Search

Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-β-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-β-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-β-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid β (Aβ) production through β-catenin-β-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αβ production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Heterozygous familial hypercholesterolemia (heFH) is an autosomal dominant lipid metabolism disorder. Its prevalence is 1:250-1:300 people in the population. Patients with heFH have an up to 13-fold increased risk of premature coronary artery disease (CAD). If left untreated, men and women with heFH typically develop early CAD before the ages of 55 and 60, respectively. There is evidence that coronary artery calcification (CAC) and aortic valve calcification (AoVC) are more prevalent in FH patients than in the general population. It is documented that CAC and AoVC are predictors of increased risk of cardiovascular morbidity and mortality in heFH patients, like in the general population. However, the etiology and pathogenesis of vascular calcification in FH patients is not well understood. Risk factors for vascular calcification include age, increased levels of atherogenic lipoproteins, Lp(a), increased blood pressure, and inflammation. There are convincing data from clinical studies and animal atherosclerotic mouse models using low-density lipoprotein receptor (LDL-R) knockout mice that the vascular calcification processes in FH are associated with LDL-R mutations, probably partly due to a higher total cholesterol burden of FH subjects. Data from animal models as well as clinical studies indicate that the Wnt/beta-catenin pathway components and LDL receptor-related proteins 5 and 6 (LRP-5/6) might be involved in calcification processes in FH patients. The purpose of the review is to describe the prevalence of coronary and aortic calcification and its risk factors in FH patients. The review covers data about the role of the Wnt/beta-catenin pathway and factors modulating calcification processes.

Sensitizing strategy is required to improve the clinical management of glioblastoma (GBM). 5-Lipoxygenase (Alox5) has been recently garnered attention due to its pro-carcinogenic roles in various cancers. This study demonstrates that Alox5 is overexpressed in GBM but not normal neuronal tissues. Alox5 depletion inhibits the growth of GBM cells, both in bulky and stem-like populations, and enhances the anti-cancer effects of temozolomide. The mechanism behind this involves a decrease in β-catenin level and activity upon Alox5 depletion. The inhibitory effects of Alox5 can be reversed by the addition of a Wnt agonist. Additionally, the study reveals that zileuton, an Alox5 inhibitor approved for asthma treatment, significantly improves the efficacy of temozolomide in mice without causing toxicity. Combination index analysis clearly demonstrates that zileuton and temozolomide act synergistically. These findings highlight the importance of Alox5 as a critical regulator of glioblastoma sensitivity and suggest the potential repurposing of zileuton for GBM treatment.

Objective: To investigate the effects of Moringa Oleifera Leaf Extract (MOLE) plus rosiglitazone (RSG) on glucose and lipid metabolism, serum leptin, and the Akt/GSK3β/β-Catenin signaling pathway in type 2 diabetic (T2D) rats., Methods: Sixty male Sprague-Dawley (SD) rats were randomly divided into six groups: the normal group, the model group, the RSG group, the low- and high-dose MOLE group, and the MOLE+RSG group. The normal group was fed a standard rat diet, while the other groups were given a single intraperitoneal injection of low-dose streptozomycin (STZ) (35 mg/kg) and fed a high-sugar and high-fat diet. After 8 weeks, the treatment outcomes were evaluated by measuring key parameters of blood glucose and lipid metabolism and the protein kinase B (AKT) / Glycogen synthase kinase 3beta (GSK3β) /β-Catenin signaling pathway in the T2D rats., Results: Compared with the normal group, the model group showed significantly increased levels of blood glucose, blood lipids, serum leptin, free fatty acid (FFA), and tumor necrosis factor-α (TNF-α). Compared with the model group, the RSG, low-dose MOLE, and high-dose MOLE groups displayed effective control of blood glucose, blood lipids, serum leptin, FFA, and TNF-α. The MOLE+RSG group surpassed the RSG group in regulating glucose, lipid metabolism, and serum leptin levels in T2D rats. In addition, the MOLE+RSG group also had superiority over the RSG group in activating the AKT/GSK3β/β-Catenin pathway., Conclusion: MOLE plus RSG can effectively reduce blood glucose and blood lipids in T2DM rats.

The molecular pathogenesis of osteosarcoma (OS), the most frequent primary malignant bone tumor of all age groups, is still obscure. Since multidrug chemotherapeutic regimens were introduced in the 1970s, survival rates have been stationary. The Wnt-β-catenin signaling cascade and SOX9 have a significant contribution to skeletal growth, development, and tumorigenesis. In the present work, an attempt was made to examine the role and clinicopathological significance of β-catenin and SOX9 in 46 cases of pre-neoadjuvant chemotherapy OS tissues compared to 10 cases of non-neoplastic bone. The mRNA levels of both markers were assessed by qRT-PCR, and protein levels of β-catenin were analyzed by immunohistochemistry. The results were correlated with different clinicopathological parameters. SOX9 mRNA levels were significantly elevated in OS compared to non-neoplastic bone, and higher levels were significantly associated with the occurrence of fluid-fluid levels (indicating blood-containing cystic spaces) and osteolytic radiological pattern. Although β-catenin mRNA and protein levels were higher in OS compared to non-neoplastic bone, only the protein levels reached statistical significance. Higher β-catenin mRNA levels were significantly associated with tumor size, while higher protein levels were significantly associated with the histologic subtype, mitotic count, and radiological pattern. No significant association was noted with any of the other evaluated parameters. OS showing higher SOX9 mRNA expression and lower β-catenin mRNA and protein expression exhibited longer estimated overall survival times approaching statistical significance. To conclude, while high expression of β-catenin and SOX9 suggests their possible involvement in OS development, their prognostic role may need further research.

Objectives: PARPs, which are members of the poly(ADP-ribose) polymerase superfamily, promote tumorigenesis and tumour-associated inflammation and are thus therapeutic targets for several cancers. The aim of the present study is to investigate the mechanistic insight into the roles PARPs for inflammation., Methods: Primary murine macrophages were cultured in the presence or absence of the PARP5 inhibitor NVP-TNKS656 to examine the role of PARP5 for cytokine production., Results: In contrast to the roles of other PARPs for induction of inflammation, we found in the present study that pharmacologic inhibition of PARP5 induces production of inflammatory cytokines in primary murine macrophages. We found that treatment with the PARP5 inhibitor NVP-TNKS656 in macrophages enhanced steady-state and LPS-mediated cytokine production through degradation of IκBα and subsequent nuclear translocation of NF-κB. We also found that pharmacologic inhibition of PARP5 stabilises the adaptor protein 3BP2, a substrate of PARP5, and that accelerated cytokine production induced by PARP5 inhibition was rescued in 3BP2-deleted macrophages. Additionally, we found that LPS increases the expression of 3BP2 and AXIN1, a negative regulator of β-catenin, through suppression of PARP5 transcripts in macrophages, leading to further activation of cytokine production and inhibition of β-catenin-mediated cell proliferation, respectively. Lastly, we found that PARP5 inhibition in macrophages promotes osteoclastogenesis through stabilisation of 3BP2 and AXIN1, leading to activation of SRC and suppression of β-catenin, respectively., Conclusions: Our results show that pharmacologic inhibition of PARP5 against cancers unexpectedly induces adverse autoinflammatory side effects through activation of innate immunity, unlike inhibition of other PARPs.

Objective: To investigate the link between EZH2 and Wnt/β-catenin signaling and its role in uterine fibroids (UFs) pathogenesis and explore the potential effect of natural compound methyl jasmonate (MJ) against UFs., Design: EZH2 overexpression or inhibition was achieved in human uterine leiomyoma (HuLM) cells using EZH2-expressing adenovirus or chemical EZH2 inhibitor (DZNep), respectively. The HuLM and normal uterine smooth muscle cells were treated with 0.1-3 mM of MJ, and several experiments were employed., Setting: Laboratory study., Patients(s): None., Intervention(s): Methyl jasmonate., Main Outcome Measure(s): Protein expression of EZH2, β-catenin, and proliferating cell nuclear antigen (PCNA) was measured by Western blot as well as gene expression alterations of Wnt ligands (Wnt5A, Wnt5b, and Wnt9A), WISP1, CTNNB1, and its responsive gene PITX2 using quantitative real-time polymerase chain reaction. The protein and ribonucleic acid (RNA) levels of several markers were measured in MJ-treated or untreated HuLM cells, including EZH2 and β-catenin, extracellular matrix markers collagen type 1 (COL1A1) and fibronectin (FN), proliferation markers cyclin D1 (CCND1) and PCNA, tumor suppressor marker p21, and apoptotic markers (BAX, cytochrome c, and cleaved caspase 3)., Result(s): EZH2 overexpression significantly increased the gene expression of several Wnt ligands (PITX2, WISP1, WNT5A, WNT5B, and WNT9A), which increased nuclear translocation of β-catenin and PCNA and eventually HuLM cell proliferation. EZH2 inhibition blocked Wnt/β-catenin signaling activation where the aforementioned genes significantly decreased as well as PCNA, cyclin D1, and PITX2 protein expression compared with those in untreated HuLM. Methyl jasmonate showed a potent antiproliferative effect on HuLM cells in a dose- and time-dependent manner. Interestingly, the dose range (0.1-0.5 mM) showed a selective growth inhibitory effect on HuLM cells, not on normal uterine smooth muscle cells. Methyl jasmonate treatment at 0.5 mM for 24 hours significantly decreased both protein and RNA levels of EZH2, β-catenin, COL1A1, FN, CCND1, PCNA, WISP1, and PITX2 but increased the protein levels of p21, BAX, cytochrome, c and cleaved caspase 3 compared with untreated HuLM. Methyl jasmonate-treated cells exhibited down-regulation in the RNA expression of 36 genes, including CTNNB1, CCND1, Wnt5A, Wnt5B, and Wnt9A, and up-regulation in the expression of 34 genes, including Wnt antagonist genes WIF1, PRICKlE1, and DKK1 compared with control, confirming the quantitative real-time polymerase chain reaction results., Conclusion(s): Our studies provide a novel link between EZH2 and the Wnt/β-catenin signaling pathway in UFs. Targeting EZH2 with MJ interferes with the activation of wnt/β-catenin signaling in our model. Methyl jasmonate may offer a promising therapeutic option as a nonhormonal and cost-effective treatment against UFs with favorable clinical utility, pending proven safe and efficient in human clinical trials., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Ovarian cancer is one of the leading causes of death in female reproductive system cancers. However, the pathogenesis of ovarian cancer remains elusive. Our aim is to investigate the potential targets for ovarian cancer. Two microarray datasets were obtained from the Gene Expression Omnibus public database. Using R package limma, the differentially expressed genes (DEGs) were identified from the datasets. There were 95 overlapping DEGs in two microarray datasets. GO, KEGG pathway analysis, and protein-protein interaction (PPI) network analysis were carried out based on the DEGs. Wnt signaling pathway and cell cycle were enriched in the KEGG pathway analysis. Moreover, the top 10 hub genes with the most nodes were determined by PPI network analysis. E2F8, one of hub genes was positively linked to a bad outcome in ovarian cancer patients. Furthermore, E2F8 knockdown suppressed cell proliferation and induced cell cycle arrest in ovarian cancer. In addition, we found that silencing E2F8 inhibited the Wnt/β-catenin signaling pathway. In ovarian cancer cells with E2F8 knockdown, overexpressing β-catenin restored both the suppressed capacity of cell proliferation and cell cycle progression. Therefore, our results revealed that E2F8 had an involvement in the development of ovarian cancer which might act as a therapeutic target., Competing Interests: None

Breast cancer is a high-risk disease with a high mortality rate among women. Chemotherapy plays an important role in the treatment of breast cancer. However, chemotherapy eventually results in tumours that are resistant to drugs. In recent years, many studies have revealed that the activation of Wnt/ β -catenin signalling is crucial for the emergence and growth of breast tumours as well as the development of drug resistance. Additionally, drugs that target this pathway can reverse drug resistance in breast cancer therapy. Traditional Chinese medicine has the properties of multi-target and tenderness. Therefore, integrating traditional Chinese medicine and modern medicine into chemotherapy provides a new strategy for reversing the drug resistance of breast tumours. This paper mainly reviews the possible mechanism of Wnt/ β -catenin in promoting the process of breast tumour drug resistance, and the progress of alkaloids extracted from traditional Chinese medicine in the targeting of this pathway in order to reverse the drug resistance of breast cancer.

Objective: To analyze the changes in the levels of bone metabolism markers related to sacroiliac joint (SIJ) inflammation in patients with axial spondyloarthritis (axSpA) after treatment with imrecoxib and celecoxib and evaluate their relationship with clinical efficacy., Methods: A total of 120 patients with axSpA with at least 2 magnetic resonance imaging (MRI) SIJ scans during a 12-week follow-up were enrolled. The levels of bone metabolism markers, including dickkopf-1(DKK-1), sclerostin, vascular endothelial growth factor (VEGF), bone morphogenetic protein-2 (BMP-2), osteoprotegerin (OPG), noggin, β-catenin, and RUNX2, were measured twice, and their association with disease activity and the Spondyloarthritis Research Consortium of Canada (SPARCC) score for SIJ were analyzed by univariate analysis of covariance., Results: A total of 116 patients completed the follow-up. The levels of sclerostin, OPG, noggin, DKK-1, and RUNX2 were increased, whereas those of VEGF and β-catenin were decreased. The levels of sclerostin and OPG were negatively correlated with disease duration. The levels of VEGF and β-catenin were significantly decreased (F = 7.866, P = 0.003; F = 4.106, P = 0.047) in patients with disease remission. A decrease in ESR was significantly correlated with decreased levels of Runx2 and SPARCC scores, with the levels of sclerostin being significantly elevated in the SPARCC-reduced group. There were no statistically significant differences between the imrecoxib and celecoxib groups (P> 0.05)., Conclusion: Imrecoxib and celecoxib affect SIJ inflammation, disease activity, and the course of disease by regulating bone metabolism and angiogenesis in axSpA. Key Points •After treatment with imrecoxib and celecoxib, the levels of sclerostin, OPG, noggin, DKK-1, and RUNX2 were increased, whereas those of VEGF and β-catenin were decreased, correlating with the course of disease, disease activity, and SIJ inflammation. • A decrease in ESR was significantly correlated with a decrease in the levels of RUNX2 and SIJ inflammation.. • The levels of sclerostin were more significantly elevated in SIJ inflammation remission group.. •Imrecoxib and celecoxib affect SIJ inflammation by regulating bone metabolism and angiogenesis in axSpA.., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Metastatic breast cancer is responsible for the death of the majority of breast cancer patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the USA and worldwide. Triple negative breast cancer (TNBC), which lacks expression of hormone receptors (ER-α and PR) and ErbB2/HER2, is especially lethal due to its highly metastatic behavior, propensity to recur rapidly, and for its resistance to standard of care therapies, through mechanisms that remain incompletely understood. WAVE3 has been established as a promoter of TNBC development and metastatic progression. In this study, we investigated the molecular mechanisms whereby WAVE3 promotes therapy-resistance and cancer stemness in TNBC, through the regulation of β-catenin stabilization., Methods: The Cancer Genome Atlas dataset was used to assess the expression of WAVE3 and β-catenin in breast cancer tumors. Kaplan-Meier Plotter analysis was used to correlate expression of WAVE3 and β-catenin with breast cancer patients' survival probability. MTT assay was used to quantify cell survival. CRISPR/Cas9-mediated gene editing, 2D and 3D tumorsphere growth and invasion assays, Immunofluorescence, Western blotting, Semi-quantitative and real-time quantitative PCR analyses were applied to study the WAVE3/β-catenin oncogenic signaling in TNBC. Tumor xenograft assays were used to study the role of WAVE3 in mediating chemotherapy resistance of TNBC tumors., Results: Genetic inactivation of WAVE3 in combination of chemotherapy resulted in inhibition of 2D growth and 3D tumorsphere formation and invasion of TNBC cells in vitro, as well as tumor growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 did not. Further studies revealed that dual blocking of WAVE3 expression or phosphorylation in combination with chemotherapy treatment inhibited the activity and expression and stabilization of β-catenin. Most importantly, the combination of WAVE3-deficiency or WAVE3-phospho-deficiency and chemotherapy suppressed the oncogenic behavior of chemoresistant TNBC cells, both in vitro and in vivo., Conclusion: We identified a novel WAVE3/β-catenin oncogenic signaling axis that modulates chemoresistance of TNBC. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors., (© 2023. The Author(s).)

Objective: Physical exercise, a common non-drug intervention, is an important strategy in cancer treatment, including hepatocellular carcinoma (HCC). However, the mechanism remains largely unknown. Due to the importance of hypoxia and cancer stemness in the development of HCC, the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness., Methods: A physical exercise intervention of swimming (30 min/d, 5 d/week, for 4 weeks) was administered to BALB/c nude mice bearing subcutaneous human HCC tumor. The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) detection of proliferating cell nuclear antigen (PCNA) and Ki67. The expression of stemness transcription factors, including Nanog homeobox (NANOG), octamer-binding transcription factor 4 (OCT-4), v-Myc avian myelocytomatosis viral oncogene homolog (C-MYC) and hypoxia-inducible factor-1α (HIF-1α), was detected using real-time reverse transcription polymerase chain reaction. A hypoxia probe was used to explore the intratumoral hypoxia status. Western blot was used to detect the expression of HIF-1α and proteins related to protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway. The IHC analysis of platelet endothelial cell adhesion molecule-1 (CD31), and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion. SMMC-7721 cells were treated with nude mice serum. The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors. The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1α. Further, the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected., Results: Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor. HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention. Swimming potently alleviated the intratumoral hypoxia, attenuated the cancer stemness, and inhibited the Akt/GSK-3β/β-catenin signaling pathway. Additionally, the desmin + /CD31 + ratio, rather than the number of CD31 + vessels, was significantly increased in swimming-treated mice. In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere, as well as the mRNA expression level of stemness transcription factors. Consistent with the in vivo results, HIF-1α and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group., Conclusion: Swimming alleviated hypoxia and attenuated cancer stemness in HCC, through suppression of the Akt/GSK-3β/β-catenin signaling pathway. The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor. Please cite this article as: Xiao CL, Zhong ZP, Lü C, Guo BJ, Chen JJ, Zhao T, Yin ZF, Li B. Physical exercise suppresses hepatocellular carcinoma progression by alleviating hypoxia and attenuating cancer stemness through the Akt/GSK-3β/β-catenin pathway. J Integr Med. 2023; 21(2): 184-193., Competing Interests: Declaration of competing interest No conflict of interest has been declared by the authors., (Copyright © 2023 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

Major obstacles in brain cancer treatment include the blood-tumor barrier (BTB), which limits the access of most therapeutic agents, and quiescent tumor cells, which resist conventional chemotherapy. Here, we show that Sox2 + tumor cells project cellular processes to ensheathe capillaries in mouse medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2 + tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of β-catenin. Piezo2 knockout reverses WNT/β-catenin signaling states between Sox2 + tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2 + tumor cells, and markedly enhances the MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie treatment failures in brain cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

One of the most lethal cancers, glioblastoma (GBM), affects 14.5% of all central nervous system (CNS) tumors. Patients diagnosed with GBM have a meager median overall survival (OS) of 15 months. Extensive genetic analysis has shown that many dysregulated pathways, including the Wnt/β-catenin signaling system, contribute to the pathogenicity of GBM. Paclitaxel (PTX) and temozolomide (TMZ) are recognized to have therapeutic potential in several types of cancer, including GBM. This work aimed to examine the impact of PTX and TMZ on the human glioma cell lines U251 and T98G using molecular docking simulations and gene expression profiles in the Wnt/β-catenin signaling pathway. Standard procedure for Molecular Docking simulation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay, and Flow Cytometry assay was used. Genes implicated in the Wnt/β-catenin signaling pathway, including Dvl, Axin, APC, β-catenin, and glycogen synthase kinase3-β (GSK3β), were subjected to real-time PCR. The estimated parameters for targets revealed that the average binding energy and inhibition constant (Ki) for the DVL, β-Catenin, and GSK3β, when targeted by PTX, were - 5.01 kcal/mol, - 5.4 kcal/mol, and - 9.06 kcal/mol, respectively. This energy range was - 6.34 kcal/mol for DVL, - 5.52 kcal/mol for β-Catenin, and - 5.66 kcal/mol for GSK3β as a result of TMZ's inhibitory actions. Gene expression analyses indicated that PTX and PTX/TMZ suppressed GSK3β (p < 0.05). GSK3β from the Wnt/β-catenin signaling pathway was significantly targeted by PTX alone, and adding TMZ to PTX may improve the efficacy of glioblastoma treatment. In addition, the GSK3β gene may help GBM therapy strategies as a potential PTX target.

Monocytes play an important role in the control of microbial infection, but monocyte biology during chronic hepatitis B virus (HBV) infection (CHI) remains inadequately studied. We investigated the frequency, phenotype, and functions of monocyte subsets in different phases of CHI, namely, immune tolerance (IT), hepatitis B early antigen (HBeAg)-positive/HBeAg-negative chronic hepatitis B (EP-/EN-CHB, respectively), and inactive carrier (IC), identified factors responsible for their functional alterations, and determined the impact of antiviral therapy on these cells. Flow cytometric analysis indicated that HLA-DR + CD14 ++ CD16 - classical monocytes were significantly reduced while HLA-DR + CD14 ++ CD16 + intermediate and HLA-DR + CD14 + CD16 ++ nonclassical monocytes were expanded in IT and EP-/EN-CHB compared with those in IC and healthy controls (HC). In comparison to IC/HC, monocytes in IT and CHB exhibited diminished expression of Toll-like receptor 2 (TLR-2)/TLR-4/TLR-9 and cytokines interleukin-12 (IL-12)/tumor necrosis factor alpha (TNF-α)/IL-6 but produced higher levels of IL-10/transforming growth factor β (TGF-β). Further, monocytes in CHB/IT showed impaired phagocytosis and oxidative response relative to those in IC/HC. In vitro assays indicated that high titers of hepatitis B surface antigen (HBsAg) present in IT/CHB and of IL-4 in CHB triggered the functional defects in monocytes via induction of β-catenin. Additionally, monocyte-derived M1 macrophages of CHB/IT produced fewer proinflammatory and more anti-inflammatory cytokines than those of IC/HC, while in CHB/IT, the monocytes skewed the differentiation of CD4 + T cells more toward regulatory T cells and a Th2 phenotype. Moreover, monocytes in CHB and IT overexpressed chemokine receptor CCR2, which coincided with increased intrahepatic accumulation of β-catenin + CD14 + cells. One year of tenofovir therapy failed to normalize monocyte functions or reduce serum HBsAg/IL-4 levels. Taken together, monocytes are functionally perturbed mostly in IT and EP-/EN-CHB phases. Targeting intramonocytic β-catenin or reducing HBsAg/IL-4 levels might restore monocyte function and facilitate viral clearance. IMPORTANCE Chronic HBV infection (CHI) is a major cause of end-stage liver disease for which pharmacological treatments currently available are inadequate. Chronically HBV-infected patients fail to mount an efficient immune response to the virus, impeding viral clearance and recovery from hepatitis. Monocytes represent a central part of innate immunity, but a comprehensive understanding on monocyte involvement in CHI is still lacking. We here report a multitude of defects in monocytes in chronically HBV-infected patients that include alteration in subset distribution, Toll-like receptor expression, cytokine production, phagocytic activity, oxidative response, migratory ability, polarization of monocyte-derived macrophages, and monocyte-T-cell interaction. We demonstrated that high levels of hepatitis B virus surface antigen and IL-4 potentiate these defects in monocytes via β-catenin induction while therapy with the nucleotide analog tenofovir fails to restore monocyte function. Our findings add to the continuing effort to devise new immunotherapeutic strategies that could reverse the immune defects in CHI.

Osteoarthritis (OA) is a disease due to the aging of the articular cartilage, a post-mitotic tissue that stays functioning until primary homeostatic processes fail. Because of pain and disability, OA significantly influences national healthcare expenses and patient quality of life. It is a whole-joint illness characterized by inflammatory and oxidative signaling pathways and significant epigenetic alterations that cause cartilage extracellular matrix degradation. The canonical Wnt pathway (Wnt/β-catenin pathway) and nuclear factor kappa B (NF-κB) signaling pathways may function in joint tissues by modulating the activity of synovial cells, osteoblasts, and chondrocytes. However, finding innovative ways to treat osteoarthritis and get the joint back to average balance is still a struggle. Nutraceuticals are dietary supplements that promote joint health by balancing anabolic and catabolic signals. New therapeutic methods for OA treatment have been developed based on many research findings that show nutraceuticals have strong anti-inflammation, antioxidant, anti-bone resorption, and anabolic properties. For the treatment of osteoarthritis, we explore the possible involvement of nutraceuticals that target the Wnt/β-catenin and NF-κB pathways. PRACTICAL APPLICATIONS: In keeping with the aging population, osteoarthritis is becoming more widespread. In this extensive research, we studied the role of the Wnt/β-catenin and NF-κB pathway in OA formation and progression. Nutraceuticals that target these OA-related signaling pathways are a viable therapy option. Wnt/β-catenin and NF-κB signaling pathway are inhibited by polyphenols, flavonoids, alkaloids, and vitamins from the nutraceutical category, making them possible therapeutic drugs for OA therapy., (© 2022 Wiley Periodicals LLC.)

EZY-1 is an antifibrosis peptide purified from Eucheuma. In this study, we explored the acute toxicology of EZY-1 and the signaling pathways involved in its antifibrotic role. The mouse model of pulmonary fibrosis was induced by bleomycin. Pathological changes in lung tissue could be effectively inhibited by EZY-1. Acute toxicity and cell proliferation tests indicated that EZY-1 had no apparent toxicity to mice and cells. We identified proteins that could bind directly to EZY-1 in vitro on the basis of liquid chromatography-tandem mass spectrometry and bioinformatics analysis. EZY-1 inhibited pulmonary fibrosis via Wnt/β-catenin, transforming growth factor (TGF)-β/Smad, phosphoinositide 3-kinase/protein kinase B/ mammalian target of rapamycin, and activator of transcription 3 and Janus kinase 2/signal transducer pathways. A transwell micropore experiment showed that EZY-1 could inhibit cell migration and invasion. Western blotting analysis on transforming growth factor-β1 (TGF-β1)-induced A549 pulmonary fibrosis cell model suggested that EZY-1 could downregulate p-Smad3 (Ser423/Ser425), Smad4, β-catenin, vimentin, and N-cadherin expression. ELISA showed that EZY-1 could inhibit collagen-I secretion. EZY-1 alleviated idiopathic pulmonary fibrosis (IPF) through regulating TGF-β/Smad pathways, epithelial-mesenchymal transition processes, and collagen secretion, which provides a potential foundation for theoretical development of EZY-1 as a potential drug against IPF. PRACTICAL APPLICATIONS: We isolated a new 16-amino-acid peptide derived from the polypeptide extract of Eucheuma, named EZY-1. In vitro and in vivo assays show peptide EZY-1 is safe. The EZY-1 peptide alleviates IPF at lower doses than pirfenidone. EZY-1 alleviated idiopathic pulmonary fibrosis (IPF) through regulating TGF-β/Smad pathways, epithelial-mesenchymal transition (EMT) processes, and collagen secretion, which provides a theoretical basis for the development of EZY-1 as a potential drug against IPF., (© 2022 Wiley Periodicals LLC.)

Objective: Traditional Chinese medicine (TCM) is an important part of the comprehensive treatment of hepatocellular carcinoma (HCC), and Chinese materia medica formulas with the effect of "Yiqi Jianpi" (replenishing qi and strengthening spleen) or "Jiedu" (removing toxicity) have been proved to be effective in treating HCC. However, mechanisms of these formulas in treating HCC remain unclear. In this paper, our goal is to explore the antitumor activity and its molecular mechanisms of Yiqi Jianpi Jiedu (YQJPJD) formula against HCC., Methods: The bioactive ingredients and targets of YQJPJD formula and HCC targets were screened by five Chinese materia medicas and two disease databases, respectively. The network pharmacology was utilized to construct the relationship network between YQJPJD formula and HCC, and the mechanisms were predicted by the protein-protein interaction (PPI) network, pathway enrichment analysis, bioinformatics, and molecular docking. Numerous in vitro assays were performed to verify the effect of YQJPJD formula on HCC cells, cancer-associated targets, and PI3K/Akt pathway., Results: The network relationship between YQJPJD formula and HCC suggested that YQJPJD formula mainly regulated the potential therapeutic targets of HCC by several key bioactive ingredients (e.g., quercetin, luteolin, baicalein, and wogonin). PPI network, bioinformatics, and molecular docking analyses displayed that YQJPJD formula may play an anti-HCC effect through key targets such as MAPK3, RAC1, and RHOA. Additionally, pathway analysis demonstrated that YQJPJD formula could play an anti-HCC effect via multiple pathways (e.g., PI3K-Akt and hepatitis B). Experimental results showed that YQJPJD formula could effectively inhibit the proliferation, migration, and invasion of HCC cells and promote HCC cell apoptosis in a concentration-dependent manner. Moreover, YQJPJD formula could decrease the mRNA expression of β -catenin, MAPK3, and RHOA and the protein expression of phosphorylated PI3K and Akt., Conclusion: YQJPJD formula mainly exerts its anti-HCC effect through multiple bioactive ingredients represented by quercetin, as well as multiple pathways and targets represented by PI3K/Akt pathway, β -catenin, MAPK3, and RHOA., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Zhulin Wu et al.)

Purpose: There remains a high unmet need for therapies with new mechanisms of action to achieve reperfusion of ischemic retina in diabetic retinopathy. We examined whether a novel frizzled class receptor 4 (FZD4) agonist could promote regeneration of functional blood vessels in animal models of retinopathy., Methods: We developed a novel Norrin mimetic (SZN-413-p) targeting FZD4 and low-density lipoprotein receptor-related protein 5 (LRP5) and examined its effect on retinal and brain endothelial cells in vitro. SZN-413-p was subsequently humanized, resulting in the therapeutic candidate SZN-413, and was examined in animal models of retinopathy. In an oxygen-induced retinopathy mouse model, avascular and neovascularization areas were measured. Furthermore, in a vascular endothelial growth factor (VEGF)-induced retinal vascular leakage rabbit model, the impact on vascular leakage by SZN-413 was examined by measuring fluorescein leakage., Results: SZN-413-p induced Wnt/β-catenin signaling and upregulated blood-brain barrier/blood-retina barrier gene expressions in endothelial cells. In the oxygen-induced retinopathy mouse model, SZN-413-p and SZN-413 significantly reduced the neovascularization area size (P < 0.001) to a level comparable to, or better than the positive control aflibercept. Both agonists also showed a reduction in avascular area size compared to vehicle (P < 0.001) and aflibercept groups (P < 0.05 and P < 0.01 for SZN-413-p and SZN-413, respectively). In the VEGF-induced retinal vascular leakage rabbit model, SZN-413 reduced retinal vascular leakage by ∼80%, compared to the vehicle-treated group (P < 0.01)., Conclusions: Reduction of neovascular tufts and avascular areas and of VEGF-driven retinal vascular leakage suggests that SZN-413 can simultaneously address retinal non-perfusion and vascular leakage., Translational Relevance: FZD4 signaling modulation by SZN-413 is a novel mechanism of action that can offer a new therapeutic strategy for diabetic retinopathy.

Mitochondria are double-membrane organelles that provide the majority of a cell's energy. Furthermore, mitochondria are involved in various cellular biological activities, including calcium signalling, reactive oxygen species production, apoptosis, cell development, and the cell cycle. Mitochondrial dysfunction is seen in various neurological conditions involving acute and chronic neural injury, including neurodegenerative diseases, hypoxia-induced brain injury, and ischemia. This review made a significant contribution to the explanation of the idea that mitochondria would both be critical targets of ischemia-induced processes, including intracellular calcium elevation and reactive oxygen species and essential sites for determining cell viability loss. As a result, it's not unexpected that attempts to prevent I/R damage have focused on mitochondria. Drugs such as vatiquinone, vitexin, dexprmipexole, baicalin, nobiletin, via promoting mitochondrial activities, can be used in future studies for protecting the brain from ischemia injury. This review summarizes mitochondrial pathways, i.e., Bad, Drp-1, JNK/caspase-3, MAPK-ERK, p53, Wnt/β-Catenin, that contribute to disease progression. We have précised the potential regulatory role of miRNA-mitochondrial dynamics in cerebral ischemic-reperfusion injury and associated molecular mechanisms; also provide insight into the potential therapies for cerebral injury-induced injuries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Sarcoma is a rare and heterogeneous class of mesenchymal malignancies with poor prognosis. Panobinostat (LBH589) as one of histone deacetylase (HDAC) inhibitors has demonstrated anti-tumor activity in patients with sarcoma, but its mechanisms remains unclear. Here, we found that LBH589 alone inhibited the proliferation and colony formation of soft tissue sarcoma (STS) cell lines. Transcriptome analysis showed that treatment with LBH589 augmented the NK cell-mediated cytotoxicity. Quantitative real-time PCR and flow cytometric analysis (FACS) further confirmed that LBH589 increased the expression of NKG2D ligands MICA/MICB. Mechanistically, LBH589 activated the Wnt/β-catenin pathway by upregulating the histone acetylation in β-catenin promoter. In vitro co-culture experiments and in vivo animal experiments showed that LBH589 increased the cytotoxicity of natural killer (NK) cells while Wnt/β-catenin inhibitor decreased the effects. Our findings suggest that LBH589 facilitates the anti-tumor effect of NK cells, highlights LBH589 an effective assistance drug in NK cell-based immunotherapies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Alzheimer's disease (AD) pathology is associated with complex interactions among multiple factors, involving an intertwined network of various signaling pathways. The polypharmacological approach is an emerging therapeutic strategy that has been proposed to overcome the multifactorial nature of AD by targeting multiple pathophysiological factors including amyloid-β (Aβ) and phosphorylated tau. We evaluated a blood-brain barrier penetrating phosphodiesterase 5 (PDE5) inhibitor, mirodenafil (5-ethyl-2-7-n-propyl-3,5-dihydrro-4H-pyrrolo[3,2-d]pyrimidin-4-one), for its therapeutic effects on AD with polypharmacological properties., Methods: To evaluate the potential of mirodenafil as a disease-modifying AD agent, mirodenafil was administered to test its effects on the cognitive behaviors of the APP-C105 AD mouse model using the Morris water maze and passive avoidance tests. To investigate the mechanisms of action that underlie the beneficial disease-modifying effects of mirodenafil, human neuroblastoma SH-SY5Y cells and mouse hippocampal HT-22 cells were used to show mirodenafil-induced alterations associated with the cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG)/cAMP-responsive element-binding protein (CREB) pathway, apoptotic cell death, tau phosphorylation, amyloidogenesis, the autophagy-lysosome pathway, glucocorticoid receptor (GR) transcriptional activity, and the Wnt/β-catenin signaling., Results: Here, mirodenafil is demonstrated to improve cognitive behavior in the APP-C105 mouse model. Mirodenafil not only reduced the Aβ and phosphorylated tau burdens in vivo, but also ameliorated AD pathology induced by Aβ through the modulation of the cGMP/PKG/CREB signaling pathway, glycogen synthase kinase 3β (GSK-3β) activity, GR transcriptional activity, and the Wnt/β-catenin signaling in neuronal cells. Interestingly, homodimerization and nuclear localization of GR were inhibited by mirodenafil, but not by other PDE5 inhibitors. In addition, only mirodenafil reduced the expression levels of the Wnt antagonist Dickkopf-1 (Dkk-1), thus activating the Wnt/β-catenin signaling., Conclusions: These findings strongly suggest that the PDE5 inhibitor mirodenafil shows promise as a potential polypharmacological drug candidate for AD treatment, acting on multiple key signaling pathways involved in amyloid deposition, phosphorylated tau burden, the cGMP/PKG/CREB pathway, GSK-3β kinase activity, GR signaling, and the Wnt/β-catenin signaling. Mirodenafil administration to the APP-C105 AD mouse model also improved cognitive behavior, demonstrating the potential of mirodenafil as a polypharmacological AD therapeutic agent., (© 2022. The Author(s).)

Context: Osteoarthritis (OA) is a high-incidence, chronic condition, with an extremely high prevalence among older adults. OA seriously compromises the normal living of OA patients, and it's imperative to find a novel therapy as soon as possible to improve their prognosis and life quality., Objective: The study intended to investigate the therapeutic effects of Curcumin (Cur) on OA and to explore its preliminary mechanism of action, with the aim of offering more accurate guidance for use of OA therapy., Design: The research team designed a prospective non-randomized controlled trial., Setting: The study took place in the Department of Orthopedics at Sir Run Run Hospital at Nanjing Medical University in Nanjing, China., Participants: Participants were 107 OA patients treated at the hospital between March 2019 and January 2020., Intervention: Participants were divided into two groups, 51 in the Cur group and 56 in the ibuprofen group., Outcome Measures: The clinical efficacy and safety of the two groups were observed. In addition, the research team performed in-vitro studies. Chondrocytes HC-a and C28/I2 were purchased to evaluate the intracellular inflammatory response and apoptosis rate under the intervention of Cur and Wnt/β-catenin pathway inhibitors., Results: No significant differences existed in the clinical-efficacy rate between the two groups (P > .05), but the Cur group show higher improvements in safety, joint mobility, and inhibition of inflammation (P < .05). In-vitro experiments showed that Cur inhibited the apoptosis rate of chondrocytes and the levels of inflammatory factors, while the Wnt/β-catenin inhibitor did the opposite (P < .05)., Conclusions: Cur can effectively decrease the pathological results of OA, with a remarkable safety profile; its mechanism may be the activation of the Wnt/β-catenin signaling pathway to inhibit the inflammatory reaction and apoptosis in chondrocytes.

Despite the availability of modern techniques for the treatment of esophageal squamous cell carcinoma (ESCC), tumor recurrence and metastasis are significant challenges in clinical management. Thus, ESCC possesses a poor prognosis and low five-year overall survival rate. Notably, the origin and recurrence of the cancer phenotype are under the control of complex cancer-related signaling pathways. In this review, we provide comprehensive knowledge about long non-coding RNAs (lncRNAs) related to Wnt/β-catenin and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in ESCC and its implications in hindering the efficacy of chemotherapeutic drugs. We observed that a pool of lncRNAs, such as HERES , TUG1 , and UCA1 , associated with ESCC, directly or indirectly targets various molecules of the Wnt/β-catenin pathway and facilitates the manifestation of multiple cancer phenotypes, including proliferation, metastasis, relapse, and resistance to anticancer treatment. Additionally, several lncRNAs, such as HCP5 and PTCSC1 , modulate PI3K/Akt/mTOR pathways during the ESCC pathogenesis. Furthermore, a few lncRNAs, such as AFAP1-AS1 and LINC01014 , block the efficiency of chemotherapeutic drugs, including cisplatin, 5-fluorouracil, paclitaxel, and gefitinib, used for ESCC treatment. Therefore, this review may help in designing a better therapeutic strategy for ESCC patients.

Introduction: Despite various treatments available, there is still a high mortality rate in breast cancer patients. Thus, there exists an unmet need for new therapeutic interventions. Studies show that the Wnt/β-catenin signaling pathway is involved in breast cancer metastasis because of its transcriptional control on epithelial to mesenchymal transition., Areas Covered: This comprehensive review explores the Wnt signaling pathway as a potential target for treating breast cancer and other breast cancer subtypes. We discuss the Wnt signaling pathway, its role in breast cancer metastasis, and its effect on breast cancer stem cells. Further, endogenous agents that cause Wnt pathway inactivation are outlined. Finally, various natural and chemical compounds modulating the Wnt pathway used in pre-clinical or clinical trials for breast cancer treatment are discussed., Expert Opinion: In vitro and in vivo studies indicate an immense potential of agents targeting the Wnt signaling pathway to prevent and manage breast cancer. Still, more clinical studies are required to support their use in humans. Apart from the agents already in clinical trials, several drug combinations discussed may be translated into clinical practice in a few years.

Background: Metastasis is the world's leading cause of colon cancer morbidity. Due to its heterogeneity, it has been challenging to understand primary to metastatic colon cancer progression and find a molecular target for colon cancer treatment., Objectives: The current investigation aimed to characterize the immune and genotypic profiles of primary and metastatic colon cancer cell lines and identify a molecular target for colon cancer treatment., Methods: Colony-forming potential, migration and invasion potential, cytokine profiling, miRNA, and mRNA expression were examined. Molecular docking for the Wnt signaling proteins with various plant compounds was performed., Results: Colony formation, migration, and invasion potential were significantly higher in metastatic cells. The primary and metastatic cells' local immune and genetic status revealed TGF β-1, IL-8, MIP-1b, I-TAC, GM-CSF, and MCP-1 were highly expressed in all cancer cells. RANTES, IL-4, IL- 6, IFNγ, and G-CSF were less expressed in cancer cell lines. mRNA expression analysis displayed significant overexpression of proliferation, cell cycle, and oncogenes, whereas apoptosis cascade and tumor suppressor genes were significantly down-regulated in metastatic cells more evidently. Most importantly, the results of molecular docking with dysregulated Wnt signaling proteins shows that peptide AGAP and coronaridine had maximum hydrogen bonds to β-catenin and GSK3β with a better binding affinity., Conclusion: This study emphasized genotypic differences between the primary and metastatic colon cancer cells, delineating the intricate mechanisms to understand the primary to metastatic advancement. The molecular docking aided in understanding the future molecular targets for bioactive- based colon cancer therapeutic interventions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The development of effective post-stroke therapy is highly demanded. Medicarpin is a key active component of a famous Chinese herbal prescription used for post-stroke treatment in Taiwan; however, little is known about its biological effects and mechanisms of action. Herein, we implemented a murine model of cerebral ischemic/reperfusional injury-related stroke to elucidate medicarpin's neuroprotective effect. In male ICR mice 24 h after stroke induction, treatment with medicarpin (0.5 and 1.0 mg/kg, i.v.) markedly enhanced the survival rates, improved moving distance and walking area coverage, reduced brain infarction, and preserved the blood-brain barrier, supporting medicarpin's protective effect on stroke-induced injury. Immunohistochemistry analysis further revealed that medicarpin treatment decreased the expression/activation of p65NF-κB and caspase 3, especially near the infarct cortex, while promoting the expression of neurogenesis-associated proteins, including doublecortin (DCX), brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB). These changes of expression levels were accompanied by GSK-3 inactivation and β-catenin upregulation. Notably, pretreatment with LY294002, a PI3K inhibitor, abolished the aforementioned beneficial effects of medicarpin, illustrating an essential role of PI3K/Akt activation in medicarpin's neuroprotective and reparative activities. In vitro studies revealed that medicarpin displayed strong anti-inflammatory activity by reducing nitric oxide (NO) production in lipopolysaccharide-stimulated microglial cells (BV2) with an IC 50 around 5 ±1 (μM) and anti-apoptotic activity in neuronal cells (N2A) subjected to oxygen-glucose deprivation with an IC 50 around 13 ± 2 (μM). Collectively, this is the first report to demonstrate that medicarpin, isolated from Radix Hedysari, ameliorates ischemic brain injury through its anti-inflammatory microglia/NO), anti-apoptotic (neuronal cells/OGD) and neuroprotective effects by activating the PI3K/Akt-dependent GSK-3 inactivation for upregulating β-catenin, which in turn decreases the expression/activation of p65NF-κB and caspase 3 and promotes the expression of neurogenic (DCX, BDNF, TrkB) and neuroprotective (Bcl2) factors in the brain.

Overexpressed Wnt/β-catenin signaling acts as a major cancer driver and plays an important role in the development of resistance against cancer chemotherapy. Therefore, the combinatorial approach of downregulating Wnt/β-catenin signaling along with using a chemotherapeutic agent may improve cancer therapy. However, systemic administration of free anticancer agents is nonspecific and poses serious side effects. Hence, the present study aimed at developing mesoporous silica nanoparticle (MSN)-based targeted combination therapy of a Wnt signaling inhibitor, niclosamide (Nic), and a conventional anticancer agent, doxorubicin (Dox). The results demonstrated the reproducible synthesis of highly stable and monodispersed sub-100 nm spherical shaped NPs. In vitro cytotoxicity studies demonstrated that the individual drug formulations caused concentration-dependent cytotoxicity to all of the three breast cancer subtypes, with higher concentrations being more cytotoxic. Further, sequential and concurrent combination of Nic-loaded MSNs with Dox-loaded MSNs was synergistic and caused significantly enhanced death in all breast cancer subtypes. Quantification of the combinatorial efficacy suggested that multiple combinatorial pairs were synergistic in all of the breast cancer types for both (sequential and concurrent) treatment regimens. However, the extent of synergism varied between the two treatment regimens in different clinical subtypes of breast cancer. Overall, the combination of Nic-loaded MSNs with Dox-loaded MSNs holds promise to be developed as an efficient therapeutic option for breast cancer irrespective of the clinical subtype in both sequential and concurrent treatment regimens.

Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we characterize differences in the tumor-initiating capacity of Wnt, Group 3, and Group 4 MB. With single cell RNA-seq technology, we demonstrate the presence of rare Wnt-active cells in non-Wnt MBs, which functionally retain the impaired tumorigenic potential of Wnt MB. In treating MB xenografts with a Wnt agonist, we provide a rational therapeutic option in which the protective effects of Wnt-driven MBs may be augmented in Group 3 and 4 MB and thereby support emerging data for a context-dependent tumor suppressive role for Wnt/β-catenin signaling.

The majority of colorectal cancers (CRCs) are characterized by a dysregulated canonical Wnt-signaling pathway leading to the stabilization and subsequent cellular increase and accumulation of β-catenin. After translocation into the nucleus, it acts as a transcription factor resulting in the expression of β-catenin target genes. These resemble most of the hallmarks of cancer except eternal life. The central mediator of this hallmark is hTERT (human telomerase reverse transcriptase). The hTERT gene is regulated, besides others, by the transcription factor c-Myc and, thus, indirectly via β-catenin as c-Myc is a β-catenin target gene. Interestingly, the expression patterns of hTERT and β-catenin, but not c-Myc are overlapping, probably because c-Myc is not only regulated by β-catenin, but also by many other transcription factors and pathways. Therefore, we argued that hTERT might be a direct target gene of β-catenin. In this study, we show evidence that β-catenin directly regulates the expression of the hTERT gene.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by destruction of the articular cartilage, subchondral bone alterations and synovitis. Current treatments are focused on symptomatic relief but they lack efficacy to control the progression of this disease which is a leading cause of disability. Therefore, the development of effective disease-modifying drugs is urgently needed. Different initiatives are in progress to define the molecular mechanisms involved in the initiation and progression of OA. These studies support the therapeutic potential of pathways relevant in joint metabolism such as Wnt/beta-catenin, discoidin domain receptor 2 or proteinase-activated receptor 2. The dysregulation in cartilage catabolism and subchondral bone remodeling could be improved by selective inhibitors of matrix metalloproteinases, aggrecanases and other proteases. Another approach would favor the activity of anabolic processes by using growth factors or regulatory molecules. Recent studies have also revealed the role of oxidative stress and synovitis in the progression of this disease, supporting the development of a number of inhibitory strategies. Novel targets in OA are represented by genes involved in OA pathophysiology discovered using gene network, epigenetic and microRNA approaches. Further insights into the molecular mechanisms involved in OA initiation and progression may lead to the development of new therapies able to control joint destruction and repair., ((c) 2010 Elsevier Inc. All rights reserved.)

Glycogen Synthase Kinase 3 beta (GSK3β) is a serine-threonine kinase originally identified for its role in the conversion of glucose to glycogen. Pharmacological inhibition can be achieved by drug binding to ATP or magnesium binding sites on the enzyme. Pharmaceutical companies have developed several small molecule GSK3β inhibitors for diabetes research. Additionally, GSK3β inhibitors are being clinically tested as therapeutics for neurological diseases, however, the mechanisms of involvement are unclear. Several studies have shown that the therapeutic effect of GSK3β inhibition is associated with the inhibition of inflammation. Similarly, the mechanisms underlying the anti-inflammatory function of GSK3β inhibition are not well understood. GSK3β inhibition attenuates activation of the pro-inflammatory transcription factor NFκB, and activates the immuno-modulatory transcription factor β-catenin. GSK3β inhibition has also been shown to induce secretion of the anti-inflammatory cytokine IL-10. In addition, pharmacological inhibition of GSK3β suppressed alloreactive T-cell responses. The combined anti-proliferative and anti-inflammatory properties of small molecule inhibitors of GSK3β make them an attractive treatment modality towards the control of inflammation.