Search Results (502)

Osteoarthritis (OA) is a chronic progressive joint disease characterized by cartilage degradation, subchondral bone remodeling, and synovial inflammation. This complex disorder arises from the interplay between mechanical stress and inflammatory processes, which is mediated by interconnected molecular signaling pathways. This review explores the dual roles of inflammatory and mechanical signaling in OA pathogenesis, focusing on crucial pathways such as NF-kB, JAK/STAT, and MAPK in inflammation, as well as Wnt/β-catenin, Integrin-FAK, and Hippo-YAP/TAZ in mechanotransduction. The interplay between these pathways highlights a vicious cycle wherein mechanical stress exacerbates inflammation, and inflammation weakens cartilage, increasing its vulnerability to mechanical damage. Additionally, we discuss emerging therapeutic strategies targeting these pathways, including inhibitors of cartilage-degrading enzymes, anti-inflammatory biologics, cell-based regenerative approaches, and non-pharmacological mechanical interventions. By dissecting the molecular mechanisms underlying OA, this review aims to provide insights into novel interventions that address both inflammatory and mechanical components of the disease, paving the way for precision medicine in OA management. Full article

Bone is the most frequent site of distant metastasis in advanced prostate cancer (PCa), contributing substantially to patient morbidity and mortality. Hypoxia, a defining feature of the solid tumour microenvironment, plays a pivotal role in driving bone-tropic progression by promoting epithelial-to-mesenchymal transition (EMT), cancer stemness, extracellular matrix (ECM) remodelling, and activation of key signalling pathways such as Wingless/Integrated (Wnt) Wnt/β-catenin and PI3K/Akt. Hypoxia also enhances the secretion of extracellular vesicles (EVs), enriched with pro-metastatic cargos, and upregulates bone-homing molecules including CXCR4, integrins, and PIM kinases, fostering pre-metastatic niche formation and skeletal colonisation. In this review, we analysed current evidence on how hypoxia orchestrates PCa dissemination to bone, focusing on the molecular crosstalk between HIF signalling, Wnt activation, EV-mediated communication, and cellular plasticity. We further explore therapeutic strategies targeting hypoxia-related pathways, such as HIF inhibitors, hypoxia-activated prodrugs, and Wnt antagonists, with an emphasis on overcoming therapy resistance in castration-resistant PCa (CRPC). By examining the mechanistic underpinnings of hypoxia-driven bone metastasis, we highlight promising translational avenues for improving patient outcomes in advanced PCa. Full article

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

The Wnt signaling pathway plays a critical role in regulating normal hematopoiesis and immune cell development. However, its dysregulation has emerged as a key driver of leukemogenesis. Leukemic stem cells exploit aberrant Wnt signaling to sustain self-renewal, evade apoptosis, and promote unchecked proliferation. In this review, we highlight the dual roles of canonical and non-canonical Wnt pathways in acute leukemia, emphasizing their distinct and overlapping contributions to disease progression. We also evaluate current preclinical and clinical strategies targeting Wnt signaling, identifying both promising advances and persistent obstacles to therapeutic translation. By elucidating the molecular mechanisms underlying Wnt pathway dysregulation in leukemic cells, this review underscores the potential of Wnt-directed therapies as a novel class of interventions to improve outcomes for patients with acute leukemia. Full article

Crohn’s disease (CD), characterized by chronic gastrointestinal inflammation, is complicated by intestinal stenosis resulting from dysregulated fibrogenesis and is marked by excessive extracellular matrix (ECM) deposition, fibroblast activation, and luminal obstruction. While biologics control inflammation, their failure to halt fibrosis underscores a critical therapeutic void. Emerging evidence highlights the multifactorial nature of stenosis-associated fibrosis, driven by profibrotic mediators and dysregulated crosstalk among immune, epithelial, and mesenchymal cells. Key pathways, including transforming growth factor (TGF-β), drosophila mothers against decapentaplegic protein (Smad) signaling, Wnt/β-catenin activation, epithelial–mesenchymal transition (EMT), and matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP)-mediated ECM remodeling, orchestrate fibrotic progression. Despite the current pharmacological, endoscopic, and surgical interventions for fibrostenotic CD, their palliative nature and inability to reverse fibrosis highlight an unmet need for disease-modifying therapies. This review synthesizes mechanistic insights, critiques therapeutic limitations with original perspectives, and proposes a translational roadmap prioritizing biomarker-driven stratification, combinatorial biologics, and mechanistically targeted antifibrotics. Full article

The transcriptional co-factor cell-cycle-related and expression-elevated protein in tumors (CREPT) has emerged as a critical driver of the cell cycle and a significant contributor to tumorigenesis. The aberrant expression or upregulation of CREPT boosts multiple signaling pathways, including Wnt/β-catenin, STAT3 and NF-κB/TNFR2, which are frequently dysregulated in various cancers and are associated with poor overall survival. In preclinical studies, CREPT knockdown via shRNA has demonstrated sustained tumor growth regression. Recent researches have uncovered additional functions of CREPT, including roles in metabolic regulation, tissue repair, and microenvironmental remodeling, further establishing it as a pleiotropic transcriptional regulator. Currently, there is no therapeutic agent that directly inhibits CREPT expression in clinic. However, miRNAs and other methods have been used to target CREPT, which have yielded useful results in inhibiting tumor growth. In this review, we discuss the role of CREPT in the hallmarks of cancer and propose that targeting CREPT will reverse tumor growth and may improve the immune checkpoint inhibitors in combination in CREPT-driven cancers. Full article

Hepatitis B virus (HBV) specifically infects hepatocytes and has a complex life cycle owing to the stabilization and pooling of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. We previously reported that the suppression of dedicator of cytokinesis 11 (DOCK11) decreases cccDNA and HBV-DNA levels and identified it as a new HBV therapeutic target. The DOCK11-associated gene, Wnt/β-catenin signaling regulator tankyrase (TNKS), was identified using in vitro methods; however, its function in the HBV life cycle remains unknown. Here, we used various inhibitors, antagonists, and short-hairpin RNA treatments related to TNKS signaling in HBV-infected hepatocytes. The role of TNKS-related Wnt/β-catenin signaling in the HBV life cycle was evaluated using immunoprecipitation assays with DOCK11 and bulk RNA sequencing methods. TNKS and Wnt/β-catenin signaling inhibitors significantly repressed cccDNA and HBV-DNA levels. Conversely, certain Wnt/β-catenin signaling agonists enhanced the HBV life cycle. DOCK11 directly binds to β-catenin to regulate HBV using its nuclear transport system. SKL2001, normally used as a Wnt/β-catenin signaling agonist, strongly reduced cccDNA in HBV-infected hepatocytes and in combination with entecavir predominantly eradicated HBV without cytotoxicity. Therefore, DOCK11 and other Wnt/β-catenin signaling molecules may be therapeutic targets to prevent persistent HBV infection. Full article

Current systemic therapies for advanced colorectal cancer (CRC) have limited efficacy, so more effective strategies for the treatment and prevention of CRC are needed. The majority of colorectal cancers are initiated by mutations in Wnt signalling pathway genes, including mutations in the APC gene, which result in a truncated APC protein and lead to excess signalling from β-catenin and the formation of pre-cancerous adenomas. The aim of this study was to determine if targeting the Wnt pathway in combination with pro-apoptotic mimetics altered the proliferative capacity or viability of human colorectal adenoma cells. Patient-derived colorectal adenoma organoid cultures were established from colon adenoma tissue collected by colonoscopy and recapitulated the histopathology of primary colorectal adenoma tissue. The growth of colorectal adenoma organoids is inhibited by the Wnt-signalling antagonist pyrvinium pamoate (PP) and a pro-apoptotic inhibitor of BCL-XL but not BCL-2 (venetoclax) or MCL-1 inhibitors. At low concentrations, the PP and the BCL-XL inhibitor combination demonstrated potent synergy and induced apoptosis in APC-defective patient-derived adenoma organoids, even in the presence of oncogenic KRAS or BRAF mutations, providing a new strategy for colon cancer prevention. Full article

Background and Objectives: Sclerostin and dickkopf-1 (DKK1), which are Wnt inhibitors, are involved in vascular calcification and atherosclerosis. Atherosclerotic peripheral artery disease (PAD) is highly prevalent, particularly in patients with hypertension. This study aimed to explore the association between serum concentrations of Wnt pathway inhibitors and PAD in patients with hypertension. Materials and Methods: This cross-sectional trial recruited 92 patients with hypertension. PAD was defined as an ankle-brachial index < 0.9. The levels of sclerostin, DKK1, C-reactive protein (CRP), and other biochemical markers were assessed using fasting blood samples. Univariate and multivariate logistic regression and receiver operating characteristic curve analyses were conducted. Results: Patients with PAD (15.2%) had significantly higher serum sclerostin (p < 0.001) and CRP (p = 0.001) levels than those without PAD. However, the two groups did not significantly differ in terms of the DKK1 levels. Based on the multivariate analysis, sclerostin was an independent predictor of PAD (odds ratio: 1.054 per 1 pmol/L increase, 95% confidence interval: 1.019–1.090, p = 0.002) after adjusting for body mass index, fasting glucose levels, diabetes, smoking, and CRP levels. Sclerostin had a strong discriminatory power for diagnosing PAD according to the receiver operating characteristic curve analysis (area under the curve: 0.806, p < 0.001), with the best cutoff value of 71.5 pmol/L (sensitivity: 71.4%, specificity: 78.2%). Further, sclerostin was negatively associated with the ankle-brachial index, renal function, and dyslipidemia markers. Conclusions: Serum sclerostin levels are independently related to an increased risk for PAD in patients with hypertension. Therefore, it can be a potential biomarker for risk stratification and early diagnosis. Full article

Colorectal cancer remains a leading malignancy. As the aberrant activation of Wnt/β-catenin signaling causes colorectal cancer, Wnt/β-catenin signaling inhibitors are potential candidates for colorectal cancer treatment. Our drug screening platform identified ursolic acid (UA), a triterpenoid with various biological activities, as a potential anticancer drug because it inhibits the T-cell factor (TCF)/β-catenin-mediated transcriptional activity. Here, we discovered that UA inhibited Wnt signaling by reducing the Wnt reporter activity and Wnt target gene expression, leading to a delay in cell cycle progression and the suppression of cell proliferation. Stepwise epistatic analyses suggested that UA functions on β-catenin protein stability in Wnt signaling. Further studies revealed that UA reduced β-catenin protein levels by Western blotting and immunofluorescent staining and induced autophagy by microtubule-associated protein 1 light chain 3 beta (LC3B) punctate staining. The cotreatment with UA and the autophagy inhibitors chloroquine and wortmannin recovered the β-catenin protein levels. Therefore, UA was confirmed to induce β-catenin degradation by the autophagy–lysosomal degradation system through inhibition in the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (protein kinase B; AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Our results not only highlight the potential of UA in Wnt-driven colorectal cancer therapy but also provide a workable Wnt signaling termination approach for the treatment of other Wnt-related diseases. Full article

We have previously demonstrated the ability of inhibitors of LSD1 and HDAC1 to block rod degeneration, preserve vision, maintain transcription of rod photoreceptor genes, and downregulate transcripts involved in cell death, gliosis, and inflammation in the mouse model of Retinitis Pigmentosa (RP), rd10. To extend our findings, we tested the hypothesis that this effect was due to altered chromatin structure by using a range of inhibitors of chromatin condensation to prevent photoreceptor degeneration in the rd10 mouse model. We used inhibitors for both G9A/GLP, which catalyzes methylation of H3K9, and EZH2, which catalyzes trimethylation of H3K27, and compared them to the actions of inhibitors of LSD1 and HDAC. All the inhibitors are likely to decondense chromatin and all preserve, to different extents, retinas from degeneration in rd10 mice, but they act through different metabolic pathways. One group of inhibitors, modifiers for LSD1 and EZH2, demonstrate a high level of maintenance of rod-specific transcripts, activation of Ca²⁺ and Wnt signaling pathways with the inhibition of antigen processing and presentation, immune response, and microglia phagocytosis. Another group of inhibitors, modifiers for HDAC and G9A/GLP, work through upregulation of NGF-stimulated transcription, while downregulating genes belong to immune response, extracellular matrix, cholesterol signaling, and programmed cell death. Our results provide robust support for our hypothesis that inhibition of chromatin condensation can be sufficient to prevent rod death in rd10 mice. Full article

Melanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise, no studies have analyzed the relationship between vemurafenib tolerance levels and metabolic plasticity. To determine how vemurafenib endurance levels drive metabolic plasticity, we developed isogenic BRAFV600E VemR melanoma models with variant vemurafenib tolerances and performed an integrative analysis of metabolomic and transcriptome alterations using metabolome, Mitoplate-S1, Seahorse, and RNA-seq assays. Regardless of drug tolerance differences, both VemR models display resistance to MEK inhibitor and sensitivity to Wnt/β-catenin inhibitor, ICG-001. β-catenin, MITF, and ABCB5 levels are upregulated in both VemR models, and ICG-001 treatment restored vemurafenib sensitivity with reductions in MITF, ABCB5, phospho-ERK1/2, and mitochondrial respiration. Whereas β-catenin signaling induced TCA cycle and OXPHOS in highly drug tolerant A2058VemR cells, it activated pentose phosphate pathway in M14VemR cells with low vemurafenib tolerance, both of which are inhibited by ICG-001. These data implicate an important role for Wnt/β-catenin signaling in VemR-induced metabolic plasticity. Our data demonstrate that drug tolerance thresholds play a direct role in driving metabolic shifts towards specific routes, thus providing a new basis for delineating VemR melanomas for metabolism-targeting therapies. Full article

Background: Tankyrase (TNKS1) regulates the WNT/β-catenin pathway, while CDK8 is a transcriptional regulator overexpressed in renal cell carcinoma (RCC). This study aims to identify novel dual inhibitors of tankyrase and Cyclin-dependent kinase 8 (CDK8), utilizing bioinformatics and in vitro methods and to assess their efficiency in renal cancer cells. Methods: To identify leads, the ChemBridge library was screening using high-throughput virtual screening (HTVS), which was followed by protein–ligand interaction analysis, Molecular Dynamics (MD) simulation, and Gibbs binding free energy estimation. A-498, Caki-1, and HK-2 cells were employed to validate in vitro efficacy. Results: TCS9725 was discovered by HTVS with binding affinities of −8.1 kcal/mol and −8.2 kcal/mol for TNKS1 and CDK8, respectively. TCS9725 had robust binding interactions with root mean square deviation values of 0.00 nm. The ΔG binding estimate was −27.45 for TNKS1 and −27.88 for CDK8, respectively. ADME predictions favored specific small-molecule inhibition profiles. TCS9725 reduced TNKS1 and CDK8 activities with IC50s of 243 nM and 403.6 nM, respectively. The compound efficiently inhibited the growth of A-498 and Caki-1 cells with GI50 values of 385.9 nM and 243.6 nM, respectively, with high selectivity compared to the non-cancerous kidney cells. TCS9725 decreased STAT1 and β-catenin positivity in A-498 and Caki-1 cells. The compound induced apoptosis and reduced TGFβ-stimulated trans-endothelial migration and p-smad2/3 signaling in both RCC cells. Conclusions: This work provides valuable insights into the therapeutic potential of TCS9725, a dual inhibitor of TNKS1 and CDK8. Further developments of this molecule could lead to new and effective treatments for this devastating disease. Full article

Colon cancer remains a significant global health challenge, with inflammatory pathways such as TNF-α playing a central role in its progression. TNF-α, a key proinflammatory cytokine, is implicated in various stages of colon cancer development, including inflammation, tumor growth, and metastasis. This review provides a comprehensive overview of the molecular mechanisms through which TNF-α contributes to colon cancer progression, with a focus on its interaction with signaling pathways like NF-κB and the Wnt/β-catenin in humans. TNF-α’s involvement in promoting tumorigenesis and its complex role in the tumor microenvironment highlight its potential as both a therapeutic target and a challenge for effective treatment. This review explores the potential of anti-TNF-α therapies and the emerging role of combination strategies with immune checkpoint inhibitors. Despite promising preclinical findings, clinical application faces challenges due to the dual role of TNF-α in both promoting and inhibiting tumor progression. Future research should aim to overcome resistance mechanisms, develop personalized therapeutic strategies, and balance the effects of TNF-α in cancer therapy. Full article

Reciprocal signaling between acute myeloid leukemia (AML) cells and the surrounding bone-marrow microenvironment (BMME) promotes AML progression through several mechanisms. One of the most important mechanisms is the induction of Galectin-3 (Gal-3) expression by AML cells and bone marrow mesenchymal stromal cells (BM-MSCs). Emerging evidence indicates that Gal-3 upregulation in the BMME promotes AML cell adhesion and survival, leading to the development of chemotherapy resistance, relapse, and poor prognosis. Identifying the biological function and critical signaling pathways of Gal-3 may contribute to overcoming acquired drug resistance and preventing post-treatment relapse. Gal-3 is involved in several molecular signaling pathways, including PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, JAK/STAT, JNK, Wnt/β-catenin, PLC/PKC and NF-κB, which are interconnected to promote AML cell survival and resistance to chemotherapy. This review focuses on the biological effects, molecular mechanisms of action and regulation of Gal-3 in the pathogenesis and progression of AML. The therapeutic potential of potent synthetic small-molecule Gal-3 inhibitors in high-risk patients with AML is also discussed based on preclinical and clinical evidence from several human diseases. Currently, the effect of these Gal-3 inhibitors in AML has not been investigated either in vitro or in vivo. The findings provide a rationale for targeting Gal-3 that may be a very promising therapeutic approach, especially for patients with relapsed/refractory AML, and may enhance the efficacy of conventional chemotherapeutic drugs and/or immune checkpoint inhibitors. Full article