From traditional Chinese medicine formulations to effective anticancer agents: Insights from Calculus bovis.

This editorial examines the therapeutic potential of traditional Chinese medicine (TCM) for aggressive cancers, particularly liver cancer. It highlights the study by Huang et al, which shows how Calculus bovis, a component of the TCM Pien Tze Huang, suppresses liver cancer by inhibiting M2 macrophage polarization via the Wnt/ß-catenin pathway. This research emphasizes the importance of transitioning from effective TCM formulations to isolating active components and understanding their mechanisms. While the study provides valuable insights, it primarily focuses on the Wnt/ß-catenin pathway and does not delve deeply into the mechanisms of individual components. Future research should aim to comprehensively study these components, explore their interactions, and validate findings through clinical trials. This approach will integrate traditional wisdom with modern scientific validation, advancing the development of innovative cancer treatments based on TCM formulations.

Calculus bovis in hepatocellular carcinoma: Tumor molecular basis, Wnt/ß-catenin pathway role, and protective mechanism.

In this editorial, we comment on the recent article by Huang et al. The editorial focuses specifically on the molecular mechanisms of hepatocellular carcinoma (HCC), mechanism of Wnt/ß-catenin pathway in HCC, and protective mechanism of Calculus bovis (CB) in HCC. Liver cancer is the fourth most common cause of cancer-related deaths globally. The most prevalent kind of primary liver cancer, HCC, is typically brought on by long-term viral infections (hepatitis B and C), non-alcoholic steatohepatitis, excessive alcohol consumption, and other conditions that can cause the liver to become chronically inflamed and cirrhotic. CB is a well-known traditional remedy in China and Japan and has been used extensively to treat a variety of diseases, such as high fever, convulsions, and stroke. Disturbances in lipid metabolism, cholesterol metabolism, bile acid metabolism, alcohol metabolism, and xenobiotic detoxification lead to fatty liver disease and liver cirrhosis. Succinate, which is a tricarboxylic acid cycle intermediate, is vital to energy production and mitochondrial metabolism. It is also thought to be a signaling molecule in metabolism and in the development and spread of liver malignancies. The Wnt/ß-catenin pathway is made up of a group of proteins that are essential for both adult tissue homeostasis and embryonic development. Cancer is frequently caused by the dysregulation of the Wnt/ß-catenin signaling pathway. In HCC liver carcinogenesis, Wnt/ß-catenin signaling is activated by the expression of downstream target genes. Communication between the liver and the gut exists via the portal vein, biliary tract, and systemic circulation. This "gut-liver axis" controls intestinal physiology. One of the main factors contributing to the development, progression, and treatment resistance of HCC is the abnormal activation of the Wnt/ß-Catenin signaling pathway. Therefore, understanding this pathway is essential to treating HCC. Eleven ingredients of CB, particularly oleanolic acid, ergosterol, and ursolic acid, have anti-primary liver cancer properties. Additionally, CB is important in the treatment of primary liver cancer through pathways linked to immune system function and apoptosis. CB also inhibits the proliferation of cancer stem cells and tumor cells and controls the tumor microenvironment. In the future, clinicians may be able to recommend one of many potential new drugs from CB ingredients to treat HCC expression, development, and progress.

Inhibition of CILP2 Improves Glucose Metabolism and Mitochondrial Dysfunction in Sarcopenia via the Wnt Signalling Pathway.

BACKGROUND: Skeletal muscle is the primary organ involved in insulin-mediated glucose metabolism. Elevated levels of CILP2 are a significant indicator of impaired glucose tolerance and are predominantly expressed in skeletal muscle. It remains unclear whether CILP2 contributes to age-related muscle atrophy through regulating the glucose homeostasis and insulin sensitivity. METHODS: Initially, the expression levels of CILP2 were assessed in elderly mice and patients with sarcopenia. Lentiviral vectors were used to induce either silencing or overexpression of CILP2 in C2C12 myoblast cells. The effects of CILP2 on proliferation, myogenic differentiation, insulin sensitivity and glucose uptake were evaluated using immunofluorescence, western blotting, real-time quantitative polymerase chain reaction, RNA sequencing, glucose uptake experiments, dual-luciferase reporter assays and co-immunoprecipitation (CO-IP). An adeno-associated virus-9 containing a muscle-specific promoter was injected into SAMP8 senile mice to observe the efficacy of CILP2 knockout. RESULTS: We found that there was more CLIP2 expressed in the skeletal muscle of ageing mice (+1.1-fold, p < 0.01) and in patients with sarcopenia (+2.5-fold, p < 0.01) compared to the control group. Following the overexpression of CILP2, Ki67 (-65%, p < 0.01), PCNA (-32%, p < 0.05), MyoD1 (-89%, p < 0.001), MyoG (-31%, p < 0.05) and MyHC (-85%, p < 0.001), which indicate proliferation and differentiation potential, were significantly reduced. In contrast, MuRF-1 (+59%, p < 0.05), atrogin-1 (+43%, p < 0.05) and myostatin (+31%, p < 0.05), the markers of muscular atrophy, were significantly increased. Overexpression of CILP2 decreased insulin sensitivity, glucose uptake (-18%, p < 0.001), GLUT4 translocation to the membrane and the maximum respiratory capacity of mitochondria. Canonical Wnt signalling was identified through RNA sequencing as a potential pathway for CILP2 regulation in C2C12, and Wnt3a was confirmed as an interacting protein of CILP2 in the CO-IP assay. The addition of recombinant Wnt3a protein reversed the inhibitory effects on myogenesis and glucose metabolism caused by CILP2 overexpression. Conversely, CILP2 knockdown promoted myogenesis and glucose metabolism. CILP2 knockdown improved muscle atrophy in mice, characterized by significant increases in time to exhaustion (+42%, p < 0.001), grip strength (+19%, p < 0.01), muscle mass (+15%, p < 0.001) and mean muscle cross-sectional area (+37%, p < 0.01). CILP2 knockdown enhanced glycogen synthesis (+83%, p < 0.001) and the regeneration of oxidative and glycolytic muscle fibres in SAMP8 ageing mice via the Wnt/ß-catenin signalling pathway. CONCLUSIONS: Our results indicate that CILP2 interacts with Wnt3a to suppress the Wnt/ß-catenin signalling pathway and its downstream cascade, leading to impaired insulin sensitivity and glucose metabolism in skeletal muscle. Targeting CILP2 inhibition could offer potential therapeutic benefits for sarcopenia.

Shuanglongjiegu pill promoted bone marrow mesenchymal stem cell osteogenic differentiation by regulating the miR-217/RUNX2 axis to activate Wnt/ß-catenin pathway.

This study aimed to investigate the effects of Shuanglongjiegu pill (SLJGP) on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and explore its mechanism based on miR-217/RUNX2 axis. Results found that drug-containing serum of SLJGP promoted BMSCs viability with a dose-dependent effect. Under osteogenic differentiation conditions, SLJGP promoted the expression of ALP, OPN, BMP2, RUNX2, and the osteogenic differentiation ability of BMSCs. In addition, SLJGP significantly reduced miR-217 expression, and miR-217 directly targeted RUNX2. After treatment with miR-217 mimic, the promoting effects of SLJGP on proliferation and osteogenic differentiation of BMSCs were significantly inhibited. MiR-217 mimic co-treated with pcDNA-RUNX2 further confirmed that the miR-217/RUNX2 axis was involved in SLJGP to promote osteogenic differentiation of BMSCs. In addition, analysis of Wnt/ß-catenin pathway protein expression showed that SLJGP activated the Wnt/ß-catenin pathway through miR-217/RUNX2. In conclusion, SLJGP promoted osteogenic differentiation of BMSCs by regulating miR-217/RUNX2 axis and activating Wnt/ß-catenin pathway.

Alveolar type 2 cells marker gene SFTPC inhibits epithelial-to-mesenchymal transition by upregulating SOX7 and suppressing WNT/ß-catenin pathway in non-small cell lung cancer.

Introduction: Surfactant Protein C gene (SFTPC) is a marker gene of alveolar type 2 cells (AT2), which are the key structures of alveoli. Mutations or deletions in SFTPC cause idiopathic pulmonary fibrosis (IPF). Importantly, IPF is an independent risk factor for non-small cell lung cancer (NSCLC). It suggests that abnormal expression of SFTPC may be relevant to development of NSCLC. However, the function and mechanism of SFTPC in NSCLC are still poor understood until now. Methods: The expression of SFTPC and the relationship between SFTPC and prognosis of NSCLC were analyzed in TCGA database and our collected clinical NSCLC tissues. Subsequently, the function and mechanism of SFTPC in NSCLC were explored by RNA-sequence, qRT-PCR, Western blot, Immunohistochemical, Wound-healing, Millicell, Transwell assays and mouse tumor xenograft model. Results: SFTPC was dramatically downregulated in NSCLC tissues from TCGA database and 40 out of 46 collected clinical LUAD tissues compared with adjacent non-tumor tissues. Low expression of SFTPC was associated with poor prognosis of LUAD by TCGA database. Importantly, we confirmed that overexpression of SFTPC significantly inhibited Epithelial-to-Mesenchymal Transition (EMT) process of NSCLC cells by upregulating SOX7 and then inactivating WNT/ß-catenin pathway in vitro and in vivo. Particularly, we discovered that low expression of SFTPC was associated with EMT process and low expression of SOX7 in NSCLC tissues. Conclusion: Our study revealed a novel mechanism of SFTPC in NSCLC development. Meanwhile, it also might provide a new clue for exploring the molecular mechanism about NSCLC development in patients with IPF in the future.

Wnt/Ca2+ pathway inhibits neural differentiation of human dental pulp stem cells in vitro.

Background/purpose: Dental pulp stem cells (DPSCs) have demonstrated significant potential for neuroregeneration. However, a full understanding of the specific mechanism underpinning the neural differentiation of DPSCs is still required. The Wnt signaling is crucial for the development of the embryonic neural system and the maintenance of adult neural homeostasis. This study aimed to investigate the role of the Wnt/Ca2+ pathway in the neural differentiation of human DPSCs (hDPSCs) and its modulation of the Wnt/ß-catenin pathway. Materials and methods: hDPSCs were cultured and divided into the control group and the neurogenic induction group (Neuro group). The mRNA and protein levels of neurogenic markers, Wnt/Ca2+, and Wnt/ß-catenin pathway indicators were determined using Quantitative real-time PCR and Western blotting. After inhibition of the Wnt/Ca2+ pathway using a WNT5A short hairpin RNA (shRNA) plasmid and subsequent neurogenic induction, neurogenic markers and Wnt/ß-catenin pathway indicators in the NC-sh-Neuro group and WNT5A-sh-Neuro group were determined using Quantitative real-time PCR and Western blotting. Results: Compared with the control group, the expression of the Wnt/Ca2+ pathway indicators (WNT5A, Frizzled 2, calmodulin-dependent protein kinase IIa, and nuclear factor of active T cells 1) decreased in the Neuro group. Conversely, the expression of WNT3A, total ß-catenin and active ß-catenin in the Wnt/ß-catenin pathway increased. Moreover, compared with the NC-sh-Neuro group, the WNT5A-sh-Neuro group exhibited a greater level of mature neural differentiation alongside elevated expression of the Wnt/ß-catenin pathway indicators. Conclusion: The Wnt/Ca2+ pathway inhibited neural differentiation of hDPSCs and has a negative effect on the Wnt/ß-catenin pathway in vitro.

Craniotubular Dysplasia Ikegawa Type: Further Delineation of the Phenotype.

Craniotubular Dysplasia Ikegawa type is a sclerosing bone disorder recently identified in five patients from four independent Indian families. It is caused by homozygous or compound heterozygous mutations in TMEM53. Deficient TMEM53 leads to overactive BMP signaling which promotes bone formation. Here, we present another three siblings with intronic mutations in TMEM53, identified by exome sequencing, from a Caucasian family. All three siblings displayed skeletal and radiographic features, similar to the earlier described individuals. All our patients had additional features such as cardiac and urogenital anomalies. Our results confirm the phenotype of CTDI. We discuss whether the additional features in our patients are separate from CTDI or reflect a broader spectrum of the syndrome.

Targeting signaling pathways with andrographolide in cancer therapy (Review).

Terpenoids are a large group of naturally occurring organic compounds with a wide range of components. A phytoconstituent in this group, andrographolide, which is derived from a plant called Andrographis paniculate, offers a number of advantages, including anti-inflammatory, anticancer, anti-angiogenesis and antioxidant effects. The present review elucidates the capacity of andrographolide to inhibit signaling pathways, namely the nuclear factor-κB (NF-κB), hypoxia-inducible factor 1 (HIF-1), the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), Wnt/ß-catenin and mitogen-activated protein kinase (MAPK) pathways, which are involved in cellular processes and responses such as the inflammatory response, apoptosis and angiogenesis. Inhibiting pathways enables andrographolide to exhibit its anticancer effects against breast, colorectal and lung cancer. The present review focuses on the anticancer effects of andrographolide, specifically in breast, colorectal and lung cancer through the NF-κB, HIF-1 and JAK/STAT signaling pathways. Therefore, the Google Scholar, PubMed and ScienceDirect databases were used to search for references to these prevalent types of cancer and the anticancer mechanisms of andrographolide associated with them. The following key words were used: Andrographolide, anticancer, JAK/STAT, HIF-1, NF-κB, PI3K/AKT/mTOR, Wnt/ß-catenin and MAPK pathways, and the literature was limited to studies published between 2010 to 2023. The present review article provides details about the different involvements of signaling pathways in the anticancer mechanisms of andrographolide.

Gradient Boosting Prediction of Overlapping Genes From Weighted Co-expression and Differential Gene Expression Analysis of Wnt Pathway: An Artificial Intelligence-Based Bioinformatics Study.

Introduction The Wnt (wingless-related integration site) signalling pathway is crucial for bone formation and remodelling, regulating the commitment of mesenchymal stem cells (MSCs) to the osteoblastic lineage. It triggers the transcriptional activation of Wnt target genes and promotes osteoblast proliferation and survival. Weighted co-expression network analysis (WGCNA) and differential gene expression analysis help researchers understand gene roles. Gradient boosting, a machine learning technique, enhances understanding of genetic and molecular mechanisms contributing to overlap genes, improving gene regulation and functional genomics. The aim is to predict overlapping genes in the Wnt signalling pathway. Methods Differential gene expression analysis was performed using the National Center for Biotechnology Information (NCBI) geo dataset-GSE251951, focusing on the effect of Wnt signaling on treatment. The WGCNA module was analyzed using the iDEP tool to identify interconnected gene clusters. Hub genes were identified by calculating module eigengenes, correlated with external traits, and ranked based on module membership values. The study utilized gradient boosting, an ensemble learning method, to predict models, evaluate their performance using metrics like accuracy, precision, recall, and F1 score, and adjust predictions based on gradient and learning rate. Results The dendrogram uses the "Dynamic TreeCut" algorithm to analyze gene clusters, aiding researchers in understanding gene modules and biological processes, identifying co-expressed genes, and discovering new pathways. The confusion matrix displays 88 actual and predicted cases. The gradient boosting model achieves 78.9% accuracy in predicting Wnt pathway overlapping genes, with a respectable area under the curve (AUC) and classification accuracy values. It accurately predicts 73.9% of samples, with a high precision ratio and low recall. Conclusion Future research should enhance differential expression analysis and WGCNA to identify key Wnt pathway genes, improve sensitivity, specificity, hyperparameter tuning, and validation experiments, and use larger datasets.

Characterizing the effects of triclosan and triclocarban on the intestinal epithelial homeostasis using small intestinal organoids.

Intestinal epithelium has the largest surface of human body, contributes dramatically to defense of toxicant-associated intestinal injury. Triclosan (TCS) and triclocarban (TCC), extensively employed as antibacterial agents in personal care products (PCPs) and healthcare facilities, caused serious damage to human intestine. However, the role of the intestinal epithelium in TCS/TCC-induced intestinal toxicity and its underlying toxic mechanisms remain incompletely understood. In this study, a novel 3D intestinal organoid model was utilized to investigate that exposure to TCS/TCC led to a compromised self-renewal and differentiation of intestinal stem cells (ISCs). Consequently, this disrupted intestinal epithelial homeostasis ultimately caused a reduction in nutrient absorption and deficient of epithelial defense to exogenous and endogenous pathogens stimulation. The inhibition of the Wnt signaling pathway in intestinal stem cell was contributed to the intestinal toxicity of TCS/TCC. These results were further confirmed in vivo with mice exposed to TCS/TCC. The findings of this study provide evidence that TCS/TCC possess the capacity to disturb the homeostasis of the intestinal epithelium, and emphasize the credibility of organoids as a valuable model for toxicological studies, as they could faithfully recapitulate in vivo phenomena.

Multi-omic analyses identified SFRP4 as a novel biomarker in abnormal uterine bleeding with ovulatory dysfunction.

The goal of the study was to explore the mechanism underlying the progression from abnormal uterine bleeding with ovulatory dysfunction (AUB-O) to AUB with atypical hyperplasia/malignancy (AUB-M). AUB-O, AUB-M and control endometrial tissues were subjected to multi-omic analyses to identify biomarkers. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs), including SFRP4, between the AUB-O and AUB-M groups were identified. The expression of SFRP4 was upregulated in endometrial tissues from AUB-O groups compared to that from AUB-M groups. SFRP4 knockdown in human endometrial epithelial cells (hEECs) promoted cell migration, invasion, proliferation and colony formation but inhibited apoptosis. Furthermore, the levels of key Wnt pathway proteins were altered by SFRP4 knockdown: Wnt-5A was downregulated and Wnt-7A was upregulated. In conclusion, we identified SFRP4 as an AUB-O-related molecule. SFRP4 might play a key role in hEECs apoptosis, migration, invasion, proliferation and colony formation via the Wnt pathway. SFRP4 may serve as a repressive factor regarding the progression of AUB-O to AUB-M. However, further studies are warranted to elucidate the exact mechanism.

Thiouracil and triazole conjugate induces autophagy through the downregulation of Wnt/ß-catenin signaling pathway in human breast cancer cells.

Autophagy is vital for maintaining cellular homeostasis by breaking down unnecessary organelles and proteins within cells. Its activity varies abnormally in several diseases, including cancer, making it a potential target for therapeutic strategies. The Wnt/ß-catenin signaling pathway significantly impacts cancer by stabilizing ß-catenin protein and promoting the transcription of its target genes. Therefore, we aimed to identify candidate substances targeting this signaling pathway. We designed and tested a thiouracil conjugate, discovering that TTP-8 had anti-tumor effects on human breast cancer cell lines MCF-7 and MDA-MB231. Our findings showed that TTP-8 upregulated the expression of LC3 protein, a marker of autophagy in breast cancer cells, suggesting that TTP-8 might induce autophagy. Further analysis confirmed an increase in autophagy-related proteins, with consistent results obtained from flow cytometry and confocal microscopy. Interestingly, the induction of LC3 expression by TTP-8 was even more pronounced in MCF-7 and MDA-MB231 cells transfected with ß-catenin siRNA. Thus, our research supports the idea that the Wnt/ß-catenin signaling pathway influences the regulation of autophagy-related proteins, thereby inducing autophagy. This suggests that TTP-8 could serve as a novel agent for treating breast cancer.

Roles and action mechanisms of NRIP1 in pre-eclampsia.

BACKGROUND: Pre-eclampsia (PE) is characterized by the onset of hypertension and proteinuria during pregnancy. Here, we aimed to explore the functions of nuclear receptor-interacting protein 1 (NRIP1) in PE mice and human placental JEG-3 cells. We evaluated its effects on JEG-3 cell proliferation, apoptosis, invasion, and inflammatory response and regulation of Wnt/ß-catenin pathway. METHODS: NRIP1 levels in human serum and placental tissues, JEG-3 cells, and mouse models were assessed via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. JEG-3 cell growth, apoptosis, migration, and invasion were evaluated via 5-ethynyl-2'-deoxyuridine, flow cytometry, and transwell assays. Levels of the inflammatory factors, matrix metalloproteinase (MMP)-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, were determined via enzyme-linked immunosorbent assay. Wnt/ß-catenin pathway was assessed via western blotting and qRT-PCR. Systolic blood pressure and proteinuria were measured using the non-invasive tail cuff method and Coomassie brilliant blue assay, respectively. TdT-mediated dUTP nick-end labeling assay was used to assess cell apoptosis in the placental tissues of PE mice. RESULTS: NRIP1 levels were upregulated in the serum and placental tissues of patients with PE. In vitro experiments revealed that NRIP1-small interfering RNA (siRNA) increased the cell viability, migration, and invasion and reduced the cell apoptosis compared to the control siRNA. Moreover, NRIP1-siRNA activated the Wnt/ß-catenin signaling pathway, as indicated by the increased Wnt3a, ß-catenin, p-glycogen synthase kinase-3ß, c-Myc, and cyclin D1 levels. Levels of the inflammatory factors, IL-6, TNF-α, and MMP-2, were decreased in the NRIP1-siRNA-treated group. Notably, NRIP1 downregulation improved the PE-like symptoms, inhibited the inflammatory responses, and reduced apoptosis in PE mice. CONCLUSION: This study revealed the crucial roles of NRIP1 in PE. Our findings revealed that NRIP1 downregulation relieved PE symptoms by inhibiting cell proliferation, migration, and invasion via the Wnt/ß-catenin pathway, thus providing a novel candidate for PE treatment.

DVL/GSK3/ISL1 pathway signaling: unraveling the mechanism of SIRT3 in neurogenesis and AD therapy.

BACKGROUND: The established association between Alzheimer's disease (AD) and compromised neural regeneration is well-documented. In addition to the mitigation of apoptosis in neural stem cells (NSCs), the induction of neurogenesis has been proposed as a promising therapeutic strategy for AD. Our previous research has demonstrated the effective inhibition of NSC injury induced by microglial activation through the repression of oxidative stress and mitochondrial dysfunction by Sirtuin 3 (SIRT3). Nonetheless, the precise role of SIRT3 in neurogenesis remains incompletely understood. METHODS: In vivo, SIRT3 overexpression adenovirus was firstly injected by brain stereotaxic localization to affect the hippocampal SIRT3 expression in APP/PS1 mice, and then behavioral experiments were performed to investigate the cognitive improvement of SIRT3 in APP/PS1 mice, as well as neurogenic changes in hippocampal region by immunohistochemistry and immunofluorescence. In vitro, under the transwell co-culture condition of microglia and neural stem cells, the mechanism of SIRT3 improving neurogenesis of neural stem cells through DVL/GSK3/ISL1 axis was investigated by immunoblotting, immunofluorescence and other experimental methods. RESULTS: Our findings indicate that the overexpression of SIRT3 in APP/PS1 mice led to enhanced cognitive function and increased neurogenesis. Additionally, SIRT3 was observed to promote the differentiation of NSCs into neurons during retinoic acid (RA)-induced NSC differentiation in vitro, suggesting a potential role in neurogenesis. Furthermore, we observed the activation of the Wnt/ß-catenin signaling pathway during this process, with Glycogen Synthase Kinase-3a (GSK3a) primarily governing NSC proliferation and GSK3ß predominantly regulating NSC differentiation. Moreover, the outcomes of our study demonstrate that SIRT3 exerts a protective effect against microglia-induced apoptosis in neural stem cells through its interaction with DVLs. CONCLUSIONS: Our results show that SIRT3 overexpressing APP/PS1 mice have improved cognition and neurogenesis, as well as improved neurogenesis of NSC in microglia and NSC transwell co-culture conditions through the DVL/GSK3/ISL1 axis.

Role of the lncRNA/Wnt signaling pathway in digestive system cancer: a literature review.

The long noncoding RNA (lncRNA)/Wingless (Wnt) axis is often dysregulated in digestive system tumors impacting critical cellular processes. Abnormal expression of specific Wnt-related lncRNAs such as LINC01606 (promotes motility), SLCO4A1-AS1 (promotes motility), and SH3BP5-AS1 (induces chemoresistance), plays a crucial role in these malignancies. These lncRNAs are promising targets for cancer diagnosis and therapy, offering new treatment perspectives. The lncRNAs, NEF and GASL1, differentially expressed in plasma show diagnostic potential for esophageal squamous cell carcinoma and gastric cancer, respectively. Additionally, Wnt pathway inhibitors like XAV-939 have demonstrated preclinical efficacy, underscoring their therapeutic potential. This review comprehensively analyzes the lncRNA/Wnt axis, highlighting its impact on cell proliferation, motility, and chemoresistance. By elucidating the complex molecular mechanisms of the lncRNA/Wnt axis, we aim to identify potential therapeutic targets for digestive system tumors to pave the way for the development of targeted treatment strategies.

Rutin suppresses the malignant biological behavior of gastric cancer cells through the Wnt/ß-catenin pathway.

Rutin is a natural flavonoid compound that is widely found in a variety of plants and has a variety of biological effects, including anti-inflammatory, antioxidant, and anti-tumor effects. Rutin has been shown to have anti-tumor effects in a variety of cancers, but its effects on gastric cancer need to be further explored. The aim of this study was to explore the effects of Rutin on gastric cancer cells and the potential molecular regulatory mechanisms. Gastric cancer cells (AGS and MGC803) were treated with different concentrations of Rutin. Cell proliferation, apoptosis, migration, and invasion were determined by MTT, flow cytometry, scratch assay, and Transwell analysis, respectively. Cell epithelial mesenchymal transition (EMT) markers and Wnt/ß-catenin pathway were analyzed by RT-qPCR and western blot assay. The results showed that Rutin significantly inhibited the proliferation, migration and invasion ability of gastric cancer cells, induced apoptosis, and suppressed the EMT process. Further experiments revealed that Rutin achieved the effect of inhibiting the biological behavior of gastric cancer cells by suppressing the activation of the Wnt/ß-catenin pathway. Therefore, Rutin may become a potential therapeutic candidate for gastric cancer.

Matrix stiffness-related extracellular matrix signatures and the DYNLL1 protein promote hepatocellular carcinoma progression through the Wnt/ß-catenin pathway.

BACKGROUND: In hepatocellular carcinoma (HCC) treatment, first-line targeted therapy in combination with immune checkpoint inhibitors (ICIs) has improved patient prognosis, but the 5-year survival rate is far from satisfactory. Studies have shown that the extracellular matrix (ECM) is an essential part of the tumour microenvironment (TME) and participates in the progression of malignant tumours. ECM remodelling can enhance matrix stiffness in cirrhosis patients, induce an immunosuppressive microenvironment network, and affect the efficacy of targeted therapies and ICIs for treating HCC. However, the exact mechanism is still unclear. METHODS: We downloaded data from public databases, selected differentially expressed ECM proteins associated with matrix stiffness, constructed and validated a prognostic model of HCC using Lasso Cox regression, and investigated the roles and mechanism of one of the ECM proteins, dynein light chain LC8-type 1 (DYNLL1), in HCC proliferation, migration, and apoptosis via in vitro experiments. RESULTS: In this study, the risk score of the matrix stiffness-related ECM protein model effectively predicted the prognosis of HCC patients. The high- and low-risk subgroups of the model also showed differences in immune cells, immune functions, and drug sensitivity. DYNLL1 promoted HCC cell progression and migration and inhibited HCC cell apoptosis through the Wnt/ß-catenin pathway in vitro. CONCLUSION: The expression of matrix stiffness-related ECM proteins could be an independent predictor of HCC prognosis. DYNLL1, an oncogenic gene in HCC, has the potential to be a new target for HCC treatment.

Hydrogelation of peptides and carnosic acid as regulators of adaptive immunity against postoperative recurrence of cutaneous melanoma.

The in-situ activation of adaptive immunity at the surgical site has demonstrated remarkable efficacy in inhibiting various forms of tumour recurrence and even holds the promise of a potential cure. However, extensive research and bioinformatic analysis conducted in this study have unveiled the formidable challenge posed by melanoma-intrinsic ß-catenin signaling, which hinders the infiltration of cytotoxic T-lymphocytes (CTLs) and their subsequent anti-tumour action. To overcome this obstacle, a ß-catenin antagonist called carnosic acid (CA) was co-assembled with a RADA-rich peptide to create a nanonet-derived hydrogel known as Supra-gelδCA. This injectable hydrogel is designed to be retained at the surgical site while simultaneously promoting hemostasis. Importantly, Supra-gelδCA directly releases CA to the site of residual tumour lesions, thereby enhancing infiltration of CTLs and subsequently activating adaptive immunity. Consequently, it effectively suppresses postoperative recurrence of skin cutaneous melanoma (SKCM) in vivo. Collectively, the presented Supra-gelδCA not only provides an efficacious immunotherapy strategy for regulating adaptive immunity by overcoming the obstacle posed by melanoma-intrinsic ß-catenin signaling-induced absence of CTLs but also offers a clinically translatable hydrogel that revolutionizes post-surgical management of SKCM.

Static magnetic field contributes to osteogenic differentiation of hPDLSCs through the H19/Wnt/ß-catenin axis.

BACKGROUND: Static magnetic field (SMF) as an effective physical stimulus is capable of osteogenic differentiation for multiple mesenchymal stem cells, including human periodontal ligament stem cells (hPDLSCs). However, the exact molecular mechanism is still unknown. Therefore, this study intends to excavate molecular mechanisms related to SMF in hPDLSCs using functional experiments. METHODS: hPDLSCs were treated with different intensities of SMF, H19 lentivirus, and Wnt/ß-catenin pathway inhibitor (XAV939). Changes in osteogenic markers (Runx2, Col Ⅰ, and BMP2), Wnt/ß-catenin markers (ß-catenin and GSK-3ß), and calcified nodules were examined using RT-qPCR, western blotting, and alizarin red staining in hPDLSCs. RESULTS: SMF upregulated the expression of H19, and SMF and overexpressing H19 facilitated the expression of osteogenic markers (Runx2, Col Ⅰ, and BMP2), activation of the Wnt/ß-catenin pathway, and mineralized sediment in hPDLSCs. Knockdown of H19 alleviated SMF function, and treatment with XAV939 limited SMF- and H19-mediated osteogenic differentiation of hPDLSCs. Notably, the expression of hsa-miR-532-3p, hsa-miR-370-3p, hsa-miR-18a-5p, and hsa-miR-483-3p in hPDLSCs was regulated by SMF, and may form an endogenous competitive RNA mechanism with H19 and ß-catenin. CONCLUSION: SMF contributes to the osteogenic differentiation of hPDLSCs by mediating the H19/Wnt/ß-catenin pathway, and hsa-miR-532-3p, hsa-miR-370-3p, hsa-miR-18a-5p, and hsa-miR-483-3p may be the key factors in it.

CCN4 (WISP-1) reduces apoptosis and atherosclerotic plaque burden in an ApoE mouse model.

BACKGROUND AND AIMS: CCN4/WISP-1 regulates various cell behaviours that contribute to atherosclerosis progression, including cell adhesion, migration, proliferation and survival. We therefore hypothesised that CCN4 regulates the development and progression of atherosclerotic plaques. METHODS: We used a high fat fed ApoE-/- mouse model to study atherosclerotic plaque progression in the brachiocephalic artery and aortic root. In protocol 1, male ApoE-/- mice with established plaques were given a CCN4 helper-dependent adenovirus to see the effect of treatment with CCN4, while in protocol 2 male CCN4-/-ApoE-/- were compared to CCN4+/+ApoE-/- mice to assess the effect of CCN4 deletion on plaque progression. RESULTS: CCN4 overexpression resulted in reduced occlusion of the brachiocephalic artery with less apoptosis, fewer macrophages, and attenuated lipid core size. The amount of plaque found on the aortic root was also reduced. CCN4 deficiency resulted in increased apoptosis and occlusion of the brachiocephalic artery as well as increased plaque in the aortic root. Additionally, in vitro cells from CCN4-/-ApoE-/- mice had higher apoptotic levels. CCN4 deficiency did not significantly affect blood cholesterol levels or circulating myeloid cell populations. CONCLUSIONS: We conclude that in an atherosclerosis model the most important action of CCN4 is the effect on cell apoptosis. CCN4 provides pro-survival signals and leads to reduced cell death, lower macrophage number, smaller lipid core size and reduced atherosclerotic plaque burden. As such, the pro-survival effect of CCN4 is worthy of further investigation, in a bid to find a therapeutic for atherosclerosis.