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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.

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.

Main Problem Glioblastoma (GB) is one of the most prevalent and devastating types of brain cancer for which efficient treatments are currently lacking because of limitations such as antitumor efficacy, brain delivery, tumor selectivity, and drug resistance. A promising strategy to overcome these obstacles is developing anticancer agents that can be delivered to GB tissues to inhibit tumors with low toxicity to normal brain tissue. Methods We developed liposomes encapsulating resveratrol (RES), a polyphenolic compound, and α‐melittin (α‐MEL), which is composed of melittin conjugated with an amphiphilic α‐helical peptide at its N‐terminus. RES‐, α‐MEL‐, and α‐MEL‐RES‐loaded liposomes (Lips) were modified with Angiopep‐2 (ANG). The effects of the above liposomes on GB cells were assessed, and the possible mechanisms were analyzed. Results ANG‐modified α‐MEL‐RES‐Lips treatment facilitated the passage of these agents through the blood–brain barrier (BBB), increased tumor targeting, and significantly reduced α‐MEL‐associated hemolysis. The combined management of α‐MEL with RES impeded GB cell growth and prolonged the lifespan of GB tumor‐bearing model mice. α‐MEL‐RES‐Lips treatment triggered GB cell apoptosis and induced pyroptosis‐associated protein expressions of gasdermin‐D (GSDMD), gasdermin E (GSDME), cleaved caspase 3, and NLR family pyrin domain containing 3 (NLRP3), and inhibited epithelial–mesenchymal transition (EMT) by modulating the Wnt/β‐catenin signaling pathway. Conclusion ANG‐modified α‐MEL‐RES‐Lips might be a potential nanosystem for GB therapy, and polyphenolic compounds combined with antimicrobial peptides may promote the induction of apoptosis, pyroptosis, and the apoptosis–pyroptosis switch in GB. ANG‐modified liposomes encapsulating α‐melittin and resveratrol increase their blood–brain barrier penetration and GB cell selectivity. The combined treatment of α‐melittin with resveratrol markedly facilitates apoptosis and pyroptosis, and promotes the apoptosis–pyroptosis switch in the GB cells via downregulating the Wnt/β‐catenin signaling.

Dysregulation of long non‐coding RNAs (lncRNAs) has been implicated in many cancer developments. Previous studies showed that lncRNA LINC00941 was aberrantly expressed in oral squamous cell carcinoma (OSCC). However, its role in OSCC development remains elusive. In this study, we demonstrated that in OSCC cells, EP300 activates LINC00941 transcription through up‐regulating its promoter H3K27ac modification. Up‐regulated LINC00941 in turn activates CAPRIN2 expression by looping to CAPRIN2 promoter. Functional assays suggest that both LINC00941 and CAPRIN2 play pivotal roles in promoting OSCC cell proliferation and colony formation. In vivo assay further confirmed the role of LINC00941 in promoting OSCC cell tumour formation. Lastly, we showed that the role of LINC00941 and CAPRIN2 in OSCC progression was mediated through activating the canonical WNT/β‐catenin signaling pathway. Thus, LINC00941/CAPRIN2/ WNT/β‐catenin signaling pathway provides new therapeutic targets for OSCC treatment.

Polyphenolic compounds, such as resveratrol, have recently received widespread interest because of their ability to mimic effects of calorie restriction. The objective of the present study was to gain more insight into the effects of 30 days resveratrol supplementation on adipose tissue morphology and underlying processes. Eleven healthy obese men were supplemented with placebo and resveratrol for 30 days (150 mg per day), separated by a 4-week washout period in a double-blind randomized crossover design. A postprandial abdominal subcutaneous adipose tissue biopsy was collected to assess adipose tissue morphology and gene expression using microarray analysis. Resveratrol significantly decreased adipocyte size, with a shift toward a reduction in the proportion of large and very-large adipocytes and an increase in small adipocytes. Microarray analysis revealed downregulation of Wnt and Notch signaling pathways and upregulation of pathways involved in cell cycle regulation after resveratrol supplementation, suggesting enhanced adipogenesis. Furthermore, lysosomal/phagosomal pathway and transcription factor EB were upregulated reflecting an alternative pathway of lipid breakdown by autophagy. Further research is necessary to investigate whether resveratrol improves adipose tissue function.

Aberrant activation of the Wnt/β‐catenin signaling pathway has been observed in a wide range of human tumors. Deregulation of the pathway is closely linked to various aspects of human carcinogenesis such as cell viability, regulation of cell cycle, epithelial‐mesenchymal transition, and maintenance of stemness. In addition, recent studies have disclosed the involvement of Wnt signaling in immune evasion of tumor cells. The accumulation of β‐catenin in the nucleus is a common feature of cancer cells carrying defects in the pathway, which leads to the continuous activation of T‐cell factor (TCF)/LEF transcription factors. Consequently, a genetic program is switched on, leading to the uncontrolled growth, prolonged survival, and acquisition of mesenchymal phenotype. As β‐catenin/TCF serves as a signaling hub for the pathway, β‐catenin/TCF‐dependent transcriptional activity is a relevant readout of the pathway. To date, a wide variety of synthetic TCF/LEF reporters has been developed, and high‐throughput screening (HTS) using these reporters has made significant contributions to the discovery of Wnt inhibitors. Indeed, HTS led to the identification of chemical probes targeting porcupine, a membrane bound O‐acyltransferase, and CREB‐binding protein, a transcriptional coactivator. This review focuses on various screening strategies for the discovery of Wnt inhibitors and their mode of action to help the creation of new concepts for assay/screening methods. Establishment of a well‐designed high‐throughput screening system is essential to identify Wnt inhibitors. We comprehensively review Wnt inhibitors and discuss the strategies involved in their identification.

Background Triple-negative breast cancer (TNBC) represents a heterogeneous group of ER- and HER2-negative tumors with poor clinical outcome. We recently reported that Pten-loss cooperates with low expression of microRNA-145 to induce aggressive TNBC-like lesions in mice. To systematically identify microRNAs that cooperate with PTEN-loss to induce aggressive human BC, we screened for miRNAs whose expression correlated with PTEN mRNA levels and determined the prognostic power of each PTEN-miRNA pair alone and in combination with other miRs. Methods Publically available data sets with mRNA, microRNA, genomics, and clinical outcome were interrogated to identify miRs that correlate with PTEN expression and predict poor clinical outcome. Alterations in genomic landscape and signaling pathways were identified in most aggressive TNBC subgroups. Connectivity mapping was used to predict response to therapy. Results In TNBC, PTEN loss cooperated with reduced expression of hsa-miR-4324, hsa-miR-125b, hsa-miR-381, hsa-miR-145, and has-miR136, all previously implicated in metastasis, to predict poor prognosis. A subgroup of TNBC patients with PTEN-low and reduced expression of four or five of these miRs exhibited the worst clinical outcome relative to other TNBCs (hazard ratio (HR) = 3.91; P  < 0.0001), and this was validated on an independent cohort (HR = 4.42; P  = 0.0003). The PTEN-low/miR-low subgroup showed distinct oncogenic alterations as well as TP53 mutation, high RB1-loss signature and high MYC, PI3K, and β-catenin signaling. This lethal subgroup almost completely overlapped with TNBC patients selected on the basis of Pten-low and RB1 signature loss or β-catenin signaling-high. Connectivity mapping predicted response to inhibitors of the PI3K pathway. Conclusions This analysis identified microRNAs that define a subclass of highly lethal TNBCs that should be prioritized for aggressive therapy.

Emerging evidence suggests that Makorin Ring Finger Proteins (MKRNs) are dysregulated in various human malignancies. However, the clinical and biological significance of MKRN2 in clear cell renal cell carcinoma (ccRCC) has been minimally explored. In this study, we investigated the exceptional role of MKRN2 in ccRCC. MKRN2 expression in ccRCC was analyzed with clinical samples and The Cancer Genome Atlas (TCGA) database. The proliferation and migration of cancer cells were assessed by transwell, colony formation, and wound healing assays. Gene expression, DNA methylation, and protein expression and ubiquitination were assessed by real-time PCR, bisulfite sequencing PCR, and western blotting assay, respectively. Protein interactions were verified by co-immunoprecipitation and immunofluorescence assays. experiments identified MKRN2 was a potential tumor inhibitor in ccRCC. Down-regulation of MKRN2 was observed in human ccRCC tissues in both public databases and our clinical samples, mechanistically linked with its promoter DNA hypermethylation. Conversely, overexpression of MKRN2 was associated with ccRCC inhibition and favorable clinical outcomes. MKRN2 interacted with Protein Phosphatase 2 Catalytic Subunit Alpha (PPP2CA) and promoted k48-linked ubiquitination at its K41 residue, leading to the proteasomal degradation of PPP2CA proteins. Consequently, MKRN2-mediated PPP2CA repression increased β-catenin phosphorylation and decreased its protein levels, causing the inactivation of Wnt signaling pathway and amplification of apoptosis in ccRCC cells. This study demonstrated that the E3 ligase activity of MKRN2 had a pivotal role in regulating the PPP2CA-β-catenin-Wnt pathway and granted MKRN2 as a candidate tumor suppressor in ccRCC.

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/β-catenin pathway protein expression showed that SLJGP activated the Wnt/β-catenin pathway through miR-217/RUNX2. In conclusion, SLJGP promoted osteogenic differentiation of BMSCs by regulating miR-217/RUNX2 axis and activating Wnt/β-catenin pathway.

The purpose of this study was (1) to determine the effect of single bouts of volume- and intensity-equated low- (LL) and high-load (HL) full-body resistance exercise (RE) on AR-DNA binding, serum/muscle testosterone and dihydrotestosterone, muscle androgen receptor (AR), and AR-DNA binding; and, (2) to determine the effect of RE on sarcoplasmic and nucleoplasmic β-catenin concentrations in order to determine their impact on mediating AR-DNA binding in the absence/presence of serum/muscle androgen and AR protein. In a cross-over design, 10 resistance-trained males completed volume- and intensity-equated LL and HL full-body RE. Blood and muscle samples were collected at pre-, 3 h-, and 24 h post-exercise. Separate 2 × 3 factorial analyses of variance (ANOVAs) with repeated measures and pairwise comparisons with a Bonferroni adjustment were used to analyze the main effects. No significant differences were observed in muscle AR, testosterone, dihydrotestosterone, or serum total testosterone in either condition (p > 0.05). Serum-free testosterone was significantly decreased 3 h post-exercise and remained significantly less than baseline 24 h post-exercise in both conditions (p < 0.05). In response to HL, AR-DNA binding significantly increased at 3 h post-exercise (p < 0.05), whereas no significant differences were observed at any time in response to LL (p > 0.05). Moreover, sarcoplasmic β-catenin was significantly greater in HL (p < 0.05) without significant changes in nucleoplasmic β-catenin (p > 0.05). In conclusion, increases in AR-DNA binding in response to HL RE indicate AR signaling may be load-dependent. Furthermore, despite the lack of increase in serum and muscle androgens or AR content following HL RE, elevations in AR-DNA binding with elevated sarcoplasmic β-catenin suggests β-catenin may be facilitating this response.