Application of metabolomics in urolithiasis: the discovery and usage of succinate

Abstract

Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate monohydrate (COM) during stone formation is regulated by crystal growth modifiers. Although crystallization inhibitors have been recognized as a therapeutic modality for decades, limited progress has been made in the discovery of effective modifiers to intervene with stone disease. In this study, we have used metabolomics technologies, a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model. By in-depth mining and analysis of metabolomics data, we have screened five differential metabolites. Through density functional theory studies and bulk crystallization, we found that three of them (salicyluric, gentisic acid and succinate) could effectively inhibit nucleation in vitro. We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones. Notably, succinate, a key player in the tricarboxylic acid cycle, could decrease kidney calcium deposition and injury in the model. Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation, inhibition of cell adhesion and osteogenic differentiation. These findings indicated that succinate may provide a new therapeutic option for urinary stones.

Unveiling of Indanone‐Benzimidazole Hybrids as Anti‐Alzheimer's Agents: Computational and Experimental Studies

“…Aggregation of A β peptide is commonly believed to be central to the induction of AD, but the mechanism of toxicity is still unclear [38] . The intensely studied nematode worm C. elegans can be transgenically engineered to express human A β .…”

“…Aggregation of Aβ peptide is commonly believed to be central to the induction of AD, but the mechanism of toxicity is still unclear. [38] The intensely studied nematode worm C. elegans can be transgenically engineered to express human Aβ. Depending on the timing of Aβ expression, these worms can have measurable phenotypes that functions as a read-out of Aβ toxicity.…”

Management of Pediatric Urolithiasis in an Italian Tertiary Referral Center: A Retrospective Analysis

“…Moreover, studying the metabolome could provide clues to systemic or intrarenal differences that influence unrecognized steps in kidney stone pathogenesis. A metabolomics approach can be used to investigate the serum and urine of patients with kidney stones, with the aim of discovering abnormal metabolic pathways involved in urolithiasis and identifying novel markers for the diagnosis of kidney diseases associated with this condition [62]. A recent study evaluated the metabolite profiles of serum from children with urolithiasis and normal controls using ultra-performance liquid chromatography-mass spectrometry [63].…”

Understanding formation processes of calcareous nephrolithiasis in renal interstitium and tubule lumen

“…Vinaiphat and colleagues demonstrated that PMCA2 acts as a receptor for COM crystals and is involved in crystal adhesion 143 . Zhang and colleagues reported that succinate can inhibit crystal adhesion, thus preventing stone formation 144 . Mulay and colleagues discovered that TNFR signalling actively contributed to the initiation of CaOx crystal adhesion, and blocking TNFR therapeutically may slow down the process of stone formation 145 .…”