Background:Core fucosylation (CF), catalyzed by α-1,6 fucosyltransferase (Fut8) in mammals, plays an important role in pathological processes through posttranslational modification of key signaling receptor proteins, including transforming growth factor (TGF)-β receptors and platelet-derived growth factor (PDGF) receptors. However, its effect on peritoneal fibrosis is unknown. Here, we investigated its influence on epithelial-mesenchymal transition (EMT) of rat peritoneal mesothelial cells (PMCs) in vitro induced by a high-glucose (HG) culture solution.Methods:Rat PMCs were first cultured in a HG (2.5%) culture solution to observe the CF expression level (fluorescein isothiocyanate-lens culinaris agglutinin), we next established a knockdown model of rat PMCs in vitro with Fut8 small interfering RNA (siRNA) to observe whether inhibiting CF decreases the messenger RNA (mRNA) expression and protein expression of Fut8 and reverses EMT status. Rat PMCs were randomly divided into control group, mock group (transfected with scrambled siRNA), Fut8 siRNA group, HG group, HG + mock group, and HG + Fut8 siRNA group. Finally, we examined the activation of TGF-β/Smad2/3 signaling and PDGF/extracellular signal-regulated kinase (ERK) signaling to observe the influence of CF on them.Results:CF, Fut8 mRNA, and protein expression were all significantly upregulated in HG- induced EMT model than those in the control rat PMCs (P < 0.05). Fut8 siRNA successfully blocked CF of TGF-β receptors and PDGF receptors and attenuated the EMT status (E-cadherin and α-SMA and phenotypic changes) in HG-induced rat PMCs. In TGF-β/Smad2/3 signaling, Fut8 siRNA did not suppress the protein expression of TGF-β receptors and Smad2/3; however, it significantly suppressed the phosphorylation of Smad2/3 (relative expression folds of HG + Fut8 group vs. HG group: 7.6 ± 0.4 vs. 15.1 ± 0.6, respectively, P < 0.05). In PDGF/ERK signaling, Fut8 siRNA did not suppress the protein expression of PDGF receptors and ERK, but it significantly suppressed the phosphorylation of ERK (relative expression folds of HG + Fut8 group vs. HG group: 8.7 ± 0.9 vs. 15.6 ± 1.2, respectively, P < 0.05). Blocking CF inactivated the activities of TGF-β and PDGF signaling pathways, and subsequently blocked EMT.Conclusions:These results demonstrate that CF contributes to rat PMC EMT, and that blocking it attenuates EMT. CF regulation is a potential therapeutic target of peritoneal fibrosis.
The modern medical education system has gradually evolved starting from 1910 incorporating the suggestions by Abraham Flexner, his public disclosure of the poor conditions at many medical schools provided a means to galvanize all the constituencies needed for reform to occur. He could say what other reformers could not, due to their links to the medical education community. But now we are again going back to a pre-Flexnerian state due to multiple reasons such as gradually diminishing importance of basic science subjects for the students, the decline in the number and quality of investigator initiated research among clinical researchers, lesser emphasis to bedside training by means of detailed clinical examination and making appropriate observation of signs to reach to a diagnosis rather than over reliance on the laboratory tests and radiological modalities for the diagnosis, poor exposure to basic clinical skills starting from college throughout residency and the trend of disrespect and absenteeism from both theoretical and clinical/practical classes. The attitude of students is just to complete their required attendance so that they are not barred from appearing in examinations. This de-Flexnerization trend and regression to pre-Flexnerian era standards, ideologies, structures, processes, and attitudes, are bound to beget pre-Flexnerian outcomes, for you get what you designed for.
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