Fig. 1.

Molecular mechanisms of the anti-urolithic effect of D. styracifolium polyphenols. These compounds influence the key links of nephrolithiasis pathogenesis: they reduce the ROS/RNS-dependent nuclear translocation of NF-κB and p38 MAPK activation, as well as inhibit the NLRP3 inflammasome, both directly and by suppressing the autophagy signalling pathway. As a result, the expression of pro-oxidant and pro-inflammatory genes (Cyp7b, Cyp2C11, Cyp2E1, gp91phox, inducible NO-synthase, tumour necrosis factor-α, interleukins 1β and 6, chemokines, cathepsins, phospholipase A2, cyclooxygenase 2, etc.) decreases, along with the attenuation of inflammasome-dependent inflammatory cytokine activation. This, in turn, interrupts positive feedback loops that amplify the production of ROS/RNS and other inducers of NF-κB, p38 MAPK, and autophagy. Moreover, several polyphenols have the ability to inhibit p38 MAPK and its dependent expression of hyaluronic acid, osteopontin, and CD44, thereby altering the adhesion of renal tubular epithelial cells to calcium oxalate crystals and lowering intensity of crystallization and nephrolithiasis. Note: CaOx – Calcium oxalate; CNP – Calcifying nanoparticles; ER – endoplasmic reticulum; HA - Hyaluronic acid; IL – Interleukin; MT-mitochondrion; NF-κB – Nuclear Factor κB; NLRP3 – NOD-like receptor pyrin domain-containing protein 3; OPN – Osteopontin; ROS – Reactive Oxygen Species; RNS – Reactive Nitrogen Species. Polyphenols: Ap – Apigenin; Ge – Genistein; Kf – Kaemferol; Lu – Luteolin; Qr – Quercetin.