pregnane X receptor and constitutive androstane receptor modulate differently CYp3A-mediated metabolism in earlyand late-stage cholestasis

AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of pregnane X receptor(PXR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3 A1 and CYP3 A2 were assessed by means of q RT-PCR and Western blot, respectively. Alterations in CYP3 A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3 A enzymes.RESULTS The m RNA and protein expression of CYP3 A1 increased significantly in mild cholestasis(P < 0.01). At variance, m RNA and protein expression of CYP3 A2 didn't change in mild cholestasis, whereas the expression and activity of both CYP3 A1 and CYP3 A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.CONCLUSION Early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3 Amediated liver detoxification.

Plasma small-extracellular vesicles enriched in miR-122-5p promote disease aggressiveness in pediatric anaplastic large-cell lymphoma

Dear Editor,Anaplastic lymphoma kinase-positive(ALK+)anaplastic large cell lymphoma(ALCL)is an aggressive peripheral Tcell lymphoma representing 10%-15%of pediatric lymphoid neoplasms.The constitutively activated nucleophosmin-ALK(NPM-ALK)fusion protein is the main driver of ALK+ALCL oncogenesis[1].Current clinical protocols can achieve high cure rates,with 75%event-free survival(EFS)at 5 years[2],but the patients’outcome with relapsed/refractory disease still remains poor[3].Liquid biopsy is widely applied for the prognostic and therapeutic stratification of onco-hematological patients.As a non-invasive procedure,it can be used to identify several biomarkers,such as small extracellular vesicles(S-EVs)[4].S-EVs are stable carriers of molecules that mediate genetic exchange between distant cells,alter the microenvironment,facilitate cancer cell progression and promote drug resistance[5].