Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat dietinduced colonic inflammation,

The precipitation of calcium oxalate can be either grown into structural support in plants or precipitated as stones in human kidneys. Previously, citrate, an effective inhibitor for oxalate stone formation, was suggested to alter the crystallization pathway of calcium oxalate and enhance the formation of less stable calcium oxalate trihydrate; however, the underlying mechanism is unknown. Herein we investigated the role of citric acid on crystallization pathways of calcium oxalate hydrates and the effect of supersaturation. It was found that the presence of citric acid can modulate the water content of amorphous nucleated precipitates by TEM and XRD and hence promote the formation of different calcium oxalate hydrates. The remaining water content in amorphous precipitates depends upon the amount of citric acid employed. FTIR and XRD analyses further reveal the extreme structural similarities between amorphous precipitates and the resultant hydrates. Additionally, the role of citric acid on crystallization pathways could be completely changed by supersaturation of calcium oxalate. High supersaturation dominated by homogeneous nucleation can diminish or even invalidate citric acid roles. The findings highlight the interplay of roles between additives and supersaturations, and could improve current understandings on the formation mechanism of oxalate stone.

We recently have proved that excessive fecal DCA caused by high-fat diet may serve as an endogenous danger-associated molecular pattern to activate NLRP3 inflammasome and thus contributes to the development of inflammatory bowel disease (IBD). Moreover, the effect of DCA on inflammasome activation is mainly mediated through bile acid receptor sphingosine-1-phosphate receptor 2 (S1PR2); however, the intermediate process remains unclear. Here, we sought to explore the detailed molecular mechanism involved and examine the effect of S1PR2 blockage in a colitis mouse model. In this study, we found that DCA could dose dependently upregulate S1PR2 expression. Meanwhile, DCA-induced NLRP3 inflammasome activation is at least partially achieved through stimulating extracellular regulated protein kinases (ERK) signaling pathway downstream of S1PR2 followed by promoting of lysosomal cathepsin B release. DCA enema significantly aggravated DSS-induced colitis in mice and S1PR2 inhibitor as well as inflammasome inhibition by cathepsin B antagonist substantially reducing the mature IL-1β production and alleviated colonic inflammation superimposed by DCA. Therefore, our findings suggest that S1PR2/ERK1/2/cathepsin B signaling plays a critical role in triggering inflammasome activation by DCA and S1PR2 may represent a new potential therapeutic target for the management of intestinal inflammation in individuals on a high-fat diet.

The solubility data of probenecid in 12 different organic solvents including methanol, methyl acetate, ethanol, ethyl acetate, n-propanol, n-butanol, butyl acetate, n-pentanol, isopropanol, isobutanol, acetone, and methyl tert-butyl ether was measured using the gravimetric method over the temperatures range from 283.15 to 323.15 K at 0.1 MPa. The acetone had much higher solubility to probenecid than to other solvents. Three models, including the modified Apelblat equation, the van’t Hoff model, and the nonrandom two-liquid (NRTL) model, were applied to correlate the measured solubility data. The correlation results were evaluated by the average relative deviation (ARD). All of the ARD values were less than 4.522%, which indicated that the three models have a satisfactory correlation. The thermodynamic properties of mixing of probenecid in 12 pure organic solvents including the enthalpy of mixing, Gibbs energy of mixing, and entropy of mixing were calculated by the NRTL model using the correlation results.

Herein, we developed the strategy of additive-induced polymorph, realizing the selective crystallization of elusive Form-II of γ-aminobutyric acid, a potent bioactive compound. A series of sodium carboxylate additives with different carbon chain lengths (C2–C8) were identified to induce the crystallization of Form-II. It was found that additive molecules will inhibit the growth of the centrosymmetric Form-I at two opposite ends, thereby precluding it, but they will inhibit the growth of the polar Form-II at only one end so that it survives. Notably, these sodium carboxylate additives exhibited distinct inducing ability for Form-II; that is, the effective critical addition amount required to induce Form-II increases with the increase of carbon chain length. However, the sodium formate is an exception and it cannot induce the Form-II. The difference of the inducing ability of additives was rationalized based on the competition of attachment and detachment behavior of additives on the growth end of Form-I. When the extent to which the attachment is more favorable than the detachment is larger, the corresponding additive exhibits a better inhibition effect on Form-I and more remarkable inducing ability for Form-II.

This study exploited a mechanochemical strategy to discover new polymorphs of a drug and meanwhile realize the selective preparation of various polymorphs without using bulk solvents. It is worth noting that in practice, the mechanochemical approach is a unique green and highly efficient method. On the one hand, about 20 years after the last discovery of the γ-aminobutyric acid (GABA) polymorph, we identified a new GABA polymorph (Form-III) by mechanochemical milling. Form-III is available exclusively by milling at present, and its crystal structure is also determined by crystal structure prediction (CSP) methods. On the other hand, through introducing a trace amount of solvents with different hydrogen bond donor/acceptor (α/β) abilities, we can achieve selective control of three GABA polymorphs during the milling process, which is not accessible by the traditional solution-based method. The mechanism of trace solvent-directed polymorphic outcomes was investigated from the change of the stability relationship between different polymorphs under milling conditions. As the milling proceeds, the crystal size decreases and the surface effect becomes significant so that the surface stability will dominate the overall stability. The adsorption of solvents with different α and β values on the crystal surface will affect the surface stability of various GABA polymorphs. Consequently, the polymorph with higher stability is able to survive under milling conditions.

No abstract

No abstract