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      KGF Is Delivered to Inflammatory and Induces the Epithelial Hyperplasia in Trinitrobenzene Sulfonic Acid-Induced Ulcerative Colitis Rats

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          KGF-modified MSCs can promote the repair of spinal cord injury and pulmonary fibrosis injury in rats. However, the effect of KGF-modified MSCs on UC rats is unclear. We aimed to explore the therapeutic effect and possible mechanism of KGF gene-modified MSCs on trinitrobenzene sulfonic acid (TNBS)-induced UC rats.


          The lentivirus-mediated KGF gene was introduced into bone marrow MSCs of male rats. Female SD rats were induced to establish a UC model by TNBS. Untreated MSCs, MSCs carrying empty vectors (MSCs-vec) or MSCs carrying KGF gene (MSCs-KGF) were transplanted into UC rats by tail vein injection.


          Significantly high expression of KGF was observed in the intestinal tissues of the MSCs-KGF group. Compared with the challenged control group, the DAI score, CMDI score and TDI score of the MSCs group, MSCs-vec group and MSCs-KGF group were markedly lower. Treatment with MSCs obviously promoted the expression of claudin-1 and PCNA in intestinal tissues of UC rats. Simultaneously, compared with the challenged control group, the levels of TNF-α, IL-6 and IL-8 in the intestinal tissues of the MSCs groups were significantly decreased, while the levels of IL-10 were significantly increased. Most importantly, we found that MSCs-KGF significantly improved colonic morphology and tissue damage and inflammation in UC rats compared with MSCs and MSCs-vec. Further analysis showed that MSCs-KGF clearly promoted phosphorylation of PI3K and Akt and inhibited nuclear translocation of NF-κB in intestinal tissues of UC rats.


          MSCs, especially KGF-modified MSCs, can improve colonic tissue damage in UC rats by promoting intestinal epithelial cell proliferation and reducing colonic inflammatory response, which may be related to activation of PI3K/Akt pathway and inhibition of NF-κB activation.

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          Most cited references 38

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          Clinicopathologic study of dextran sulfate sodium experimental murine colitis.

          We undertook this study in order to fully characterize the clinical and histopathology features of the dextran sulfate sodium (DSS) model of experimental murine colitis and to discover the earliest histopathologic changes that lead to colitis. Acute colitis was induced in Swiss-Webster mice by 7 days of oral DSS with animals sacrificed daily. Chronic colitis was induced by: (a) 7 days of oral DSS followed by 7 days of H2O (for 1, 2, and 3 cycles) and (b) 7 days of oral DSS followed by 14 and 21 days of H2O. In each experimental group, the entire colons were examined histologically and correlated with clinical symptoms. Acute clinical symptoms (diarrhea and/or grossly bloody stool) were associated with the presence of erosions and inflammation. More importantly, the earliest histologic changes which predated clinical colitis was loss of the basal one-third of the crypt (day 3), which progressed with time to loss of the entire crypt resulting in erosions on day 5. The earliest changes were very focal and not associated with inflammation. Inflammation was a secondary phenomena and only became significant after erosions appeared. Animals treated with only 7 days of DSS followed by 14 and 21 days of H2O developed a chronic colitis with the following histologic features: areas of activity (erosions and inflammation), inactivity, crypt distortion, florid epithelial proliferation and possible dysplasia. These changes were similar to animals given 3 cycles of DSS. The clinical disease activity index correlated significantly with pathologic changes in both the acute and chronic phases of the disease. The mechanism of DSS colitis is presently unknown. However, the finding of crypt loss without proceeding or accompanying inflammation suggests that the initial insult is at the level of the epithelial cell with inflammation being a secondary phenomena. This may be a good model to study how early mucosal changes lead to inflammation and the biology of the colonic enterocyte. Chronic colitis induced after only 7 days of DSS may serve as a useful model to study the effects of pharmacologic agents in human inflammatory disease and mechanisms of perpetuation of inflammation. Finally, we believe that this model has the potential to study the dysplasia cancer sequence in inflammatory disease.
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            Protection of the intestinal mucosa by intraepithelial gamma delta T cells.

            gammadelta intraepithelial T lymphocytes (IEL) represent a major T cell population within the intestine of unclear functional relevance. The role of intestinal gammadelta IEL was evaluated in the dextran sodium sulfate (DSS) induced mouse colitis model system. Large numbers of gammadelta T cells, but not alphabeta T cells, were localized at sites of DSS-induced epithelial cell damage. gammadelta IEL in DSS treated mice expressed keratinocyte growth factor (KGF), a potent intestinal epithelial cell mitogen. gammadelta cell-deficient mice (TCRdelta(-/-)) and KGF-deficient mice (KGF(-/-)), but not alphabeta cell-deficient mice (TCRalpha(-/-)), were more prone than wild-type mice to DSS-induced mucosal injury and demonstrated delayed tissue repair after termination of DSS treatment. Termination of DSS treatment resulted in vigorous epithelial cell proliferation in wild-type mice but not in TCRdelta(-/-) mice or KGF(-/-) mice. These results suggest that gammadelta IEL help preserve the integrity of damaged epithelial surfaces by providing the localized delivery of an epithelial cell growth factor.
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              Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway.

              The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was recently shown to negatively regulate LPS-induced acute inflammatory responses. We previously observed that the metabolic thiol antioxidant alpha-lipoic acid (LA) inhibits LPS-induced expression of cellular adhesion molecules and adherence of monocytes to human aortic endothelial cells. Here we investigated the mechanism by which LA attenuates LPS-induced monocyte activation in vitro and acute inflammatory responses in vivo. Incubation of human monocytic THP-1 cells with LA induced phosphorylation of Akt in a time- and dose-dependent manner. In cells pretreated with LA followed by LPS, Akt phosphorylation was elevated initially and further increased during incubation with LPS. This LA-dependent increase in Akt phosphorylation was accompanied by inhibition of LPS-induced NF-kappaB DNA binding activity and up-regulation of TNFalpha and monocyte chemoattractant protein 1. Lipoic acid-dependent Akt phosphorylation and inhibition of NF-kappaB activity were abolished by the PI3K inhibitors LY294002 and wortmannin. Furthermore, LA treatment of LPS-exposed C57BL/6N mice strongly enhanced phosphorylation of Akt and glycogen synthase kinase 3beta in blood cells; inhibited the LPS-induced increase in serum concentrations and/or tissue expression of adhesion molecules, monocyte chemoattractant protein 1, and TNFalpha; and attenuated NF-kappaB activation in lung, heart, and aorta. Lipoic acid also improved survival of endotoxemic mice. All of these antiinflammatory effects of LA were abolished by treatment of the animals with wortmannin. We conclude that LA inhibits LPS-induced monocyte activation and acute inflammatory responses in vitro and in vivo by activating the PI3K/Akt pathway. Lipoic acid may be useful in the prevention of sepsis and inflammatory vascular diseases.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                16 January 2020
                : 14
                : 217-231
                [1 ]Department of Nutrition, Beijing Chao-Yang Hospital, Capital Medical University , Beijing, People’s Republic of China
                Author notes
                Correspondence: Kai Jia Department of Nutrition, Beijing Chao-Yang Hospital , No. 8 Gongti South Road, Chaoyang District, Beijing100020, People’s Republic of ChinaTel +86-85231275Fax +86-10-83911276 Email kaijiamyemail@sina.com

                These authors contributed equally to this work

                © 2020 Jia et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 8, Tables: 3, References: 43, Pages: 15
                Original Research


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