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Cystic fibrosis (CF) is a multiorgan progressive genetic disease caused by loss of functional cystic fibrosis transmembrane conductance regulator (CFTR) channel. Previously, we identified a significant dysfunction in CF cells and model mice of the transcription factor nuclear factor E2-related factor-2 (Nrf2), a major regulator of redox balance and inflammatory signaling. Here we report that the approved F508del CFTR correctors VX809 and VX661 recover diminished Nrf2 function and colocalization with CFTR in CF human primary bronchial epithelia by proximity ligation assay, immunoprecipitation, and immunofluorescence, concordant with CFTR correction. F508del CFTR correctors induced Nrf2 nuclear translocation, Nrf2-dependent luciferase activity, and transcriptional activation of target genes. Rescue of Nrf2 function by VX809/VX661 was dependent on significant correction of F508del and was blocked by inhibition of corrected channel function, or high-level shRNA knockdown of CFTR or F508del CFTR. Mechanistically, F508del CFTR modulation restored Nrf2 phosphorylation and its interaction with the coactivator CREB-binding protein (CBP). Our findings demonstrate that sufficient modulation of F508del CFTR function corrects Nrf2 dysfunction in CF., Introduction Cystic fibrosis (CF) is an autosomal recessive disease characterized by progressive loss of lung function, pancreatic exocrine dysfunction, and gastrointestinal complications, which culminate in dramatically shortened life expectancy. CF [...]

Aim: This study was designed to compare the efficacy and tolerability of bowel preparations with and without the higher first-dose volume of polyethylene glycol (PEG) solution or exercise after drinking PEG solution in Chinese people.Methods: A total of 330 participants who had a colonoscopy done in Peking Union Medical College Hospital were randomly and evenly assigned to three groups. Participants in Group A ingested 1 L PEG solution and then ingested 2 L PEG solution at a rate of 250 mL every 15 minutes. Participants in Group B ingested 3 L PEG solution at a rate of 250 mL every 15 minutes and then exercised more than 10 minutes after ingesting each liter of PEG solution. Participants in Group C ingested 3 L PEG solution at a rate of 250 mL every 15 minutes. Experienced gastrointestinal endoscopists rated the efficacy of bowel preparations based on the Boston Bowel Preparation Scale score. A questionnaire regarding participants' symptoms associated with bowel preparations was administered to evaluate participants' tolerability.Results: The three groups had insignificant difference in the percentages of participants' symptoms including dizziness, nausea, stomach ache, bloating, and asthenia. However, the percentages of participants having hunger sensation, sleep disturbance, and anal discomfort were significantly higher in groups with the higher first-dose volume of PEG solution or exercise after drinking PEG solution than without them. The three groups had insignificant difference in the Boston Bowel Preparation Scale score.Conclusion: Whether to add the higher first-dose volume of PEG solution and exercise after drinking PEG solution or not, all participants achieved a similar quality of bowel preparations. Bowel preparations without the additional first-dose volume of PEG solution or exercise after drinking PEG solution showed the advantage of high participant tolerability. [ABSTRACT FROM AUTHOR]

Background & Aims: Diarrhea results from reduced net fluid and salt absorption caused by an imbalance in intestinal absorption and secretion. The bulk of sodium and water absorption in the intestine is mediated by Na+/H+ exchanger 3 (NHE3), located in the luminal membrane of enterocytes. We investigated the effect of lysophosphatidic acid (LPA) on Na+/H+ exchanger activity and Na+-dependent fluid absorption in the intestine. Methods: We analyzed the effects of LPA on fluid absorption in intestines of wild-type mice and mice deficient in Na+/H+ exchanger regulatory factor 2 (NHERF2; Nherf2 −/− ) or LPA2 (Lpa 2 −/− ). Roles of LPA5 and NHERF2 were determined by analysis of heterologous expression. Results: Under basal conditions, LPA increased fluid absorption in an NHE3-dependent manner and restored the net fluid loss in a mouse model of acute diarrhea. Expression of the LPA receptor LPA5 was necessary for LPA-induced stimulation of NHE3 activity in colonic epithelial cells. Stimulation of NHE3 by the LPA-LPA5 signaling required coexpression of NHERF2, which interacted with LPA5. LPA-mediated intestinal fluid absorption was impaired in Nherf2 −/− mice, demonstrating the requirement for NHERF2 in LPA5 activity. However, fluid absorption was unaltered in Lpa 2 −/− mice. LPA stimulated NHE3 and fluid absorption in part by increasing NHE3 protein abundance at the brush border membrane of intestinal epithelial cells. Conclusions: LPA is a potent stimulant of NHE3 and fluid absorption in the intestine, signaling through LPA5. Regulation by LPA5 depends on its interaction with NHERF2. LPA might be useful in the treatment of certain diarrheal diseases. [Copyright &y& Elsevier]

Background & Aims: Chronic inflammation is a risk factor for colon cancer (CC). Lysophosphatidic acid (LPA), a naturally produced phospholipid, mediates multiple effects that are vital to disease process, including inflammation and cancer. The expression of LPA receptor 2 (LPA2) is up-regulated in several types of cancer, including ovarian and colon cancer, but the importance of LPA and LPA2 in the development and progression of CC is unclear. In this study, we sought to determine whether LPA and LPA2 regulate the progression of CC in vivo. Methods: We examined the potential role of LPA in CC progression by administering LPA to mice heterozygous for the adenomatous polyposis coli (Apc) allele. We determined the loss of LPA2 function in tumorigenesis in the colon by treating mice with genetic deletion of LPA2 (LPA2 −/−) with azoxymethane and dextran sulfate sodium. Results: We found that LPA increased tumor incidence in Apcmin/+ mice. LPA2 −/− mice showed reduced mucosal damage and fewer tumors than wild-type (WT) mice. Reduced epithelial cell proliferation and decreases in β-catenin, Krüppel-like factor 5, and cyclooxygenase-2 expression were observed in LPA2 −/− mice. Unlike WT mice, induction of monocyte chemoattractant protein-1 and macrophage migration inhibitory factor was significantly attenuated in LPA2 −/− mice with reduced infiltration by macrophages. Conclusions: These results show that LPA is capable of promoting tumorigenesis in the colon. The absence of LPA2 attenuates several effects that contribute to cancer progression in vivo, and, hence, the current study identifies LPA2 as an important modulator of CC. [Copyright &y& Elsevier]

Crohn's disease (CD) is a chronic, relapsing, inflammatory disease that is often associated with malnutrition because of inflammation in the small intestine. Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidic acid. Increasing evidence suggests that ATX is upregulated during inflammation, and inhibition of ATX has been effective in attenuating chronic inflammatory conditions, such as arthritis and pulmonary fibrosis. This study aims to determine whether inhibition of ATX alleviates CD-associated inflammation and malnutrition by using SAMP1/Fc mice, a model of CD-like ileitis. SAMP1/Fc mice were treated the ATX inhibitor PF-8380 for 4 wk. Inhibition of ATX led to increased weight gain in SAMP1/Fc mice, decreased T helper 2 cytokine expression, including IL-4, IL-5, and IL-13, and attenuated immune cell migration. SAMP1/Fc mice have low expression of Na + -dependent glucose transporter 1 (SGLT1), suggesting impaired nutrient absorption associated with ileitis. PF-8380 treatment significantly enhanced SGLT1 expression in SAMP1/Fc mice, which could reflect the increased weight changes. However, IL-4 or IL-13 did not alter SGLT1 expression in Caco-2 cells, ruling out their direct effects on SGLT1 expression. Immunofluorescence analysis showed that the expression of sucrase-isomaltase, a marker for intestinal epithelial cell (IEC) differentiation, was decreased in inflamed regions of SAMP1/Fc mice, which was partially restored by PF-8380. Moreover, expression of Na + /H + exchanger 3 was also improved by PF-8380, suggesting that suppression of inflammation by PF-8380 enhanced IEC differentiation. Our study therefore suggests that ATX is a potential target for treating intestinal inflammation and restoration of the absorptive function of the intestine. NEW & NOTEWORTHY This study is the first, to our knowledge, to determine whether autotoxin (ATX) inhibition improves inflammation and body weights in SAMP1/Fc mice, a mouse model of ileitis. ATX inhibition increased body weights of SAMP1/Fc mice and increased Na + -dependent glucose transporter 1 (SGLT1) expression. Increased SGLT1 expression in the inflamed regions was not a direct effect of cytokines but an indirect effect of increased epithelial cell differentiation upon ATX inhibition.

Aim: This study was designed to compare the efficacy and tolerability of bowel preparations with and without the higher first-dose volume of polyethylene glycol (PEG) solution or exercise after drinking PEG solution in Chinese people., Methods: A total of 330 participants who had a colonoscopy done in Peking Union Medical College Hospital were randomly and evenly assigned to three groups. Participants in Group A ingested 1 L PEG solution and then ingested 2 L PEG solution at a rate of 250 mL every 15 minutes. Participants in Group B ingested 3 L PEG solution at a rate of 250 mL every 15 minutes and then exercised more than 10 minutes after ingesting each liter of PEG solution. Participants in Group C ingested 3 L PEG solution at a rate of 250 mL every 15 minutes. Experienced gastrointestinal endoscopists rated the efficacy of bowel preparations based on the Boston Bowel Preparation Scale score. A questionnaire regarding participants' symptoms associated with bowel preparations was administered to evaluate participants' tolerability., Results: The three groups had insignificant difference in the percentages of participants' symptoms including dizziness, nausea, stomach ache, bloating, and asthenia. However, the percentages of participants having hunger sensation, sleep disturbance, and anal discomfort were significantly higher in groups with the higher first-dose volume of PEG solution or exercise after drinking PEG solution than without them. The three groups had insignificant difference in the Boston Bowel Preparation Scale score., Conclusion: Whether to add the higher first-dose volume of PEG solution and exercise after drinking PEG solution or not, all participants achieved a similar quality of bowel preparations. Bowel preparations without the additional first-dose volume of PEG solution or exercise after drinking PEG solution showed the advantage of high participant tolerability.

Na(+)/H(+) exchanger 3 (NHE3) is the major Na(+) transporter in the intestine. Serum- and glucocorticoid-induced kinase (SGK) 1 interacts with NHE regulatory factor 2 (NHERF2) and mediates activation of NHE3 by dexamethasone (Dex) in cultured epithelial cells. In this study, we compared short-term regulation of NHE3 by Dex in SGK1-null and NHERF2-null mice. In comparison to wild-type mice, loss of SGK1 or NHERF2 significantly attenuated regulation of NHE3 by Dex but did not completely obliterate the effect. We show that transfection of SGK2 or SGK3 in PS120 cells resulted in robust activation of NHE3 by Dex. However, unlike SGK1 or SGK2, SGK3 rapidly activated NHE3 within 15 min of Dex treatment in both PS120 and Caco-2bbe cells. Immunofluorescence analysis showed that SGK3 colocalized with NHE3 in recycling endosomes, whereas SGK1 and SGK2 were diffusely distributed. Mutation of Arg-90 of SGK3 disrupted the endosomal localization of SGK3 and delayed NHE3 activation. Activation of SGK3 and NHE3 by Dex was dependent on phosphoinositide 3-kinase (PI3K) and phosphoinositide-dependent kinase 1 (PDK1), and Dex induced translocation of PDK1 to endosomes. Our study identifies SGK3 as a novel endosomal kinase that acutely regulates NHE3 in a PI3K-dependent mechanism.

Lysophosphatidic acid (LPA) is a lipid mediator that mediates several effects that promote cancer progress. The LPA receptor type 2 (LPA(2)) expression is often elevated in several types of cancers, including colorectal cancer (CRC). In this study, we investigated the role of LPA(2) in the development of intestinal adenomas by comparing Apc(Min/+) mice with Apc(Min/+)/Lpar2(-/-) mice. There were 50% fewer intestinal adenomas in Apc(Min/+)/Lpar2(-/-) mice than Apc(Min/+) mice. Smaller-size adenomas (<1 mm) were found at higher frequencies in Apc(Min/+)/Lpar2(-/-) mice compared with Apc(Min/+) mice at the two age groups examined. The expression level of LPA(2) correlated with increased size of intestinal adenomas. Reduced tumor multiplicity and size in Apc(Min/+)/Lpar2(-/-) mice correlated with decreased proliferation of intestinal epithelial cells. Apc(Min/+)/Lpar2(-/-) mice showed an increased level of apoptosis, suggesting that LPA(2)-mediated signaling stimulates intestinal tumor development and progress by regulating both cell proliferation and survival. In addition, the expression levels of Krüpple-like factor 5 (KLF5), β-catenin, cyclin D1, c-Myc, and hypoxia-inducible factor-1α (HIF-1α) were significantly altered in Apc(Min/+)/Lpar2(-/-) mice compared with Apc(Min/+) mice. In vitro studies using HCT116 cells showed that LPA induced cyclin D1, c-Myc, and HIF-1α expression, which was attenuated by knockdown of LPA(2). In summary, intestinal tumor initiated by Apc mutations is altered by LPA(2)-mediated signaling, which regulates tumor growth and survival by altering multiple targets.