A novel model of adenine-induced chronic kidney disease-associated gastrointestinal dysfunction in mice: The gut-kidney axis.

Although constipation is a common complication of chronic kidney disease (CKD), there is no animal model that can be used to study the association between renal impairment and gastrointestinal function without interfering with the gastrointestinal tract of the model. Therefore, we determined whether adenine could induce CKD in association with gastrointestinal dysfunction. Six-week-old ICR mice were intraperitoneally injected with saline, 25, 50, or 75 mg adenine/kg body weight for 21 days. Blood urea nitrogen (BUN), plasma creatinine, and renal histopathology were evaluated. Defecation status was evaluated from defecation frequency and fecal water content. Colonic smooth muscle contraction was measured by the organ bath technique, and transepithelial electrical resistance (TEER) was measured using an Ussing chamber. In the 50 mg/kg treatment group, BUN and creatinine were significantly increased compared with control, and inflammatory cell infiltration, glomerular necrosis, tubular dilatation, and interstitial fibrosis were observed in renal tissues. Mice in this group also showed a significant decrease in defecation frequency, fecal water content, colonic motility index, and TEER. Overall, 50 mg/kg of adenine was the best dose to induce CKD with associated constipation and intestinal barrier impairment. Therefore, this adenine administration model can be recommended for CKD-associated gastrointestinal dysfunction research.

Asperidines A-C, pyrrolidine and piperidine derivatives from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178.

One new pyrrolidine derivative, asperidine A (1), and two new piperidine derivatives, asperidines B (2) and C (3), were isolated from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178 together with two known alkaloids. Compound 3 possessed an unprecedented 7-oxa-1-azabicyclo[3.2.1]octane skeleton with four chiral centers. Their structures were determined by spectroscopic evidence. The absolute configurations of compounds 2 and 3 were established using Mosher's method and further confirmed for compound 3 by X-ray crystallographic data. Compound 2 dose-dependently inhibited the CFTR-mediated chloride secretion in T84 cells with an IC50 value of 0.96 µM whereas 3 displayed the same activity with the IC50 value of 58.62 µM. Compounds 2 and 3 also significantly reduced intracellular ROS under both normal and H2O2-treated conditions compared with their respective controls in a dose-dependent manner without cytotoxic effect on Caco-2 cells. In addition, compound 3 was inactive against noncancerous Vero cells whereas compound 2 was considered to be inactive with the IC50 value of >10 µM.

A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas.

Overstimulation of CFTR-mediated Cl- secretion plays an important role in the pathogenesis of secretory diarrheas, which remain an important global health problem. This study aimed to identify inhibitors of CFTR-mediated Cl- secretion from a library of fungus-derived compounds and to evaluate their pharmacological properties and anti-diarrheal utility. We identified zearalenone, 7'-dehydrozearalenone and 8'-hydroxyzearalenone isolated from the seagrass-derived fungus Fusarium sp. PSU-ES123 as inhibitors of CFTR-mediated Cl- secretion in human intestinal epithelial (T84) cells. Being the most potent fungal metabolite capable of inhibiting CFTR-mediated Cl- secretion, zearalenone reversibly inhibited CFTR Cl- channel activity in T84 cells with an IC50 of ∼0.5 µM. Functional and biochemical analyses and molecular docking studies indicate that zearalenone binds to the ß-estradiol binding sites in the ATP-binding pockets on NBD1 and NBD2 of CFTR. Mechanisms of CFTR inhibition by zearalenone do not involve activation of phosphodiesterases, protein phosphatases, multidrug-resistance protein 4 and AMP-activated protein kinases. Importantly, zearalenone significantly inhibited cholera toxin (CT)-induced Cl- secretion in T84 cells and blocked CT-induced intestinal fluid secretion in mice. Collectively, our study indicates that zearalenone represents the first class of fungus-derived CFTR inhibitors. Further development of this class of compounds may provide an effective treatment of secretory diarrheas.