BACKGROUND Hepatocellular carcinoma(HCC)exhibits high invasiveness and mortality rates,and the molecular mechanisms of HCC have gained increasing research interest.The abnormal DNA damage response has long been recogn...BACKGROUND Hepatocellular carcinoma(HCC)exhibits high invasiveness and mortality rates,and the molecular mechanisms of HCC have gained increasing research interest.The abnormal DNA damage response has long been recognized as one of the important factors for tumor occurrence and development.Recent studies have shown the potential of the protein RING finger and WD repeat domain 3(RFWD3)that positively regulates p53 stability in response to DNA damage as a therapeutic target in cancers.AIM To investigate the relationship between HCC and RFWD3 in vitro and in vivo and explored the underlying molecular signalling transduction pathways.METHODS RFWD3 gene expression was analyzed in HCC tissues and adjacent normal tissues.Lentivirus was used to stably knockdown RFWD3 expression in HCC cell lines.After verifying the silencing efficiency,Celigo/cell cycle/apoptosis and MTT assays were used to evaluate cell proliferation and apoptosis.Subsequently,cell migration and invasion were assessed by wound healing and transwell assays.In addition,transduced cells were implanted subcutaneously and injected into the tail vein of nude mice to observe tumor growth and metastasis.Next,we used lentiviral-mediated rescue of RFWD3 shRNA to verify the phenotype.Finally,the microarray,ingenuity pathway analysis,and western blot analysis were used to analyze the regulatory network underlying HCC.RESULTS Compared with adjacent tissues,RFWD3 expression levels were significantly higher in clinical HCC tissues and correlated with tumor size and TNM stage(P<0.05),which indicated a poor prognosis state.RFWD3 silencing in BEL-7404 and HCC-LM3 cells increased apoptosis,decreased growth,and inhibited the migration in shRNAi cells compared with those in shCtrl cells(P<0.05).Furthermore,the in vitro results were supported by the findings of the in vivo experiments with the reduction of tumor cell invasion and migration.Moreover,the rescue of RFWD3 shRNAi resulted in the resumption of invasion and metastasis in HCC cell lines.Finally,gene expression profiling and subsequent experimental verification revealed that RFWD3 might influence the proliferation and metastasis of HCC via the Wnt/β-catenin signalling pathway.CONCLUSION We provide evidence for the expression and function of RFWD3 in HCC.RFWD3 affects the prognosis,proliferation,invasion,and metastasis of HCC by regulating the Wnt/β-catenin signalling pathway.展开更多
Liver cancer,and in particular hepatocellular carcinoma(HCC)is a disease of rising prevalence and incidence.To date,definitive treatment options include either surgical excision or ablation of the affected area.With i...Liver cancer,and in particular hepatocellular carcinoma(HCC)is a disease of rising prevalence and incidence.To date,definitive treatment options include either surgical excision or ablation of the affected area.With increasing research on several pathways that could be involved in the progression of HCC,new elements within these pathways emerge as potential targets for novel therapies.The WNT/β-catenin pathway favors the presence of M2 tumor-associated macrophages which in turn promote tumor growth and metastasis.The inhibition of this pathway is considered a good candidate for such targeted therapeutic interventions.Interestingly,as Huang et al show in their recently published article,Calculus bovis which is used in traditional Chinese medicine can exert an inhibitory effect on theβ-catenin pathway and become a potential candidate for targeted pharmacotherapy against liver cancer.展开更多
Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy pre...Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.展开更多
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
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
OBJECTIVE:To investigate the effect of icariin on proliferation of bone marrow mesenchymal stem cells(BMSCs)in Sprague-Dawley(SD)rats.METHODS:BMSCs were obtained from SD rat bone marrow with differential time adherent...OBJECTIVE:To investigate the effect of icariin on proliferation of bone marrow mesenchymal stem cells(BMSCs)in Sprague-Dawley(SD)rats.METHODS:BMSCs were obtained from SD rat bone marrow with differential time adherent method.Its characteristic was identified through differentiation cell surface antigens and the multi-lineage(osteo/adipo/chondo)differentiation potential.3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)method and 5-Bromo-2-Deoxyuridine(Brd U)incorporation were applied to detect the effect of icariin on BMSCs proliferation.Flow cytometry was used to detect proliferation in-dex of BMSCs.The m RNA level and the distribution ofβ-catenin were evaluated by Real-time Polymerase Chain Reaction(PCR)and Immunofluorescent staining respectively.Western blot was used to detect protein expression levels ofβ-catenin,glycogen synthase kinase-3 beta(GSK-3β),phospho-glycogen synthase kinase-3 beta(p GSK-3β)and cyclin D1.RESULTS:Icariin promoted BMSCs proliferation at the concentration of 0.05-2.0 mg/L.The percentage of Brd U positive cells of BMSCs was increased from40.98%to 70.42%,and the proliferation index value was increased from 8.9%to 17.5%with the treatment of 0.05 mg/L icariin,which significance values were both less than 0.05.Compared with the control group,total and nuclearβ-catenin proteins,as well asβ-catenin m RNA expression,were all increased with icariin treatment.Meanwhile,the phosphorylation level of GSK-3βand cyclin D1 protein expressions were also increased in BMSCs with icariin treatment.CONCLUSION:The findings of the present study demonstrated that low dosage of icariin could promote BMSCs proliferation.The activation of Wnt/β-catenin pathways was involved in this process.展开更多
OBJECTIVE:To evaluate the molecular mechanism underlying the beneficial effect of Bushen Qiangjin capsule(补肾强筋胶囊,BSQJ),a Traditional Chinese Medicine,on knee osteoarthritis(KOA).METHODS:In the present study,32 f...OBJECTIVE:To evaluate the molecular mechanism underlying the beneficial effect of Bushen Qiangjin capsule(补肾强筋胶囊,BSQJ),a Traditional Chinese Medicine,on knee osteoarthritis(KOA).METHODS:In the present study,32 female Sprague-Dawley rats were randomly divided into four groups:control,KOA,high-dose BSQJ(H-BSQJ),and low-dose BSQJ(L-BSQJ).After successfully establishing the KOA model by intra-articular injection of papain,H-BSQJ and L-BSQJ groups were intragastrically administered 0.243 and 0.122 g/kg BSQJ,respectively,daily for 6 weeks.At the end of the experiment,knee articular cartilage tissues of rats were collected for evaluation by hematoxylin and eosin staining,Safranin O-Fast Green staining,and terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling assay.Serum interleukin-1βand tumor necrosis factor-αlevels of rats were detected with an enzyme-linked immunosorbent assay method.Gene expression of Wnt-4,β-catenin,Frizzled-2,glycogen synthase kinase-3β(GSK-3β),cysteinyl aspartate-specific proteinases 3 and 9(caspases 3 and 9),collagen typeⅡalpha 1(Col2 a1),and matrix metalloproteinases 1 and 13(MMP-1 and MMP-3)of rat knee articular cartilage was quantified by reverse transcription-quantitative polymerase chain reaction analysis.Wnt-4,β-catenin,Frizzled-2,GSK-3β,cleaved caspase-3,and cleaved caspase-9 protein expression in rat knee articular cartilage was determined by western blot analysis.RESULTS:BSQJ obviously reduced pathological damage and matrix degradation of articular cartilage in KOA rats.Compared with the KOA group,H-BSQJ rats exhibited downregulated m RNA and protein expression of Wnt-4,β-catenin,Frizzled-2,and caspase-3,as well as upregulated m RNA and protein expression of GSK-3β.In addition,H-BSQJ significantly increased m RNA expression of Col2 a1 and decreased m RNA expression of MMP-1 and MMP-13.CONCLUSION:BSQJ exerted a beneficial effect on KOA by a mechanism involving downregulation of the Wnt/β-catenin pathway,which inhibited both cartilage extracellular matrix degradation and chondrocyte apoptosis to ameliorate KOA in rats.展开更多
AIM： To investigate the effect of activation of canonical Wnt signaling pathway on the proliferation and differentiation of hepatic oval cells in vitro. METHODS： WB-F344 cells were treated with recombinant Wnt3a （2...AIM： To investigate the effect of activation of canonical Wnt signaling pathway on the proliferation and differentiation of hepatic oval cells in vitro. METHODS： WB-F344 cells were treated with recombinant Wnt3a （20, 40, 80, 160, 200 ng/mL） in serum-free medium for 24 h. Cell proliferation was measured by Brdu incorporation analysis; untreated WB-F344 cells were taken as controls. After treatment with Wnt3a （160 ng/mL） for 24 h, subcellular localization and protein expression of p-catenin in WB-F344 cells treated and untreated with Wnt3a were examined by immunofluorescence staining and Western blot analysis. CyclinD1 mRNA expression was determined by semi-quantitative reverse-transcript polymerase chain reaction （RT-PCR）. The mRNA levels of some phenotypic markers （AFP, CK-19, ALB） and two hepatic nuclear factors （HNF-4, HIVF-6） were measured by RT-PCR. Expressions of CK-19 and AFP protein were detected by Western blot analysis. RESULTS： Wnt3a promoted proliferation of WB-F344 cells. Stimulation of WB-F344 cells with recombinant Wnt3a resulte^l in accumulation of the transcriptional activator β-catenin, together with its translocation into the nuclei, and up-regulated typical Wnt target gene CyclinD1. After 3 d of Wnt3a treatment in the absence of serum, WB-F344 cells retained their bipotential to express several specific phenotypic markers of hepatocytes and cholangiocytes, such as AFP and CK-19, following activation of the canonical Wnt signaling pathway. CONCLUSION： The canonical Wnt signaling pathway promotes proliferation and self-renewal of rat hepatic oval cells.展开更多
AIM: To explore the contribution of AXIN1, AXIN2 and beta-catenin, components of Wnt signaling pathway, to the carcinogenesis of gastric cancer (GC), we examined AXIN1, AXIN2 exon7 and CTNNB1 (encoding beta- catenin) ...AIM: To explore the contribution of AXIN1, AXIN2 and beta-catenin, components of Wnt signaling pathway, to the carcinogenesis of gastric cancer (GC), we examined AXIN1, AXIN2 exon7 and CTNNB1 (encoding beta- catenin) exon3 mutations in 70 GCs. METHODS: The presence of mutations was identified by polymerase chain reaction (PCR)-based denaturing high-performance liquid chromatography and direct DNA sequencing. Beta-catenin expression was detected by immunohistochemical analysis. RESULTS: Among the 70 GCs, 5 (7.1%) had mutations in one or two of these three components. A frameshift mutation (1 bp deletion) in exon7 of AXIN2 was found in one case. Four cases, including the case with a mutation in AXIN2, had frameshift mutations and missense mutations in AXIN1. Five single nucleotide polymorphisms (SNPs), 334 C>T, 874 C>T, 1396 G>A, 1690 C>T and 1942 T>G, were identified in AXIN1. A frameshift mutation (27 bp deletion) spanning exon3 of CTNNB1 was observed in one case. All four cases with mutations in AXIN1 and AXIN2 showed nuclear beta- catenin expression. CONCLUSION: These data indicate that the mutationsin AXIN1 and AXIN2 may contribute to gastric carcino- genesis.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
AIM To investigate the potential role of micro RNA-30 a(mi R-30 a) in esophageal squamous cell carcinoma(ESCC).METHODS Expression of mi R-30 a-3 p/5 p was analyzed using microarray data and fresh ESCC tissue samples. ...AIM To investigate the potential role of micro RNA-30 a(mi R-30 a) in esophageal squamous cell carcinoma(ESCC).METHODS Expression of mi R-30 a-3 p/5 p was analyzed using microarray data and fresh ESCC tissue samples. Both in vitro and in vivo assays were used to investigate the effects of mi R-30 a-3 p/5 p on ESCC cell proliferation. Furthermore,Kyoto Encyclopedia of Genes and Genomes analysis was performed to explore underlying mechanisms involved in ESCC,and then,assays were carried out to verify the potential molecular mechanism of mi R-30 a in ESCC.RESULTS Low expression of mi R-30 a-3 p/5 p was closely associated with advanced ESCC progression and poor prognosis of patients with ESCC. Knock-down of mi R-30 a-3 p/5 p promoted ESCC cell proliferation. Increased mi R-30 a-3 p/5 p expression inhibited the Wnt signaling pathway by targeting Wnt2 and Fzd2.CONCLUSION Down-regulation of mi R-30 a-3 p/5 p promotes ESCC cell proliferation by activating the Wnt signaling pathway through inhibition of Wnt2 and Fzd2.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
基金Supported by National Natural Science Foundation of China,No.82172944 and No.81900558Co-operation Research Plan of Medical Science and Technology of Henan Province,No.LHGJ20190149the Key Scientific Research Projects of Universities of Henan Province,No.21A320052。
文摘BACKGROUND Hepatocellular carcinoma(HCC)exhibits high invasiveness and mortality rates,and the molecular mechanisms of HCC have gained increasing research interest.The abnormal DNA damage response has long been recognized as one of the important factors for tumor occurrence and development.Recent studies have shown the potential of the protein RING finger and WD repeat domain 3(RFWD3)that positively regulates p53 stability in response to DNA damage as a therapeutic target in cancers.AIM To investigate the relationship between HCC and RFWD3 in vitro and in vivo and explored the underlying molecular signalling transduction pathways.METHODS RFWD3 gene expression was analyzed in HCC tissues and adjacent normal tissues.Lentivirus was used to stably knockdown RFWD3 expression in HCC cell lines.After verifying the silencing efficiency,Celigo/cell cycle/apoptosis and MTT assays were used to evaluate cell proliferation and apoptosis.Subsequently,cell migration and invasion were assessed by wound healing and transwell assays.In addition,transduced cells were implanted subcutaneously and injected into the tail vein of nude mice to observe tumor growth and metastasis.Next,we used lentiviral-mediated rescue of RFWD3 shRNA to verify the phenotype.Finally,the microarray,ingenuity pathway analysis,and western blot analysis were used to analyze the regulatory network underlying HCC.RESULTS Compared with adjacent tissues,RFWD3 expression levels were significantly higher in clinical HCC tissues and correlated with tumor size and TNM stage(P<0.05),which indicated a poor prognosis state.RFWD3 silencing in BEL-7404 and HCC-LM3 cells increased apoptosis,decreased growth,and inhibited the migration in shRNAi cells compared with those in shCtrl cells(P<0.05).Furthermore,the in vitro results were supported by the findings of the in vivo experiments with the reduction of tumor cell invasion and migration.Moreover,the rescue of RFWD3 shRNAi resulted in the resumption of invasion and metastasis in HCC cell lines.Finally,gene expression profiling and subsequent experimental verification revealed that RFWD3 might influence the proliferation and metastasis of HCC via the Wnt/β-catenin signalling pathway.CONCLUSION We provide evidence for the expression and function of RFWD3 in HCC.RFWD3 affects the prognosis,proliferation,invasion,and metastasis of HCC by regulating the Wnt/β-catenin signalling pathway.
文摘Liver cancer,and in particular hepatocellular carcinoma(HCC)is a disease of rising prevalence and incidence.To date,definitive treatment options include either surgical excision or ablation of the affected area.With increasing research on several pathways that could be involved in the progression of HCC,new elements within these pathways emerge as potential targets for novel therapies.The WNT/β-catenin pathway favors the presence of M2 tumor-associated macrophages which in turn promote tumor growth and metastasis.The inhibition of this pathway is considered a good candidate for such targeted therapeutic interventions.Interestingly,as Huang et al show in their recently published article,Calculus bovis which is used in traditional Chinese medicine can exert an inhibitory effect on theβ-catenin pathway and become a potential candidate for targeted pharmacotherapy against liver cancer.
基金Beijing Natural Science Foundation,Grant/Award Number:L222145 and L222030Emerging Engineering Interdisciplinary Project and the Fundamental Research Funds for the Central Universities,Grant/Award Number:PKU2022XGK008Peking University Medicine Fund of Fostering Young Scholars’Scientific&Technological Innovation,Grant/Award Number:BMU2022PY010。
文摘Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.
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.
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the the National Natural Science Foundation of China(Study on the Bushen Chinese Medicine on the BMSCs Differentiation,No.81173619,81403479)Natural Science Foundation of the Jiangsu Province of China(Study of Acupuncture on Ischemic Stroke,No.BK20130956)Specialized Research Fund for the Doctoral Program of Higher Education of China(Epigenetic Mechanism of Acupuncture on Brain Injury,No.20133237120002)
文摘OBJECTIVE:To investigate the effect of icariin on proliferation of bone marrow mesenchymal stem cells(BMSCs)in Sprague-Dawley(SD)rats.METHODS:BMSCs were obtained from SD rat bone marrow with differential time adherent method.Its characteristic was identified through differentiation cell surface antigens and the multi-lineage(osteo/adipo/chondo)differentiation potential.3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)method and 5-Bromo-2-Deoxyuridine(Brd U)incorporation were applied to detect the effect of icariin on BMSCs proliferation.Flow cytometry was used to detect proliferation in-dex of BMSCs.The m RNA level and the distribution ofβ-catenin were evaluated by Real-time Polymerase Chain Reaction(PCR)and Immunofluorescent staining respectively.Western blot was used to detect protein expression levels ofβ-catenin,glycogen synthase kinase-3 beta(GSK-3β),phospho-glycogen synthase kinase-3 beta(p GSK-3β)and cyclin D1.RESULTS:Icariin promoted BMSCs proliferation at the concentration of 0.05-2.0 mg/L.The percentage of Brd U positive cells of BMSCs was increased from40.98%to 70.42%,and the proliferation index value was increased from 8.9%to 17.5%with the treatment of 0.05 mg/L icariin,which significance values were both less than 0.05.Compared with the control group,total and nuclearβ-catenin proteins,as well asβ-catenin m RNA expression,were all increased with icariin treatment.Meanwhile,the phosphorylation level of GSK-3βand cyclin D1 protein expressions were also increased in BMSCs with icariin treatment.CONCLUSION:The findings of the present study demonstrated that low dosage of icariin could promote BMSCs proliferation.The activation of Wnt/β-catenin pathways was involved in this process.
基金Supported by Guangdong Basic and Applied Basic Research Foundation,China(No.2018A030313584)Science and Technology Planning Project of Guangzhou,China(No.201804010217)Project of Administration of Traditional Chinese Medicine of Guangdong Province,China(No.20194002,20183001,and 20164002)。
文摘OBJECTIVE:To evaluate the molecular mechanism underlying the beneficial effect of Bushen Qiangjin capsule(补肾强筋胶囊,BSQJ),a Traditional Chinese Medicine,on knee osteoarthritis(KOA).METHODS:In the present study,32 female Sprague-Dawley rats were randomly divided into four groups:control,KOA,high-dose BSQJ(H-BSQJ),and low-dose BSQJ(L-BSQJ).After successfully establishing the KOA model by intra-articular injection of papain,H-BSQJ and L-BSQJ groups were intragastrically administered 0.243 and 0.122 g/kg BSQJ,respectively,daily for 6 weeks.At the end of the experiment,knee articular cartilage tissues of rats were collected for evaluation by hematoxylin and eosin staining,Safranin O-Fast Green staining,and terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling assay.Serum interleukin-1βand tumor necrosis factor-αlevels of rats were detected with an enzyme-linked immunosorbent assay method.Gene expression of Wnt-4,β-catenin,Frizzled-2,glycogen synthase kinase-3β(GSK-3β),cysteinyl aspartate-specific proteinases 3 and 9(caspases 3 and 9),collagen typeⅡalpha 1(Col2 a1),and matrix metalloproteinases 1 and 13(MMP-1 and MMP-3)of rat knee articular cartilage was quantified by reverse transcription-quantitative polymerase chain reaction analysis.Wnt-4,β-catenin,Frizzled-2,GSK-3β,cleaved caspase-3,and cleaved caspase-9 protein expression in rat knee articular cartilage was determined by western blot analysis.RESULTS:BSQJ obviously reduced pathological damage and matrix degradation of articular cartilage in KOA rats.Compared with the KOA group,H-BSQJ rats exhibited downregulated m RNA and protein expression of Wnt-4,β-catenin,Frizzled-2,and caspase-3,as well as upregulated m RNA and protein expression of GSK-3β.In addition,H-BSQJ significantly increased m RNA expression of Col2 a1 and decreased m RNA expression of MMP-1 and MMP-13.CONCLUSION:BSQJ exerted a beneficial effect on KOA by a mechanism involving downregulation of the Wnt/β-catenin pathway,which inhibited both cartilage extracellular matrix degradation and chondrocyte apoptosis to ameliorate KOA in rats.
文摘AIM： To investigate the effect of activation of canonical Wnt signaling pathway on the proliferation and differentiation of hepatic oval cells in vitro. METHODS： WB-F344 cells were treated with recombinant Wnt3a （20, 40, 80, 160, 200 ng/mL） in serum-free medium for 24 h. Cell proliferation was measured by Brdu incorporation analysis; untreated WB-F344 cells were taken as controls. After treatment with Wnt3a （160 ng/mL） for 24 h, subcellular localization and protein expression of p-catenin in WB-F344 cells treated and untreated with Wnt3a were examined by immunofluorescence staining and Western blot analysis. CyclinD1 mRNA expression was determined by semi-quantitative reverse-transcript polymerase chain reaction （RT-PCR）. The mRNA levels of some phenotypic markers （AFP, CK-19, ALB） and two hepatic nuclear factors （HNF-4, HIVF-6） were measured by RT-PCR. Expressions of CK-19 and AFP protein were detected by Western blot analysis. RESULTS： Wnt3a promoted proliferation of WB-F344 cells. Stimulation of WB-F344 cells with recombinant Wnt3a resulte^l in accumulation of the transcriptional activator β-catenin, together with its translocation into the nuclei, and up-regulated typical Wnt target gene CyclinD1. After 3 d of Wnt3a treatment in the absence of serum, WB-F344 cells retained their bipotential to express several specific phenotypic markers of hepatocytes and cholangiocytes, such as AFP and CK-19, following activation of the canonical Wnt signaling pathway. CONCLUSION： The canonical Wnt signaling pathway promotes proliferation and self-renewal of rat hepatic oval cells.
文摘AIM: To explore the contribution of AXIN1, AXIN2 and beta-catenin, components of Wnt signaling pathway, to the carcinogenesis of gastric cancer (GC), we examined AXIN1, AXIN2 exon7 and CTNNB1 (encoding beta- catenin) exon3 mutations in 70 GCs. METHODS: The presence of mutations was identified by polymerase chain reaction (PCR)-based denaturing high-performance liquid chromatography and direct DNA sequencing. Beta-catenin expression was detected by immunohistochemical analysis. RESULTS: Among the 70 GCs, 5 (7.1%) had mutations in one or two of these three components. A frameshift mutation (1 bp deletion) in exon7 of AXIN2 was found in one case. Four cases, including the case with a mutation in AXIN2, had frameshift mutations and missense mutations in AXIN1. Five single nucleotide polymorphisms (SNPs), 334 C>T, 874 C>T, 1396 G>A, 1690 C>T and 1942 T>G, were identified in AXIN1. A frameshift mutation (27 bp deletion) spanning exon3 of CTNNB1 was observed in one case. All four cases with mutations in AXIN1 and AXIN2 showed nuclear beta- catenin expression. CONCLUSION: These data indicate that the mutationsin AXIN1 and AXIN2 may contribute to gastric carcino- genesis.
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.
基金Supported by the Youth Fund of the First Affiliated Hospital of Xinxiang Medical University(Type A-4)
文摘AIM To investigate the potential role of micro RNA-30 a(mi R-30 a) in esophageal squamous cell carcinoma(ESCC).METHODS Expression of mi R-30 a-3 p/5 p was analyzed using microarray data and fresh ESCC tissue samples. Both in vitro and in vivo assays were used to investigate the effects of mi R-30 a-3 p/5 p on ESCC cell proliferation. Furthermore,Kyoto Encyclopedia of Genes and Genomes analysis was performed to explore underlying mechanisms involved in ESCC,and then,assays were carried out to verify the potential molecular mechanism of mi R-30 a in ESCC.RESULTS Low expression of mi R-30 a-3 p/5 p was closely associated with advanced ESCC progression and poor prognosis of patients with ESCC. Knock-down of mi R-30 a-3 p/5 p promoted ESCC cell proliferation. Increased mi R-30 a-3 p/5 p expression inhibited the Wnt signaling pathway by targeting Wnt2 and Fzd2.CONCLUSION Down-regulation of mi R-30 a-3 p/5 p promotes ESCC cell proliferation by activating the Wnt signaling pathway through inhibition of Wnt2 and Fzd2.
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.
