l-Proline-based-cyclic dipeptides from Pseudomonas sp. (ABS-36) inhibit pro-inflammatory cytokines and alleviate crystal-induced renal injury in mice

Abstract Study on the constituents of bioactive culture broth extract (CBE) of Pseudomonas sp. (ABS-36) explored the secretion of an array of cyclic dipeptides (CDPs) and twenty of them had been isolated and reported in the present paper. Six major CDPs [(cyclo(Leu-Pro) ( 1 ), cyclo(Val-Pro) ( 2 ), cyclo(Leu-hydroxy-Pro) ( 9 ), cyclo(Pro-Tyr) ( 10 ), cyclo(Pro-Ala) ( 11 ) and cyclo(Gly-Pro) ( 12 )] exhibited pan cytokine inhibition effect by inhibiting key pro-inflammatory cytokines IL-1β, TNF-α and IL-6 tested under various cell based assays. With this background, the effect of these six CDPs in treating renal inflammation was screened using crystal-induced nephropathy model in mice at 50 mg/kg body weight through oral administration. cis -Cyclo(Val-Pro) ( 2 ) exhibited 57% inhibition of plasma IL-1β protein expression and 35.2% inhibition of elevated blood urea nitrogen. Further, cis -cyclo(Val-Pro) ( 2 ) attenuated renal injury as demonstrated by significant reduction of mRNA expressions of IL-1β ( P P cis -cyclo(Val-Pro) ( 2 ). All the tested CDPs reduced the nitrite production and were interestingly non-cytotoxic.