Is lactic acid a misunderstood trigger of gout attack for a century?

A gout attack could be viewed as a nucleation event. Many reports have shown that the typical molecular structure of crystallization inhibitors usually contains carboxyl and hydroxyl groups, which could interact with solute molecules through hydrogen bonding, thereby suppressing the nucleation and growth of crystals. Since 1923, l-lactic acid (LA), a molecule with structural features of inhibitors, has been speculated to be a trigger for acute gout because metabolized LA temporarily reduces uric acid excretion and leads to a slow increase in serum uric acid concentration. However, many cases of gout presumably triggered by elevated lactate in a very short period of 4 h are often inexplicable. Here, we present the unexpected result that LA has a significant "opposite effect" on the nucleation and growth of gouty pathological crystals, which is that as the concentration of the additive LA increases, the nucleation and growth of the crystals is suppressed and then facilitated. This approach may help our clarifying the long-standing "misunderstandings" and further understanding the association between metabolized LA and increased risk of gout attacks. Finally, a novel mechanism called "tailed-made occupancy (TMO)" was used to explain the nucleation and crystallization effects of LA on sodium urate monohydrate (MSUM).

Modulation of the dissolution with ASP from a supersaturated solution on a bionic platform for gout pathology crystals.

The core to the treatment of gout is the elimination of pathologic crystal, monosodium urate monohydrate (MSUM). The primary treatment available is to gradually dissolve the "culprit crystals" by lowering the blood uric acid concentration with medications, which often takes a long time and in severe cases must still be treated surgically. Herein, we developed a dynamic bionic platform based on a hydrogel composite membrane (HCM) to screen the direct facilitated solubilization of MSUM crystals by small organic molecules in bionic saturated, or even supersaturated, solutions. The customized and biologically safe (NAGA/PEGDA/NIPAM) HCM, which is consistent with the main amino acid composition of articular cartilage, well mimics the entire process of organic molecules leading to the dissolution of MSUM crystals in the joint system. With the verifications of this platform, it is shown that l-aspartic acid (ASP) significantly promotes the dissolution of MSUM crystals not only in saturated but also in supersaturated solutions. Furthermore, a novel mechanism called "crane effect" was used to explain this "dissolution effect" of ASP on MSUM, which stems from the ability of ASP to lock onto the surface of MSUM crystals through hydrogen bonding by virtue of its two carboxyl groups, and simultaneously its amino group lifts the uric acid molecules from the surface of MSUM crystals by virtue of interactions of hydrogen bonding. The results of bulk crystallization, scanning electron microscopy (SEM), powder X-diffraction (PXRD), and density-functional theory (DFT) studies are quantitatively consistent with this hypothetical "crane effect" mechanism. Hence, this HCM-based functional platform could provide entirely novel ideas and methods for drug design and screening for the treatment of pathological crystal diseases of gout.

Elucidating the mechanism of nucleation inhibition of pathology crystallization of gout based on the evidence from amorphous form and in solution.

The first gout attack in a hyperuricaemic patient may be regarded as a nucleation event which is caused by monosodium urate monohydrate (MSUM) deposition in the synovial fluid. The effect of Tailor-Made Inhibition (TMI) may be effective as drugs for the prevention of aberrant nucleation and crystallization. Therefore, the understanding of the underlying mechanisms in inhibiting the MSUM nucleation by TMI has proven to be of great significance. Yet most of the published studies about nucleation inhibition have tended to focus on simpler molecular models with a hydrogen-bonded acceptor and donor, which may be not suitable for the uric acid molecule with multiple hydrogen-bonded acceptors and donors under physiological conditions. Herein, the mechanisms of nucleation inhibition of MSUM were explored in a simulated biological environment (0.15 M Na+ and pH 7.40) in the presence and absence of TMI. And the evidence of nucleation inhibition by TMI in solution and the amorphous form of MSUM was investigated by HNMR, IR, Raman, PXRD, Dynamic light scattering (DLS), induction time measurements, and density functional theory (DFT) calculations. Results showed that the inhibition comes from a combination of kinetic and thermodynamic effects, with an impact of kinetics as the TMI inhibition effects far exceeded what could be accounted for by changes in usual factors of classical nucleation theory. The data demonstrated that the complex between urate and TMI disturbed the formation of two-dimensional sheets of sodion and purine rings parallel to the (011) plane and further impeded the formation of a three-dimensional structure with aromatic stacking interactions in solution. To our knowledge, the nucleation inhibition of TMI is achieved by suppressing interplanar stacking, which is a mechanism proposed for the first time.