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Bone Regeneration Effect of Cassia occidentalis Linn. Extract and Its Isolated Compounds
Published in Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay, Phytochemistry of Plants of Genus Cassia, 2021
Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay
In cultures of rat chondrocytes, emodin suppressed the cytotoxic impact of IL-1β, downregulated the expressions of MMP-1 and MMP-13 and inhibited the ERK and Wnt/β-catenin signaling (Liu et al., 2018). In murine chondrogenic cell line, ATDC5, emodin treatment caused the loss of cell viability at 15- and 20 μM. However, at 10 μM, emodin blocked the LPS-induced apoptosis of and production of proinflammatory cytokines (TNFα, IL-6 and MCP1) from ATDC5 cells. The pro-survival, anti-apoptotic and anti-inflammatory roles of emodin in ATDC5 were likely regulated by the long noncoding RNA, taurine upregulated gene 1-mediated notch and NFκB pathways (Liang and Ren, 2018). Given this action mechanism of emodin chondrocytes, a salutary role of this compound in OA is surmised.
Familial Adenomatous Polyposis
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Mariann Unhjem Wiik, Bente A. Talseth-Palmer
APC plays a significant role as a tumor suppressor gene in the Wnt signaling pathway, which in turn regulates phosphorylation and degradation of β-catenin [16,25,77]. The protein β-catenin binds to the E-cadherin (a cell adhesion molecule) and links it to the actin cytoskeleton [25]. Not only FAP, but also the majority of sporadic cases of CRC (∼80%) are associated with somatic mutations in APC [14,32,78].
Breast Cancer Stem Cells and Their Niche: Lethal Seeds in Lethal Soil
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Danuta Balicki, Brian Leyland-Jones, Max S. Wicha
The Wnt family of secreted proteins includes the well-characterized canonical Wnt signaling pathway, in which Wnt ligands signal through the stabilization of β-catenin. In this pathway, Wnt proteins bind to a family of frizzled receptors in a complex with the low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6) coreceptors to activate Dishevelled (Dsh). Subsequently, Dsh inhibits the activity of the β-catenin destruction complex [adenomatous polyposis coli (APC), axin, and glycogen synthase kinase-3β (GSK-3β)], which phosphorylates β-catenin in the absence of the ligands. As a result, β-catenin is stabilized and translocated to the nucleus, where it recruits transactivators to high mobility group (HMG)-box DNA-binding proteins of the lymphoid-enhancer factor/T-cell factor (LEF/TCF) family. In the absence of Wnt signaling, β-catenin remains in the cytoplasm, where it forms the β-catenin destruction complex. GSK-3β phosphorylates β-catenin, which targets the protein for ubiquitin-mediated degradation. When the Wnt pathway is activated, GSK-3β is inhibited, blocking β-catenin phosphorylation and its subsequent degradation (71). In addition, several β-catenin-independent Wnt signaling pathways, known as noncanonical, have been shown to be crucial for different aspects of vertebrate embryo development (71).
Synthesis and biological evaluation of thieno[3,2-c]pyrazol-3-amine derivatives as potent glycogen synthase kinase 3β inhibitors for Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ning Yan, Xiao-Long Shi, Long-Qian Tang, De-Feng Wang, Xun Li, Chao Liu, Zhao-Peng Liu
GSK-3β is implicated in the Wnt/β-catenin signalling pathway, which plays an important role in neuronal development29. GSK-3β, together with adenomatous polyposis coli (APC), Axin, and casein kinase 1 (CK1), form a ploy-protein complex that regulates the hyperphosphorylation of β-catenin. Phospho-β-catenin is recognised by ubiquitin and degraded by proteasomes52–54. Pharmacological inhibition of GSK-3β leads to the activation and stabilisation of β-catenin, subsequently resulting in the accumulation of β-catenin in cytoplasm55–57. The activation of Wnt/β-catenin signalling pathway can promote synaptic growth, alleviate spatial memory impairment and neurodegeneration in Alzheimer’s models 58–60. Moreover, β-catenin also plays a pivotal role in cell adhesion complexes. The combination of β-catenin and N-cadherin elevates cell-to-cell interactions which is prerequisite for neuronal differentiation61,62. Therefore, we further evaluated the effect of 16b on β-catenin. In agreement with its GSK-3β inhibitory activity on SH-SY5Y cells, 16b increased β-catenin abundance in a dose-dependent manner. As shown in Figure 6(B), after treatment with 16b at the concentration of 5 μM, 10 μM and 20 μM, the β-catenin/GADPH ratio increased from 0.41 of the control to 0.54, 0.64, 0.76, respectively.
Iguratimod alleviates tubulo-interstitial injury in mice with lupus
Published in Renal Failure, 2022
Leixi Xue, Jiajun Xu, Wentian Lu, Jinxiang Fu, Zhichun Liu
As we have known, many pro-fibrosis factors involved in EMT regulation; among them, TGF-β1 is considered to be the most important one [45–47]. After TGF- β1 stimulation, TGFβRII undergo autophosphorylation, then bind to TGF-βRI and phosphorylate TGFβRI to form TGFβRII-TGFβRI complexes, which then lead to the phosphorylation and activation of downstream signal proteins, such as Smad and p38 MAPK [25,26]. The present results showed that iguratimod not only inhibited TGFβRII phosphorylation induced by TGF-β1, but also negatively regulated activation of the Smad and p38 MAPK signaling pathway. β-catenin, a key regulator of the canonical Wnt/β-catenin pathway, has been linked to renal fibrosis [48]. Upon activation, β-catenin is increased and translocated from the cytoplasm to the nucleus to induce the expression of its downstream target genes. Studies have found that TGF-β1 could induces nuclear accumulation of β-catenin in tubular cells, and that β-catenin targeting of certain genes results in EMT [49,50]. Gong et al. found that miRNA-200a could inhibit TGF-β1-induced EMT by directly targeting β-catenin in HK2 cells [26]. The present study found that iguratimod blocked the nuclear translocation of β-catenin. Therefore, iguratimod inhibited the TGF-β1-induced tubular EMT process maybe through suppressing activation of TGFβRII-Smad/p38 MAPK/β-catenin signaling pathways.
Cldn-7 deficiency promotes experimental colitis and associated carcinogenesis by regulating intestinal epithelial integrity
Published in OncoImmunology, 2021
Kun Wang, Yuhan Ding, Chang Xu, Mengdi Hao, Huimin Li, Lei Ding
To explore molecular mechanisms underlying how Cldn-7 participate in intestinal carcinogenesis, potential effects of Cldn-7 deletion on cell proliferation and Wnt/β-catenin pathway were evaluated. Consistent with colon tumor burden, epithelial proliferation rate in tumor tissues and paracancerous tissues derived from CreERT2 group was higher than that of control group (P < .05, Figure 7a). It is well known that β-catenin dysregulation is a key indicator of Wnt signaling overactivation. In paracancerous tissues, β-catenin was expressed on the cell membrane, and nuclear c-Myc and Cyclin D1 were restricted to cells at the base of crypts. The expression of β-catenin and downstream target genes c-Myc and Cyclin D1 were significantly up-regulated in cancer tissues as compared to adjacent tissues, and β-catenin showed cytoplasmic and nuclear localization (P < .05, Figure 7b). Cldn-7 deletion further promoted the expression of c-Myc and Cyclin D1, while β-catenin only had an upward trend compared with CreW tumor tissues, and there was no statistical difference. It suggested that Cldn-7 knockout might promote proliferation of intestinal epithelial cells and activate Wnt/β-catenin signaling pathway to spur CAC development.