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Blood–Retinal Barrier
Published in Glenn J. Jaffe, Paul Ashton, P. Andrew Pearson, Intraocular Drug Delivery, 2006
David A. Antonetti, Thomas W. Gardner, Alistair J. Barber
A positive effect of glucocorticoids on barrier properties has also been observed in epithelial cells. Dexamethasone treatment for four days increases the electrical resistance and reduces radiolabeled mannitol and insulin flux across 31EG4 nontransformed epithelial cells (86) and the Con8 mammary epithelial tumor cell line (87). Dexamethasone treatment increased ZO-1 content in the 31EG4 cells by slightly more than twofold after four days treatment while RNA content did not change (88). This is in contrast with the finding in bovine retinal endothelial cells in which ZO-1 content did not change but its redistribution to the cell border dramatically increased with hydro-cortisone treatment (84). The redistribution of ZO-1 was also observed in epithelial cells and may be related to fascin expression, which is thought to bind to ZO-1 and retain the protein in the cytoplasm (89,90). Glucocorticoids downregulate fascin and allow redistribution of ZO-1 to the cell border and organization of tight junctions. Whether a similar mechanism contributes to endothelial barrier induction in response to glucocorticoids remains unknown at present. Furthermore, others have demonstrated an increase in occludin in response to glucocorticoids in epithelial cells (91). Thus, steroids induce tight junction protein expression and redistribution to the plasma membrane in epithelial and endothelial cell systems. Localized delivery of glucocorticoids may provide a means to restore barrier integrity and reduce inflammation in diabetic retino-pathy (Fig. 2). However, given the risks associated with prolonged steroid use, it is imperative to determine the molecular mechanisms by which glucocorticoids control barrier properties so that novel, more specific therapies may be developed.
Computational characterization and integrative analysis of proteins involved in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Pranitha Jenardhanan, Manivel Panneerselvam, Premendu P. Mathur
Their studies highlight that adjudin more prominently exerts its effects in the proteins localized in the apical ectoplasmic specialization (ES).82–84 Apical ES is the testis-specific cell junction constituted by adherens junctions, focal contact, and tight junction proteins.85 Adjudin is observed to disrupt F-actin organization at apical ES, downregulate the expression of actin bundling/barbed end capping protein Eps8, palladin, and barbed end nucleation complex Arp2/3.86 By downregulating the expression of proteins adjudin typically affects the apical ES restructuring, leading to the release of immature spermatids into the lumen. Adjudin also affects the dynamics of the Sertoli cell microtubule network by downregulating the expression of microtubule affinity regulating kinase 4 (MARK4).87 MARK4 is a typical member of the MARK family that shows direct binding with microtubules.88,89 Adjudin treatment is shown to delocalize MARK4 from the concave side of the spermatid head, affecting sperm polarity and resulting in premature release of immature spermatid into the lumen.87 The adjudin model has also highlighted the function of the Fascin 1 protein.90 The Fascin protein (Fascin 1-3) is involved in binding with and bundling actin filaments by cross-linking acting filaments to form tight bundles.91 Fascin 1 is highly expressed in Sertoli cells and in germ cells. Its localization has been observed up to stage VIII near the basal ES at the BTB, in stages VII to late-stage VIII in apical ES, and is restricted to stage 19 spermatids of the seminiferous epithelium. Adjudin-based models highlight that Fascin 1 is crucial for conferring polarity to the sperm head of spermatids adhered to apical ES and its targeted disruption affects sperm polarity and results in premature sperm release into the lumen.90
Characteristics, Events, and Stages in Tumorigenesis
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Metastasis is a pathological process involving a spatiotemporal sequence of events. Liu and Cao (2016) proposed four sequential and distinct phases/steps to explain metastasis, namely priming, licensing, initiation, and progression [545]. The priming stage involves the production of various soluble factors by primary tumor cells and, along with other molecular constituents (e.g., miRNA), stimulate the assembling of an immature niche (i.e., premetastatic) in a distant, secondary organ site or within the same organ away from the primary or originating tumor [545]. The licensing stage is a process that takes place in preparation for potential seeding and colonization of circulating tumor cells (CTCs), and as a response to the summoning of the tumor via tumor-derived molecular factors and the mobilization and recruitment of regulatory/suppressive immune cells, bone marrow-derived dendritic cells (BMDCs), and other components to the new site (distant/secondary) for the purpose of sustaining dynamic interactions amongst recruited cells, immigrated factors, and host stroma. These interactions enrich the surrounding microenvironment and institute the mature premetastatic niche (PMN) [545]. The initiation stage is welcoming to CTCs that arrive at their new destination, the fertile well-prepared PMN, and support the process of helping them to colonize, proliferate, and survive [545]. However, not all CTCs survive, and others enter dormancy until better conditions appear in their environment resulting in a dormant niche [545]. The progression stage is the “outstanding host phase” where the PMN embraces more migrated tumor cells and makes the necessary provisions to directly benefit metastatic outgrowth, expansion, and further progression resulting in macrometastases or detectable tumors, and even additional metastases [545]. It is possible that some CTCs may travel back to the primary tumor location for recolonization and may evolve into a more aggressive phenotype, the so-called tumor self-seeding model. Tumor-derived factors such as the cytokines, IL6 and IL8, matrix metalloproteinases-1/collagenase-1, and actin cytoskeleton component, fascin-1, may assist in this process [562–565].
Virtual screening and zebrafish models in tandem, for drug discovery and development
Published in Expert Opinion on Drug Discovery, 2023
David Hernández-Silva, Francisca Alcaraz-Pérez, Horacio Pérez-Sánchez, Maria Luisa Cayuela
Xenograft. Fascin 1 is a vital actin-bundling protein involved in cancer invasion and metastasis whose expression goes hand in hand with poor prognosis. Therefore, Fascin 1 is an excellent therapeutic target in cancer treatment. In silico screening calculations of 9591 compounds, including 2037 approved by the FDA, were performed and analyzed by VS to identify a potential fascin1 blocker [88]. Among the 20–30 top candidate compounds, imipramine (antidepressants) and raltegravir (anti-retroviral) were selected by different techniques such as thermofluor, fluorescence titration, and in vitro characterization. Finally, both compounds were tested using the process of xenograft transplantation into larvae to evaluate their inhibitory activity in tumor growth, invasion, and metastasis. Imipramine is being tested in an approved phase II clinical trial [89]. The combination screenings allowed the repurposing to take place in less than 3 years, and the number of compounds tested in vitro/in vivo was greatly reduced (99,5% of the library were eliminated in silico)
Molecular Targets of Curcumin and Its Therapeutic Potential for Ovarian Cancer
Published in Nutrition and Cancer, 2022
Malihe Mohamadian, Afsane Bahrami, Maryam Moradi Binabaj, Fereshteh Asgharzadeh, Gordon A. Ferns
It is well established that the Wnt/β-catenin signaling pathway is important in carcinogenesis and cancer cell proliferation (68, 69). Curcumin has moderate cytotoxicity in both SKOV3 and OVCAR3 cells from the spheroids, according to an MTT experiment. Curcumin therapy (60 µM) resulted in a significant decrease in Aldehyde Dehydrogenase one Family Member A1 (ALDH1A1) expression as well as a total disruption of epithelial OC spheroids (EOC) cell sphere formation. ALDH1A1 is a marker of cancer stem cells and ALDH1A1/β-catenin interplay triggers spheroid formation (70, 71). In addition to subverting the sphere-forming capacity, curcumin significantly inhibited the adhesion and mesothelial invasiveness of OC spheroids (72). It has been reported that high fascin expression is related to poor prognosis and metastasis in different types of cancers (73, 74). Curcumin can suppress fascin expression through STAT3 inhibition in SKOV3 cells, which ultimately decreases cell migration and invasion in OC cells (44).
The therapeutic effects of blocking IGF-R1 on mice model of skin cancer
Published in Journal of Dermatological Treatment, 2021
Matrix metalloproteases (MMP) plays a crucial role in tumor proliferation, invasion and metastasis. It is has the ability to hydrolyze the major compound in the basement membrane, type IV collagen (23). Moreover, it destructed the basement membranes in blood vessels as well as is engaged in angiogenesis and neovascularization (24). MMP9 helps in the proteolytic conversion of syndecan-1 to be a soluble molecule instead of membrane bound enhancing tumor metastasis. Syndecan-1 possesses the ability to interact with extracellular matrix growth factors such as fibroblast growth factor (FGF) family leading to antigenic stimulation (25). In addition, fascin-1, actin-binding protein, is highly expressed in many cancers such as skin, lung, breast, colon cancers and leukemia. It established the formation of invadopodia in cancer cells (26). Upregulation of fascin causes modifications in the cytoskeleton altering extracellular matrix and enhances tumor metastasis. However, blocking or knocking down of fascin-1 blocked the migration and invasion ability of cancer cells in some cancer types such as hepatocellular carcinoma (27). In skin cancer, fascin is reported to be over expressed leading to locally infiltrate and substitutes the surrounding tissues affecting cell–cell and cell–matrix interaction, enhancing cell adhesion, motility and invasiveness increasing the risk of metastasis (28). However, we found significant increase in the gene and protein expression of MMP9, syndecan-1 and fascin-1 in skin cancer, which are attenuated by treating cancer mice with PQ401 without affecting the control mice.