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Antiviral Drugs as Tools for Nanomedicine
Published in Devarajan Thangadurai, Saher Islam, Charles Oluwaseun Adetunji, Viral and Antiviral Nanomaterials, 2022
Figure 12.3 depicts the various steps of cancer development (Witsch et al. 2011). In brief, cancer is instigated by a somatic mutation conferring considerable survival and growth advantages to the initiated cell (1). GFs like EGF and IGF1 help the resulting expansion of clones having mutations (2), this results in intra-luminal lesions (3), such as carcinoma at the site or neoplasia, which are surrounded by the basal membrane. (4) Next step is migration and penetration by cancer cells into neighbouring tissues called invasion. Loss of epithelial polarity, motility attainment, changing phenotype to mesenchymal-like, and secretion of enzymes like proteases. The various oncogenes and tumour suppressors, with the involvement of different growth factors, control the critical phase of tumour development. The extravasation of transformed cells - cancer cells from the site and intravasation into the lymphatic and blood vessels results in metastasis (5) to distant organs. Extra- and intravasation require the assistance of macrophages, platelets, and endothelial cells. At this stage of resulting micro-metastases, (6) the cells usually are sensitive to chemotherapy and radiotherapy. However, constant accumulation of mutation leads to the acquisition of further mutations and makes the cancer cells proficient to produce growth factors. This leads to autocrine loops that propel the development of resistant clones (7). Angiogenesis (8) is an indispensable factor for the establishment of secondary tumours. In the last phase, large metastases (9) move to a distinct set of target organs leading to metastases.
The female reproductive system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
CIN is defined as replacement of the normal squamous cervical mucosa by neoplastic cells, but with an intact basement membrane. The neoplastic cells are identified by the presence of classic morphological features of malignancy, i.e. nuclear hyperchromasia, pleomorphism, abnormal mitoses, and loss of epithelial polarity (see Chapter 6). The lesion is then graded on the basis of the proportion, in thirds, of the epithelium that is occupied by abnormal ‘basaloid’ cells showing no evidence of cytoplasmic maturation to give grades 1, 2, and 3 (Figures 15.4 and 15.5). It should be noted that nuclear abnormality is present throughout the epithelial thickness in all grades of CIN. An alternative grading system, used particularly in the USA, divides these lesions into low- and high-grade squamous intraepithelial lesions (SILs), with low-grade SIL corresponding approximately to CIN 1 and high-grade SIL, to CIN 2 and 3. This two-grade system is perhaps more logical, given what is known of the biology of HPV infection (see Special Study Topic 15.1), and is now recommended by the World Health Organization, for cervical lesions. In the UK, currently, cervical smears are reported using the two-grade system, with the three-tier equivalent given in brackets. For example, a cytological abnormality approximately equivalent to CIN 2 would be designated high-grade dyskaryosis (moderate), where dyskaryosis means nuclear abnormality. There is an ongoing debate about whether cervical biopsies should be assessed in the same way.
In Vitro Systems for the Study of the Intrahepatic Biliary Epithelium
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Ruth Joplin, Shahnaz Gill, Sarah Ward, Stivelia Kachilele
Historically epithelia in general have proven more difficult than many other cell types to maintain in culture. This is due in part to their propensity to terminally differentiate in culture and senesce.14 In vivo epithelia obtain specific growth and differentiation signals from the surrounding stroma. Because of the polarised disposition of epithelia and their intimate association and interaction with the underlying basement membrane, essential nutritive, metabolic, growth and differentiated functions may be lost by adopting in vitro techniques in common usage (e.g., monolayer culture, which severely disrupts the polar nature of cells). To obtain an acceptable in vitro model of epithelial polarity, adaptation of standard culture methods may be required. In this chapter, the source of IBEC for in vitro studies will be considered along with some strategies aimed at maintaining these cells in vitro including adaptations employed to maintain a polarised disposition (Fig. 1).
MRCK: a master regulator of tissue remodeling or another ‘ROCK’ in the epithelial block?
Published in Tissue Barriers, 2021
In summary, an increasing body of evidence suggests that MRCK plays a major role in apical domain organization and morphogenesis, in different developmental and homeostatic contexts. The spatiotemporal functional relationship between MRCK and ROCK may be a major defining factor in the fate of the apical domain. Future work to understand the interplay between MRCK and ROCK signaling at the cell cortex, is therefore likely to provide insight into control mechanisms of cell and tissue morphogenesis. For example, it would be of interest to determine whether an antagonistic relationship affects tension gradients at the cortex to control apical domain development during epithelial polarity establishment and morphogenesis. Another important question is whether MRCK plays a role in controlling the apical cortex during tissue-specific functions by the mature epithelium. Since, MRCK and ROCK also possess the ability to function in both polarity and tumorigenesis, understanding their complex relationship is likely to provide important insight into cancer progression.
Comparative proteomics analysis indicates that palmatine contributes to transepithelial migration by regulating cellular adhesion
Published in Pharmaceutical Biology, 2020
Wang Hui, Yang Feng, Yan Baoqi, Dong Shuwei, Xin Ruihua, He Jiongjie, Cui Dongan, Sun Yan, Zhang Shidong, Yan Zuoting
Palmatine may play a role in the regulation of intercellular junctions. Mucosal epithelial cells often form functional barriers that separate organs or tissues from the external environment. Formation of these barriers by epithelial cells requires neighbouring cells to interact via intercellular junctions, including tight junctions (TJs) and adherens junctions (AJs) (Balda and Matter 2016). These junctions consist of some important components. Claudins, occludins and junctional adhesion molecules (JAMs) are the major CaMs in TJs, whereas cadherins and nectins are the major CaMs in AJs (Ooshio et al. 2010). Many studies have reported that pathogenic bacteria can disrupt the function and structure of cell–cell junctions and epithelial polarity (Tapia et al. 2017). In this study, LPS downregulated NECT1, and palmatine downregulated the crucial molecules JAM1, NECT1 and CHD5 (Figure 6). This finding demonstrates that palmatine can inhibit the formation of two junctional complexes, particularly AJs, in LPS-stimulated cells.
Clinical utility of microRNAs in renal cell carcinoma: current evidence and future perspectives
Published in Expert Review of Molecular Diagnostics, 2018
Panagiotis Tsiakanikas, Constantinos Giaginis, Christos K. Kontos, Andreas Scorilas
In addition, inadequate cell cycle regulation has been linked to the reduction of miR-200c expression in RCC. More specifically, it has been reported that miR-200c inhibited cell growth by repressing cyclin-dependent kinase 2 (CDK2), blocking the entry into S phase and provoking G0/G1 cell cycle arrest [44]. It should be noted that miR-200 family is organized in two clusters located on chromosomes 1 (miR-200b/200a/429) and 12 (miR-200c/141). The observed downregulation of miR-200 family members may be proved to significantly affect RCC development, progression and metastasis [45,46]. The aforementioned miRNAs, especially the miR-200c/141 cluster, have been considered as EMT operators. Moreover, it was suggested that these miRNAs may supervise a circuit of transcriptional repressors that seem to regulate multiple genes responsible for epithelial polarity maintenance. It has been found that downregulation of miR-200 family induced overexpression of both ZEB1 and ZEB2, leading to reduced cadherin 1 (CDH1; also known as E-cadherin, ECAD) levels [44,46–49]. miR-141 has been demonstrated as a key tumor-suppressive miRNA in ccRCC reducing proliferation and metastasis by targeting EPH receptor A2 (EPHA2). Reduced EPHA2 levels as result of miR-141 overexpression modulated crucial downstream effectors such as AKT, protein tyrosine kinase 2 (PTK2) and matrix metallopeptidases (MMP2, MMP9) [50].