Low-density lipoprotein receptor-related protein 1(LRP1)is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip,osteoporosis and osteoarthritis.Our work addresses the ...Low-density lipoprotein receptor-related protein 1(LRP1)is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip,osteoporosis and osteoarthritis.Our work addresses the critical question of how these skeletal pathologies emerge.Here,we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.5 and onwards,especially in the perichondrium,the stem cell layer surrounding developing limbs essential for bone formation.Lrp1 deficiency in these stem cells causes joint fusion,malformation of cartilage/bone template and markedly delayed or lack of primary ossification.展开更多
Irradiation from diverse sources is ubiquitous and closely associated with human activities. Radiation therapy (RT), an important component of multiple radiation origins, is a common therapeutic modality for cancer. M...Irradiation from diverse sources is ubiquitous and closely associated with human activities. Radiation therapy (RT), an important component of multiple radiation origins, is a common therapeutic modality for cancer. More importantly, RT provides significant contribution to oncotherapy by killing tumor cells. However, during the course of therapy, irradiation of normal tissues can result in a wide range of side effects, including self-limited acute toxicities, mild chronic symptoms, or severe organ dysfunction. Although numerous promising radioprotective agents have emerged, only a few have successfully entered the market because of various limitations. At present, the widely accepted hypothesis for protection against radiation-caused injury involves the Wnt canonical pathway. Activating the Wnt/β-catenin signaling pathway may protect the salivary gland, oral mucosa, and gastrointestinal epithelium from radiation damage. The underlying mechanisms include inhibiting apoptosis and preserving normal tissue functions. However, aberrant Wnt signaling underlies a wide range of pathologies in humans, and its various components contribute to cancer. Moreover, studies have suggested that Wnt/ β-catenin signaling may lead to radioresistance of cancer stem cell. These facts markedly complicate any definition of the exact function of the Wnt pathway.展开更多
Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeu...Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O^(6)-methylguanine(O^(6)-MG)-DNA-methyltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensitivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.展开更多
OBJECTIVE:To investigate if the Liuwei Dihuang pill(LWDHP)can inhibit metastasis to the liver and lungs in mice bearing triple-negative breast cancer(TNBC),and the molecular mechanism underpinning this action.METHODS:...OBJECTIVE:To investigate if the Liuwei Dihuang pill(LWDHP)can inhibit metastasis to the liver and lungs in mice bearing triple-negative breast cancer(TNBC),and the molecular mechanism underpinning this action.METHODS:Ninety-nine TNBC bearing-mice were distributed randomly to five groups:control(Con),paclitaxel(PTX),low-dose LWDHP(LLP,2.3 g·kg^-1·d^-1),middle-dose LWDHP(MLP,4.6 g·kg^-1·d^-1)and high-dose LWDHP(HLP,9.2 g·kg^-1·d^-1).The LWDHP were administered(p.o.)to the agonal stage.The morphology of BC cells was observed by hematoxylin&eosin staining.Expression of axin-2,β-catenin,T cell factor(TCF),cyclin-D1 and vascular endothelial growth factor(VEGF)was detected by western blotting or immunofluorescence.β-catenin/TCF-1 interaction was measured using a co-immunoprecipitation assay.RESULTS:After LWDHP treatment,metastasis of BC cells to the lungs and liver was inhibited,expression of axin-2 was increased,expression of TCF-1,β-catenin,cyclin-D1 and VEGF was decreased,andβ-catenin/TCF-1 interaction was disrupted.CONCLUSION:The LWDHP could inhibit metastasis of BC cells to the liver and lungs.The molecular mechanism underlying this action may be regulation of protein expression andβ-catenin/TCF-1 interactions in the Wnt pathway.展开更多
In this manuscript,we comment on the article,which explores the anti-cancer effects of Calculus bovis(CB)in tumor biology.We highlight its potential,particularly in hepatocellular carcinoma(HCC),where it inhibits the ...In this manuscript,we comment on the article,which explores the anti-cancer effects of Calculus bovis(CB)in tumor biology.We highlight its potential,particularly in hepatocellular carcinoma(HCC),where it inhibits the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathways and induces apoptosis.CB contains compounds such as oleanolic acid and ursolic acid that target interleukin-6,mitogen-activated protein kinase 8,vascular endothelial growth factor,and caspase-3,offering anti-inflammatory and hepatoprotective benefits.The manuscript also discusses CB sativus(CBS),an artificial substitute,which has shown efficacy in reducing hepatic inflammation and oxidative stress in animal models.We emphasize the need for further research on the effects of CBS on the gut-liver axis and gut microbiota,and on targeting Wnt signaling and M2 tumor-associated macrophage as potential therapeutic strategies against HCC.展开更多
Objective: To investigate the effect of Tip60 gene silencing on the ABCE1 acetylation level and cell proliferation, migration and invasion in TE-1 cells of oesophageal cancer. Methods: The siRNA sequence of Tip60 was ...Objective: To investigate the effect of Tip60 gene silencing on the ABCE1 acetylation level and cell proliferation, migration and invasion in TE-1 cells of oesophageal cancer. Methods: The siRNA sequence of Tip60 was transfected with esophageal cancer TE-1 cells. Transfected siRNA vector cells were used as experimental group (si-T), siRNA no-loaded somatic cells were transfected as control group (si-NC), and untransfected TE-1 cells were used as blank group (Group N). ABCE1 mRNA was detected by qRT-PCR, the expression of ABCE1 protein, proliferation-related protein β catenin (β-catenin), GSK3β, and c-myc by Western blot, the protein acetylation level by immunoprecipitation, MTT assay for cell viability, scratch healing and Transwell compartment assay for migration and invasion ability. Results: After 48 h downregulation of the Tip60 gene, TE-1 cells showed no significant changes in the ABCE1 mRNA and protein expression. The acetylation level of ABCE1 decreased significantly, compared with the control group and the blank group. After Tip60 gene silencing, the expression of β-catenin and c-myc protein decreased, while the expression of GSK-3β protein increased. Cytofunctology experiments showed that the proliferative activity, migration and invasion ability of TE-1 cells in the experimental group were significantly inhibited. Conclusion: Down regulation of Tip60 gene can deacetylate ABCE1 protein and inhibit the proliferation activity, migration and invasion ability of esophageal cancer by blocking the conduction of Wnt signaling pathway.展开更多
Polyphenols,a diverse group of naturally occurring compounds found in plants,have garnered significant attention for their potential therapeutic properties in treating neurodegenerative diseases(NDs).The Wnt/β-cateni...Polyphenols,a diverse group of naturally occurring compounds found in plants,have garnered significant attention for their potential therapeutic properties in treating neurodegenerative diseases(NDs).The Wnt/β-catenin(WβC)signaling pathway,a crucial player in neurogenesis,neuronal survival,and synaptic plasticity,is involved in several cellular mechanisms related to NDs.Dysregulation of this pathway is a hallmark in the development of various NDs.This study explores multiple polyphenolic compounds,such as flavonoids,stilbenes,lignans,and phenolic acids,and their potential to protect the nervous system.It provides a comprehensive analysis of their effects on the WβC pathway,elucidating their modes of action.The study highlights the dual function of polyphenols in regulating and protecting the nervous system,providing reassurance about the research benefits.This review provides a comprehensive analysis of the results obtained from both in vitro studies and in vivo research,shedding light on how these substances influence the various components of the pathway.The focus is mainly on the molecular mechanisms that allow polyphenols to reduce oxidative stress,inflammation,and apoptotic processes,ultimately improving the function and survival of neurons.This study aims to offer a thorough understanding of the potential of polyphenols in targeting the WβC signaling pathway,which could lead to the development of innovative therapeutic options for NDs.展开更多
In this article,we comment on the work published by Huang et al,which explores the mechanisms by which Calculus bovis(CB)modulates the liver cancer immune microenvironment via the Wnt/β-catenin signalling pathway.The...In this article,we comment on the work published by Huang et al,which explores the mechanisms by which Calculus bovis(CB)modulates the liver cancer immune microenvironment via the Wnt/β-catenin signalling pathway.The study demon-strates that active components in CB effectively inhibit the activation of the Wnt/β-catenin pathway,significantly reducing the polarization of M2 tumor-associated macrophages.Both in vivo and in vitro experiments have validated the anti-tumour effects of CB,revealing its complex mechanisms of action through the modulation of immune cell functions within the tumour microenvironment.This article highlights CB’s therapeutic potential in liver cancer treatment and calls for further investigations into its mechanisms and clinical applications to develop safer,more effective options for patients.The study also revealed that key com-ponents of CB,such as bilirubin and bile acids,inhibit tumour cell proliferation and promote apoptosis through multiple pathways.Future research should explore the mechanisms of action of CB and its potential integration with existing treatments to improve the therapeutic outcomes of liver cancer patients.With multidisciplinary collaboration and advanced research,CB could become a key component of comprehensive liver cancer treatment,offering new hope for patients.展开更多
OBJECTIVE:To explore the therapeutic potential of the Dujieqing(DJQ)decoction(毒结清复方)for multiple myeloma(MM)and elucidate its mechanism of action.METHODS:RPMI8226 cells were treated with DJQcontaining serum(DJQ-C...OBJECTIVE:To explore the therapeutic potential of the Dujieqing(DJQ)decoction(毒结清复方)for multiple myeloma(MM)and elucidate its mechanism of action.METHODS:RPMI8226 cells were treated with DJQcontaining serum(DJQ-CS)and a Wnt/β-catenin pathway inhibitor,XAV-939.Cell counting kit-8 assay was used to examine cell viability,and flow cytometry was performed to examine apoptosis.Real-time polymerase chain reaction and Western blotting were used to evaluate the Wnt/β-catenin pathway family members in the cells.Subsequently,the RPMI8226 cells were subcutaneously injected into the left flank of none obesity disease and server combined immune-deficiency mice to replicate the xenograft tumor mouse models,which were treated with the DJQ decoction for 14 d.Hematoxylin and eosin staining was used to examine the pathological changes of the liver and kidney tissues,and to detect xenograft tumors.Wnt/β-catenin pathway family members were evaluated via Western blotting.RESULTS:DJQ-CS significantly reduced the m RNA and protein expression levels ofβ-catenin,c-myc,cyclin D1,and lymphoid enhancer binding factor 1(LEF1)while inhibiting the proliferation of RPMI8226 cells and inducing their apoptosis.Similar results were observed when the Wnt/β-catenin pathway was suppressed by inhibitors.Moreover,in the mouse model of xenograft tumors,DJQ decoction not only reduced the tumor volume but also inhibited the protein levels ofβ-catenin,c-myc,cyclin D1,and LEF1.The histopathology of the mice also showed increased apoptosis in tumor tissues,while the DJQ decoction treatment did not cause any pathological damage to the kidneys or liver.CONCLUSION:Our results indicate that the DJQ decoction suppresses tumor progression by inhibiting the Wnt/β-catenin pathway,offering a promising treatment approach for MM.展开更多
Human cytomegalovirus(HCMV)poses a significant risk of neural damage during pregnancy.As the most prevalent intrauterine infectious agent in low-and middle-income countries,HCMV disrupts the development of neural stem...Human cytomegalovirus(HCMV)poses a significant risk of neural damage during pregnancy.As the most prevalent intrauterine infectious agent in low-and middle-income countries,HCMV disrupts the development of neural stem cells,leading to fetal malformations and abnormal structural and physiological functions in the fetal brain.This review summarizes the current understanding of how HCMV infection dysregulates the Wnt signaling pathway to induce fetal malformations and discusses current management strategies.展开更多
OBJECTIVE:To determine the mechanism of electroacupuncture(EA)effect by the wingless-related integration site(Wnt)/β-catenin pathway in the guinea pig myopia model.METHODS:Following myopia induction and EA,guinea pig...OBJECTIVE:To determine the mechanism of electroacupuncture(EA)effect by the wingless-related integration site(Wnt)/β-catenin pathway in the guinea pig myopia model.METHODS:Following myopia induction and EA,guinea pigs were treated with biometry to evaluate refraction and axial length.Hematoxylin and eosin(HE)staining was used to observe that the retina,choroid,and sclera had abnormal morphology.At 4,6,and 8 weeks,quantitative polymerase chain reaction(q PCR)was used to identify the expression of matrix metallopeptidase-2(MMP-2)/MMP-3/tissue inhibitor of metalloprotease-2(TIMP-2)/TIMP-3/Wnt family member 2B(WNT2B)/WNT3A/WNT7B/beta-catenin 1(CTNNB1),and dickkopf wnt signaling pathway inhibitor 1(DKK-1)m RNAs in the retina,choroid,and sclera.Western blot was used to detect the protein expression of WNT7B/2B/3A,CTNNB1 and DKK-1 in retina,choroid and sclera at 4 weeks.Enzyme-linked immunosorbent assay was used to detect the protein expression of MMP-2/TIMP-2 and MMP-3/TIMP-3 in serum at 4 weeks.Moreover,a DKK-1 inhibitor was injected into the vitreous cavity,and the expression of the above molecules was detected.RESULTS:EA could reduce the optic axial length and diopter and ameliorate ocular pathology,inhibited the expression of MMP-2/MMP-3 and WNT2B/WNT3A/WNT7B/CTNNB1,while increased the expression levels of TIMP-2/TIMP-3 and DKK-1.However,the expression levels of WNT2B/WNT3A/WNT7B/CTNNB1 and MMP-2/MMP-3 were significantly increased,and the TIMP-2/TIMP-3 and DKK-1 expression levels were decreased after injected DKK-1 inhibitor.CONCLUSION:The mechanism of EA's effects on myopia may involve the downregulation of the Wnt/β-catenin pathway and correct MMP-2/MMP-3/TIMP-2/TIMP-3 balance.展开更多
Objective:Anillin(ANLN)is considered an oncogene in various cancers,but its effect on cervical cancer remains poorly understood.Hence,this study aimed to describe the action of ANLN on cervical cancer development and ...Objective:Anillin(ANLN)is considered an oncogene in various cancers,but its effect on cervical cancer remains poorly understood.Hence,this study aimed to describe the action of ANLN on cervical cancer development and investigate the potential mechanism.Methods:Analysis of ANLN expression and its association with survival in carcinoma and endocervical adenocarcinoma(CESC)patients based on GEO and UALCAN databases.The tumor and adjacent normal tissues of 100 cervical cancer cases were harvested to detect the ANLN expression and explore its relationship with patient survival.Cell proliferation,apoptosis,migration,and invasion were measured by utilizing 5-ethynyl-2′-deoxyuridine(EdU)staining,Flow cytometry,and Transwell assay,respectively.ANLN andWnt expression were analyzed by RT-qPCR andWestern Blot.Results:ANLN was significantly elevated in tumor tissues,and cervical cancer cases with high ANLN expression exhibited poor survival and high dead proportion.Besides,ANLN induced cervical cancer cell proliferation,migration,and invasion and restrained cell apoptosis.In addition,ANLN promoted Wnt/β-catenin pathway activation.Furthermore,ANLN accelerated cell aggressive behaviors and suppressed cell apoptosis via activating the Wnt/β-catenin signaling in cervical cancer.Conclusion:ANLN was enhanced in cervical cancer tissues and related to poor prognosis.ANLN accelerated cervical cancer cell aggressive behaviors and suppressed cell apoptosis via activating theWnt/β-catenin pathway.展开更多
In this editorial,we discuss the article by Fu Y et al,indicating that hair deve-lopment is influenced by exosomes from human adipose-derived stem/stromal cell-mediated cell-to-cell communication via the Wnt/β-cateni...In this editorial,we discuss the article by Fu Y et al,indicating that hair deve-lopment is influenced by exosomes from human adipose-derived stem/stromal cell-mediated cell-to-cell communication via the Wnt/β-catenin pathway.In recent years,mesenchymal stem cells(MSCs)and MSC-derived exosomes(MSC-Exos)have emerged as a promising cell-free therapeutic strategy due to their robust regenerative capabilities across multiple tissues.MSC-Exos are enriched with bioactive molecules,including proteins,microRNAs,and growth factors,which activate critical signaling pathways,notably the Wnt/β-catenin pathway,to promote cell proliferation,differentiation,and tissue repair.This editorial system-atically examines the application of MSC-Exos in regenerating diverse tissues such as hair follicles and kidney,lung,and cardiac muscle tissue.Central to their mechanism is the activation of the Wnt/β-catenin pathway,which drives cell cycle progression(via cyclin B1/cyclin-dependent kinase 1),suppresses apoptosis(through Bcl-2/Bax modulation),and attenuates fibrosis(by inhibiting transforming growth factor-β/alpha-smooth muscle actin).The challenges related to the clinical translation of exosome-based therapies,including standardization of isolation protocols,optimization of dosing and delivery methods,and safety evaluation,are discussed.The most important challenge is standardizing isolation protocols because exosomes obtained from different sources or treatment methods are different,which leads to differences in the therapeutic effects of exosomes.Overall,MSC-Exos provide an effective cell-free strategy for tissue repair and offer a robust foundation to develop personalized regenerative medicine.展开更多
Liver cancer remains a significant global health challenge,characterized by high incidence and mortality rates.Despite advancements in medical treatments,the prognosis for liver cancer patients remains poor,highlighti...Liver cancer remains a significant global health challenge,characterized by high incidence and mortality rates.Despite advancements in medical treatments,the prognosis for liver cancer patients remains poor,highlighting the urgent need for novel therapeutic approaches.Traditional Chinese medicine(TCM),particularly Calculus bovis(CB),has shown promise in addressing this need due to its multitarget therapeutic mechanisms.CB refers to natural or synthetic gallstones,traditionally sourced from cattle,and used in TCM for their anti-inflammatory,detoxifying,and therapeutic properties.In modern practice,synthetic CB is often utilized to ensure consistent supply and safety.This article aims to discuss the findings of Huang et al,who investigated the anti-liver cancer properties of CB,focusing on its ability to inhibit M2 tumor-associated macrophage(TAM)polarization via modulation of the Wnt/β-catenin pathway.Huang et al employed a comprehensive approach integrating chemical analysis,animal model testing,and advanced bioinformatics.They identified active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms through network pharmacology,transcriptomics,and molecular docking studies.The study demonstrated that CB significantly inhibited liver tumor growth in vivo,as evidenced by reduced tumor size and weight in treated mice.Histological analyses confirmed signs of tumor regression.CB was found to modulate the tumor microenvironment by inhibiting the polarization of M2 phenotype-TAMs,as shown by reduced expression of M2 markers and downregulation of mRNA levels of C-C motif chemokine 22,arginase-1,transforming growth factor-beta 2,and interleukin-10.The study further revealed that CB’s antineoplastic activity involved the downregulation of Wnt5B andβ-catenin and upregulation of Axin2,thus inhibiting the Wnt/β-catenin signaling pathway.These findings highlight the therapeutic potential of CB in liver cancer treatment through its modulation of the Wnt/β-catenin pathway and suppression of M2 phenotype-TAM polarization.This study underscores the value of integrating TCM with modern therapeutic strategies to develop novel effective treatments for liver cancer.展开更多
Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways...Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.展开更多
Wnt signaling pathways,including the canonical Wnt/β-catenin pathway,planar cell polarity pathway,and Wnt/Ca2+signaling pathway,play important roles in neural development during embryonic stages.The DVL genes encode ...Wnt signaling pathways,including the canonical Wnt/β-catenin pathway,planar cell polarity pathway,and Wnt/Ca2+signaling pathway,play important roles in neural development during embryonic stages.The DVL genes encode the hub proteins for Wnt signaling pathways.The mutations in DVL2 and DVL3 were identified from patients with neural tube defects(NTDs),but their functions in the pathogenesis of human neural diseases remain elusive.Here,we sequenced the coding regions of three DVL genes in 176 stillborn or miscarried fetuses with NTDs or Dandy-Walker malformation(DWM)and 480 adult controls from a Han Chinese population.Four rare mutations were identified:DVL1 p.R558 H,DVL1 p.R606 C,DVL2 p.R633 W,and DVL3 p.R222 Q.To assess the effect of these mutations on NTDs and DWM,various functional analyses such as luciferase reporter assay,stress fiber formation,and in vivo teratogenic assay were performed.The results showed that the DVL2 p.R633 W mutation destabilized DVL2 protein and upregulated activities for all three Wnt signalings(Wnt/β-catenin signaling,Wnt/planar cell polarity signaling,and Wnt/Ca2+signaling)in mammalian cells.In contrast,DVL1 mutants(DVL1 p.R558 H and DVL1 p.R606 C)decreased canonical Wnt/β-catenin signaling but increased the activity of Wnt/Ca2+signaling,and DVL3 p.R222 Q only decreased the activity of Wnt/Ca2+signaling.We also found that only the DVL2 p.R633 W mutant displayed more severe teratogenicity in zebrafish embryos than wild-type DVL2.Our study demonstrates that these four rare DVL mutations,especially DVL2 p.R633 W,may contribute to human neural diseases such as NTDs and DWM by obstructing Wnt signaling pathways.展开更多
Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.H...Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.展开更多
BACKGROUND Cardiovascular diseases particularly myocardial infarction(MI)are the leading cause of mortality and morbidity around the globe.As cardiac tissue possesses very limited regeneration potential,therefore use ...BACKGROUND Cardiovascular diseases particularly myocardial infarction(MI)are the leading cause of mortality and morbidity around the globe.As cardiac tissue possesses very limited regeneration potential,therefore use of a potent small molecule,inhibitor Wnt production-4(IWP-4)for stem cell differentiation into cardiomyocytes could be a promising approach for cardiac regeneration.Wnt pathway inhibitors may help stem cells in their fate determination towards cardiomyogenic lineage and provide better homing and survival of cells in vivo.Mesenchymal stem cells(MSCs)derived from the human umbilical cord have the potential to regenerate cardiac tissue,as they are easy to isolate and possess multilineage differentiation capability.IWP-4 may promote the differentiation of MSCs into the cardiac lineage.AIM To evaluate the cardiac differentiation ability of IWP-4 and its subsequent in vivo effects.METHODS Umbilical cord tissue of human origin was utilized to isolate the MSCs which were characterized by their morphology,immunophenotyping of surface markers specific to MSCs,as well as by tri-lineage differentiation capability.Cytotoxicity analysis was performed to identify the optimal concentration of IWP-4.MSCs were treated with 5μM IWP-4 at two different time intervals.Differentiation of MSCs into cardiomyocytes was evaluated at DNA and protein levels.The MI ratmodel was developed.IWP-4 treated as well as untreated MSCs were implanted in the MI model,then the cardiac function was analyzed via echocardiography.MSCs were labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate(DiI)dye for tracking,while the regeneration of infarcted myocardium was examined by histology and immunohistochemistry.RESULTS MSCs were isolated and characterized.Cytotoxicity analysis showed that IWP-4 was non-cytotoxic at 5μM concentration.Cardiac specific gene and protein expression analyses exhibited more remarkable results in fourteen days treated group that was eventually selected for in vivo transplantation.Cardiac function was restored in the IWP-4 treated group in comparison to the MI group.Immunohistochemical analysis confirmed the homing of pre-differentiated MSCs that were labeled with DiI cell labeling dye.Histological analysis confirmed the significant reduction in fibrotic area,and improved left ventricular wall thickness in IWP-4 treated MSC group.CONCLUSION Treatment of MSCs with IWP-4 inhibits Wnt pathway and promotes cardiac differentiation.These pre-conditioned MSCs transplanted in vivo improved cardiac function by cell homing,survival,and differentiation at the infarcted region,increased left ventricular wall thickness,and reduced infarct size.展开更多
The present study was designed to investigate the role of estrogen receptorα(ERα)in biaxial tensile strain(BTS)regulated osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells(rBMSCs).rBMSCs we...The present study was designed to investigate the role of estrogen receptorα(ERα)in biaxial tensile strain(BTS)regulated osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells(rBMSCs).rBMSCs were derived fromrats and overexpressed ERα.The rBMSCs were subjected to BTS at 1Hz with a strain of 2%for 4 h per day,3 days,with or without ERαinhibitor ICI 182,780(ICI).Then,bone mineralization was performed by Alizarin Red Staining.The markers of osteogenic differentiation and downstream Wnt3a/β-catenin signaling were detected by western blotting.Results showed that BTS enhanced the osteogenic differentiation of rBMSCs,increased protein expression levels of alkaline phosphatase(ALP),runt-related transcription factor 2(Runx2),collagen type I(Col I)and osteocalcin(OCN),and it increased the protein expression levels of estrogen receptor(ER)α(ERα),Wnt3a,andβ-catenin.BTS The activated Wnt3a/β-catenin signaling pathway induced by BTS was abolished by ICI 182,780(ICI).In addition,overexpressing ERαin rBMSCs promoted the osteogenic differentiation by BTS.Taken together,BTS induced osteogenic differentiation of rBMSCs via the ERαand downstream canonical Wnt3a/β-catenin pathway.展开更多
Objective:To investigate the effects and mechanisms of genistein on the gene expression in the Wnt pathway in acute leukemia(AL)cells.Methods:The expression of Wnt pathway genes and cell cycle-related genes were analy...Objective:To investigate the effects and mechanisms of genistein on the gene expression in the Wnt pathway in acute leukemia(AL)cells.Methods:The expression of Wnt pathway genes and cell cycle-related genes were analyzed in two AL cell lines.Pyrophosphate sequencing was performed to determine the methylation degree.Then,the enrichment of H4K20mel and H3K9ac was determined using ChIP-qPCR.Flow cytometry was used to analyze the cell cycle.Results:The IC_(50) of genistein in the two AL cell lines was lower than that for the bone marrow mesenchymal stem cell line.Genistein upregulated H4K20mel,KMT5A and Wnt suppressor genes,including Wnt5a,and downregulated the downstream target genes of Wnt,such as c-myc and β-catenin.The methylation degree and H3K9ac enrichment in the Wnt5a promoter region remained unchanged.However,the enrichment of H4K20mel in the Wnt5a promoter and coding regions increased.In addition,genistein upregulated Phospho-cdc2,Mytl,Cyclin A,Cyclin E2,p21 and Phospho-histone H3,but downregulated Phospho-weel.Cell cycle arrest was induced in the G2/M phase.Conclusion:Genistein inhibits the activation of the Wnt pathway by promoting the expression of Wnt5a through the activation of KMT5A and enrichment of H4K20mel in the Wnt5a gene promoter and coding regions,rather than demethylation.Genistein also blocks the cell cycle in the G2/M phase.Therefore,genistein is a potential anti-leukemia drug.展开更多
基金The Andor dragonfly Spinning Disk microscope in the CCI was funded by the BBSRC(BB/R01390X/1)This work was supported by the ministry of education of the Kingdom of Saudi Arabia(to M.Alhashmi)+6 种基金Libyan Ministry of Higher Education and Scientific Research and ECMage(to A.M.E.Gremida)Qatar National Research Fund(to N.A.Al-Maslamani)European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement(860635 to M.Antonaci and A.Kerr)BBSRC Grants(BB/T00715X/1 to S.K.Maharana and G.N.WheelerBB/X000907/1 to D.A.Turner)Versus Arthritis Career Development Fellowship(21447 to K.Yamamoto)Versus Arthritis Bridging Fellowship(23137 to K.Yamamoto).
文摘Low-density lipoprotein receptor-related protein 1(LRP1)is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip,osteoporosis and osteoarthritis.Our work addresses the critical question of how these skeletal pathologies emerge.Here,we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.5 and onwards,especially in the perichondrium,the stem cell layer surrounding developing limbs essential for bone formation.Lrp1 deficiency in these stem cells causes joint fusion,malformation of cartilage/bone template and markedly delayed or lack of primary ossification.
文摘Irradiation from diverse sources is ubiquitous and closely associated with human activities. Radiation therapy (RT), an important component of multiple radiation origins, is a common therapeutic modality for cancer. More importantly, RT provides significant contribution to oncotherapy by killing tumor cells. However, during the course of therapy, irradiation of normal tissues can result in a wide range of side effects, including self-limited acute toxicities, mild chronic symptoms, or severe organ dysfunction. Although numerous promising radioprotective agents have emerged, only a few have successfully entered the market because of various limitations. At present, the widely accepted hypothesis for protection against radiation-caused injury involves the Wnt canonical pathway. Activating the Wnt/β-catenin signaling pathway may protect the salivary gland, oral mucosa, and gastrointestinal epithelium from radiation damage. The underlying mechanisms include inhibiting apoptosis and preserving normal tissue functions. However, aberrant Wnt signaling underlies a wide range of pathologies in humans, and its various components contribute to cancer. Moreover, studies have suggested that Wnt/ β-catenin signaling may lead to radioresistance of cancer stem cell. These facts markedly complicate any definition of the exact function of the Wnt pathway.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.:82003807,82173394)the Shaanxi Province Science Foundation,China(Grant No.:2023-GHZD-19)+1 种基金the Medical Foundation-Clinical Integration Program of Xi'an Jiaotong University,China(Grant No.:YXJLRH2022043)the Xi'an Jiaotong University Free Exploration and Innovation-Teacher Project Foundation,China(Grant No.:xzy012023104).
文摘Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O^(6)-methylguanine(O^(6)-MG)-DNA-methyltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensitivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.
基金Supported by the Chinese National Natural Science Foundation(No.81160531)Jiangxi Natural Science Foundation(No.20161BAB205223,20192ACBL21032)Scientific Research Fund of Jiangxi Provincial Education Department(No.GJJ180648)
文摘OBJECTIVE:To investigate if the Liuwei Dihuang pill(LWDHP)can inhibit metastasis to the liver and lungs in mice bearing triple-negative breast cancer(TNBC),and the molecular mechanism underpinning this action.METHODS:Ninety-nine TNBC bearing-mice were distributed randomly to five groups:control(Con),paclitaxel(PTX),low-dose LWDHP(LLP,2.3 g·kg^-1·d^-1),middle-dose LWDHP(MLP,4.6 g·kg^-1·d^-1)and high-dose LWDHP(HLP,9.2 g·kg^-1·d^-1).The LWDHP were administered(p.o.)to the agonal stage.The morphology of BC cells was observed by hematoxylin&eosin staining.Expression of axin-2,β-catenin,T cell factor(TCF),cyclin-D1 and vascular endothelial growth factor(VEGF)was detected by western blotting or immunofluorescence.β-catenin/TCF-1 interaction was measured using a co-immunoprecipitation assay.RESULTS:After LWDHP treatment,metastasis of BC cells to the lungs and liver was inhibited,expression of axin-2 was increased,expression of TCF-1,β-catenin,cyclin-D1 and VEGF was decreased,andβ-catenin/TCF-1 interaction was disrupted.CONCLUSION:The LWDHP could inhibit metastasis of BC cells to the liver and lungs.The molecular mechanism underlying this action may be regulation of protein expression andβ-catenin/TCF-1 interactions in the Wnt pathway.
文摘In this manuscript,we comment on the article,which explores the anti-cancer effects of Calculus bovis(CB)in tumor biology.We highlight its potential,particularly in hepatocellular carcinoma(HCC),where it inhibits the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathways and induces apoptosis.CB contains compounds such as oleanolic acid and ursolic acid that target interleukin-6,mitogen-activated protein kinase 8,vascular endothelial growth factor,and caspase-3,offering anti-inflammatory and hepatoprotective benefits.The manuscript also discusses CB sativus(CBS),an artificial substitute,which has shown efficacy in reducing hepatic inflammation and oxidative stress in animal models.We emphasize the need for further research on the effects of CBS on the gut-liver axis and gut microbiota,and on targeting Wnt signaling and M2 tumor-associated macrophage as potential therapeutic strategies against HCC.
文摘Objective: To investigate the effect of Tip60 gene silencing on the ABCE1 acetylation level and cell proliferation, migration and invasion in TE-1 cells of oesophageal cancer. Methods: The siRNA sequence of Tip60 was transfected with esophageal cancer TE-1 cells. Transfected siRNA vector cells were used as experimental group (si-T), siRNA no-loaded somatic cells were transfected as control group (si-NC), and untransfected TE-1 cells were used as blank group (Group N). ABCE1 mRNA was detected by qRT-PCR, the expression of ABCE1 protein, proliferation-related protein β catenin (β-catenin), GSK3β, and c-myc by Western blot, the protein acetylation level by immunoprecipitation, MTT assay for cell viability, scratch healing and Transwell compartment assay for migration and invasion ability. Results: After 48 h downregulation of the Tip60 gene, TE-1 cells showed no significant changes in the ABCE1 mRNA and protein expression. The acetylation level of ABCE1 decreased significantly, compared with the control group and the blank group. After Tip60 gene silencing, the expression of β-catenin and c-myc protein decreased, while the expression of GSK-3β protein increased. Cytofunctology experiments showed that the proliferative activity, migration and invasion ability of TE-1 cells in the experimental group were significantly inhibited. Conclusion: Down regulation of Tip60 gene can deacetylate ABCE1 protein and inhibit the proliferation activity, migration and invasion ability of esophageal cancer by blocking the conduction of Wnt signaling pathway.
基金financially supporting this work through the Large Research Group Project under Grant no.R.G.P.2/509/45
文摘Polyphenols,a diverse group of naturally occurring compounds found in plants,have garnered significant attention for their potential therapeutic properties in treating neurodegenerative diseases(NDs).The Wnt/β-catenin(WβC)signaling pathway,a crucial player in neurogenesis,neuronal survival,and synaptic plasticity,is involved in several cellular mechanisms related to NDs.Dysregulation of this pathway is a hallmark in the development of various NDs.This study explores multiple polyphenolic compounds,such as flavonoids,stilbenes,lignans,and phenolic acids,and their potential to protect the nervous system.It provides a comprehensive analysis of their effects on the WβC pathway,elucidating their modes of action.The study highlights the dual function of polyphenols in regulating and protecting the nervous system,providing reassurance about the research benefits.This review provides a comprehensive analysis of the results obtained from both in vitro studies and in vivo research,shedding light on how these substances influence the various components of the pathway.The focus is mainly on the molecular mechanisms that allow polyphenols to reduce oxidative stress,inflammation,and apoptotic processes,ultimately improving the function and survival of neurons.This study aims to offer a thorough understanding of the potential of polyphenols in targeting the WβC signaling pathway,which could lead to the development of innovative therapeutic options for NDs.
文摘In this article,we comment on the work published by Huang et al,which explores the mechanisms by which Calculus bovis(CB)modulates the liver cancer immune microenvironment via the Wnt/β-catenin signalling pathway.The study demon-strates that active components in CB effectively inhibit the activation of the Wnt/β-catenin pathway,significantly reducing the polarization of M2 tumor-associated macrophages.Both in vivo and in vitro experiments have validated the anti-tumour effects of CB,revealing its complex mechanisms of action through the modulation of immune cell functions within the tumour microenvironment.This article highlights CB’s therapeutic potential in liver cancer treatment and calls for further investigations into its mechanisms and clinical applications to develop safer,more effective options for patients.The study also revealed that key com-ponents of CB,such as bilirubin and bile acids,inhibit tumour cell proliferation and promote apoptosis through multiple pathways.Future research should explore the mechanisms of action of CB and its potential integration with existing treatments to improve the therapeutic outcomes of liver cancer patients.With multidisciplinary collaboration and advanced research,CB could become a key component of comprehensive liver cancer treatment,offering new hope for patients.
基金Supported by National Science Foundation-Funded Project:based on the Connection Sclerostin with Wnt/β-catenin Pathway to Explored the Effect Mechanism of Dujieqing Oral Liquid on the Inhibit Tumor and Promote Bone Formation in Multiple Myeloma(No.81960839)Innovation Project of Guangxi Graduate Education-Funded Project:Sclerostin Regulates Wnt/β-catenin Pathway to Explore the Mechanism of Dujieqing Decoction in Inhibiting Tumor Growth and Promoting Osteogenesis of Multiple Myeloma(No.YCSW2021224)To Investigate the Effect and Mechanism of Dujiangqing Oral Liquid on Osteogenic Differentiation of Mesenchymal Stem Cells in Multiple Myeloma Mice based on Wnt/β-catenin Signaling Pathway(No.YCSW2023386)。
文摘OBJECTIVE:To explore the therapeutic potential of the Dujieqing(DJQ)decoction(毒结清复方)for multiple myeloma(MM)and elucidate its mechanism of action.METHODS:RPMI8226 cells were treated with DJQcontaining serum(DJQ-CS)and a Wnt/β-catenin pathway inhibitor,XAV-939.Cell counting kit-8 assay was used to examine cell viability,and flow cytometry was performed to examine apoptosis.Real-time polymerase chain reaction and Western blotting were used to evaluate the Wnt/β-catenin pathway family members in the cells.Subsequently,the RPMI8226 cells were subcutaneously injected into the left flank of none obesity disease and server combined immune-deficiency mice to replicate the xenograft tumor mouse models,which were treated with the DJQ decoction for 14 d.Hematoxylin and eosin staining was used to examine the pathological changes of the liver and kidney tissues,and to detect xenograft tumors.Wnt/β-catenin pathway family members were evaluated via Western blotting.RESULTS:DJQ-CS significantly reduced the m RNA and protein expression levels ofβ-catenin,c-myc,cyclin D1,and lymphoid enhancer binding factor 1(LEF1)while inhibiting the proliferation of RPMI8226 cells and inducing their apoptosis.Similar results were observed when the Wnt/β-catenin pathway was suppressed by inhibitors.Moreover,in the mouse model of xenograft tumors,DJQ decoction not only reduced the tumor volume but also inhibited the protein levels ofβ-catenin,c-myc,cyclin D1,and LEF1.The histopathology of the mice also showed increased apoptosis in tumor tissues,while the DJQ decoction treatment did not cause any pathological damage to the kidneys or liver.CONCLUSION:Our results indicate that the DJQ decoction suppresses tumor progression by inhibiting the Wnt/β-catenin pathway,offering a promising treatment approach for MM.
基金supported by the Natural Science Foundation of Shandong Province(ZR2019MC059)the Traditional Chinese Medicine Science Project of Shandong Province(M-2023093)the Weifang Municipal Science and Technology Development Program(2025YX037).
文摘Human cytomegalovirus(HCMV)poses a significant risk of neural damage during pregnancy.As the most prevalent intrauterine infectious agent in low-and middle-income countries,HCMV disrupts the development of neural stem cells,leading to fetal malformations and abnormal structural and physiological functions in the fetal brain.This review summarizes the current understanding of how HCMV infection dysregulates the Wnt signaling pathway to induce fetal malformations and discusses current management strategies.
基金Supported by the National Natural Youth Science Foundation:Research on the Mechanism of Acupuncture in Modulating the Inflammatory Microenvironment via the Muscarinic Acetylcholine Receptor(mAChR1)Signaling Pathway for Myopia Intervention(82205198)China Postdoctoral Science Foundation Project:Research on the Mechanism of Acupuncture in Modulating the Inflammatory Microenvironment via the mAChR1 Signaling Pathway for Myopia Intervention(2022M711984)+5 种基金Shandong Provincial Natural Science Foundation General Program:to Investigate the Underlying Mechanism of Acupuncture in Treating Myopia Associated eith Kidney Yang Deficiency Syndrome through the Muscarinic Acetylcholine Receptors(M-AChRs)Signaling Pathway(ZR2020MH393)Postdoctoral Innovation Project of Shandong Province:Research on the Mechanism of Electroacupuncture in Treating Myopia with"Kidney Yang Deficiency Syndrome"through the M-AChRs/Gamma-Aminobutyric Acid Signaling Pathway(202101012)China Postdoctoral Foundation General Program:to Investigate the Underlying Mechanism of Acupuncture in Treating Myopia Associated with Kidney Yang Deficiency Syndrome through the M-AChRs Signaling Pathway(2020M672127)National Natural Science Foundation:Research on the Influence of Acupuncture on the Accommodative Function and Visual Cortex Functional Network of Myopia and its Mechanism(82074498)National Key R&D Project:National Key Research and Development Program"Basic Research on High Myopia"(2019YFC1710200)National Natural Science Foundation of China:Research on the Relationship between Lens-Induced Myopia based on Omics Technology and Traditional Chinese Medicine Syndrome Types and its Molecular Mechanism(82474579)。
文摘OBJECTIVE:To determine the mechanism of electroacupuncture(EA)effect by the wingless-related integration site(Wnt)/β-catenin pathway in the guinea pig myopia model.METHODS:Following myopia induction and EA,guinea pigs were treated with biometry to evaluate refraction and axial length.Hematoxylin and eosin(HE)staining was used to observe that the retina,choroid,and sclera had abnormal morphology.At 4,6,and 8 weeks,quantitative polymerase chain reaction(q PCR)was used to identify the expression of matrix metallopeptidase-2(MMP-2)/MMP-3/tissue inhibitor of metalloprotease-2(TIMP-2)/TIMP-3/Wnt family member 2B(WNT2B)/WNT3A/WNT7B/beta-catenin 1(CTNNB1),and dickkopf wnt signaling pathway inhibitor 1(DKK-1)m RNAs in the retina,choroid,and sclera.Western blot was used to detect the protein expression of WNT7B/2B/3A,CTNNB1 and DKK-1 in retina,choroid and sclera at 4 weeks.Enzyme-linked immunosorbent assay was used to detect the protein expression of MMP-2/TIMP-2 and MMP-3/TIMP-3 in serum at 4 weeks.Moreover,a DKK-1 inhibitor was injected into the vitreous cavity,and the expression of the above molecules was detected.RESULTS:EA could reduce the optic axial length and diopter and ameliorate ocular pathology,inhibited the expression of MMP-2/MMP-3 and WNT2B/WNT3A/WNT7B/CTNNB1,while increased the expression levels of TIMP-2/TIMP-3 and DKK-1.However,the expression levels of WNT2B/WNT3A/WNT7B/CTNNB1 and MMP-2/MMP-3 were significantly increased,and the TIMP-2/TIMP-3 and DKK-1 expression levels were decreased after injected DKK-1 inhibitor.CONCLUSION:The mechanism of EA's effects on myopia may involve the downregulation of the Wnt/β-catenin pathway and correct MMP-2/MMP-3/TIMP-2/TIMP-3 balance.
文摘Objective:Anillin(ANLN)is considered an oncogene in various cancers,but its effect on cervical cancer remains poorly understood.Hence,this study aimed to describe the action of ANLN on cervical cancer development and investigate the potential mechanism.Methods:Analysis of ANLN expression and its association with survival in carcinoma and endocervical adenocarcinoma(CESC)patients based on GEO and UALCAN databases.The tumor and adjacent normal tissues of 100 cervical cancer cases were harvested to detect the ANLN expression and explore its relationship with patient survival.Cell proliferation,apoptosis,migration,and invasion were measured by utilizing 5-ethynyl-2′-deoxyuridine(EdU)staining,Flow cytometry,and Transwell assay,respectively.ANLN andWnt expression were analyzed by RT-qPCR andWestern Blot.Results:ANLN was significantly elevated in tumor tissues,and cervical cancer cases with high ANLN expression exhibited poor survival and high dead proportion.Besides,ANLN induced cervical cancer cell proliferation,migration,and invasion and restrained cell apoptosis.In addition,ANLN promoted Wnt/β-catenin pathway activation.Furthermore,ANLN accelerated cell aggressive behaviors and suppressed cell apoptosis via activating the Wnt/β-catenin signaling in cervical cancer.Conclusion:ANLN was enhanced in cervical cancer tissues and related to poor prognosis.ANLN accelerated cervical cancer cell aggressive behaviors and suppressed cell apoptosis via activating theWnt/β-catenin pathway.
基金Supported by the Natural Science Research Project of Basic Research Program in Shanxi Province,No.202203021221268the National Natural Science Foundation of China,No.82305030.
文摘In this editorial,we discuss the article by Fu Y et al,indicating that hair deve-lopment is influenced by exosomes from human adipose-derived stem/stromal cell-mediated cell-to-cell communication via the Wnt/β-catenin pathway.In recent years,mesenchymal stem cells(MSCs)and MSC-derived exosomes(MSC-Exos)have emerged as a promising cell-free therapeutic strategy due to their robust regenerative capabilities across multiple tissues.MSC-Exos are enriched with bioactive molecules,including proteins,microRNAs,and growth factors,which activate critical signaling pathways,notably the Wnt/β-catenin pathway,to promote cell proliferation,differentiation,and tissue repair.This editorial system-atically examines the application of MSC-Exos in regenerating diverse tissues such as hair follicles and kidney,lung,and cardiac muscle tissue.Central to their mechanism is the activation of the Wnt/β-catenin pathway,which drives cell cycle progression(via cyclin B1/cyclin-dependent kinase 1),suppresses apoptosis(through Bcl-2/Bax modulation),and attenuates fibrosis(by inhibiting transforming growth factor-β/alpha-smooth muscle actin).The challenges related to the clinical translation of exosome-based therapies,including standardization of isolation protocols,optimization of dosing and delivery methods,and safety evaluation,are discussed.The most important challenge is standardizing isolation protocols because exosomes obtained from different sources or treatment methods are different,which leads to differences in the therapeutic effects of exosomes.Overall,MSC-Exos provide an effective cell-free strategy for tissue repair and offer a robust foundation to develop personalized regenerative medicine.
文摘Liver cancer remains a significant global health challenge,characterized by high incidence and mortality rates.Despite advancements in medical treatments,the prognosis for liver cancer patients remains poor,highlighting the urgent need for novel therapeutic approaches.Traditional Chinese medicine(TCM),particularly Calculus bovis(CB),has shown promise in addressing this need due to its multitarget therapeutic mechanisms.CB refers to natural or synthetic gallstones,traditionally sourced from cattle,and used in TCM for their anti-inflammatory,detoxifying,and therapeutic properties.In modern practice,synthetic CB is often utilized to ensure consistent supply and safety.This article aims to discuss the findings of Huang et al,who investigated the anti-liver cancer properties of CB,focusing on its ability to inhibit M2 tumor-associated macrophage(TAM)polarization via modulation of the Wnt/β-catenin pathway.Huang et al employed a comprehensive approach integrating chemical analysis,animal model testing,and advanced bioinformatics.They identified active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms through network pharmacology,transcriptomics,and molecular docking studies.The study demonstrated that CB significantly inhibited liver tumor growth in vivo,as evidenced by reduced tumor size and weight in treated mice.Histological analyses confirmed signs of tumor regression.CB was found to modulate the tumor microenvironment by inhibiting the polarization of M2 phenotype-TAMs,as shown by reduced expression of M2 markers and downregulation of mRNA levels of C-C motif chemokine 22,arginase-1,transforming growth factor-beta 2,and interleukin-10.The study further revealed that CB’s antineoplastic activity involved the downregulation of Wnt5B andβ-catenin and upregulation of Axin2,thus inhibiting the Wnt/β-catenin signaling pathway.These findings highlight the therapeutic potential of CB in liver cancer treatment through its modulation of the Wnt/β-catenin pathway and suppression of M2 phenotype-TAM polarization.This study underscores the value of integrating TCM with modern therapeutic strategies to develop novel effective treatments for liver cancer.
基金supported by the German Research Council(Deutsche Forschungsgemeinschaft,HA3309/3-1/2,HA3309/6-1,HA3309/7-1)。
文摘Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.
基金supported by Research and Development Program of China(2016YFC1000500)to H.W.and W.T.the National Natural Science Foundation of China(81430005,31521003,31771669)to H.W.and(31601029)to Y.G.the Commission for Science and Technology of Shanghai Municipality(17JC1400902)to H.W.
文摘Wnt signaling pathways,including the canonical Wnt/β-catenin pathway,planar cell polarity pathway,and Wnt/Ca2+signaling pathway,play important roles in neural development during embryonic stages.The DVL genes encode the hub proteins for Wnt signaling pathways.The mutations in DVL2 and DVL3 were identified from patients with neural tube defects(NTDs),but their functions in the pathogenesis of human neural diseases remain elusive.Here,we sequenced the coding regions of three DVL genes in 176 stillborn or miscarried fetuses with NTDs or Dandy-Walker malformation(DWM)and 480 adult controls from a Han Chinese population.Four rare mutations were identified:DVL1 p.R558 H,DVL1 p.R606 C,DVL2 p.R633 W,and DVL3 p.R222 Q.To assess the effect of these mutations on NTDs and DWM,various functional analyses such as luciferase reporter assay,stress fiber formation,and in vivo teratogenic assay were performed.The results showed that the DVL2 p.R633 W mutation destabilized DVL2 protein and upregulated activities for all three Wnt signalings(Wnt/β-catenin signaling,Wnt/planar cell polarity signaling,and Wnt/Ca2+signaling)in mammalian cells.In contrast,DVL1 mutants(DVL1 p.R558 H and DVL1 p.R606 C)decreased canonical Wnt/β-catenin signaling but increased the activity of Wnt/Ca2+signaling,and DVL3 p.R222 Q only decreased the activity of Wnt/Ca2+signaling.We also found that only the DVL2 p.R633 W mutant displayed more severe teratogenicity in zebrafish embryos than wild-type DVL2.Our study demonstrates that these four rare DVL mutations,especially DVL2 p.R633 W,may contribute to human neural diseases such as NTDs and DWM by obstructing Wnt signaling pathways.
基金This study was financially supported by the National Key Research and Development Program of China(2022YFC2804100,2021YFF0502400,2022YFC2804300)National Natural Science Foundation of China(82073713,22137006,82104033,82173730,81903499,32070070,82160669)Innovative research team of highlevel local universities in Shanghai(SHSMU-ZDCX20212702,China).We thank Dr.Juncheng Su from Shanghai Jiao-Tong University School of Medicine(Shanghai,China)for providing the LoVo and COLO 320DM cell lines.
文摘Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.
文摘BACKGROUND Cardiovascular diseases particularly myocardial infarction(MI)are the leading cause of mortality and morbidity around the globe.As cardiac tissue possesses very limited regeneration potential,therefore use of a potent small molecule,inhibitor Wnt production-4(IWP-4)for stem cell differentiation into cardiomyocytes could be a promising approach for cardiac regeneration.Wnt pathway inhibitors may help stem cells in their fate determination towards cardiomyogenic lineage and provide better homing and survival of cells in vivo.Mesenchymal stem cells(MSCs)derived from the human umbilical cord have the potential to regenerate cardiac tissue,as they are easy to isolate and possess multilineage differentiation capability.IWP-4 may promote the differentiation of MSCs into the cardiac lineage.AIM To evaluate the cardiac differentiation ability of IWP-4 and its subsequent in vivo effects.METHODS Umbilical cord tissue of human origin was utilized to isolate the MSCs which were characterized by their morphology,immunophenotyping of surface markers specific to MSCs,as well as by tri-lineage differentiation capability.Cytotoxicity analysis was performed to identify the optimal concentration of IWP-4.MSCs were treated with 5μM IWP-4 at two different time intervals.Differentiation of MSCs into cardiomyocytes was evaluated at DNA and protein levels.The MI ratmodel was developed.IWP-4 treated as well as untreated MSCs were implanted in the MI model,then the cardiac function was analyzed via echocardiography.MSCs were labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate(DiI)dye for tracking,while the regeneration of infarcted myocardium was examined by histology and immunohistochemistry.RESULTS MSCs were isolated and characterized.Cytotoxicity analysis showed that IWP-4 was non-cytotoxic at 5μM concentration.Cardiac specific gene and protein expression analyses exhibited more remarkable results in fourteen days treated group that was eventually selected for in vivo transplantation.Cardiac function was restored in the IWP-4 treated group in comparison to the MI group.Immunohistochemical analysis confirmed the homing of pre-differentiated MSCs that were labeled with DiI cell labeling dye.Histological analysis confirmed the significant reduction in fibrotic area,and improved left ventricular wall thickness in IWP-4 treated MSC group.CONCLUSION Treatment of MSCs with IWP-4 inhibits Wnt pathway and promotes cardiac differentiation.These pre-conditioned MSCs transplanted in vivo improved cardiac function by cell homing,survival,and differentiation at the infarcted region,increased left ventricular wall thickness,and reduced infarct size.
基金This work was supported by grants from the Nature Science Foundation of China(11572209,11272225).
文摘The present study was designed to investigate the role of estrogen receptorα(ERα)in biaxial tensile strain(BTS)regulated osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells(rBMSCs).rBMSCs were derived fromrats and overexpressed ERα.The rBMSCs were subjected to BTS at 1Hz with a strain of 2%for 4 h per day,3 days,with or without ERαinhibitor ICI 182,780(ICI).Then,bone mineralization was performed by Alizarin Red Staining.The markers of osteogenic differentiation and downstream Wnt3a/β-catenin signaling were detected by western blotting.Results showed that BTS enhanced the osteogenic differentiation of rBMSCs,increased protein expression levels of alkaline phosphatase(ALP),runt-related transcription factor 2(Runx2),collagen type I(Col I)and osteocalcin(OCN),and it increased the protein expression levels of estrogen receptor(ER)α(ERα),Wnt3a,andβ-catenin.BTS The activated Wnt3a/β-catenin signaling pathway induced by BTS was abolished by ICI 182,780(ICI).In addition,overexpressing ERαin rBMSCs promoted the osteogenic differentiation by BTS.Taken together,BTS induced osteogenic differentiation of rBMSCs via the ERαand downstream canonical Wnt3a/β-catenin pathway.
基金supported by grants from the National Natural Science Foundation of China(No.81800167)the Natural Science Foundation of Fujian Province(No.2017J05132)+4 种基金the Fujian Provincial Health Technology Project(No.2018-ZQN-40)the Start-up Fund Project of Fujian Medical University(No.2016QH020)the Construction Project of Fujian Medical Center of Hematology(No.Min201704)the National and Fujian Provincial Key Clinical Specialty Discipline Construction Program,ChinaClinical Research Center for Hematological Malignancies of Fujian Province.
文摘Objective:To investigate the effects and mechanisms of genistein on the gene expression in the Wnt pathway in acute leukemia(AL)cells.Methods:The expression of Wnt pathway genes and cell cycle-related genes were analyzed in two AL cell lines.Pyrophosphate sequencing was performed to determine the methylation degree.Then,the enrichment of H4K20mel and H3K9ac was determined using ChIP-qPCR.Flow cytometry was used to analyze the cell cycle.Results:The IC_(50) of genistein in the two AL cell lines was lower than that for the bone marrow mesenchymal stem cell line.Genistein upregulated H4K20mel,KMT5A and Wnt suppressor genes,including Wnt5a,and downregulated the downstream target genes of Wnt,such as c-myc and β-catenin.The methylation degree and H3K9ac enrichment in the Wnt5a promoter region remained unchanged.However,the enrichment of H4K20mel in the Wnt5a promoter and coding regions increased.In addition,genistein upregulated Phospho-cdc2,Mytl,Cyclin A,Cyclin E2,p21 and Phospho-histone H3,but downregulated Phospho-weel.Cell cycle arrest was induced in the G2/M phase.Conclusion:Genistein inhibits the activation of the Wnt pathway by promoting the expression of Wnt5a through the activation of KMT5A and enrichment of H4K20mel in the Wnt5a gene promoter and coding regions,rather than demethylation.Genistein also blocks the cell cycle in the G2/M phase.Therefore,genistein is a potential anti-leukemia drug.
