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Engineered Extracellular Vesicle-Based Therapeutics for Liver Cancer
Published in Peixuan Guo, Kirill A. Afonin, RNA Nanotechnology and Therapeutics, 2022
HCC is remarkably heterogeneous and can be related to alterations in several signaling pathways (Breuhahn, Longerich, and Schirmacher 2006). Several genetic alterations have been described in HCC. Among the most commonly encountered mutations in HCC are those associated with the β-catenin gene and the activation of Wnt/β-catenin pathway. This pathway plays an important role in tumor proliferation, maintenance of tumor initiating cells and metastasis (Thompson and Monga 2007; Anastas and Moon 2013). Aberrant activation of Wnt signaling has been associated with carcinogenesis. Mutations in genes encoding for β-catenin or CTNNB1 (Gao et al. 2018; de La Coste et al. 1998) occur in up to 40% of HCCs. The presence of CTNNB1 mutations is related to aberrant β-catenin signaling and tumor aggressiveness (Cieply et al. 2009). Specific therapy targeting β-catenin could therefore be beneficial for a subset of HCC or other types of cancers that are characterized by mutations or aberrant activations in this pathway. However, there are no current therapeutic agents that can directly target this pathway. We have developed and reported the use of a therapeutic approach based on delivery of β-catenin siRNA to tumor cells using MNV as a biological nanoparticle delivery carrier (Matsuda and Patel 2018). The therapeutic MNV (tMNV) were generated by loading MNV with β-catenin siRNA using lipid-based transfection. The use of tMNV provides an efficient and effective means of hepatic delivery of RNA-based therapeutics (Table 38.1).
Next Generation Tissue Engineering Strategies by Combination of Organoid Formation and 3D Bioprinting
Published in Naznin Sultana, Sanchita Bandyopadhyay-Ghosh, Chin Fhong Soon, Tissue Engineering Strategies for Organ Regeneration, 2020
Shikha Chawla, Juhi Chakraborty, Sourabh Ghosh
The spatio-temporal levels of Wnt signaling are one of the key signaling events during embryogenesis and adult tissue homeostasis. In vivo, 19 Wnt family genes are associated with regulating cell proliferation, gene expression, differentiation, migration, adhesion, maintenance of cell polarity and apoptosis etc. (de Lau et al. 2014). Wnt Signaling can be categorized into two pathways: canonical and non-canonical pathways (Veeman et al. 2003). β-catenin, Cytoplasmic Dishevelled protein (Dsh) and Frizzled (Fz) transmembrane receptor initiates the canonical Wnt pathway to initiate transcription of target genes, for example, tight control of genes involved in vertebrate development (Wodarz and Nusse 1998). Wnt signaling also plays a critical role in maintaining the stem cell microenvironment by conserving their self-renewal capability, as well as also helps to define the lineage commitment in other cell types.
Osteoimmunomodulation with Biomaterials
Published in Nihal Engin Vrana, Biomaterials and Immune Response, 2018
Bengü Aktaş, Bora Garipcan, Zehra Betül Ahi, Kadriye Tuzlakoğlu, Emre Ergene, Pınar Yılgör Huri
Apart from these, there is another pathway called Wnt signalling that is considered a key regulator for bone formation. According to studies, OPG expression is mediated by the Wnt signalling pathway [71,72]. The binding of Wnt signalling molecules activates two different signalling pathways, known as the β/catenin-dependent canonical and independent non-canonical pathway. The β/catenin-dependent canonical pathway has an essential role in promoting the differentiation of osteoblast precursor cells to mature osteoblasts. In a similar manner, this pathway has the property of suppressing bone resorption by changing the RANKL/OPG ratio [73]. In the study of Diarra et al., they indicate that TNF-mediated expression of Dickkopf-1 (DKK1) suppress Wnt signalling, thus this action hamper bone formation, meanwhile bone resorption is increased with the expression of RANKL in an inflammatory arthritis condition. Therefore, the blockade of DKK-1 induces bone formation since Wnt proteins are able to induce OPG expression [71]. On the other hand, Maeda et al. showed that Wnt5a, which is a non-canonical Wnt ligand, expressed by osteoblast-lineage cells, enhanced RANK expression through Ror-2 signalling in osteoclast precursors, thereby enhancing osteoclastogenesis, by effecting JNK and c-Jun pathways on the promoter of encoding RANK in both physiological and pathological conditions [74]. The above findings reveal that bone mass is commonly regulated by the combination of two signalling pathways; RANK/RANKL and Wnt/β-catenin.
Agrochemical-mediated cardiotoxicity in zebrafish embryos/larvae: What we do and where we go
Published in Critical Reviews in Environmental Science and Technology, 2023
Yang Yang, Yue Tao, Zixu Li, Yunhe Cui, Jinzhu Zhang, Ying Zhang
In early development, the constitutively activated Wnt/β-catenin signaling pathway in zebrafish embryos exhibits multiple visceral developmental abnormalities such as enlarged ear sacs, smaller eyes, and curved bodies, the most prominent of which are cardiac defects (Hurlstone et al., 2003). Specifically, the Wnt/β-catenin signaling pathway promotes cardiogenesis from the zebrafish blastula period to the early gastrula period and then determines the size of the cardiac-forming region at the end of the gastrula period. Perturbation of the this process directly leads to ectopic heart formation or even death (Ueno et al., 2007). Compared to wild-type zebrafish, the APC mutant has an activated Wnt signaling pathway and exhibits significant pericardial edema, blood stagnation, and loss of endocardial cushions (valve precursor cells) at 48 hpf. Moreover, the mutant cardiac chambers show blood reflux as development continues, indicating defective valve formation. In contrast, blocking the endogenous Wnt/β-catenin signaling pathway also caused endocardial cushion defects in zebrafish, without significant pericardial edema or blood stagnation (Hurlstone et al., 2003). The formation of cardiac valves depends on the correct communication between cardiomyocytes and endocardial cells and involves multiple signaling pathways (Brown et al., 1999). Thus, abnormal expression of the Wnt/β-catenin signaling pathway is only one way in which cardiac valve defects are induced. Endocardial cushion loss due to an imbalance between endocardial cell proliferation and differentiation is the most direct adverse outcome of abnormal expression of the Wnt/β-catenin signaling pathway.
LDL receptor-related protein 5 rs648438 polymorphism is associated with the risk of skeletal fluorosis
Published in International Journal of Environmental Health Research, 2023
Meichen Zhang, Haili Xu, Qun Lou, Fanshuo Yin, Ning Guo, Liaowei Wu, Wei Huang, Yi Ji, Liu Yang, Qiao Li, Sa Wang, Zhizhong Guan, Yanmei Yang, Yanhui Gao
Skeletal fluorosis is characterized by accelerated bone turnover accompanied by abnormal activation of osteoblasts. The proliferation and activation of osteoblasts are closely related to skeletal fluorosis (Luo et al. 2021). Wnt/β-catenin signaling pathway induces the formation and differentiation of osteoblast cell lines and inhibits the differentiation of osteoclasts (Maeda et al. 2019). Studies have found that fluoride promotes osteoblast differentiation through the typical Wnt/β-catenin signaling pathway (Pan et al. 2014). In vivo experiments have also shown that Wnt/β-catenin can mediate fluoride-induced abnormal osteoblast activity and osteogenesis (Chu et al. 2020). These results suggest that the Wnt/β-catenin signaling pathway participated in the development of skeletal fluorosis. It is worth noting that polymorphisms in Frizzled-related protein (FRZB1), a secreted Wnt antagonist, have been reported to be associated with susceptibility to skeletal fluorosis (Yang et al. 2018). Low-density lipoprotein receptor-associated protein 5 (LRP5) is an amino acid transmembrane receptor of the conserved Wnt/β-catenin signaling pathway (Gong et al. 2001). The LRP5 gene is located in the 11q13 region of the human genome chromosome, where it contains quantitative trait loci regulating bone mineral density (Kaufman et al. 2008). It has also been reported that LRP5 polymorphisms influence bone mineral density (Mencej-Bedrac et al. 2009; Pepe et al. 2018). In particular, rs648438 polymorphism, locating in the intron region of the LRP5 gene, has been reported to be associated with osteoporosis (Pepe et al. 2018). However, whether LRP5 rs648438 polymorphism is related to skeletal fluorosis remains unclear. Therefore, in this study, we conducted a cross-sectional case–control study in Shanxi, China, to investigate whether the polymorphism of LRP5 rs648438 is associated with the risk of skeletal fluorosis.
Effects of running a marathon on sclerostin and parathyroid hormone concentration in males aged over 50
Published in Journal of Sports Sciences, 2023
Aleksandra Zagrodna, Anna Książek, Małgorzata Słowińska-Lisowska, Jan Chmura, Piotr Ponikowski, Giovanni Lombardi
Sclerostin is expressed and released by mature osteocytes and acts on osteoblast progenitors to inhibit their differentiation. The expression of this protein is primarily dependent upon mechanical stimulation of a bony segment (Amrein et al., 2012; Khosla et al., 2008). Osteocytes, indeed, are detectors of mechanical tensions in bones and microtraumas, mechanosensitive cells with processes that branch out within the canalicular system to reach other osteocytes and bone lining cells (osteoblasts) on the bone surface. The cellular processes are equipped with sensor proteins (cadherins, integrins, ion channels, G protein-coupled receptors) that sense both extracellular matrix and cell membrane deformations as well as modifications of the intracanalicular fluid shear stresses, determined by loadings, and activate intracellular cascades that bring, among the other responses, to either induction (under unloading conditions) or suppression (under loading conditions) of sclerostin (Ardawi et al., 2012; Gaudio et al., 2010; Gerosa & Lombardi, 2021). Sclerostin acts as an inhibitor of Wnt (Armamento-Villareal et al., 2012; Kramer et al., 2010). The Wnt/β-catenin pathway is critical in osteoblast differentiation and bone tissue formation (Yavropoulou & Yovos, 2007). Inhibition of sclerostin and the consequent activation of the Wnt/β-catenin signalling pathway are tantamount to the anabolic effect and thus to the prevalence of osteogenic mechanisms (Bonnet & Ferrari, 2010; Sims & Chia, 2012). Animal studies have consistently shown that mechanical loading suppresses transcription of the SOST gene and sclerostin production, and this is associated with an increase in bone mass (Bonnet & Ferrari, 2010; Moustafa et al., 2012). In humans, sclerostin response to exercise is not yet clear and may be related to the type, duration, and intensity of exercise, as the osteogenic response is known to desensitise quickly during prolonged stimulation, while it can be maintained by the application of intermittent loadings (Lombardi et al., 2012; Robling et al., 2000). Importantly, the differential acute response of sclerostin to long-lasting physical effort has not been examined and could provide insight into the specificity of bone response to different modes of exercise.