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Mechanotransduction in Cardiovascular Development and Regeneration: A Genetic Zebrafish Model
Published in Juhyun Lee, Sharon Gerecht, Hanjoong Jo, Tzung Hsiai, Modern Mechanobiology, 2021
Rongsong Li, Kyung In Baek, Chih-Chiang Chang, Bill Zhou, Tzung Hsiai
Extensive studies have demonstrated the role of Ang-1 and Ang-2 in vascular development. Shear stress–mediated Ang-2 in mature vascular endothelium was recently reported to play a role in tubulogenesis [65] and to confer atheroprotection [66]. While Ang-1 is constitutively released by the perivascular cells, Ang-2 is expressed in ECs released from the Weibel–Palade bodies upon signal cues [67, 68]. Ang-2, like Ang-1, binds to endothelial–specific receptor tyrosine kinase 2 (TIE-2) and acts as a negative regulator of Ang-1/TIE-2 signaling to promote angiogenesis [69]. Earlier studies demonstrated that Ang-2 could be released by a mechanical force, such as the endothelial stretch that occurs during hypertension [70]. Our recent work and work from Dr. Jo’s lab demonstrated that Ang-2 is a mechanosensitive gene involved in shear stress–mediated tubule formation and migration of ECs [71, 72]. In the mouse artery occlusion model, femoral artery ligation caused a disturbed flow to stimulate Ang-2 expression and arteriogenesis in mice [73].
Pro- and Anti-Inflammatory Cytokine Signaling within 3D Tissue Models
Published in Karen J.L. Burg, Didier Dréau, Timothy Burg, Engineering 3D Tissue Test Systems, 2017
Stephen L. Rego, Tian McCann, Didier Dréau
The anti-inflammatory cytokine also activates numerous signaling cascades. For example, upon activation, the IL10 receptors (IL10R1 and IL10R2) form heteromers, leading to phosphorylation of their associated proteins JAK and Tyrosine Kinase-2 (TYK2) (Shouval et al. 2014; Shouval et al. 2014). Subsequently, STAT3 is recruited to the receptor complexes and phosphorylated. Following phosphorylation, STAT3 dimerizes and activates the expression of antiapoptotic and cell cycle genes, leading to cell survival. IL10 also activates other anti-inflammatory signaling pathways and inhibits the pro-inflammatory NFκB pathway (Riley et al. 1999).
Skeletal Mechanobiology
Published in Jiro Nagatomi, Eno Essien Ebong, Mechanobiology Handbook, 2018
Alesha B. Castillo, Christopher R. Jacobs
As integrins do not possess intrinsic catalytic activity, ECM-intracellular signal transduction is carried out by activation of downstream signaling molecules comprising focal adhesions. FAK, a nonreceptor tyrosine kinase,188 is one of the first molecules recruited to focal adhesions upon integrin binding189 and has been shown to be important in cell migration, proliferation, and survival. FAK has also been implicated in cellular mechanotransduction,190,191 including bone cells.192–194 The activation of FAK results in the autophosphorylation of tyrosine 397 creating a high-affinity binding site for the Src-homology 2 (SH2) domain195 of the Src family protein tyrosine kinases. FAK and SH2 binding activates MAPK signaling196 though interaction with c-src, Grb2, and the small GTPase Ras.197,198 Fluid flow leads to FAK phosphorylation199 and MAPK activation in bone and endothelial cells.200,201 FAK phosphorylation has also been linked to NFκB activation202 as well as calcium release via large conductance calcium channels.203 Disruption of FAK in osteoblasts leads to decreases in the fluid flow-induced ERK phosphorylation, expression of c-fos and Cox-2, as well as PGE-2 release,194 all of which are important signaling events in osteoblast function. Interestingly, preliminary data suggest that osteocyte-specific gene ablation of FAK does not affect load-induced cortical bone formation in vivo (unpublished data). Thus, FAK appears to play a lesser role in the sensing of and response to fluid flow in osteocytes in vivo, and a more prominent role in downstream bone formation events, such as osteoblast differentiation and recruitment. Indeed, the disruption of FAK in osteoblasts abolishes the response of bone marrow cells to mechanical stimuli in a tibial injury model204 indicating a potential role for FAK in osteoprogenitor recruitment and homing. Recent data suggest that proline-rich tyrosine kinase 2 (Pyk2) may compensate for loss of FAK in various cell types including endothelial cells205 and fibroblasts.206 However, Pyk2 expression was not enhanced in FAK−/− osteoblasts,194 and it is unclear whether Pyk2 has a compensatory effect on load-induced bone formation in vivo. In fact, Pyk2 null mice exhibit increased bone mass and bone formation suggesting that Pyk2 normally represses osteoblast differentiation.207
Targeting gap junctional intercellular communication by hepatocarcinogenic compounds
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Kaat Leroy, Alanah Pieters, Andrés Tabernilla, Axelle Cooreman, Raf Van Campenhout, Bruno Cogliati, Mathieu Vinken
GJIC is mainly controlled at 2 levels, namely at the expression level and at the functionality level (Figure 2) (Nielsen et al. 2012). The latter, also called gap junction gating, encompasses many different factors, such as pH, calcium levels, transmembrane voltage, redox potential, interactions with other proteins and posttranslational modifications, including phosphorylation, glycosylation, N-acetylation, ubiquitination, methylation, S-tyrosination and SUMOylation (Garcia et al. 2018; Leithe, Mesnil, and Aasen 2018; Sorgen et al. 2018; Vinken 2016). Phosphorylation is probably the best-studied posttranslational connexin modification, being well documented for Cx43. Phosphorylation predominantly occurs at serine, threonine and tyrosine residues of the C-terminal tail, and might be generated by a multitude of kinases, such as protein kinase C (PKC), protein kinase A, tyrosine kinase 2, mitogen-activated protein kinase (MAPK), Rous sarcoma oncogene (v-Src) and casein kinase 1 (Leithe, Mesnil, and Aasen 2018). Another gating mechanism relates to changes in intracellular pH or calcium levels (Garciarena et al. 2018; Wei et al. 2019). Thus, Cx43 gap junctions open in alkaline conditions, whereas they close upon acidification (Garciarena et al. 2018). Gating in response to calcium is mediated by calmodulin, since gap junctions themselves do not possess high affinity for this ion (Peracchia 2020). Further, functional control also includes voltage gating depending upon the voltage gradient alongside the pore (Bargiello et al. 2018).
Benzo[a]pyrene osteotoxicity and the regulatory roles of genetic and epigenetic factors: A review
Published in Critical Reviews in Environmental Science and Technology, 2022
Jiezhang Mo, Doris Wai-Ting Au, Jiahua Guo, Christoph Winkler, Richard Yuen-Chong Kong, Frauke Seemann
The fusion of OCPs to MOCs involves recognizing and binding the integrins expressed in OCPs to the amino acid motif Arg-Gly-Asp (RGD) presented in various proteins (such as osteopontin and bone sialoprotein) at the surface of the bone matrix (Boyle et al., 2003). The binding of αvβ3 integrin then activates cytoskeletal reorganization within the OCPs, inducing podosome formation. Integrin signaling and subsequent podosome formation depend on several adhesion kinases including the tyrosine kinases c-Src, proline-rich tyrosine kinase 2 (PYK2), and spleen tyrosine kinase (SYK) (Crockett et al., 2011; Hadjidakis & Androulakis, 2006). Polarized MOCs contain numerous transport vesicles loaded with lysosomal enzymes, such as TRAcP and CTSK. When MOCs begin bone resorption, the cell develops special membrane domains, such as a sealing zone, a ruffled border and a functional secretory domain (Boyle et al., 2003). MOCs resorb bone through the acidification and proteolysis of the bone matrix and hydroxyapatite crystals in the sealing zone. The hydroxyapatite crystals are first mobilized by the enzymatic digestion of the collagen connection. Alternatively, smooth bone resorption without formation of sealing zone by single-nuclear OCs can play a significant role in some teleost such as medaka (Witten & Huysseune, 2009). The residual collagen fibers are then digested by both cathepsins, such as CTSK and collagenases (MMP-9 and MMP-2, for example) (Hadjidakis & Androulakis, 2006). Bone resorption produces a high level of degraded collagen fragments, calcium and phosphate in the resorption lacuna. These fragments and minerals are endocytosed by MOCs, transported through the cell and released at the functional secretory domain. OC activity is regulated by both cytokines and hormones. Notably, receptors for calcitonin, androgens, thyroid hormone, insulin, PTH, IGF-1, IL-1, CSF-1, and PDGF were also identified in OCs (Boyle et al., 2003; Crockett et al., 2011).
Gold nanorods conjugated upconversion nanoparticles nanocomposites for simultaneous bioimaging, local temperature sensing and photothermal therapy of OML-1 oral cancer cells
Published in International Journal of Smart and Nano Materials, 2021
Duc Tu Vu, Thanh Thu Vu-Le, Van Nghia Nguyen, Quoc Minh Le, Churng-Ren Chris Wang, Lai-Kwan Chau, Tzyy-Schiuan Yang, Michael W. Y. Chan, Cheng-I Lee, Chu-Chi Ting, Jiunn-Yuan Lin, Hung-Chih Kan, Chia Chen Hsu
The determination of ErbB2 receptor tyrosine kinase 2 (ERBB2) or human epidermal growth factor receptor 2 (Her2) overexpression, a member of the epidermal growth factor (EGF) receptor family [38,59], in the cancer classification is an effective procedure. Anti-Her2 monoclonal antibody, the antibody directed to the extracellular domain of Her2 is used for the replacement or combinatorial therapy of Her2-overexpressing cancer cell. In addition, streptavidin (SA) has been widely employed in immunofluorescence labeling to improve in vitro targeting to tumor or cancer cell in the biotin-streptavidin labeling system. To evaluate the immunolabeling of the SA-conjugated nanocomposite probes, we incubated the probes (NR980@Silica-UCNPs@SA with 20 nm thick of silica layer) together with biotinylated goat anti-rabbit IgG and anti-Her2 antibody to OML-1 oral cancer cells. Figure 5(a) shows an overlay of the bright and dark field microscopy images (see Figure S9) of OML-1 cells after being incubated with the aforementioned materials. The bright UCL microscopy image of OML-1 cells confirms that the nanocomposite probes (NR980@Silica-UCNPs@SA) were effectively bounded onto the membrane of OML-1 oral cancer cells through the conjugation with biotinylated goat anti-rabbit IgG and anti-Her2 antibody. The green luminescence is the UCL emitted from the NaYF4:Yb3+,Er3+ UCNPs of the nanocomposite probes. The shape and position of the cells in bright field are overlapped well with dark field, showing the good specific interactions between the nanocomposite probes and the cells (see Figure S9(a,b)). In contrast, when the SA-conjugated nanocomposite probes were incubated alone (not incubated with anti-Her2 and biotinylated goat anti-rabbit IgG antibodies) with OML-1 cell or incubated with antibody (both anti-Her2 antibody and biotinylated goat anti-rabbit IgG) in immortalized ovarian surface epithelial (IOSE) cells [60] as shown in Figure 5(b) and (c), respectively, only week green luminescence was observed on the cell surface. Furthermore, as indicated in Figure S10, no UCL signal was observed from the OML-1 cells incubated with NR980@Silica as well as the control cells (not incubated with the hybrid nanocomposites), because of the absence of UCNPs in both cases. These results prove that the hybrid nanocomposite probes with antibodies can bind with OML-1 cells. After examining superior UCL imaging, LT sensing and photothermal properties offered by the hybrid nanocomposite probes, it is worth to investigate the performance of the hybrid nanocomposites in PTT test.