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Type 2 diabetes mellitus (T2DM) is one of the major chronic diseases, whose prevalence is increasing dramatically worldwide and can lead to a range of serious complications. Wnt ligands (Wnts) and their activating Wnt signalling pathways are closely involved in the regulation of various processes that are important for the occurrence and progression of T2DM and related complications. However, our understanding of their roles in these diseases is quite rudimentary due to the numerous family members of Wnts and conflicting effects via activating the canonical and/or non‐canonical Wnt signalling pathways. In this review, we summarize the current findings on the expression pattern and exact role of each human Wnt in T2DM and related complications, including Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wnt11 and Wnt16. Moreover, the role of main antagonists (sFRPs and WIF‐1) and coreceptor (LRP6) of Wnts in T2DM and related complications and main challenges in designing Wnt‐based therapeutic approaches for these diseases are discussed. We hope a deep understanding of the mechanistic links between Wnt signalling pathways and diabetic‐related diseases will ultimately result in a better management of these diseases.

Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.

Endothelial cells play a key role in the regulation of disease. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells or neighboring cell types, and in both cases contributes to organ fibrosis. Regulatory control of endothelial cell homeostasis is not well studied. Diabetes accelerates renal fibrosis in mice lacking the endothelial glucocorticoid receptor (GR), compared to control mice. Hypercholesterolemia further enhances severe renal fibrosis. The fibrogenic phenotype in the kidneys of diabetic mice lacking endothelial GR is associated with aberrant cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation. Both neutralization of IL-6 and Wnt inhibition improve kidney fibrosis by mitigating mesenchymal transition. Conditioned media from endothelial cells from diabetic mice lacking endothelial GR stimulate Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic molecule in diabetes. The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.

Neurodegenerative diseases (NDs) are conditions characterized by sensory, motor, and cognitive impairments due to alterations in the structure and function of neurons in the central nervous system (CNS). Despite their widespread occurrence, the exact causes of NDs remain largely elusive, and existing treatments fall short in efficacy. The Wnt signaling pathway is an emerging molecular pathway that has been linked to the development and progression of various NDs. Wnt signaling governs numerous cellular processes, such as survival, polarity, proliferation, differentiation, migration, and fate specification, via a complex network of proteins. In the adult CNS, Wnt signaling regulates synaptic transmission, plasticity, memory formation, neurogenesis, neuroprotection, and neuroinflammation, all essential for maintaining neuronal function and integrity. Dysregulation of both canonical and non-canonical Wnt signaling pathways contributes to neurodegeneration through various mechanisms, such as amyloid-β accumulation, tau protein hyperphosphorylation, dopaminergic neuron degeneration, and synaptic dysfunction, prompting investigations into Wnt modulation as a therapeutic target to restore neuronal function and prevent or delay neurodegenerative processes. Modulating Wnt signaling has the potential to restore neuronal function and impede or postpone neurodegenerative processes, offering a therapeutic approach for targeting NDs. In this article, the current knowledge about how Wnt signaling works in Alzheimer’s disease and Parkinson’s disease is discussed. Our study aims to explore the molecular mechanisms, recent discoveries, and challenges involved in developing Wnt-based therapies.

Glioblastoma multiforme (GBM) is one of the most malignant human intracranial tumors. Temozolomide (TMZ) is the primary alkylating agent for GBM patients. However, many GBM patients are resistant to TMZ. Therefore, patients with GBM urgently need more effective therapeutic options. 20(S)‐ginsenoside‐Rg3 (20(S)‐Rg3) is a natural chemical with anti‐tumor effects, but at present there is little understanding of its functional mechanism. Several research reports have demonstrated that O6‐methylguanine DNA‐methyltransferase (MGMT) repairs damaged DNA and contributes to TMZ resistance in gliomas. In addition, recent studies have shown that MGMT gene expression could be regulated by the Wnt/β‐catenin pathway. However, whether 20(S)‐Rg3 inhibits MGMT expression and augments chemosensitivity to Temozolomide (TMZ) in glioma cells remains unclear. In this study, we explored the modulating effects of 20(S)‐Rg3 on MGMT. We used glioma cell lines, primary cell strain (including T98G, U118 and GBM‐XX; all of them are MGMT‐positive glioma cell lines) and xenograft glioma models to examine whether 20(S)‐Rg3 increased the sensitivity to TMZ and to reveal the underlying mechanisms. We found that the MGMT expression was effectively downregulated by 20(S)‐Rg3 via the Wnt/β‐catenin pathway in glioma cell lines, and TMZ resistance was significantly reversed by 20(S)‐Rg3. Meanwhile, 20(S)‐Rg3 shows no obvious cytotoxicity at its effective dose and is well tolerated in vivo. In addition, we found that 20(S)‐Rg3 significantly restrains the epithelial‐mesenchymal transition (EMT) progression of glioma cells. Taken together, these results indicate that 20(S)‐Rg3 may be a novel agent to use in treatment of GBM, especially in TMZ‐resistant GBM with high MGMT expression. In this study, we demonstrated, for the first time to the best of our knowledge, that 20(S)‐Rg3 potentiates chemosensitivity to TMZ in MGMT‐positive glioma cells by modulating Wnt/β‐catenin/MGMT pathways. We revealed that 20(S)‐Rg3 effectively restrains the epithelial‐mesenchymal transition progression of glioma cells.

Guanine nucleotide‐binding protein gamma 10 (GNG10) is implicated in various biological processes, yet its specific oncogenic role in colorectal cancer (CRC) remains poorly defined. This study aimed to elucidate the expression patterns, biological functions, and underlying mechanisms of GNG10 in CRC progression. We integrated TCGA datasets with tissue microarray immunohistochemistry and multivariate Cox regression models to evaluate the clinical significance of GNG10. Functional impacts on CRC malignant phenotypes and cancer stemness were assessed through gain‐ and loss‐of‐function models in vitro and in vivo. Mechanistic insights were gained via GSEA, Western blotting, and dual rescue strategies employing both pharmacological inhibition (Box5) and genetic depletion (shRHOA). We found that GNG10 was markedly overexpressed in CRC tissues, correlating with advanced pathological stage and poor overall survival. Multivariate analysis indicated that the prognostic value of GNG10 is closely associated with tumour progression. Functionally, GNG10 knockdown inhibited CRC cell proliferation, migration, and stemness while promoting apoptosis. Mechanistically, GNG10 activated the non‐canonical Wnt/RHOA/JNK/NFATc1 signalling axis. Crucially, manipulation of GNG10 did not affect active or total β‐catenin levels, thereby excluding canonical Wnt involvement. Both pharmacological inhibition with Box5 and genetic ablation of RHOA effectively abrogated GNG10‐induced oncogenic phenotypes and the upregulation of cancer stem cell markers (CD44, CD133, OCT4, Nanog, SOX2). In vivo xenograft models confirmed that GNG10 knockdown suppressed tumour growth and decreased the expression of proliferation and stemness markers. Our findings demonstrate that GNG10 promotes CRC progression and stemness via the non‐canonical Wnt signalling pathway. These findings highlight GNG10 as a promising prognostic indicator and a vulnerable target in CRC.

The canonical Wnt/β‐catenin pathway plays an important role in different developmental processes through the regulation of stem cell functions. In the activation of the canonical Wnt/β‐catenin pathway, β‐catenin protein is imported into the nucleus and activates transcription of target genes including cyclin D1 and c‐myc. Aberrant activation of the Wnt/β‐catenin pathway contributes to carcinogenesis and malignant behaviors, and Wnt signaling is essential for the maintenance of cancer stem cells. The canonical Wnt/β‐catenin pathway has been investigated extensively as a target in cancer treatment and several specific inhibitors of this signaling pathway have been identified through high‐throughput screening. In this review, the significance of the canonical Wnt/β‐catenin pathway in hematological carcinogenesis and screening methods for specific inhibitors are discussed. The canonical Wnt/ß‐catenin pathway has been investigated extensively as a target in cancer treatment and several specific inhibitors of this signaling pathway have been identified through high‐throughput screening. In this review, the significance of the canonical Wnt/ß‐catenin pathway in hematological carcinogenesis and screening methods for specific inhibitors are discussed.

Dysregulation of wingless‐type (Wnt) signaling is implicated in hepatocellular carcinoma (HCC). Wnt family member 8B (Wnt8B), one of the canonical Wnt ligands, is implicated in oncogenesis. However, the role of Wnt8B in human HCCs and its transcriptional regulation mechanism are presently unknown . Here, we report that Wnt8B expression was frequently increased in HCCs and was significantly associated with poorer patient prognosis. Wnt8B knockdown suppresses HCC cell growth both in vitro and in vivo via inhibiting the canonical Wnt signaling. Zinc finger transcription factor 191 (ZNF191) can positively regulate Wnt8B mRNA and protein expression, and promoter luciferase assay indicated that ZNF191 can increase the transcription activity of the 2‐Kbps WNT8B promoter. Chromatin immunoprecipitation‐qPCR and electrophoretic mobility shift assay showed that ZNF191 protein directly binds to the WNT8B promoter, and the binding sites are at nt‐1491(ATTAATT) and nt‐1178(ATTCATT). Moreover, Wnt8B contributes to the effect of ZNF191 on cell proliferation, and Wnt8B expression correlates positively with ZNF191 in human HCCs. Our findings suggested that Wnt8B, directly transcriptionally regulated by ZNF191, plays a pivotal role in HCC proliferation via the canonical Wnt pathway and may serve as a new prognostic biomarker and a potential therapeutic target for HCC patients. Aberrant activation of the canonical wingless‐type (Wnt) signaling is involved in hepatocellular carcinoma (HCC). Here, we report Wnt8B, one of the canonical Wnt ligands, is upregulated in human HCCs and is significantly associated with poorer prognosis. Zinc finger transcription factor 191 (ZNF191) can directly bind to the WNT8B promoter and transactivate the WNT8B gene and subsequently activate the Wnt pathway to promote cell proliferation. Wnt8B expression correlates positively with ZNF191 in HCC specimens. Thus, Wnt8B may serve as a new prognostic biomarker and a potential therapeutic target for HCC patients.

Background Nanopesticides have been progressively incorporated into contemporary agricultural systems owing to their distinctive physicochemical characteristics and superior pest management capabilities. Given their environmental persistence and propensity for bioaccumulation, nanopesticides are increasingly recognized as emerging cardiovascular toxicants, thus warranting systematic investigation of their exposure-associated cardiotoxic effects. Methods In the present study, the impact of Cu(OH) 2 nanopesticide on cardiac homeostasis was systematically investigated in a C57BL/6 mouse model following one-month exposure administered via oral gavage, with copper concentrations set at 0 (vehicle control), 1, and 5 mg/kg bw. Multiple molecular biology techniques were employed to elucidate the nanopesticide-induced cardiac impairment and the underlying mechanisms. Results It was demonstrated that prolonged exposure to this copper-based nanopesticide resulted in significant deterioration of ventricular systolic and diastolic function, induction of ventricular chamber remodeling, disturbance of hemodynamic stability, and dysregulation of cardiac substructural gene expression, collectively mirroring the characteristic phenotypic manifestations and underlying molecular hallmarks of clinical heart failure. The dysregulation of Cu(OH) 2 nanopesticide in the Wnt/β-catenin signaling pathway through the targeting of mmu-miRNA-590-3p and mmu-miRNA-338-5p provided a proposed explanation for the underlying mechanism of the nanopesticide-induced imbalance of cardiac homeostasis. Conclusion The present findings provide new insights into the cardiovascular hazards posed by Cu(OH) 2 nanopesticide, advancing the development of a more rigorous risk assessment protocol for this emerging category of agricultural nanomaterial. Graphical abstract

Background Circular RNAs are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. In the current study, we evaluate the function of a novel circRNA derived from the β-catenin gene locus, circβ-catenin. Results Circβ-catenin is predominantly localized in the cytoplasm and displays resistance to RNase-R treatment. We find that circβ-catenin is highly expressed in liver cancer tissues when compared to adjacent normal tissues. Silencing of circβ-catenin significantly suppresses malignant phenotypes in vitro and in vivo, and knockdown of this circRNA reduces the protein level of β-catenin without affecting its mRNA level. We show that circβ-catenin affects a wide spectrum of Wnt pathway-related genes, and furthermore, circβ-catenin produces a novel 370-amino acid β-catenin isoform that uses the start codon as the linear β-catenin mRNA transcript and translation is terminated at a new stop codon created by circularization. We find that this novel isoform can stabilize full-length β-catenin by antagonizing GSK3β-induced β-catenin phosphorylation and degradation, leading to activation of the Wnt pathway. Conclusions Our findings illustrate a non-canonical function of circRNA in modulating liver cancer cell growth through the Wnt pathway, which can provide novel mechanistic insights into the underlying mechanisms of hepatocellular carcinoma.