Effect of Steel Slag on Hydration Kinetics and Rheological Properties of Alkali-Activated Slag Materials: A Comparative Study with Fly Ash.

The effects of steel slag (SS) and fly ash (FA) on hydration heat, fluidity, setting time and rheological properties of alkali-activated slag (AAS) pastes with different silicate modulus (Ms) values were comparatively investigated. The results show that the incorporation of SS shortens the induction period, increases the cumulative hydration heat, improves the initial fluidity and decreases the setting time at low Ms, but the opposite trend is found at high Ms. FA significantly retards the reaction, reduces the hydration heat, increases the fluidity and prolongs the setting time. The addition of SS or FA reduces the yield stress and plastic viscosity of AAS paste. SS improves the rheological properties of AAS paste more significantly than that of FA at high Ms. The yield stress and plastic viscosity of AAS paste with SS or FA rise with the increasing Ms and decline with the increasing water/binder (w/b) ratio.

Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones.

The shortage of cholesterol gallstones treatment intensifies the need to discover of effective small molecule drugs. Clinical follow-up and studies have found that activation of somatostatin receptor subtype 5 (SSTR5) reduce gallbladder contraction and thus increase the risk of cholesterol gallstones, implying that antagonizing SSTR5 may promote gallbladder emptying and reduce the formation of gallstones. Herein, we discovered novel SSTR5 antagonists and firstly investigated its effects on cholesterol gallstone. From loperamide, a reported seed structure with micromole activity, we identified optimal compound 23 as an SSTR5 antagonist exhibiting single-digit nanomolar potency, low hERG inhibition and oral availability. Further in vivo evaluation revealed that 23 significantly promoted gallbladder emptying. Moreover, in a mouse cholesterol gallstone model, 23 (3 mg/kg) effectively reduced the cholesterol gallstones formation, showing better efficacy than the clinical first-line drug UDCA (60 mg/kg), providing a new insight into the development of anti-gallstone drugs.

TGR5 agonist inhibits intestinal epithelial cell apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway and ameliorates dextran sulfate sodium-induced ulcerative colitis.

Excessive apoptosis of intestinal epithelial cell (IEC) is a crucial cause of disrupted epithelium homeostasis, leading to the pathogenesis of ulcerative colitis (UC). The regulation of Takeda G protein-coupled receptor-5 (TGR5) in IEC apoptosis and the underlying molecular mechanisms remained unclear, and the direct evidence from selective TGR5 agonists for the treatment of UC is also lacking. Here, we synthesized a potent and selective TGR5 agonist OM8 with high distribution in intestinal tract and investigated its effect on IEC apoptosis and UC treatment. We showed that OM8 potently activated hTGR5 and mTGR5 with EC50 values of 202 ± 55 nM and 74 ± 17 nM, respectively. After oral administration, a large amount of OM8 was maintained in intestinal tract with very low absorption into the blood. In DSS-induced colitis mice, oral administration of OM8 alleviated colitis symptoms, pathological changes and impaired tight junction proteins expression. In addition to enhancing intestinal stem cell (ISC) proliferation and differentiation, OM8 administration significantly reduced the rate of apoptotic cells in colonic epithelium in colitis mice. The direct inhibition by OM8 on IEC apoptosis was further demonstrated in HT-29 and Caco-2 cells in vitro. In HT-29 cells, we demonstrated that silencing TGR5, inhibition of adenylate cyclase or protein kinase A (PKA) all blocked the suppression of JNK phosphorylation induced by OM8, thus abolished its antagonizing effect against TNF-α induced apoptosis, suggesting that the inhibition by OM8 on IEC apoptosis was mediated via activation of TGR5 and cAMP/PKA signaling pathway. Further studies showed that OM8 upregulated cellular FLICE-inhibitory protein (c-FLIP) expression in a TGR5-dependent manner in HT-29 cells. Knockdown of c-FLIP blocked the inhibition by OM8 on TNF-α induced JNK phosphorylation and apoptosis, suggesting that c-FLIP was indispensable for the suppression of OM8 on IEC apoptosis induced by OM8. In conclusion, our study demonstrated a new mechanism of TGR5 agonist on inhibiting IEC apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway in vitro, and highlighted the value of TGR5 agonist as a novel therapeutic strategy for the treatment of UC.

Design and exploration of gut-restricted bifunctional molecule with TGR5 agonistic and DPP4 inhibitory effects for treating ulcerative colitis.

Ulcerative colitis (UC) is a gastrointestinal disease with complex etiology, and the shortage of the treatment further intensifies the need to discover new therapies based on novel mechanisms and strategies. TGR5 and DPP4 are beneficial to treat UC through multiple mechanisms, notably increasing GLP-2 levels by promoting secretion and inhibiting degradation respectively. However, some unwanted systemic effects caused by systemic exposure hinder development, especially the gallbladder-filling effects. Herein, we firstly reported a series of high-potency gut-restricted TGR5-DPP4 bifunctional molecules by gut-restriction and multitarget strategies to utilize the positive impacts of TGR5 and DPP4 on UC and avoid unwanted systemic effects. In particularly, racemic compound 15, a high-potency TGR5-DPP4 bifunctional molecule, showed favorable intestinal distribution, preferable efficacy in mice colitis model and good gallbladder safety. Therefore, the feasibility of gut-restricted TGR5-DPP4 bifunctional molecule was confirmed for the treatment UC, providing a new insight into the development of anti-UC drugs.

Influence of Copper and Zinc Tailing Powder on the Hydration of Composite Cementitious Materials.

Copper and zinc tailing powder (CZTP) is finely ground waste after copper minerals and zinc minerals have been extracted from ores during beneficiation. CZTP has certain potential cementitious properties and can be used in composite cementitious materials. The pore size distribution and hydrate phase assemblage of the hardened samples are investigated using MIP and XRD. SEM is employed to examine the microstructure of the specimens. The chemically bonded water is used to measure the degree of hydration. CZTP lowers the hydration heat evolution rate and the total hydration heat. The hydration heat evolution rate reduces as the w/b ratio rises, whereas the total hydration heat of blended cement paste rises. CZTP diminishes the strength development of the Portland-CZTP system, and the strength decreases as the CZTP level increases. CZTP reduces the critical pore diameters of the Portland-CZTP system with w/b = 0.3 after curing for 3 d and 28 d, while increasing the critical pore diameters of samples with w/b = 0.45 at the same age. CZTP increases the gel micropores of Portland-CZTP. Although CZTP increases the pore volume content of blended cement pastes with w/b = 0.3, the volume of harmful pores decreases. The pore volume content of the Portland-CZTP system decreases as the w/b ratio increases. However, the volume of harmful pores increases with a higher w/b ratio. The main hydration products in the Portland-CZTP system are portlandite, ettringite, and C-S-H. CZTP mainly played the role of filling or acting as a microaggregate in the Portland-CZTP system.

Hydration and Properties of Magnesium Potassium Phosphate Cement Modified by Granulated Blast-Furnace Slag: Influence of Fineness.

Magnesium potassium phosphate cement (MKPC) is an excellent rapid repair material for concrete, and many mineral admixtures have been applied to promote its performance. This study focuses on the quantitative characterization of the physical and chemical contributions of granulated blast-furnace slag with various finenesses to the performance development of MKPC. It was found that the addition of slag could increase the setting time, which is mainly due to the dilution of cement. Fine slag tends to decrease the fluidity of MKPC mortar. The physical contributions of ordinary and ultrafine slag to the early performance of MKPC mortar are 23% and 30%, while the chemical contributions are only 6%~10%. At late ages, the physical contribution is less than 10% and the chemical contribution of slag is even slightly negative. The addition of slag is beneficial to the compact packing of MKPC, which is the main reason for the physical contribution. Slag could react in the MKPC system, and increasing the fineness significantly promotes the reaction kinetics.

Properties of Blended Cement Containing Iron Tailing Powder at Different Curing Temperatures.

The properties of blended cement containing 0%, 20%, and 50% iron tailing powder (ITP) at 20 °C and 60 °C were investigated by determining the hydration heat, microstructure, and compressive strength. The addition of ITP decreases the exothermic rate and cumulative hydration heat of blended cement at 20 °C. The high temperature increases the hydration rate and leads to the hydration heat of blended cement containing 20% ITP higher than that of Portland cement. Increasing the amount of ITP decreases the non-evaporable water content and Ca(OH)2 content as well as compressive strength at both of the two studied temperatures. The addition of ITP coarsens the early-age pore structure but improves the later-age pore structure at 20 °C. The high temperature significantly improves the early-age properties of blended cement containing ITP, but it is detrimental to the later-age properties development. The reaction of ITP is limited even at high temperature. The large ITP particles bond poorly with surrounding hydration products under early high-temperature curing condition. The properties of blended cement containing a large amount of ITP are much poorer at high temperature.

Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects.

The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 agonists with soft-drug designation had been designed and synthesized with the properties of rapid metabolized after drug effect. Among them, compound 19 showed negligible systemic exposure and favorable gallbladder safety on a 3-day continuous administration, providing a novel strategy for developing TGR5 agonists.

Quantification of microbiota-related phenols and aromatic acids in mouse feces of a diabetic nephropathy model by simultaneous BDAPE derivatization using ultra-performance liquid chromatography-tandem mass spectrometry.

In the intestine, several phenols and aromatic acids are generated by microbiota and are highly related to the formation of uremic toxins. Herein, we developed a new derivatization reagent, 2-bromo-1-[4-(dimethylamino)phenyl] ethyl ketone (BDAPE), that reacted simultaneously with phenols and aromatic acids. Following a reaction within 2 h at 60 °C in the presence of 200 mM potassium carbonate (K2CO3), the obtained BDAPE derivatives were separated on a reversed-phase C18 column and quantified by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in positive electrospray ionization mode. This method allowed a lower limit of quantification (LLOQ) of 0.090 µΜ for 3-indolepropionic acid (3IPA), indole-3-acetic acid (3IAA), p-cresol (PC), benzoic acid (BA), and phenol (PN); 0.30 µΜ for phenylacetic acid (PAA); 0.45 µΜ for 4-hydroxyphenylacetic acid (4HPAA); and 0.60 µΜ for 3-phenylpropionic acid (PPA). Methodological validation further demonstrated acceptable accuracy (%RE < 16.1) and precision (%RSD < 16.2), suggesting that this is a sensitive and robust method for simultaneous quantification of phenols and aromatic acids. The method was successfully applied to analyze these microbiota-related analytes in mouse feces of a diabetic nephropathy model. Graphical abstract.