| Kidney stone is a common disease of urinary system with high prevalence and recurrence rate.Recently,developing inhibitors is regarded as an important strategy for stones treatment.However,ambiguous crystallization pathways and regulation mechanism of stone components and complex inhibitor-crystal surface interactions cannot give inspire of the development of new inhibitor drugs.To break through above problems and guide the development of stone inhibitors,this paper discovers new stone inhibitors from the ingredients of traditional Chinese medicines used for the treatment of kidney stones,reveals the nucleation and growth mechanism of calcium oxalate crystal(Ca Ox,the main component of kidney stones),and investigates the interaction mode between inhibitors and crystals.Firstly,by quantifying the inhibition efficacy of Chinese medicine extracts on Ca Ox crystallization kinetics and identifying the active ingredients,13 kinds of new and effective Ca Ox inhibitors have been discovered,wherein polyphenols display the most effective inhibition performance.Moreover,the protection of inhibitor molecules on renal epithelial cells in supersaturated Ca Ox solution,inhibition of supersaturated solution nucleation and crystal adhesion on surface of cells confirm the potential of natural inhibitors on inhibition of stone formation.Structure-performance relationship analysis shows that the potential of inhibitors on Ca Ox crystallization suppression mainly depends on p Ka values(<3.5)and the number of donor hydrogen in molecular structure(>0.1 mmol).Secondly,this work explored the regulation mechanism and influence factors of new inhibitors action on the nucleation of different Ca Ox hydrates.The results reveal that in different supersaturated solutions pre-nucleation Ca Ox clusters with different structures firstly form,leading to the nucleation of amorphous Ca Ox with different short-range structures and final transformation of different hydrates crystals.Based on the nucleation differences,we investigated the role of inhibitors with different structures on Ca Ox nucleation,and the aim of Ca Ox monohydrate(COM)inhibition and promotion of dihydrate(COD)and trihydrate(COT)was accomplished.Moreover,the molecular simulation reveals the important role of the affinity between inhibitors and water molecules in solution in controlling nucleation of Ca Ox hydrates.Subsequently,this paper explored the action mechanism of several natural polyphenols on Ca Ox crystal growth.The bulk crystallization experiment shows that the number of gallic group in structure were found to affect the inhibition of natural polyphenols on Ca Ox crystallization.But online and in situ single crystal growth experiments show that these polyphenols serve as both growth promotor and inhibitor for COM crystal growth.At lower concentration,we found these polyphenols can alter fundamental growth mode from spiral to 2D layer growth,resulting in the formation of macroscopically single crystal whiskers.While at higher concentration,polyphenol molecules,adsorbing on crystal surfaces and suppressing step advancement,show complete inhibition of nucleation and growth with far better inhibitory efficacy than commercial inhibitor,citrate.The governing regime between growth promotion and inhibition is determined by concentration of inhibitor,but can be influenced by crystallization driving force.Finally,based on the investigation of inhibition mechanism of natural small polyphenols(ellagic acid,gallic acid,pyrogallol and protocatechuic acid)on Ca Ox crystal growth,and the cooperativity of inhibitor pairs was investigated.It was found that whether inhibitors possess the identical action mechanisms on COM crystal growth,the combination of Ca Ox inhibitors show the synergistic cooperativity of "1+1>2".This conclusion provides a new idea for the development of drugs in the treatment of stones and drug-drug combinations may achieve better stone inhibition effects. |
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