Background: MRP4 is an endogenous transporter of cyclic nucleotides that can regulate cell migration. The role of MRP4 in fibroblast migration is unknown. Results: MRP4-deficient fibroblasts migrate faster and have a moderately higher level of intracellular cyclic nucleotides. Conclusion: Inhibition of MRP4 increases fibroblast migration via alteration of intracellular cyclic nucleotide levels. Significance: Inhibition of MRP4 facilitates wound repair.
Cystic
fibrosis (CF) is a recessive genetic disease caused by mutations
in CFTR, a plasma-membrane-localized anion channel. The most common
mutation in CFTR, deletion of phenylalanine at residue 508 (ΔF508),
causes misfolding of CFTR resulting in little or no protein at the
plasma membrane. The CFTR corrector VX-809 shows promise for treating
CF patients homozygous for ΔF508. Here, we demonstrate the significance
of protein–protein interactions in enhancing the stability
of the ΔF508 CFTR mutant channel protein at the plasma membrane.
We determined that VX-809 prolongs the stability of ΔF508 CFTR
at the plasma membrane. Using competition-based assays, we demonstrated
that ΔF508 CFTR interacts poorly with Na+/H+ exchanger regulatory factor 1 (NHERF1) compared to wild-type CFTR,
and VX-809 significantly increased this binding affinity. We conclude
that stabilized CFTR–NHERF1 interaction is a determinant of
the functional efficiency of rescued ΔF508 CFTR. Our results
demonstrate the importance of macromolecular-complex formation in
stabilizing rescued mutant CFTR at the plasma membrane and suggest
this to be foundational for the development of a new generation of
effective CFTR-corrector-based therapeutics.
Background: Diarrhea is an adverse side effect associated with many therapeutics. Results: Irinotecan induced hyperactive cystic fibrosis transmembrane conductance regulator (CFTR) function by inhibiting multidrug resistance protein 4 (MRP4) and formation of MRP4-CFTR macromolecular complexes. Conclusion: MRP4-CFTR-containing macromolecular complexes play an important role in drug-induced diarrhea. Significance: These studies help define molecular mechanisms of drug-induced diarrhea.
The antidepressant drug amitriptyline hydrochloride was obtained in a dry powder form and was screened against 253 strains of bacteria which included 72 Gram positive and 181 Gram negative bacteria and against 5 fungal strains. The minimum inhibitory concentration (MIC) was determined by inoculating a loopful of an overnight peptone water culture of the organism on nutrient agar plates containing increasing concentrations of amitriptyline hydrochloride (0, 10 µg/mL, 25 µg/mL, 50 µg/mL, 100 µg/mL, 200 µg/mL). Amitriptyline hydrochloride exhibited significant action against both Gram positive and Gram negative bacteria at 25-200 µg/mL. In the in vivo studies it was seen that amitriptyline hydrochloride at a concentration of 25 µg/g and 30 µg/g body weight of mouse offered significant protection to Swiss strain of white mice when challenged with 50 median lethal dose (MLD) of a virulent strain of Salmonella typhimurium NCTC 74. The in vivo data were highly significant (p<0.001) according to the chi-square test.
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