Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

Yang, Yang; Yu, Qiuhan; Song, Han; Ran, Ling; Wang, Kai; Xie, Luyi; Huang, Sung-Wei; Niu, Zhenbin; Zhang, Yilin; Kan, Zifei; Yan, Tao; Song, Zhenhui

doi:10.1016/j.virusres.2020.197901

Cited by 7 publications

(3 citation statements)

References 27 publications

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“…Disability in NHE3 (SLC9A3) in humans or mice induced chloride-losing diarrhea [29]. Another study has shown that the infection of TGEV can supress NHE3 translocation and down-regulate sodium-hydrogen exchange activity by the p38MAPK/AKt2 signaling pathway, inducing electrolyte absorption and leading to diarrhea, which indicated the inhibition of the activity of NHE3 was related to cellular electrolyte absorption and diarrhea [30]. In the present study, the activity and expression of NHE3 were signi cantly reduced after WYF treatment, which indicated that WYF might disturb cellular electrolyte absorption and relieve constipation.…”

Section: Discussionmentioning

confidence: 99%

Wenyang Yiqi Formula improves Na + /H + ion transport by inhibiting NHE3 via activation of gastrin/CCKBR pathway

Wang

et al. 2023

Preprint

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Background: STC is a common digestive disorder and WYF is a Chinese medicine used to treat it. NHE3 is a protein that helps absorb sodium ions and its inhibition has been linked to various diarrheal diseases. There is little research on the effects of WYF on NHE expression and the treatment of STC, and the mechanism behind it is not understood. Objective: This study aimed to investigate the effects of the WYF on Na+/H+ ion transport in vivo and in vitro and to uncover the mechanism of the WYF in treating STC. Methods: The effectiveness of WYF in treating STC was tested on rats with induced STC and Caco-2 cells in a laboratory setting. The study compared the impact of WYF on several factors, including the rate of intestinal transit, colon tissue pathology, characteristics of feces, and stool volume among five groups (n=6/group). The researchers also evaluated the effects of WYF on cell viability, NHE3 activity and expression, and markers in two signaling pathways (gastrin/CCKBR and PI3K/PLC/PKC). Results: WYF improved the rate of intestinal transit and colon tissue pathology in STC rats, and reduced cell viability and NHE3 activity and expression in Caco-2 cells. The concentration of gastrin and the level of CCKBR increased with WYF treatment, while NHE3 activity had opposite trends in response to WYF and the sh-CCKBR group. Adding gastrin reversed these effects in the sh-CCKBR group. The activity of NHE3 was decreased in the WYF (20%)+gastrin (300 nmol) group, but significantly upregulated in the sh-CCKBR group with or without serum containing 20% WYF, which was reversed after adding gastrin. The ratios of p-PI3K to PI3K, p-PLC to PLC, and p-PKC to PKC in the serum containing 20% WYF were significantly increased, but decreased in the LY294002 group. After adding serum containing WYF, the reduction of these ratios was reversed. The activity of NHE3 had opposite trends to the ratios of p-PI3K to PI3K, p-PLC to PLC, and p-PKC to PKC. Conclusion: The WYF can be used to treat STC, possibly by improving Na+/H+ ion transport through inhibiting NHE3, activating the gastrin/CCKBR pathway, and PI3K/PLC/PKC-dependent pathways.

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Section: Discussionmentioning

confidence: 99%

Wenyang Yiqi Formula improves Na + /H + ion transport by inhibiting NHE3 via activation of gastrin/CCKBR pathway

Wang

et al. 2023

Preprint

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“…The following regulatory mechanisms exist for EGFR and NHE3 in porcine transmissible gastroenteritis virus (TGEV), which is also an alphacoronavirus: infection with TGEV enhances intestinal glucose uptake and increases the expression of EGFR, SGLT1, and GLUT2 in intestinal epithelial cells, and there is a positive regulatory relationship between EGFR and SGLT1 (Ren et al, 2013;Dai et al, 2016). In the case of TGEV infection, down-regulation of SGLT1 expression promotes the translocation of NHE3, which increases the expression of NHE3 on the plasma membrane (Yang et al, 2020). Inhibition of EGFR activity can promote the fluidity of NHE3 on the plasma membrane and promote the absorption of Na + (Yang Z. et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Porcine epidemic diarrhea virus causes diarrhea by activating EGFR to regulates NHE3 activity and mobility on plasma membrane

Zhang,

Sun

et al. 2023

Front. Microbiol.

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As part of the genus Enteropathogenic Coronaviruses, Porcine Epidemic Diarrhea Virus (PEDV) is an important cause of early diarrhea and death in piglets, and one of the most difficult swine diseases to prevent and control in the pig industry. Previously, we found that PEDV can block Na+ absorption and induce diarrhea in piglets by inhibiting the activity of the sodium-hydrogen ion transporter NHE3 in pig intestinal epithelial cells, but the mechanism needs to be further explored. The epidermal growth factor receptor (EGFR) has been proved to be one of the co-receptors involved in many viral infections and a key protein involved in the regulation of NHE3 activity in response to various pathological stimuli. Based on this, our study used porcine intestinal epithelial cells (IPEC-J2) as an infection model to investigate the role of EGFR in regulating NHE3 activity after PEDV infection. The results showed that EGFR mediated viral invasion by interacting with PEDV S1, and activated EGFR regulated the downstream EGFR/ERK signaling pathway, resulting in decreased expression of NHE3 and reduced NHE3 mobility at the plasma membrane, which ultimately led to decreased NHE3 activity. The low level of NHE3 expression in intestinal epithelial cells may be a key factor leading to PEDV-induced diarrhea in newborn piglets. This study reveals the importance of EGFR in the regulation of NHE3 activity by PEDV and provides new targets and clues for the prevention and treatment of PEDV-induced diarrhea in piglets.

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“…TGEV causes acute enteric disease in pigs, characterized by vomiting, severe diarrhea and dehydration. The mortality of TGEV often reaches 100% in suckling piglets less than two weeks of age, and causes huge economic losses in pig industry around the world [ 1 , 2 ]. Until now, there is no effective drug to treat TGEV infection, and vaccination should be the effective measure to control the disease caused by TGEV [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Assessments of different inactivating reagents in formulating transmissible gastroenteritis virus vaccine

Zhao

Liu

et al. 2020

Virol J

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Background Transmissible gastroenteritis virus (TGEV) causes enteric infection in piglets, characterized by vomiting, severe diarrhea and dehydration, and the mortality in suckling piglets is often high up to 100%. Vaccination is an effective measure to control the disease caused by TGEV. Methods In this study, cell-cultured TGEV HN-2012 strain was inactivated by formaldehyde (FA), β-propiolactone (BPL) or binaryethylenimine (BEI), respectively. Then the inactivated TGEV vaccine was prepared with freund's adjuvant, and the immunization effects were evaluated in mice. The TGEV-specific IgG level was detected by ELISA. The positive rates of CD4+, CD8+, CD4+IFN-γ+, CD4+IL-4+ T lymphocytes were detected by flow cytometry assay. Lymphocyte proliferation assay and gross pathology and histopathology examination were also performed to assess the three different inactivating reagents in formulating TGEV vaccine. Results The results showed that the TGEV-specific IgG level in FA group (n = 17) was earlier and stronger, while the BEI group produced much longer-term IgG level. The lymphocyte proliferation test demonstrated that the BEI group had a stronger ability to induce spleen lymphocyte proliferation. The positive rates of CD4+ and CD8+ T lymphocyte subsets of peripheral blood lymphocyte in BEI group was higher than that in FA group and BPL groups by flow cytometry assay. The positive rate of CD4+IFN-γ+ T lymphocyte subset was the highest in the BPL group, and the positive rate of CD4+IL-4+ T lymphocyte subset was the highest in the FA group. There were no obvious pathological changes in the vaccinated mice and the control group after the macroscopic and histopathological examination. Conclusions These results indicated that all the three experimental groups could induce cellular and humoral immunity, and the FA group had the best humoral immunity effect, while the BEI group showed its excellent cellular immunity effect.

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Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

Cited by 7 publications

References 27 publications

Wenyang Yiqi Formula improves Na + /H + ion transport by inhibiting NHE3 via activation of gastrin/CCKBR pathway

Wenyang Yiqi Formula improves Na + /H + ion transport by inhibiting NHE3 via activation of gastrin/CCKBR pathway

Porcine epidemic diarrhea virus causes diarrhea by activating EGFR to regulates NHE3 activity and mobility on plasma membrane

Assessments of different inactivating reagents in formulating transmissible gastroenteritis virus vaccine

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