Abstract
Ceterach officinarum Willd is a plant widespread throughout Europe and used in southern Italy as a diuretic. Beliefs in the benefits of C. officinarum aqueous extract in the treatment of calcium oxalate kidney stones are widely held. Little is known, however, about the actual mechanism of its antilithiatic action. Our results in this in vitro study corroborate C. officinarum aqueous extract as a good source of antioxidants with a high antioxidant effects. Our results also demonstrate a major impact of C. officinarum aqueous extract on in vitro induced calcium oxalate crystallization kinetics and crystal morphology, showing its critical role in kidney stone formation and/or elimination. We show that progressively increasing doses of C. officinarum aqueous extract cause a sequence of effects. A powerful inhibitory action on calcium oxalate monohydrate (COM) growth and aggregation is first observed. C. officinarum aqueous extract also appears highly effective in stimulating nucleation increasing the number and reducing the size of COM crystals, which become progressively thinner, rounded and concave in a dose-dependent manner. These shape-modified COM crystals are known to be less adherent to renal tubular cells and more easily excreted through the urinary tract preventing kidney stone formation. Further, C. officinarum aqueous extract promotes the formation of calcium oxalate dihydrate (COD) rather than the monohydrate so that, at the highest concentrations used, only COD crystals are observed, in significant greater numbers with a clear reduction in their size, in a dose-dependent manner. Furthermore, AFM analyses allowed us to reveal the presence of C. officinarum component(s) on the surfaces of COD and modified COM crystals. The crystal surface adsorbed component(s) are shown to be similarly active as the total aqueous extract, suggesting a trigger factor which may direct crystal modification towards COD forms. In urolithiasis pathogenesis COD crystals are less dangerous than the COM forms due to their lower affinity for renal tubular cells. Our results are important in understanding the mechanisms which guide the modification induced by C. officinarum on the crystallization process. Based on these data, together with no adverse toxic effect being observed on the in vitro model of human intestinal enterocytes, C. officinarum aqueous extract could represent an attractive natural therapy for the treatment of urolithiasis.
Highlights
Urolithiasis is a common and frequent human pathology [1] characterized by a high recurrence rate, complex pathophysiological bases and multifactorial etiology [2]
The antioxidant activity of C. officinarum aqueous extract (AE) was measured in terms of radical scavenging ability using Oxygen radical absorbance capacity (ORAC) [38] and DPPH radical scavenging assays [39]
Because crystal retention has been shown to be a critical factor in stone generation [6,7,8,9,10,11], the interference with calcium oxalate (CaOx) crystallization and retention processes could provide a useful therapeutic approach to preventing and controlling recurrent stone formation
Summary
Urolithiasis is a common and frequent human pathology [1] characterized by a high recurrence rate, complex pathophysiological bases and multifactorial etiology [2]. Stone formation proceeds through various and complex physicochemical steps beginning with crystal nucleation and growth, followed by aggregation, crystal adhesion on renal tubular cells, and internalization into renal epithelial cells [4]. All of these processes occur in a complex environment containing both promoters and inhibitors [5] and when crystals nucleate, grow and are retained within the kidney, they lead to injuries in renal epithelial cells creating stone nidi [6]. Renal exposure to oxalate leads to reactive oxygen species products with subsequent lipid peroxidation and modification of cell structure, physiology, gene expression and cell death [2, 12,13]
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