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Background Fibrosis is a common pathogenesis in most diseases, thus different diseases may share targets and drugs related to fibrosis. For a drug that targets fibrotic process, it is likely an effective drug for treating diseases other than its original purpose. Therefore, the current study aimed to investigate the anti-fibrosis characteristic of drugs for repositioning purpose. Method Anti-fibrosis compounds identified from PubMed and ClinicalTrials.gov were selected as positive samples. FDA-approved drugs from DrugBank and compounds from Connectivity Map (CMap) were selected as potential negative samples after excluding those compounds known as anti-fibrosis drugs. MACCS Keys fingerprint (RDKit) and molecule-stimulated gene signatures (CMap) are collected as the structural descriptors and transcriptomic profiles of compounds respectively. OneClassSVM was used to remove outliers. Gradient Boosting Classifier was performed to build a Structural Model based on molecular structures and to build a Gene Mode...

In the present study, the intracellular regulatory pathways involved in the adrenalin-stimulated chloride secretion across T84 cells were investigated. Biphasic characteristics were observed in the Isc response to the basolateral addition of adrenalin (0.25 nM–100 μM). The biphasic response was almost abolished by removing ambient Cl − . Chloride secretion was found to depend on the activities of basolaterally located Na + -K + -2Cl − cotransporters and K + channels. The α-adrenoceptor antagonist phentolamine did not have any effect on either phase of adrenalin-induced Isc, while after pretreatment of the β-adrenoceptor antagonist propranolol, the adrenalin-induced Isc was substantially abolished, suggesting the biphasic response may be mediated by the β-adrenoceptor. Under whole cell patch-clamp conditions, T84 cells responded to adrenalin with a rise in inward current. The current, which exhibited a linear I–V relationship and time- and voltage-independent characteristics, was inhibited by the chloride channel blocker DPC and the reverse potential was close to the equilibrium potential for Cl − (0 mV), implying that the current was Cl − selective. When preloaded with a Ca 2+ -chelating agent, BAPTA/AM did not affect the Isc response to adrenalin, whereas the Isc was destroyed by pretreating the cells with an adenyl cyclase inhibitor, MDL12330A. These observations were further supported by the intracellular [cAMP] measurement experiment, indicating that adrenalin induced chloride secretion could be mediated by a beta-adrenoceptor only involving cAMP as an intracellular second messenger.

TMT (trimethyltin chloride), an organotin, is ubiquitous in the environment. The consumption of contaminated food may cause exposure of the human diet to this toxic compound. The present study was to investigate the effects of TMT on the regulation of ion transport across the rat distal colon. The rat colonic mucosa was mounted in Ussing chambers. The effects of TMT were assessed using the Isc (short-circuit current). Both apical and basolateral TMT induced, dose-dependently, an increase in Isc, which was due to a stimulation of Cl- secretion as measured using ion substitution experiments and pharmacological manoeuvres. The secretion was also inhibited by several K+ channel blockers administrated at the basolateral side. When the apical side was permeabilized by nystatin, the TMT-induced K+ conductance was effectively blocked by tetrapentylammonium, a Ca2+-sensitive K+ channel blocker. The response of TMT was sensitive to the basolateral Ca2+ and the intracellular Ca2+ store, which could be disclosed by applying the inhibitors of ryanodine receptors and inositol 1,4,5-trisphosphate receptors. In conclusion, TMT led to Cl- secretion, which was essentially regulated by basolateral Ca2+-sensitive K+ channels. These results suggest the importance of K+ channels in the toxicity hazard of TMT.