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The main cause of gastric cancer (GC)-related death is due to malignant cell unregulated distant metastasis and proliferation. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) has been shown to play an important role in carcinogenesis and the development of metastasis in several tumors. However, its downstream regulatory mechanism in GC is not well defined. Our study aims to investigate the function and regulatory mechanism of hnRNPA1 in GC. We analyzed the differential expression of hnRNPA1 in gastric cancer and paired adjacent normal tissues in the TCGA database. Kaplan-Meier analysis was employed for survival assessment. The expressions of hnRNPA1 in GC cells were measured by qRT-PCR and Western blot. Transwell assay, CCK8 and colony formation assay were used to detect the effect of hnRNPA1 on the metastasis and proliferation ability of GC cells. Additionally, Western blotting was performed to examine the expression of proteins related to the Wnt/ß-catenin signaling pathway as well as epithelial-mesenchymal transition (EMT), while further investigations were carried out to explore potential regulatory mechanisms. The results showed that hnRNPA1 was highly expressed differentially in GC over normal gastric tissue. Knocking down hnRNPA1 inhibited the metastasis and proliferation of human gastric cancer cells. Overexpression of hnRNPA1 significantly enhanced the metastatic potential and proliferative capacity of human GC cells. Further mechanism exploration revealed that knocking down hnRNPA1 inhibited the Wnt/ß-catenin signaling pathway and WNT1 inducible signaling pathway protein-2 (WISP2), an activator of the Wnt/ß-catenin signaling pathway. Whereas overexpression of hnRNPA1 had the opposite effects. Our results demonstrated that hnRNPA1 promoted metastasis and proliferation of GC cells by activating Wnt/ß-catenin signaling pathway via WISP2. hnRNPA1 may serve as a potential biomarker and novel therapeutic targets for GC.
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Atrial fibrillation (AF) is a common cardiac arrhythmia that seriously affects the quality of life of patients. Effective treatment and prevention are important to control the morbidity and mortality of AF. It has been found that cardiac fibrosis promotes the onset and progression of AF. It is now known that transforming growth factor ß (TGF-ß), an important fibrotic cytokine, plays an important role in cardiac fibrosis by inducing myofibroblast activation via the activation of classical (SMAD-based) and non-classical (non-SMAD-based) signaling pathways. In addition, specific activation of the Wnt/ß-catenin pathway has been shown to promote the transformation of fibroblasts into myofibroblasts. In recent years, a new family of proteins, namely Disheveled-associated antagonist of beta-catenin (DACT) 2, can affect the Wnt/ß-catenin and TGF-ß signaling pathways by regulating the phosphorylation levels of these target proteins, which in turn affects the progression of fibrosis. The present study focuses on the effect of DACT2-guided ß-catenin on atrial fibrosis. It is expected that the summarized information can be helpful in the treatment of AF.
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Clinical trials and studies have implicated that E3 ubiquitin ligase BTBD3 (BTB Domain Containing 3) is a cancer-associated gene. However, the role and underlying mechanism of BTBD3 in colorectal cancer (CRC) is not fully understood yet. Herein, our study demonstrated that the mRNA and protein levels of BTBD3 were decreased in CRC tissues and associated with TYPO3 and Wnt/ß-catenin pathway. Our results showed that circRAE1 knockdown and TYRO3 overexpression activated Wnt/ß-catenin signaling pathway and the EMT process-associated markers, indicating that circRAE1/miR-388-3p/TYRO3 axis exacerbated tumorigenesis of CRC by activating Wnt/ß-catenin signaling pathway. In addition, overexpression of BTBD3 reduced CRC cell migration and invasion in vitro and inhibited tumor growth in vivo. Our data demonstrated that BTBD3 suppressed CRC progression through negative regulation of the circRAE1/miR-388-3p/TYRO3 axis and the Wnt/ß-catenin pathway. Our data further confirmed that BTBD3 bound and ubiquitinated ß-catenin and led to ß-catenin degradation, therefore blocked the Wnt/ß-catenin pathway and suppressed the CRC tumorigenesis. This study explored the mechanism of BTBD3 involved in CRC tumorigenesis and provided a new theoretical basis for the prevention and treatment of CRC.
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Hydroquinone (HQ), a metabolite of benzene, is frequently utilized as a surrogate for benzene in in vitro studies and is associated with the development of acute myeloid leukemia (AML). In the hemotoxicity caused by benzene and HQ, cell apoptosis plays a key role. However, the molecular mechanisms underlying HQ are unknown. Studies have indicated that Suv39h1 is involved in regulating cell division and proliferation by regulating histone H3K9me3. Meanwhile, the Wnt/ß-catenin signaling pathway also plays a significant role in cell proliferation and apoptosis. Therefore, this study was aimed at exploring the regulatory role of Suv39h1 and the Wnt/ß-catenin signaling pathway in the effects of HQ on bone marrow mesenchymal stem cells (BMSCs), as well as its influence on cell proliferation and apoptosis. The results demonstrated that HQ elevated the levels of Suv39h1 and H3K9me3 and activated the Wnt/ß-catenin signaling pathway by upregulating ß-catenin, Wnt2b, C-myc, and Cyclin D1 and downregulating Wnt5a, resulting in an increase in cell growth and a decrease in apoptosis. Suv39h1 knockdown inhibited the Wnt/ß-catenin signaling pathway. Meanwhile, inhibition of the Wnt/ß-catenin signaling pathway resulted in the down-regulation of Suv39h1 and H3K9me3 in BMSCs. They both promoted cell proliferation and inhibited apoptosis in the effects of HQ on BMSCs by downregulating the expression of Cyt-C, Bax, Caspase 3, and Caspase 9 and upregulating the expression of Bcl-xl. Therefore, we concluded that Suv39h1 and the Wnt/ß-catenin signaling pathway may mutually regulate each other in the effects of HQ on BMSCs in order to ameliorate the altered function of BMSCs.
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Apoptosis , Proliferación Celular , Hidroquinonas , Células Madre Mesenquimatosas , Vía de Señalización Wnt , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Apoptosis/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Animales , Hidroquinonas/toxicidad , Células Cultivadas , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , beta Catenina/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , MasculinoRESUMEN
Cartilage defects caused by joint diseases are difficult to treat clinically. Tissue engineering materials provide a new means to promote the repair of cartilage defects. The purpose of this study is to design a novel scaffold of porous magnesium alloy loaded with icariin and sustained release in order to explore the effect and possible mechanism of this scaffold in repairing SD rat knee articular cartilage defect. We constructed a novel type of icariin/porous magnesium alloy scaffold, observed the structure of the scaffold by electron microscope, detected the drug release of icariin in the scaffold and the biological safety, and established an animal model of cartilage defect in the femoral intercondylar fossa of the knee joint in rats; the scaffold was placed in the defect. After 12 weeks of repair, the rat knee articular cartilage repair was evaluated by gross specimens and micro-CT, HE, safranin O-fast green, and toluidine blue staining combined with the modified Mankin's score. The protein expressions of the Wnt/ß-catenin signaling pathway-related factors (ß-catenin, Wnt5a, Wnt1, sFRP1) and chondrogenic differentiation-related factors (Sox9, Aggrecan, Col2α1) were detected by immunohistochemical staining. We found that the novel scaffold of icariin/porous magnesium alloy can release icariin slowly and has biosafety in rats. Compared with other groups, icariin/porous magnesium alloy can significantly promote the repair of cartilage defects and the expressions of ß-catenin, Wnt5a, Wnt1, Sox9, Aggrecan, and Col2α1 (P < 0.05). This novel scaffold can promote the repair of rat knee cartilage defects, and this process may be achieved by activating the Wnt/ß-catenin signaling pathway.
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Aleaciones , Cartílago Articular , Flavonoides , Magnesio , Andamios del Tejido , Vía de Señalización Wnt , Animales , Masculino , Ratas , Aleaciones/química , Aleaciones/farmacología , beta Catenina/metabolismo , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Cartílago Articular/patología , Flavonoides/farmacología , Flavonoides/química , Articulación de la Rodilla/patología , Articulación de la Rodilla/efectos de los fármacos , Magnesio/química , Magnesio/farmacología , Porosidad , Ratas Sprague-Dawley , Andamios del Tejido/química , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
BACKGROUND: Increasing evidence shows the pivotal significance of miRNAs in the pathogenesis of osteoporosis. miR-381-3p has been identified as an inhibitor of osteogenesis. This study explored the role and mechanism of miR-381-3p in postmenopausal osteoporosis (PMOP), the most common type of osteoporosis. METHODS: Bilateral ovariectomy (OVX) rat model was established and miR-381-3p antagomir was administrated through the tail vein in vivo. The pathological changes in rats were assessed through the evaluation of serum bone turnover markers (BALP, PINP, and CTX-1), hematoxylin and eosin (H&E) staining, as well as the expression of osteoblast differentiation biomarkers. Moreover, isolated bone marrow mesenchymal stem cells from OVX-induced rats (OVX-BMMSCs) were utilized to explore the impact of miR-381-3p on osteoblast differentiation. In addition, the target gene and downstream pathway of miR-381-3p were further investigated both in vivo and in vitro. RESULTS: miR-381-3p expression was elevated, whereas KLF5 was suppressed in OVX rats. miR-381-3p antagomir decreased serum levels of bone turnover markers, improved trabecular separation, promoted osteoblast differentiation biomarker expression in OVX rats. ALP activity and mineralization were suppressed, and levels of osteoblast differentiation biomarkers were impeded after miR-381-3p overexpression during osteoblast differentiation of OVX-BMMSCs. While contrasting results were found after inhibition of miR-381-3p. miR-381-3p targets KLF5, negatively affecting its expression as well as its downstream Wnt/ß-catenin pathway, both in vivo and in vitro. Silencing of KLF5 restored Wnt/ß-catenin activation induced by miR-381-3p antagomir. CONCLUSION: miR-381-3p aggravates PMOP by inhibiting osteogenic differentiation through targeting KLF5/Wnt/ß-catenin pathway. miR-381-3p appears to be a promising candidate for therapeutic intervention in PMOP.
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Diferenciación Celular , Factores de Transcripción de Tipo Kruppel , MicroARNs , Osteogénesis , Osteoporosis Posmenopáusica , Ovariectomía , Vía de Señalización Wnt , Animales , Femenino , Humanos , Ratas , Células Cultivadas , Modelos Animales de Enfermedad , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Células Madre Mesenquimatosas/metabolismo , MicroARNs/genética , Osteoblastos/metabolismo , Osteogénesis/genética , Osteogénesis/fisiología , Osteoporosis/genética , Osteoporosis/etiología , Osteoporosis/metabolismo , Osteoporosis Posmenopáusica/genética , Osteoporosis Posmenopáusica/metabolismo , Ovariectomía/efectos adversos , Ratas Sprague-Dawley , Vía de Señalización Wnt/fisiología , Vía de Señalización Wnt/genéticaRESUMEN
(+)4-cholesten-3-one has been proved to have potential wound healing effect in the process of wound regeneration. This study aimed to evaluate the effect of (+)4-cholesten-3-one/sodium alginate/gelatin on skin injury and reveal its potential molecular mechanism. First, we prepared sodium alginate/gelatin hydrogel (SA/Gel hydrogel) with different ratios and tested their characteristics. Based on these results, different concentrations of (+)4-cholesten-3-one were added into SA/Gel hydrogel. A full-thickness skin injury model was successfully established to evaluate wound healing activityin vivo. HE staining and Masson staining were used to evaluate the thickness of granulation tissue and collagen deposition level. Immunohistochemical staining and immunofluorescence staining were applied to detect the level of revascularization and proliferation in each group of wounds. Western blot, quantitative-PCR and immunofluorescence staining were used to detect the expression of proteins related to Wnt/ß-catenin signaling pathway in each group of wounds.In vitroresults showed that the hydrogel not only created a 3D structure for cell adhesion and growth, but also exhibited good swelling ability, excellent degradability and favorable bio-compatibility. Most importantly,in vivoexperiments further indicated that (+)4-cholesten-3-one/SA/Gel hydrogel effectively enhanced wound healing. The effectiveness is due to its superior abilities in accelerating healing process, granulation tissue regeneration, collagen deposition, promoting angiogenesis, tissue proliferation, as well as fibroblast activation and differentiation. The underlying mechanism was related to the Wnt/ß-catenin signaling pathway. This study highlighted that (+)4-cholesten-3-one/SA/Gel hydrogel holds promise as a wound healing dressing in future clinical applications.
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Alginatos , Gelatina , Hidrogeles , Regeneración , Piel , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Alginatos/química , Animales , Gelatina/química , Hidrogeles/química , Hidrogeles/farmacología , Piel/lesiones , Piel/efectos de los fármacos , Piel/metabolismo , Regeneración/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Masculino , Ratones , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ratas , Colágeno/química , Vía de Señalización Wnt/efectos de los fármacos , HumanosRESUMEN
Oral squamous cell carcinoma (OSCC) is one of the most common human malignancies worldwide. The molecular mechanisms of OSCC pathogenesis are still unknown; however, in recent years, several reports have focused on the role of enhancer of zeste homolog 2 (EZH2) in OSCC. Therefore, in this study we aimed to investigate the effects of GSK343, a selective EZH2 inhibitor, and its impact on the signaling pathways in OSCC, using an in vitro and in vivo orthotopic model. In the in vitro model, GSK343 (1, 10, and 25 µM) significantly decreased OSCC cell viability and cell migration through EZH2 inhibition, modulating NF-κB/IκBα pathway activation and eNOS, VEGF, and TGFß expression, important markers of angiogenesis. In the in vivo model, GSK343 (5 mg/kg and 10 mg/kg) restored tongue tissue architecture and reduced tumor progression through EZH2 inhibition and Wnt/ß-catenin signaling pathway modulation. Moreover, GSK343 reduced the expression of inflammatory mediators; eNOS and TGFß, markers of angiogenesis; and CD31 and CD34, markers of micro vessel density, respectively. In conclusion, our data demonstrate that GSK343 counteracts oral cancer progression through EZH2/Wnt/ß-catenin pathway modulation, suggesting that it could be a promising therapeutic approach for OSCC management.
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Deterioration in the neurocognitive function of cancer patients referred to as "Chemobrain" is a devastating obstacle associated with cyclophosphamide (CYP). CYP is an alkylating agent, clinically utilized as an efficient anticancer and immunosuppressant. Coenzyme Q10 (CoQ10) is a worthwhile micronutrient with diverse biological activities embracing antioxidant, anti-apoptotic, and neuroprotective effects. The current experiment was designed for investigating the neuroprotective capability of CoQ10 versus CYP-elicited chemobrain in rats besides elucidating the causal molecular mechanisms. Male Sprague Dawley rats received CoQ10 (10â¯mg/kg, orally, once daily, for 10 days) and/or a single dose of CYP (200â¯mg/kg i.p. on day 7). CoQ10 counteracted CYP-induced cognitive and motor dysfunction as demonstrated by the findings of neurobehavioral tests (passive avoidance, Y maze, locomotion, and rotarod tests). Histopathological analysis further affirmed the neuroprotective abilities of CoQ10. CoQ10 effectually diminished CYP-provoked oxidative injury by restoring the antioxidant activity of catalase (CAT) enzyme while reducing malondialdehyde (MDA) levels. Besides, CoQ10 efficiently repressed CYP-induced neuronal apoptosis by downregulating the expression of Bax and caspase-3 while upregulating the Bcl-2 expression. Moreover, CoQ10 hampered CYP-provoked upregulation in acetylcholinesterase (AChE) activity. Furthermore, CoQ10 considerably augmented hippocampal neurogenesis by elevating the expressions of brain-derived neurotrophic factor (BDNF) and Ki-67. These promising neuroprotective effects can be credited to upregulating Wnt/ß-catenin pathway as evidenced by the elevated expressions of Wnt-3a, ß-catenin, and Phoshpo-glycogen synthase kinase-3 ß (p-GSK-3ß). Collectively, these findings proved the neuroprotective capabilities of CoQ10 against CYP-induced chemobrain through combating oxidative injury, repressing intrinsic apoptosis, boosting neurogenesis, and eventually upregulating the Wnt/ß-catenin pathway.
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Stroke is a prominent contributor to mortality and impairment on a global scale. Ischemic stroke accounts for approximately 80% of stroke cases and is caused by occlusion of cerebral blood vessels. Enhancing neurogenesis through the modulation of the neural stem cell niche in the adult brain is a promising therapeutic strategy for individuals afflicted with ischemic stroke. Neurogenesis results in the generation of newborn neurons that serve as replacements for deceased neural cells within the ischemic core, thereby playing a significant role in the process of neural restoration subsequent to cerebral ischemia. Research has shown that activation of the Wnt/ß-catenin pathway can augment neurogenesis following cerebral ischemia, suggesting that this pathway is a potentially beneficial therapeutic target for managing ischemic stroke. This review provides an extensive analysis of the current knowledge regarding the involvement of the Wnt/ß-catenin pathway in promoting neurogenesis, thereby offering a promising avenue for therapeutic intervention in the context of ischemic stroke or other neurological impairments.
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Accidente Cerebrovascular Isquémico , Células-Madre Neurales , Neurogénesis , Vía de Señalización Wnt , Humanos , Vía de Señalización Wnt/fisiología , Animales , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/terapia , Neurogénesis/fisiología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/fisiología , Nicho de Células Madre/fisiología , Células Madre Adultas/fisiología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapiaRESUMEN
Hair follicle (HF) regeneration during wound healing continues to present a significant clinical challenge. Dermal papilla cell-derived exosomes (DPC-Exos) hold immense potential for inducing HF neogenesis. However, the accurate role and underlying mechanisms of DPC-Exos in HF regeneration in wound healing remain to be fully explained. This study, represents the first analysis into the effects of DPC-Exos on fibroblasts during wound healing. Our findings demonstrated that DPC-Exos could stimulate the proliferation and migration of fibroblasts, more importantly, enhance the hair-inducing capacity of fibroblasts. Fibroblasts treated with DPC-Exos were capable of inducing HF neogenesis in nude mice when combined with neonatal mice epidermal cells. In addition, DPC-Exos accelerated wound re-epithelialization and promoted HF regeneration during the healing process. Treatment with DPC-Exos led to increased expression levels of the Wnt pathway transcription factors ß-catenin and Lef1 in both fibroblasts and the dermis of skin wounds. Specifically, the application of a Wnt pathway inhibitor reduced the effects of DPC-Exos on fibroblasts and wound healing. Accordingly, these results offer evidence that DPC-Exos promote HF regeneration during wound healing by enhancing the hair-inducing capacity of fibroblasts and activating the Wnt/ß-catenin signaling pathway. This suggests that DPC-Exos may represent a promising therapeutic strategy for achieving regenerative wound healing.
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Proliferación Celular , Exosomas , Fibroblastos , Folículo Piloso , Ratones Desnudos , Regeneración , Vibrisas , Vía de Señalización Wnt , Cicatrización de Heridas , beta Catenina , Animales , Ratones , Fibroblastos/metabolismo , Exosomas/metabolismo , Vibrisas/fisiología , beta Catenina/metabolismo , Dermis/metabolismo , Movimiento Celular , Factor de Unión 1 al Potenciador Linfoide/metabolismoRESUMEN
Trophinin-associated protein (TROAP), a cytoplasmic protein essential for spindle assembly and centrosome integrity during mitosis, has been reported to serve as an oncogene in various tumors. However, its role in endometrial cancer (EC) progression is still undefined. TROAP expression in EC was analyzed via GEPIA and HPA databases. The diagnostic and prognostic values of TROAP were examined by ROC curve analysis and Kaplan-Meier plotter, respectively. Cell proliferation was evaluated using CCK-8 and EdU incorporation assays. Apoptosis was assessed using TUNEL and flow cytometry assays. GSEA was performed to explore TROAP-related pathways in EC. Expression of TROAP, proliferating cell nuclear antigen (PCNA), Ki-67, cleaved-caspase-3 (cl-caspase-3), caspase-3, active ß-catenin, and total ß-catenin was detected using western blot analysis. TROAP was upregulated in EC. TROAP served as a potential diagnostic and prognostic marker in EC patients. TROAP silencing suppressed proliferation and enhanced apoptosis in EC cells. GSEA revealed that EC and Wnt signaling pathways were related to the expression of TROAP. We further demonstrated that TROAP knockout repressed the Wnt/ß-catenin pathway in EC cells. Moreover, SKL2001, a Wnt/ß-catenin activator, partially abrogated the effects of TROAP silencing on EC cell proliferation and apoptosis, while the signaling inhibitor XAV-939 had the opposite effect. In conclusion, TROAP knockout retarded proliferation and elicited apoptosis in EC cells by blocking the Wnt/ß-catenin pathway.
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BACKGROUND: Pien Tze Huang (PZH), a traditional Chinese medicine formulation, is recognized for its therapeutic effect on colitis and colorectal cancer. However, its protective role and underlying mechanism in colitis-associated colorectal cancer (CAC) remain to be elucidated. METHODS: A CAC mouse model was established using AOM/DSS. Twenty mice were randomly divided into four groups (n = 5/group): Control, PZH, AOM/DSS, and AOM/DSS + PZH groups. Mice in the PZH and AOM/DSS + PZH group were orally administered PZH (250 mg/kg/d) from the first day of experiment, while the control and AOM/DSS group received an equivalent volume of distilled water. Parameters such as body weight, disease activity index (DAI), colon weight, colon length, colon histomorphology, intestinal tumor formation, serum concentrations of pro-inflammatory cytokines, proliferation and apoptosis in colon tissue were assessed. RNA sequencing was employed to identify the differentially expressed transcripts (DETs) in colonic tissues and related signaling pathways. Wnt/ß-Catenin Pathway-Related genes in colon tissue were detected by QPCR and immunohistochemistry (IHC). RESULTS: PZH significantly attenuated AOM/DSS-induced weight loss, DAI elevation, colonic weight gain, colon shortening, histological damage, and intestinal tumor formation in mice. PZH also notably decreased serum concentration of IL-6, IL-1ß, and TNF-α. Furthermore, PZH inhibited cell proliferation and promote apoptosis in tumor tissues. RNA-seq and KEGG analysis revealed key pathways influenced by PZH, including Wnt/ß-catenin signaling pathway. IHC staining confirmed that PZH suppressed the expression of ß-catenin, cyclin D1 and c-Myc in colonic tissues. CONCLUSIONS: PZH ameliorates AOM/DSS-induced CAC in mice by suppressing the activation of Wnt/ß-catenin signaling pathway.
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CONTEXT: Breast cancer stem cells (BCSCs) are a small subset of cells within breast tumors with characteristics similar to normal stem cells. Despite advancements in chemotherapy and targeted therapy for breast cancer, the prognosis for breast cancer patients has remained poor due to drug resistance, reoccurrence, and metastasis. Growing evidence suggests that deregulation of the self-renewal pathways, like the Wnt signaling pathway mediated by ß-catenin, plays a crucial role in the survival of breast cancer stem cells. Targeting the Wnt signaling pathway in breast cancer stem cells offers a promising avenue for developing effective therapeutic strategies targeting these cells, potentially leading to improved patient outcomes and reduced tumor recurrence. METHODS: For this purpose, we have screened a 1615 FDA-approved drug library against our target protein, ß-catenin, which is involved in the Wnt signaling pathway using molecular docking analysis, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. RESULTS: Molecular docking studies showed that the Lumacaftor- ß-catenin complex had the lowest docking score of - 8.7 kcal/mol towards ß-catenin protein than the reference inhibitor. Molecular dynamic simulations and MM/PBSA calculations were also performed for the Lumacaftor-ß-catenin complex to establish the stability of the interactions involved. Considering its promising attributes and encouraging results, Lumacaftor holds significant potential as a novel therapeutic option to target BCSCs. This study opens avenues for further investigation and may pave the way for developing therapeutic potential in breast cancer treatment. Further confirmation is warranted through in vitro and clinical studies to validate the findings of this study.
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Benzodioxoles , Neoplasias de la Mama , Reposicionamiento de Medicamentos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Células Madre Neoplásicas , Vía de Señalización Wnt , beta Catenina , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Benzodioxoles/farmacología , Benzodioxoles/química , beta Catenina/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Aminopiridinas/farmacología , Aminopiridinas/química , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
This study aimed to explore naringin's potential to promote the osteogenic differentiation of MC3T3-E1 under oxidative stress. It delved into Nar's connection with the Wnt/ß-catenin and PI3K/Akt signaling pathways. Initially, 2911 OP-related genes were analyzed, revealing close ties with the PI3K/Akt and Wnt pathways alongside oxidative stress. Nar's potential targets-ESR1, HSP90AA1, and ESR2-were identified through various databases and molecular docking studies confirmed Nar's affinity with ESR1 and HSP90AA1. Experiments established optimal concentrations for Nar and H2O2. H2O2 at 0.3 mmol/L damaged MC3T3-E1 cells, alleviated by 0.1 µmol/L Nar. Successful establishment of oxidative stress models was confirmed by DCFH-DA probe and NO detection. Nar exhibited the ability to enhance osteogenic differentiation, counteracting oxidative damage. It notably increased osteoblast-related protein expression in MC3T3-E1 cells under oxidative stress. The study found Nar's positive influence on GSK-3ß phosphorylation, ß-catenin accumulation, and pathway-related protein expression, all critical in promoting osteogenic differentiation. The research concluded that Nar effectively promotes osteogenic differentiation in MC3T3-E1 cells under oxidative stress. It achieved this by activating the Wnt/ß-catenin and PI3K/Akt pathways, facilitating GSK-3ß phosphorylation, and enhancing ß-catenin accumulation, pivotal in osteogenesis.
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Diferenciación Celular , Flavanonas , Osteogénesis , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Vía de Señalización Wnt , beta Catenina , Flavanonas/farmacología , Estrés Oxidativo/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Animales , Ratones , Diferenciación Celular/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Peróxido de Hidrógeno , Línea Celular , Simulación del Acoplamiento Molecular , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Intervertebral disc degeneration (IDD) is a common musculoskeletal degenerative disease, which often leads to low back pain and even disability, resulting in loss of labor ability and decreased quality of life. Although many progresses have been made in the current research, the underlying mechanism of IDD remains unclear. The apoptosis of nucleus pulposus (NP) cells (NPCs) is an important pathological mechanism in intervertebral disc degeneration (IDD). This study evaluated the relationship between S100A6 and NPCs and its underlying mechanism. METHODS: Mass spectrometry, bioinformatics, and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were used to screen and verify hub genes for IDD in human IVD specimens with different degeneration degrees. Western blotting, immunohistochemistry (IHC), and/or immunofluorescence (IF) were used to detect the expression level of S100A6 in human NP tissues and NPCs. The apoptotic phenotype of NPCs and Wnt/ß-catenin signaling pathway were evaluated using flow cytometry, western blotting, and IF. S100A6 was overexpressed or knocked down in NPCs to determine its impact on apoptosis and Wnt/ß-catenin signaling pathway activity. Moreover, we used the XAV-939 to inhibit and SKL2001 to activate the Wnt/ß-catenin signaling pathway. The therapeutic effect of S100A6 inhibition on IDD was also evaluated. RESULTS: S100A6 expression increased in IDD. In vitro, increased S100A6 expression promoted apoptosis in interleukin (IL)-1ß-induced NPCs. In contrast, the inhibition of S100A6 expression partially alleviated the progression of annulus fibrosus (AF) puncture-induced IDD in rats. Mechanistic studies revealed that S100A6 regulates NPC apoptosis via Wnt/ß-catenin signaling pathway. CONCLUSIONS: This study showed that S100A6 expression increased during IDD and promoted NPCs apoptosis by regulating the Wnt/ß-catenin signaling pathway, suggesting that S100A6 is a promising new therapeutic target for IDD.
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Apoptosis , Degeneración del Disco Intervertebral , Núcleo Pulposo , Proteína A6 de Unión a Calcio de la Familia S100 , Vía de Señalización Wnt , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patología , Apoptosis/genética , Humanos , Proteína A6 de Unión a Calcio de la Familia S100/metabolismo , Proteína A6 de Unión a Calcio de la Familia S100/genética , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/patología , Animales , Masculino , Femenino , Ratas , Adulto , Persona de Mediana Edad , beta Catenina/metabolismo , beta Catenina/genética , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Proteínas de Ciclo CelularRESUMEN
Background: In recent years, there are few reports on non-SMC condensin I complex subunit G (NCAPG) in osteosarcoma. Our study aims to explore the biological role of NCAPG in osteosarcoma and its underlying molecular mechanism and to further clarify the reasons for the abnormal expression of NCAPG in osteosarcoma. Methods: Here, we mined The Cancer Genome Atlas (TCGA) Program public database through bioinformatics methods, analyzed the differential expression of NCAPG in sarcoma tissue and normal tissue, and explored the relationship between NCAPG expression level and sarcoma tissue differentiation, including tumor recurrence, metastasis, and patient survival. Next, the transcription factors responsible for the abnormal expression of NCAPG in osteosarcoma tumors were predicted by multiple online website tools and verified via cellular experiments. Subsequently, loss of function and cell phenotype experiments were performed to confirm the effect of NCAPG on the malignant biological behavior of osteosarcoma cells. Mechanistically, by reviewing the literature, we found that NCAPG can affect the malignant progression of many solid tumors by regulating the Wnt/ß-catenin signaling pathway. Therefore, we preliminarily investigated the potential effect of NCAPG on this pathway via western blot experiments in osteosarcoma. Results: Increased expression of NCAPG was found in sarcoma compared to normal tissues, which was positively correlated with poor differentiation, metastasis, and poor prognosis. Combining the transcription factor prediction results, correlation analysis, and expression level in the TCGA public database with validation outcomes of in vitro cell assays, we found that E2F transcription factor 1 (E2F1) regulated the increased expression of NCAPG in osteosarcoma. The results of cell phenotype experiments showed that silencing NCAPG could inhibit the proliferation, migration, and invasion of osteosarcoma cells. The preliminary mechanistic investigation suggested that NCAPG may affect osteosarcoma progression through the Wnt/ß-catenin pathway. Conclusions: Our data reveal that E2F1 facilitates NCAPG expression in osteosarcoma by regulating the transcription of the NCAPG gene. Up-regulation of NCAPG promotes osteosarcoma progression via the Wnt/ß-catenin signaling axis.
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Breast cancer (BC) is one of the most common malignant tumors in women. Angelica sinensis polysaccharide (ASP) is one of the main components extracted from the traditional Chinese medicine Angelica sinensis. Research has shown that ASP affects the progression of various cancers by regulating miRNA expression. This study aimed to explore the specific molecular mechanism by which ASP regulates BC progression through miR-3187-3p. After the overexpression or knockdown of miR-3187-3p and PDCH10 in BC cells, the proliferation, migration, invasion, and phenotype of BC cells were evaluated after ASP treatment. Bioinformatics software was used to predict the target genes of miR-3187-3p, and luciferase gene reporter experiments reconfirmed the targeted binding relationship. Subcutaneous tumor formation experiments were conducted in nude mice after the injection of BC cells. Western blot and Ki-67 immunostaining were performed on the tumor tissues. The results indicate that ASP can significantly inhibit the proliferation, migration, and invasion of BC cells. ASP can inhibit the expression of miR-3187-3p in BC cells and upregulate the expression of PDCH10 by inhibiting miR-3187-3p. A regulatory relationship exists between miR-3187-3p and PDCH10. ASP can inhibit the expression of ß-catenin and phosphorylated glycogen synthase kinase-3ß (p-GSK-3ß) proteins through miR-3187-3p/PDCH10 and prevent the occurrence of malignant biological behavior in BC. Overall, this study revealed the potential mechanism by which ASP inhibits the BC process. ASP mediates the Wnt/ß-catenin signaling pathway by affecting the miR-3187-3p/PDCH10 molecular axis, thereby inhibiting the proliferation, migration, invasion, and other malignant biological behaviors of BC cells.
Asunto(s)
Angelica sinensis , Neoplasias de la Mama , MicroARNs , Polisacáridos , Vía de Señalización Wnt , Animales , Femenino , Humanos , Ratones , Angelica sinensis/química , beta Catenina/metabolismo , beta Catenina/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Polisacáridos/farmacología , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Targeting specific molecular drivers of tumor growth is a key approach in cancer therapy. Among these targets, the low-density lipoprotein receptor-related protein 6 (LRP6), a vital component of the Wnt signaling pathway, has emerged as an intriguing candidate. As a cell-surface receptor and vital co-receptor, LRP6 is frequently overexpressed in various cancer types, implicating its pivotal role in driving tumor progression. The pursuit of LRP6 as a target for cancer treatment has gained substantial traction, offering a promising avenue for therapeutic intervention. Here, this comprehensive review explores recent breakthroughs in our understanding of LRP6's functions and underlying molecular mechanisms, providing a profound discussion of its involvement in cancer pathogenesis and drug resistance. Importantly, we go beyond discussing LRP6's role in cancer by discussing diverse potential therapeutic approaches targeting this enigmatic protein. These approaches encompass a wide spectrum, including pharmacological agents, natural compounds, non-coding RNAs, epigenetic factors, proteins, and peptides that modulate LRP6 expression or disrupt its interactions. In addition, also discussed the challenges associated with developing LRP6 inhibitors and their advantages over Wnt inhibitors, as well as the drugs that have entered phase II clinical trials. By shedding light on these innovative strategies, we aim to underscore LRP6's significance as a valuable and multifaceted target for cancer treatment, igniting enthusiasm for further research and facilitating translation into clinical applications.
Asunto(s)
Antineoplásicos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad , Terapia Molecular Dirigida , Neoplasias , Animales , Humanos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Previous reports have established that rESWT fosters angiogenesis, yet the mechanism by which rESWT promotes cerebral angiogenesis remains elusive. rESWT stimulated HUVECs proliferation as evidenced by the CCK-8 test, with an optimal dosage of 2.0 Bar, 200 impulses, and 2 Hz. The tube formation assay of HUVECs revealed that tube formation peaked at 36 h post-rESWT treatment, concurrent with the lowest expression level of Bach1, as detected by both Western blot and immunofluorescence. The expression level of Wnt3a, ß-catenin, and VEGF also peaked at 36 h. A Bach1 overexpression plasmid was transfected into HUVECs, resulting in a decreased expression level of Wnt3a, ß-catenin, and VEGF. Upon treatment with rESWT, the down-regulation of Wnt3a, ß-catenin, and VEGF expression in the transfected cells was reversed. The Wnt/ß-catenin inhibitor DKK-1 was utilized to suppress Wnt3a and ß-catenin expression, which led to a concurrent decrease in VEGF expression. However, rESWT treatment could restore the expression of these three proteins, even in the presence of DKK-1. Moreover, in the established OGD model, it was observed that rESWT could inhibit the overexpression of Bach1 and enhance VEGF and VEGFR-2 expression under the OGD environment.