetic material mismatch correction, tumor development, and invasion, which justifies medication combinations. GSK-3 controls various cell processes, including metabolism, signaling, and structural proteins. It modulates programmed cell death-ligand 1 (PD-L1) by phosphorylating target pro-oncogenes. New evidence on GSK-3 as a modulator of the antineoplastic immune response further highlights the potential uses of new GSK-3β selective antagonists currently being tested in humans. Indole, indazole, oxadiazole, isothiazolidinedione, and morpholine congeners are the privileged heterocyclic nucleus in drug discovery. These scaffolds produced numerous biological activities in which anticancer is important. The structure activity relationship studies may support to explore the design and synthesis of potential scaffolds in short time period. Therefore, in the present review, we tried to explore the structural aspects of GSK-3β with their structure–activity relationship against various targets for developing potential compounds. The GSK3β antagonists in clinical and preclinical trials have been reviewed in this study. And we tried to explore the structural aspects of several GSK-3β inhibitors with their structure–activity relationship for developing potential anticancer compounds, which will aid scientists in developing more target-specific therapeutic compounds with lower toxicity in the future.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a bladder syndrome of unknown etiology. Reactive oxygen species (ROS) plays a major role in ferroptosis and bladder dysfunction of IC/BPS, while the role of ferroptosis in IC/BPS progression is still unclear. This study aims to investigate the role and mechanism of ROS-induced ferroptosis in IC/BPS using cell and rat model., Methods: We collected IC/BPS patient bladder tissue samples and established a LPS-induced IC/BPS rat model (LRM). The level of oxidative stress and ferroptosis in IC/BPS patients and LRM rats was analyzed. Function and regulatory mechanism of ferroptosis in IC/BPS were explored by in vitro and in vivo experiments., Results: The patients with IC/BPS showed mast cells and inflammatory cells infiltration in bladder epithelial tissues. Expression of NRF2 was up-regulated, and GPX4 was decreased in IC/BPS patients compared with normal tissues. IC model cells underwent oxidative stress, which induced ferroptosis. These above results were validated in LRM rat models, and inhibition of ferroptosis ameliorated bladder dysfunction in LRM rats. Wnt/β-catenin signaling was deactivated in IC/BPS patients and animals, and activation of Wnt/β-catenin signaling reduced cellular free radical production, thereby inhibited ferroptosis in IC model cells. Mechanistically, the Wnt/β-catenin signaling pathway inhibited oxidative stress-induced ferroptosis by down-regulating NF-κB, thus contributing to recover IC/BPS both in vitro and in vivo., Conclusions: We demonstrate for the first time that oxidative stress-induced ferroptosis plays an important role in the pathology of IC/BPS. Mechanistically, the Wnt/β-catenin signaling suppressed oxidative stress-induced ferroptosis by down-regulating NF-κB to improve bladder injury in IC/BPS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Myocardial fibrosis is an important pathological feature of dilated cardiomyopathy (DCM). The roles of SOCS2 in fibrosis of different organs are controversial. Herein, we investigated the function and potential mechanism of SOCS2 in myocardial fibrosis., Methods: Bioinformatics, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), real-time fluorescence quantitative PCR (qPCR), rat primary myocardial fibroblasts (rCFs) culture, doxorubicin (DOX) induced mouse dilated cardiomyopathy (DCM) model, and in vivo adeno-associated virus (AAV) infection were used to explore the role of SOCS2 in DCM., Results: Bioinformatics analysis showed that SOCS2 was positively correlated with fibrosis related factors. SOCS2 was significantly upregulated in patients and mice with DCM. In vivo experiments showed that targeted inhibition of cardiac SOCS2 could improve mouse cardiac function and alleviate myocardial fibrosis. Further research demonstrated that SOCS2 promoted the transformation of myofibroblasts. Knockdown of SOCS2 reduced the nuclear localization of β-catenin, which inhibited the fibrogenic effect of Wnt/β-catenin pathway. In addition, bioinformatics analysis suggested that lymphoid enhancer binding factor 1 (LEF1) was significantly positively correlated with SOCS2. Finally, dual luciferase assays demonstrated that LEF1 could bind to the promoter region of SOCS2, thereby mediating its transcriptional activation., Conclusion: SOCS2 could activate the Wnt/β-catenin by regulating the nuclear translocation of β-catenin, which induces the transcriptional activation of SOCS2. Overall, these results indicated a positive feedback activation phenomenon between SOCS2, β-catenin and LEF1 in DCM. These results suggested that inhibition of SOCS2 could effectively alleviate the progression of myocardial fibrosis and improve cardiac function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

After winemaking, tannins with high polymerization remain in the pomace. Utilizing these tannin fractions is a concern for the wine industry. While tannins show potential in treating hyperpigmentation, their mechanisms in vivo and at the cellular level are unclear. Herein, pomace tannin fractions (PTFs) were isolated post-winemaking. Nuclear magnetic resonance spectroscopy and mass spectrometry analysis showed PTFs were composed of (epi)catechin gallate and (epi)catechin as terminal and extensional units, with polymerization degrees of 10, 16, and 35. In vivo studies demonstrated that PTFs removed ∼76 % of skin melanin, comparable to hydroquinone. The inhibition by PTFs is due to: (1) Inhibition of the Wnt and melanogenesis pathways, downregulating key melanin synthesis proteins (TYR, TYRP1, TYRP2); (2) Inducing cell cycle arrest at the G1/S checkpoint, disrupting DNA, decreasing mitochondrial membrane potential and integrity, and slowing melanocyte proliferation; (3) Superior tyrosinase inhibitory activity by binding to tyrosinase, chelating copper ions, and demonstrating antioxidant properties. These findings suggest that PTFs inhibit melanin synthesis by the combination of the above mentioned ways, supporting the medical use of winemaking tannins., Competing Interests: Declaration of competing interest Bo Teng reports financial support was provided by 2022 Science and Technology Special Fund of Guangdong Province (Major Projects + Task list) [STKJ202209024] and [STKJ202209059]. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

With the aging of the global demographic, the prevention and treatment of osteoporosis are becoming crucial issues. The gradual loss of self-renewal and osteogenic differentiation capabilities in bone marrow stromal cells (BMSCs) is one of the key factors contributing to osteoporosis. To explore the regulatory mechanisms of BMSCs differentiation, we collected bone marrow cells of femoral heads from patients undergoing total hip arthroplasty for single-cell RNA sequencing analysis. Single-cell RNA sequencing revealed significantly reduced CRIP1 (Cysteine-Rich Intestinal Protein 1) expression and osteogenic capacity in the BMSCs of osteoporosis patients compared to non-osteoporosis group. CRIP1 is a gene that encodes a member of the LIM/double zinc finger protein family, which is involved in the regulation of various cellular processes including cell growth, development, and differentiation. CRIP1 knockdown resulted in decreased alkaline phosphatase activity, mineralization and expression of osteogenic markers, indicating impaired osteogenic differentiation. Conversely, CRIP1 overexpression, both in vitro and in vivo, enhanced osteogenic differentiation and rescued bone mass reduction in ovariectomy-induced osteoporosis mice model. The study further established CRIP1's modulation of osteogenesis through the Wnt signaling pathway, suggesting that targeting CRIP1 could offer a novel approach for osteoporosis treatment by promoting bone formation and preventing bone loss., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ethoprophos is an effective and widely pesticide that used in controlling nemathelminth and soil insect. However, ethoprophos has been frequently detected in environment and freshwater. The potential toxicity to aquatic organisms is still not be explored. In this study, zebrafish embryo model was used to evaluated the toxicity of ethoprophos during cardiovascular developmental process of zebrafish. Zebrafish embryos were separately exposed to 10 mg/L, 20 mg/L, 30 mg/L, 40 mg/L and 50 mg/L of ethoprophos exposure at 96 h post-fertilization (hpf), which induced cardiac defects, such as low heart rate, pericardium edema and long SV-BA distance, but had no influence to vascular development. Mechanistically, the expression of cardiac-related genes were abnormal. Moreover, ethoprophos exposure significantly increased oxidative stress in zebrafish embryos by inhibiting the production of antioxidant enzyme (SOD) and activating reactive oxygen species. Expectedly, some apoptosis genes were induced and the apoptotic cardiomyocytes were detected by acridine orange staining. In addition, ethoprophos exposure also inhibited the expression of genes in wnt signaling pathway, such as β-catenin, Axin2, GSK3β and Sox9b. BML284, an activator of wnt signaling pathway, can rescue the cardiotoxic effect of embryos. These results indicated that oxidative stress and blocking wnt signaling pathway were molecular basis of ethoprophos-induced injure in zebrafish. Generally, our study showed that ethoprophos exposure led to severe cardiotoxicity to zebrafish embryo.

Cancer stem cells (CSCs) are a subset of tumor cells that can initiate and sustain tumor growth and cause recurrence and metastasis. CSCs are particularly resistant to conventional therapies compared to their counterparts, owing greatly to their intrinsic metabolic plasticity. Metabolic plasticity allows CSCs to switch between different energy production and usage pathways based on environmental and extrinsic factors, including conditions imposed by conventional cancer therapies. To cope with nutrient deprivation and therapeutic stress, CSCs can transpose between glycolysis and oxidative phosphorylation (OXPHOS) metabolism. The mechanism behind the metabolic pathway switch in CSCs is not fully understood, however, some evidence suggests that the tumor microenvironment (TME) may play an influential role mediated by its release of signals, such as Wnt/β-catenin and Notch pathways, as well as a background of hypoxia. Exploring the factors that promote metabolic plasticity in CSCs offers the possibility of eventually developing therapies that may more effectively eliminate the crucial tumor cell subtype and alter the disease course substantially., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The renal tubular epithelial cells (TEC) have a strong capacity for repair after acute injury, but when this mechanism becomes uncontrollable, it leads to chronic kidney diseases (CKD). Indeed, in progress toward CKDs, the TECs may dedifferentiate, undergo epithelial-to-mesenchyme transition (EMT), and promote inflammation and fibrosis. Given the critical role of Wnt4 signaling in kidney ontogenesis, we addressed whether changes in this signaling are connected to renal inflammation and fibrosis by taking advantage of a knock-in Wnt4 mCh/mCh mouse. While the Wnt4 mCh/mCh embryos appeared normal, the corresponding mice, within one month, developed CKD-related phenotypes, such as pro-inflammatory responses including T-cell/macrophage influx, expression of fibrotic markers, and epithelial cell damage with a partial EMT. The Wnt signal transduction component β-catenin remained unchanged, while calcium signaling is induced in the injured TECs involving Nfat and Tfeb transcription factors. We propose that the Wnt4 signaling pathway is involved in repairing the renal injury, and when the signal is overdriven, CKD is established., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is an enigmatic neurological illness that offers few treatment options. Recent exploration has highlighted the crucial connection of the Wnt signaling pathway in AD pathogenesis, shedding light on potential therapeutic targets. The present study focuses on the dual targeting of glycogen synthase kinase-3β (GSK-3β) and casein kinase-1δ (CK-1δ) within the framework of the Wnt signaling pathway as a possible technique for AD intervention. GSK-3β and CK-1δ are multifunctional kinases known for their roles in tau hyperphosphorylation, amyloid processing, and synaptic dysfunction, all of which are major hallmarks of Alzheimer's disease. They are intricately linked to Wnt signaling, which plays a pivotal part in sustaining neuronal function and synaptic plasticity. Dysregulation of the Wnt pathway in AD contributes to cognitive decline and neurodegeneration. This review delves into the molecular mechanisms by which GSK-3β and CK-1δ impact the Wnt signaling pathway, elucidating their roles in AD pathogenesis. We discuss the potential of small-molecule inhibitors along with their SAR studies along with the multi-targetd approach targeting GSK-3β and CK-1δ to modulate Wnt signaling and mitigate AD-related pathology. In summary, the dual targeting of GSK-3β and CK-1δ within the framework of the Wnt signaling pathway presents an innovative and promising avenue for future AD therapies, offering new hope for patients and caregivers in the quest to combat this challenging condition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Endometritis is a disease caused by a postpartum bacterial infection with a poor prognosis that primarily affects dairy cows. Three-dimensional organoids have been used as a model for endometritis, because they exhibit a structure comparable to that of the endometrium, demonstrating both expansibility and hormone responsiveness. These characteristics render them an ideal platform for in vitro investigations of endometrial diseases. Estradiol (E2) is an endogenous steroid hormone with demonstrated anti-inflammatory properties, and the objective of this study was to determine the mechanism by which E2 modulates the inflammatory response and the Wnt signal transduction pathway in bovine endometrial epithelial cells and organoids following E. coli infection. We present the techniques for isolating and culturing primary bovine endometrial epithelial cells (BEECs), and producing endometrial organoids. For the experiments, the endometrial epithelial cells and organoids were infected with E. coli for 1 h, followed by incubation with E2 for 12 h. The mRNA and protein expressions of the inflammation-related genes, IL-1β, IL-6, TLR4, and NF-κB, as well as the Wnt pathway-related genes, Wnt4, β-catenin, c-Myc, and CyclinD1, were assessed using real-time quantitative-PCR and western blotting, respectively. The CCK8 viable cell counting assay was utilized to determine the optimal concentration of the Wnt inhibitor, IWR-1. The mRNA and protein expression of Wnt pathway-related genes was assessed following IWR-1 treatment, while the expression levels of proliferation-associated genes (Ki67, PCNA) and barrier repair genes (occludin, claudin, and Zo-1) in BEECs and organoids were evaluated after E2 treatment. The results of this study show that mRNA expression of the inflammatory genes, IL-1β, TLR4, and NF-κB (P < 0.05) decreased in BEECs following E2 treatment compared to the E. coli group. The protein expression of the IL-1β, IL-6, TLR4 and NF-κB genes was also inhibited (P < 0.05). Similar results were observed in tests on the organoids. Our findings demonstrate that E2 significantly upregulates the expression of Wnt-related genes, including β-catenin and c-Myc, while concurrently downregulating the expression of GSK3β (P < 0.05). Next, we treated E. coli-infected BEECs and organoids with the Wnt inhibitor, IWR-1. Compared with E. coli and E. coli + E2, the expression of mRNA and protein from Wnt 4, β-catenin, and CyclinD1 in E. coli + E2 and E. coli + IWR-1 was down-regulated (P < 0.05). The expression of the proliferation genes, Ki67, PCNA, and the tight junction genes, occludin, claudin1, and Zo-1, in organoids was significantly higher than that in BEECs (P < 0.05). In summary, we found strong potential for E2 mitigation of the E. coli-induced inflammatory response in BEECs and organoids, through activation of the Wnt pathway. In addition, the proliferation and repair capacity of organoids was much higher than that of BEECs., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Goose down feather has become one of the most important economical products in the goose breeding industry and it provides several essential physiological roles in birds. Therefore, understanding and regulating the development of skin and feather follicles during embryogenesis is critical for avian biology and the poultry industry. MicroRNAs are known to play an important role in controlling gene expression during skin and feather follicle development. In this study, bioinformatics analysis was conducted to select miR-140-y as a potential miRNA involved in skin and feather follicle development and to predict TCF4 as its target gene. This gene was expressed at significant levels during embryonic feather follicle development, as identified by qPCR and Western blot. The targeting relationship was confirmed by a dual-luciferase assay in 293T cells. Then, the miR-140-y/TCF4 function in dermal fibroblast cells was explored. The results showed that miR-140-y could suppress the proliferation of goose embryonic dermal fibroblast cells (GEDFs) by suppressing the activity of some Wingless-types (Wnt) pathway related genes and proliferation marker genes, while miR-140-y inhibition led to the opposite effect. Similarly, the inhibition of the TCF4 gene results in blocking the proliferation of GEDFs by reducing the activity of some Wnt pathway-related genes. Finally, the co-transfection of miR-140-y inhibitor and siRNA-TCF4 results in a rescue of the TCF4 function and an increase of the Wnt signaling pathway and GEDFs proliferation. In conclusion, these results demonstrated that the miR-140-y-TCF4 axis influences the activity of the Wnt signaling pathway and works as a dynamic regulator during skin and feather follicle development., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A series of designed stilbenoid-flavanone hybrids featuring sp 3 -hybridized C2 and C3 atoms of C-ring was evaluated against colorectal cancers presented compounds 4, 17, and 20 as the most potential compounds among explored compounds. Evaluation of the anticancer activity spectrum of compounds 4, 17, and 20 against diverse solid tumors presented compounds 17 and 20 with interesting anticancer spectrum. The potencies of compounds 17 and 20 were assessed in comparison with FDA-approved anticancer drugs. Compound 17 was the, in general, the most potent showing low micromolar GI 50 values that were more potent than the standard FDA-approved drugs against several solid tumors including colon, brain, skin, renal, prostate and breast tumors. Compound 17 was subjected for evaluation against normal cell lines and was subjected to a mechanism study in HCT116 colon cancer cells which presented it as an inhibitor of Wnt signaling pathway triggering G 2 /M cell cycle arrest though activation of p53-p21 pathway as well as intrinsic and extrinsic apoptotic death of colon cancer cells. Compound 17 might be a candidate for further development against diverse solid tumors including colon cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The scaffold protein 14-3-3ζ is an established regulator of adipogenesis and postnatal adiposity. We and others have demonstrated the 14-3-3ζ interactome to be diverse and dynamic, and it can be examined to identify novel regulators of physiological processes, including adipogenesis. In the present study, we sought to determine if factors that influence adipogenesis during the development of obesity could be identified in the 14-3-3ζ interactome found in white adipose tissue of lean or obese TAP-tagged-14-3-3ζ overexpressing mice. Using mass spectrometry, differences in the abundance of novel, as well as established, adipogenic factors within the 14-3-3ζ interactome could be detected in adipose tissues. One novel candidate was revealed to be plakoglobin, the homolog of the known adipogenic inhibitor, β-catenin, and herein, we report that plakoglobin is involved in adipocyte differentiation. Plakoglobin is expressed in murine 3T3-L1 cells and is primarily localized to the nucleus, where its abundance decreases during adipogenesis. Depletion of plakoglobin by siRNA inhibited adipogenesis and reduced PPARγ2 expression, and similarly, plakoglobin depletion in human adipose-derived stem cells also impaired adipogenesis and reduced lipid accumulation post-differentiation. Transcriptional assays indicated that plakoglobin does not participate in Wnt/β-catenin signaling, as its depletion did not affect Wnt3a-mediated transcriptional activity. Taken together, our results establish plakoglobin as a novel regulator of adipogenesis in vitro and highlights the ability of using the 14-3-3ζ interactome to identify potential pro-obesogenic factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

As a common organophosphorus flame retardant, tris (2-butoxyethyl) phosphate (TBOEP) is detected in water environment and aquatic animals extensively. Despite previous researches have reported the developmental toxicity of TBOEP in zebrafish (Danio rerio) larvae, few research focused on its underlying mechanisms. In this study, zebrafish embryos were exposed to 0, 20, 200, 1000 and 2000 µg/L TBOEP from 2 until 120 h post-fertilization (hpf) to determine potential mechanisms of developmental toxicity of this compound. Early developmental stage parameters such as body length, survival rate, hatching rate and heart rate were decreased, while malformation rate was ascended. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay was carried out at 12, 24, 72 and 120 hpf to demonstrate alterations in expression of genes of Wnt signaling pathway. The results indicated that axin1 was significantly up-regulated, while β-catenin, pkc and wnt11 were down-regulated. Correlation analysis indicated that expression of these genes was significantly correlated with body length. Furthermore, apoptosis was detected in heart region by acridine orange (AO) staining and terminal deoxynucleotide transferase-mediated deoxy-UTP nick end labeling (TUNEL) assay. In addition, at 120 hpf, occurrence of oxidative stress was observed in zebrafish larvae. Moreover, 6-Bromoindirubin-3′-oxime (BIO)， an activator of Wnt pathway, was found to alleviate the inhibiting effects of TBOEP on zebrafish growth. The overall outcomes offered novel viewpoints in toxic effects of TBOEP, and down-regulating Wnt signaling pathway were able to reveal some potential mechanisms of developmental toxicity of TBOEP in zebrafish larvae.

Periodontitis is the most common chronic inflammatory disease, and a leading cause of tooth loss. Characterized by resorption of alveolar process and destruction of periodontal ligaments, periodontitis can impact not only periodontal tissues but also systemic diseases, such as diabetes, cardiovascular diseases, and respiratory infections. Currently, it is a hotspot to manage destruction and gain regeneration of periodontal tissues. Increasing evidence indicates that the Wnt signaling plays an important role in homeostasis of periodontal tissues, functions of periodontal derived cells, and progression of periodontitis. Its molecule expressions were abnormal in periodontitis. As such, modulators targeting the Wnt signaling may be an adjuvant therapy for periodontitis treatment. This review elucidates the role of Wnt signaling and its molecules, with a view to develop a potential application of drugs targeting the Wnt signaling for periodontitis treatment.

Dysregulation of the Wnt signaling pathway contributes to the development of many cancer types. Natural compounds produced with biotechnological systems have been the focus of research for being a new drug candidate both with unlimited resources and cost-effective production. In this study, it was aimed to reveal the effects of isopropylchaetominine on cytotoxic, cytostatic, apoptotic and Wnt signaling pathways in brain, pancreatic and prostate cancer. The IC 50 values of isopropylchaetominine in U-87 MG, PANC1, PC3 and LNCaP cells were calculated as 91.94 μM, 41.68 μM, 54.54 μM and 7.86 μM in 72nd h, respectively. The metabolite arrests the cell cycle in G 0 /G 1 phase in each cancer cells. Iso-propylchaetominine induced a 4.3-fold and 1.9-fold increase in apoptosis in PC3 and PANC1 cells, respectively. The toxicity of isopropylchaetominine in healthy fibroblast cells was assessed using the annexin V method, and no significant apoptotic activity was observed between the groups treated with the active substance and untreated. In U-87 MG, PANC1, PC3, and LNCaP cells under treatment with isopropylchaetominin, the expression levels of DKK3, TLE1, AES, DKK1, FRZB, DAB2, AXIN1/2, PPARD, SFRP4, APC and SOX17 tumor suppressor genes increased significantly. Decreases in expression of Wnt1, Wnt2, Wnt3, Wnt4, Wnt5, Wnt6, Wnt10, Wnt11, FRZ2, FRZ3, FRZ7, TCF7L1, BCL9, PYGO, CCND2, c-MYC, WISP1 and CTNNB1 oncogenic genes were detected. All these result shows that isopropylchaetominine can present promising new treatment strategy in different cancer types., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The oxidative microenvironment in fibrotic livers often diminishes the effectiveness of mesenchymal stem cells (MSCs)-based therapy. Recent research suggests that pharmacological pre-treatment could enhance the therapeutic performance of MSCs. In this study, we assessed the impact of Arctium lappa L. polysaccharides (ALP) on the biological properties of nasal ectomesenchymal stem cells (EMSCs) and investigated the augmenting effect of ALP pretreatment on EMSCs (ALP-EMSCs) for the treatment of liver fibrosis. ALP treatment demonstrated multiple biological impacts on EMSC functions regarding liver fibrosis: firstly, it maintained the stemness of the cells while boosting the EMSCs' paracrine effects; secondly, it increased the expression of anti-inflammatory and antioxidant factors; thirdly, it inhibited the activation of hepatic stellate cells (HSCs) and liver collagen build-up by modulating the Wnt/β-catenin signaling pathways. Collectively, these effects helped to halt the progression of liver fibrosis. Therefore, the use of ALP-EMSCs presents an innovative and promising approach for treating hepatic fibrosis in clinical scenarios., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Type 2 diabetes mellitus (T2DM) is a major worldwide chronic disease and can lead to serious diabetic complications. Despite the availability of many anti-diabetic agents in the market, they are unable to meet the long-term treatment goals. Also, they cause many side effects which justify the need for novel class of anti-diabetic drugs with newer mechanism of action. Wnt signaling is one of such novel target pathways which can be explored for metabolic disorders. Many key components of the Wnt signaling are involved in the regulation of glucose homeostasis. Polymorphism in the Transcription factor 7-like 2 (TCF7L2) gene, and mutations in the LRP5 (LDL Receptor Related Protein 5) gene lead to disturbed glucose metabolism and obesity. Despite of several years of research in this field, there is no concrete proof of concept available on whether Wnt activation or Wnt inhibition is the beneficial approach for the treatment of T2DM. Here, we have summarized the conclusions of relevant published research studies to give structured insights into possibilities to explore Wnt modulation as a novel target pathway for the treatment of T2DM. The review also highlights the present challenges and future opportunities towards the development of anti-diabetic small molecules targeting the Wnt signaling pathway., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ruchi Yadav reports financial support was provided by Indian Council of Medical Research (ICMR), New Delhi, India. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Zymosan is a β-glucan isolated from Saccharomyces cerevisiae that could be employed for drug delivery. We synthesized zymosan nanoparticles and measured their structural and morphological properties using XRD, UV-Vis spectroscopy, TEM and AFM. The loading of doxorubicin (DOX) onto the nanoparticles was confirmed by FT-IR, and the DOX release was shown to be pH-dependent. The effect of these agents on C26 cell viability was evaluated by MTT tests and the expression of genes connected with the Wnt/β-catenin pathway and apoptosis were analyzed by RT-qPCR and Western blotting. Treatments were able to suppress the proliferation of C26 cells, and the zymosan nanocarriers loaded with DOX enhanced the anti-proliferative effect of DOX in a synergistic manner. Zymosan nanoparticles were able to suppress the expression of cyclin D1, VEGF, ZEB1, and Twist mRNAs. Treatment groups upregulated the expression of caspase-8, while reducing the Bax/Bcl-2 ratio, thus promoting apoptosis. In conclusion, zymosan nanoparticles as DOX nanocarriers could provide a more targeted drug delivery through pH-responsiveness, and showed synergistic cytotoxicity by modifying Wnt/β-catenin signaling and apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Feather is an important economic trait of poultry, and growth and development state of feathers plays an important role in the economic value of poultry. Dermal fibroblasts are required for structural integrity of the skin and for feather follicle development. How FOXO3 affects feather follicle development as skin tissues change during goose embryo (Anser cygnoides) development and growth is not well understood. Here, we demonstrate that in vitro culture of single feathers and skin tissue results in changes in feather morphological structure by adding drugs to the culture medium that affect FOXO3 expression. We used feather follicles to show that during growth, the root location of feathers, the dermis layer, affects cell proliferation and apoptosis and regulates the expression of major genes in the Wingless-types/beta-catenin (Wnt/β-catenin) signaling pathway through the activity of FOXO3 in dermal fibroblasts. Feathers and dorsal skin tissues develop the correct structure, but feather length and width and feather follicle diameter change significantly (p < 0.05) without significant changes in feather follicle density (p > 0.05). Transfected dermal fibroblasts also showed that FOXO3 affected the formation and development of feather follicles in the embryonic stage by regulating the Wnt/β-catenin signaling pathway. Therefore, this study reveals the critical role of dermal fibroblast-FOXO3-induced Wnt/β-catenin signaling in promoting the formation and development of embryonic feather follicles., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Waardenburg syndrome type 1 (WS1) is a hereditary disease mainly characterized by sensorineural hearing loss, dystopia canthorum, and pigmentary defects. To elucidate molecular mechanisms underlying PAX3-associated hearing loss, we developed inner ear organoids model using induced pluripotent stem cells (iPSCs) derived from WS1 patient and healthy individual. Our results revealed a significant reduction in the size of inner ear organoids, accompanied by an increased level of apoptosis in organoids derived from WS1 patient-iPSCs carrying PAX3 c.214A > G. Transcriptome profiling analysis by RNA-seq indicated that inner ear organoids from WS1 patients were associated with suppression of inner ear development and WNT signaling pathway. Furthermore, the upregulation of the WNT1/β-catenin pathway which was achieved through the correction of PAX3 isogenic mutant iPSCs using CRISPR/Cas9, contributed to an increased size of inner ear organoids and a reduction in apoptosis. Together, our results provide insight into the underlying mechanisms of hearing loss in WS., Competing Interests: Declaration of competing interest The authors have declared that they do not have any conflicts of interest in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Addressing drug resistance poses a significant challenge in cancer treatment, as cancer cells develop diverse mechanisms to evade chemotherapy drugs, leading to treatment failure and disease relapse. Three-dimensional (3D) cell culture has emerged as a valuable model for studying drug resistance, although the underlying mechanisms remain elusive. By obtaining a better understanding of drug resistance within the 3D culture environment, we can develop more effective strategies to overcome it and improve the success of cancer treatments. Notably, the physical structure undergoes notable changes in 3D culture, with mechanical effects believed to play a pivotal role in drug resistance. Hence, our study aimed to explore the influence of mechanical effects on drug resistance by analyzing data related to "drug resistance" and "mechanobiology". Through this analysis, we identified β-catenin and JNK1 as potential factors, which were further examined in MCF-7 cells cultivated under both 2D and 3D culture conditions. Our findings demonstrate that β-catenin is activated through canonical and non-canonical pathways and associated with the drug resistance, particularly in organoids obtained under 3D culture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Zinc finger proteins (ZFPs) constitute a crucial group of transcription factors widely present in various organisms. They act as transcription factors, nucleases, and RNA-binding proteins, playing significant roles in cell differentiation, growth, and development. With extensive research on ZFPs, their roles in the determination of mesenchymal stem cells (MSCs) fate during osteogenic and adipogenic differentiation processes have become increasingly clear. ZFP521, for instance, is identified as an inhibitor of the Wnt signaling pathway and RUNX2's transcriptional activity, effectively suppressing osteogenic differentiation. Moreover, ZFP217 contributes to the inhibition of adipogenic differentiation by reducing the M6A level of the cell cycle regulator cyclin D1 (CCND1). In addition, other ZFPs can also influence the fate of mesenchymal stem cells (MSCs) during osteogenic and adipogenic differentiation through various signaling pathways, transcription factors, and epigenetic controls, participating in the subsequent differentiation and maturation of precursor cells. Given the prevalent occurrence of osteoporosis, obesity, and related metabolic disorders, a comprehensive understanding of the regulatory mechanisms balancing bone and fat metabolism is essential, with a particular focus on the fate determination of MSCs in osteogenic and adipogenic differentiation. In this review, we provide a detailed summary of how zinc finger proteins influence the osteogenic and adipogenic differentiation of MSCs through different signaling pathways, transcription factors, and epigenetic mechanisms. Additionally, we outline the regulatory mechanisms of ZFPs in controlling osteogenic and adipogenic differentiation based on various stages of MSC differentiation., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The dysregulation of deubiquitination has been shown to affect the development of pre-eclampsia (PE). A disintegrin and metalloprotease 9 (ADAM9) plays roles in diverse physiological contexts, including PE. Here, this study aimed to investigate whether ADAM9 regulated trophoblast cell dysfunction through ubiquitin-specific protease 22 (USP22) deubiquitinase-mediated deubiquitination during PE., Methods: Levels of genes and proteins were tested via qRT-PCR and western blotting assays. Cell proliferation, migration, and invasion were detected using cell counting kit-8, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell and wound healing assays, respectively. Epithelial-mesenchymal transition related markers were assayed using western blotting. Proteins between USP22 and ADAM9 were identified by co-immunoprecipitation assay., Results: ADAM9 was highly expressed in PE patients, functionally, ADAM9 overexpression weakened the proliferation, migration, invasion, and EMT progression in trophoblast cells. Mechanistically, the deubiquitinase USP22 removed ubiquitination on ADAM9 and maintained its stability. Forced expression of USP22 also suppressed the proliferation and mobility in trophoblast cells. Moreover, the regulatory effects of USP22 on trophoblast cells were reversed by ADAM9 silencing. In addition, USP22 interacted with ADAM9 to regulate the activation of Wnt/β-catenin pathway., Discussion: ADAM9 was deubiquitinated and stabilized by USP22 and then suppressed the proliferation, migration, invasion, and EMT progression in trophoblast cells, indicating a new pathway of USP10/RUNX1 axis in PE process., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The survival benefit for patients with gastric cancer (GC) is modest due to its high transfer potential. Targeted therapy for metastasis-related genes in GC may be a viable approach, however, inhibitors specifically targeting GC are limited. In this study, GC patient-derived xenografts (PDX) with metastatic burden were established via orthotopic transplantation. PCR-Array analysis of primary and metastatic tumors revealed EPH receptor B2 (EPHB2) as the most significantly upregulated gene. The interaction between the EPHB2 receptor and its cognate-specific EFNB1 ligands was high in GC and correlated with a poor prognosis. Fc-EFNB1 treatment increased the invasion and migration abilities of GC cells and induced a high EPHB2 expression. EPHB2 knockdown in GC cells completely abolished the ephrin ligand-induced effects on invasion and migration abilities. Signal transduction analysis revealed Wnt/β-catenin and FAK as downstream signaling mediators potentially inducing the EPHB2 phenotype. In conclusion, the observed deregulation of EPHB2/EFNB1 expression in GC enhances the invasive phenotype, suggesting a potential role of EPHB2/EFNB1 compound in local tumor cell invasion and the formation of metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Fibroblast growth factor 21 (FGF21) is a key regulator of energy metabolism. Recent studies suggested that serum FGF21 levels increase with declining renal function. However, the link between FGF21 and kidney diseases and the direct effect of FGF21 in renal fibrosis remains unclear. In this study, FGF21 was upregulated in unilateral ureteral obstruction (UUO)-induced renal fibrosis and cellular fibrosis induced by transforming growth factor-β, and renal expression of FGF21 was positively correlated with fibrosis markers. Additionally, FGF21 was regulated by Wnt/β-catenin signaling pathway. The knockdown and overexpression of FGF21 in mouse tubular epithelial cells demonstrated that FGF21 alleviates renal fibrosis by inhibiting the Wnt/β-catenin signaling pathway. To investigate the effect of FGF21 on renal fibrosis in vivo, we established an overexpression model by injecting the plasmid in mice and found that FGF21 overexpression relieved UUO-induced renal fibrosis and renal inflammatory response. Taken together, FGF21 is upregulated with the activation of Wnt/β-catenin signaling pathway and alleviates renal fibrosis by inhibiting the activation of Wnt/β-catenin signaling pathway in a negative feedback mode. These results provide a new understanding for the source of elevated serum FGF21 in patients with chronic kidney disease and prove that FGF21 is a direct inhibitor of the progression of renal fibrosis, thus providing novel therapeutic intervention insights for renal fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Activation of Wnt/β-catenin signaling supports the self-renewal of mouse embryonic stem cells. We aimed to understand the effects of Wnt signaling activation or inhibition on chicken embryonic stem cells (chESCs), as these effects are largely unknown. When the glycogen synthase kinase-3 β inhibitor CHIR99021-which activates Wnt signaling-was added to chESC cultures, the colony shape flattened, and the expression levels of pluripotency-related (NANOG, SOX2, SOX3, OCT4, LIN28A, DNMT3B, and PRDM14) and germ cell (CVH and DAZL) markers showed a decreasing trend, and the growth of chESCs was inhibited after approximately 7 d. By contrast, when the Wnt signaling inhibitor XAV939 was added to the culture, dense and compact multipotent colonies (morphologically similar to mouse embryonic stem cell colonies) showing stable expression of pluripotency-related and germline markers were formed. The addition of XAV939 stabilized the proliferation of chESCs in the early stages of culture and promoted their establishment. Furthermore, these chESCs formed chimeras. In conclusion, functional chESCs can be stably cultured using Wnt signaling inhibitors. These findings suggest the importance of Wnt/β-catenin signaling in avian stem cells, offering valuable insights for applied research using chESCs., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Typical plasticizer di (2-ethylhexyl) phthalate (DEHP) has been demonstrated to induce cardiotoxicity in zebrafish, but the potential molecular mechanisms involved have not been fully elucidated. Aryl hydrocarbon receptor (AhR), an essential protein for inducing developmental abnormalities, has been demonstrated to be activated by DEHP in other species, but whether the AhR signaling pathway also contributes to DEHP-mediated cardiac developmental toxicity in zebrafish remains unclear. Firstly, molecular docking simulations initially confirmed the possibility that DEHP has AhR agonistic activity. To further confirm this conjecture, this work analyzed the changes of cardiac-related indexes in zebrafish stressed by DEHP at individual, protein, and gene levels. The results showed that DEHP mediated cardiac phenotypic developmental defects, increased CYP1A1 activity, and oxidative stress as well as significant changes in the expression levels of key proteins and genes of AhR, Wnt/β-catenin, and Nrf2-Keap1 signaling pathways. Notably, the addition of AhR inhibitors effectively alleviated the above negative effects, indicating that the AhR signaling pathway and its crosstalk with the Wnt/β-catenin signaling pathway is an essential pathway for DEHP-mediated cardiac developmental toxicity. Overall, this work enriches the molecular mechanism of DEHP-mediated cardiac developmental defects in zebrafish and provides a reliable biomarker for future environmental risk assessment of DEHP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)