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The Silver Lining
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Mark R Frey, Misty Good, Steven J. McElroy
The claudin family includes at least 24 members that have tissue- and organ-specific distribution and have great variability in their distribution (28, 29). Claudins form pores across the TJ that contain charged loops of amino acids. These loops regulate the size, strength, and specificity of the ions that are allowed through the junction and are believed to be the reason why different epithelia have distinctive permeabilities. As such, claudins are key components of TJs, and Claudin-1 knockout mice die 24 hours after birth due to a dramatic loss of fluid and electrolytes (30).
Arcobacter
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Nuria Salas-Massó, Alba Perez-Cataluña, Luis Collado, Arturo Levican, Maria José Figueras
The mechanism by which Arcobacter produces diarrhea was illustrated by Collado and Figueras [1 and references therein] in a scheme that shows the interaction of the bacteria with intestinal epithelial cells. This interaction produces a decreasing expression of Claudin in the tight junctions of the colon intestinal epithelial cells that alter the epithelial barrier, leading to the production of a leak-flux type of diarrhea. A recent in vitro study confirmed again the cytotoxicity of strains of A. butzleri (isolated from chicken, pork meat, human samples, and water) to the human colon (HT-29/B6) but not to the porcine intestinal (IPEC-J2) epithelial cells [99]. In addition, the latter study ratified that the epithelial barrier alteration observed in the HT-29/B6 cells resulted in a leak-flux type of diarrhea.
Anatomy of the Cochlea and Vestibular System: Relating Ultrastructure to Function
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
The basal cells are flattened and elongated, forming between one and three layers delimiting the basal aspect of SV (Figure 47.8b). They arise during development from the mesenchymal cells that also form the spiral ligament. Basal cells closely appose each other and there is extensive sealing of the intercellular spaces between them by tight junctions.137,144 This creates an impermeable barrier between the perilymph in the underlying spiral ligament and the body of SV. During development, the initial formation of these tight junctions and the increase in their complexity coincides with onset of EP,137 suggesting that these junctions are necessary to provide the electrical insulation required for the potential difference to be generated and maintained within the body of SV. Mutations in the gene for the protein claudin 11, which is present in the basal cell tight junctions, cause the loss of EP and so hearing impairment.145
Perspectives on the pharmacological management of esophageal cancer: where are we now and where do we need to go?
Published in Expert Opinion on Pharmacotherapy, 2022
Jane E. Rogers, Jaffer A. Ajani
Claudins are a family of tight cell junction proteins that have been identified as a potential drug target. Claudin 18 isoform 2 (CLDN18.2) is reportedly expressed in primary GAC (14–87%) [49,50]. Information on its occurrence in EAC is not yet known. Zolbetuximab, anti-CLDN18.2 mAb, has shown promising phase 2 data as both monotherapy via the MONO study and in combination with chemotherapy via the FAST trial [51,52]. Early data shows the higher percentage of CLDN18.2 expression (≥ 70%) appears to show the most benefit. Those with high expression in the MONO trial showed an ORR 14% [51]. In the FAST trial, median PFS and OS was improved with the addition of zolbetuximab to chemotherapy (9 months vs. 5.7 months; p < 0.0005) [52]. Zolbetuximab plus front-line fluoropyrimidine + platinum is now under phase 3 investigation through the SPOTLIGHT and GLOW trial [53,54]. Additionally, other agents are under investigation targeting CLDN18.2 through additional mAbs, ADCs, and T-cell therapy [55–61]. We believe this will be an important target for gastroesophageal adenocarcinomas in the near future. The role of claudins in EAC and ESCC still need to be further defined.
Bioinformatics analyses reveal cell-barrier junction modulations in lung epithelial cells on SARS-CoV-2 infection
Published in Tissue Barriers, 2022
Mir S. Adil, Daulat Khulood, S. Priya Narayanan, Payaningal R. Somanath
On the other hand, TJs revealed remarkable changes in the expression of several core proteins upon CoV-2 infection in the lung epithelial cells. Alterations in the expression of several claudins in the pathological states reflect the critical role of these elements. CLDN4 is one such claudin elevated in acute lung injury,41 which is characterized by aberrant vascular leakage.42 Interestingly, it is one of the four claudins up-regulated in the current analysis in A549 cells on CoV-2 injury. Another notable finding among claudins is related to CLDN16, which is absent in the human lungs [60], but CoV-2 injury on A549 cells led to a significant increase in the expression of CLDN16, thereby signifying a critical role of this gene in the pathophysiological state. CLDN16 is well known to interact with CLDN19 to form a TJ complex,43 and interestingly CLDN19 was also modulated in our study in the NHBE cells but not in the A549 cell line. Similarly, CoV-2 induced upregulation of CLDN1, a barrier-forming claudin similar to CLDN5 [38], is anticipated to rescue the barrier integrity in the injured A549 cells. These findings collectively reveal modulation of claudins in CoV-2 infection in vitro and signify the likelihood of similar changes in these TJ elements during the same infection in vivo.
Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials
Published in Tissue Barriers, 2022
Daisuke Kyuno, Akira Takasawa, Kumi Takasawa, Yusuke Ono, Tomoyuki Aoyama, Kazufumi Magara, Yuna Nakamori, Ichiro Takemasa, Makoto Osanai
Claudins have three main functions: barrier, fence, and intracellular signaling.1,10 The barrier function is the ability to selectively regulate paracellular permeation of water, ions, macromolecules, and immune cells, whereas the fence function separates the apical and basolateral domains and regulates the movement of substances within the plasma membrane.10,11 Tight junctions, including claudins, also act as signaling hubs by binding to multiple signaling molecules. Claudins in cancer cells are known to activate signaling pathways associated with tumor progression and metastasis. For example, claudin-1 activates the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway in hepatocellular carcinoma12 and the Notch/phosphoinositide-3-kinase (PI3K)/Akt signaling pathway in colitis-associated cancer.13 Claudin-2 in colon cancer is substantially upregulated via the epidermal growth factor receptor-ERK1/2 kinase axis and overexpressed claudin-2 increases cell proliferation and tumor growth in vivo.14 Claudin-3 has a suppressive role in epithelial-mesenchymal transition via activation of the Wnt/beta-catenin signaling pathway in lung squamous cell carcinoma15 and hepatocellular carcinoma.16 Thus, the impact of claudins on carcinogenesis has been investigated in various types of cancer cells.