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

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.

Ginsenoside modified lipid-coated perfluorocarbon nanodroplets: A novel approach to reduce complement protein adsorption and prolong in vivo circulation

Lipid-coated perfluorocarbon nanodroplets(lp-NDs)hold great promise in bio-medicine as vehicles for drug delivery,molecular imaging and vaccine agents.However,their clinical utility is restricted by limited targeted accumulation,attributed to the innate immune system(IIS),which acts as the initial defense mechanism in humans.This study aimed to optimize lp-ND formulations to mini-mize non-specific clearance by the IIS.Ginsenosides(Gs),the principal components of Panax ginseng,possessing complement inhibition ability,structural similarity to cholesterol,and comparable fat solubi-lity to phospholipids,were used as promising candidate IIS inhibitors.Two different types of ginsenoside-based Ip-NDs(Gs Ip-NDs)were created,and their efficacy in reducing IS recognition was examined.The Gs p-NDs were observed to inhibit the adsorption of C3 in the protein corona(PC)and the generation of SC5b-9.Adding Gs to Ip-NDs reduced complement adsorption and phagocytosis,resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs.These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants,potentially reducing non-specific clear-ance by the IS and improving lifespan.

FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury

Acute kidney injury(AKI)is a serious clinical complication with high morbidity and mortality rates.Despite substantial progress in understanding the mechanism of AKI,no effective therapy is available for treatment or prevention.We previously found that G protein-coupled receptor(GPCR)family member free fatty acid receptor 4(FFAR4)agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice.However,the versatile role of FFAR4 in kidney has not been well characterized.In the study,the expression of FFAR4 was abnormally decreased in tubular epithelial cells(TECs)of cisplatin,cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice,respectively.Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage,whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice.Notably,FFAR4,as a key determinant,was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs,which was indicated by senescence-associatedβ-galactosidase(SA-β-gal)activity,marker protein p53,p21,Lamin B1,phospho-histone H2A.X,phospho-Rb expression,and secretory phenotype IL-6 level.Mechanistically,pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein,where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and TECs.These findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.

Application of antibody-conjugated small intestine submucosa to capture urine-derived stem cells for bladder repair in a rabbit model

The need for bladder reconstruction and side effects of cystoplasty have spawned the demand for the development of alternative material substitutes.Biomaterials such as submucosa of small intestine(SIS)have been widely used as patches for bladder repair,but the outcomes are not fully satisfactory.To capture stem cells in situ has been considered as a promising strategy to speed up the process of re-cellularization and functionalization.In this study,we have developed an anti-CD29 antibody-conjugated SIS scaffold(AC-SIS)which is capable of specifically capturing urine-derived stem cells(USCs)in situ for tissue repair and regeneration.The scaffold has exhibited effective capture capacity and sound biocompatibility.In vivo experiment proved that the AC-SIS scaffold could promote rapid endothelium healing and smooth muscle regeneration.The endogenous stem cell capturing scaffolds has thereby provided a new revenue for developing effective and safer bladder patches.

Procyanidins-crosslinked small intestine submucosa: A bladder patch promotes smooth muscle regeneration and bladder function restoration in a rabbit model

Currently the standard surgical treatment for bladder defects is augmentation cystoplasty with autologous tissues,which has many side effects.Biomaterials such as small intestine submucosa(SIS)can provide an alternative scaffold for the repair as bladder patches.Previous studies have shown that SIS could enhance the capacity and compliance of the bladder,but its application is hindered by issues like limited smooth muscle regeneration and stone formation since the fast degradation and poor mechanical properties of the SIS.Procyanidins(PC),a natural bio-crosslinking agent,has shown anti-calcification,anti-inflammatory and anti-oxidation properties.More importantly,PC and SIS can crosslink through hydrogen bonds,which may endow the material with enhanced mechanical property and stabilized functionalities.In this study,various concentrations of PC-crosslinked SIS(PC-SIS)were prepared to repair the full-thickness bladder defects,with an aim to reduce complications and enhance bladder functions.In vitro assays showed that the crosslinking has conferred the biomaterial with superior mechanical property and anti-calcification property,ability to promote smooth muscle cell adhesion and upregulate functional genes expression.Using a rabbit model with bladder defects,we demonstrated that the PC-SIS scaffold can rapidly promote in situ tissue regrowth and regeneration,in particular smooth muscle remodeling and improvement of urinary functions.The PC-SIS scaffold has therefore provided a promising material for the reconstruction of a functional bladder.