Plant-derived biochar amendment for compost maturity improvement and gaseous emission reduction in food waste composting: Insight from bacterial community and functions.

This study assessed the impact of different plant-derived biochar (cornstalk, rice husk, and sawdust) on bacterial community and functions for compost maturity and gaseous emissions during the composting of food waste. Results showed that all biochar strengthened organic biotransformation and caused a higher germination index on day 12 (over 100%), especially for rice husk biochar to enhance the growth of Thermobifida related to aerobic chemoheterotrophy. Rice husk biochar also achieved a relatively higher reduction efficiency of methane (85.8%) and ammonia (82.7%) emissions since its greater porous structure. Besides, the growth of Pseudomonas, Pusillimonas, and Desulfitibacter was restricted to constrict nitrate reduction, nitrite respiration, and sulfate respiration by optimized temperature and air permeability, thus reducing nitrous oxide and hydrogen sulfide emissions by 48.0-57.3% by biochar addition. Therefore, rice husk biochar experienced the optimal potential for maturity increment and gaseous emissions mitigation.

Identification of 5-[5-cyano-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamido] thiazole-4-carboxylic acid as a promising dual inhibitor of urate transporter 1 and xanthine oxidase.

In combination with allopurinol, tranilast is used as an urate transporter 1 (URAT1) inhibitor for the treatment of hyperuricemia, but its structure-activity relationship concerning URAT1 inhibitory activity is rarely studied. In this paper, analogs 1-30 were designed and synthesized using scaffold hopping strategy on the basis of tranilast and the privileged scaffold indole. Then, URAT1 activity was evaluated using 14C-uric acid uptake assay with HEK293-URAT1 overexpressing cells. Compared with tranilast (inhibitory rate = 44.9% at 10 µM), most compounds displayed apparent inhibitory effects, ranging from 40.0% to 81.0% at 10 µM on URAT1. Surprisingly, along with the bringing in of a cyano group at the 5-position of indole ring, compounds 26 and 28-30 exerted xanthine oxidase (XO) inhibitory activity. In particular, compound 29 presented potency on URAT1 (48.0% at 10 µM) and XO (IC50 = 1.01 µM). Molecular simulation analysis revealed that the basic structure of compound 29 had an affinity with URAT1, and XO. Furthermore, compound 29 demonstrated a significant hypouricemic effect in a potassium oxonate-induced hyperuricemia rat model at an oral dose of 10 mg/kg during in vivo tests. In summary, tranilast analog 29 was identified as a potent dual-target inhibitor of URAT1 and XO, and a promising lead compound for further investigation.

A global meta-analysis of greenhouse gas emissions and carbon and nitrogen losses during livestock manure composting: Influencing factors and mitigation strategies.

The management of manure composting contributes to alleviate the global greenhouse effect. To improve our understanding of this process, we conducted a meta-analysis of 371 observations from 87 published studies in 11 countries. The results showed that the difference in nitrogen content in feces significantly affected the greenhouse gas (GHG) emissions and nutrient losses of subsequent composting, with NH3-N, CO2-C, and CH4-C losses all increasing with its rise. Windrow pile composting (especially compared to trough composting) had lower GHG emissions and nutrient loss. C/N ratio, aeration rate, and pH value significantly affected NH3 emission, and a decrease in the latter two can reduce it by 31.8 % and 42.5 %, respectively. Decreasing the moisture content or increasing the turning frequency could decrease CH4 by 31.8 % and 62.6 %, respectively. The addition of biochar or superphosphate had a synergistic emission reduction. The emission reduction of N2O and CH4 by biochar was more prominent (44 % and 43.6 %), while superphosphate on NH3 (38.0 %) was better. And the latter was more suitable if added in 10-20 % of dry weight. Dicyandiamide was the only chemical additive (59.4 %) with better N2O emission reduction performance. Microbial agents with different functions had certain effects on NH3-N emission reduction, while the mature compost had a certain effect on N2O-N emissions (67.0 %). In general, N2O had the highest contribution to the greenhouse effect during composting (74.22 %).

Silencing of PFKFB3 protects podocytes against high glucose­induced injury by inducing autophagy.

Diabetic nephropathy (DN) is a diabetic complication that threatens the health of patients with diabetes. In addition, podocyte injury can lead to the occurrence of DN. The protein 6­phosphofructo­2­kinase/fructose­2,6-biphosphatase 3 (PFKFB3) may be associated with diabetes; however, the effects of PFKFB3 knockdown by small interfering (si)RNA on the growth of podocytes remains unknown. To investigate the mechanism by which PFKFB3 mediates podocyte injury, MPC5 mouse podocyte cells were treated with high­glucose (HG), and cell viability and apoptosis were examined by Cell Counting Kit­8 assay and flow cytometry, respectively. In addition, the expression of autophagy­related proteins were measured using western blot analysis and immunofluorescence staining. Cell migration was investigated using a Transwell assay and phalloidin staining was performed to observe the cytoskeleton. The results revealed that silencing of PFKFB3 significantly promoted MPC5 cell viability and inhibited apoptosis. In addition, the migration of the MPC5 cells was notably downregulated by siPFKFB3. Moreover, PFKFB3 silencing notably reversed the HG­induced decrease in oxygen consumption rate, and the HG­induced increase in extracellular acidification rate was rescued by PFKFB3 siRNA. Furthermore, silencing of PFKFB3 induced autophagy in HG­treated podocytes through inactivating phosphorylated (p­)mTOR, p­AMPKα, LC3 and sirtuin 1, and activating p62. In conclusion, silencing of PFKFB3 may protect podocytes from HG­induced injury by inducing autophagy. Therefore, PFKFB3 may serve as a potential target for treatment of DN.

Design, synthesis and biological evaluation of novel FXIa inhibitors with 2-phenyl-1H-imidazole-5-carboxamide moiety as P1 fragment.

Factor XIa, as a blood coagulation enzyme, amplifies the generation of the last enzyme thrombin in the blood coagulation cascade. It was proved that direct inhibition of factor XIa could reduce pathologic thrombus formation without an enhanced risk of bleeding. WSJ-557, a nonpurine imidazole-based xanthine oxidase inhibitor in our previous reports, could delay blood coagulation during its animal experiments, which prompted us to investigate its action mechanism. Subsequently, during the exploration of the action mechanism, it was found that WSJ-557 exhibited weak in vitro factor XIa binding affinity. Under the guide of molecular modeling, we adopted molecular hybridization strategy to develop novel factor XIa inhibitors with WSJ-557 as an initial compound. This led to the identification of the most potent compound 44g with a Ki value of 0.009 µM, which was close to that of BMS-724296 (Ki = 0.0015 µM). Additionally, serine protease selectivity study indicated that compound 44g display a desired selectivity, more 400-fold than those of thrombin, factor VIIa and factor Xa in coagulation cascade. Moreover, enzyme kinetics studies suggested that the representative compound 44g acted as a competitive-type inhibitor for FXIa, and molecular modeling revealed that it could tightly bind to the S1, S1' and S2' pockets of factor XIa. Furthermore, in vivo efficacy in the rabbit arteriovenous shunt model suggested that compound 44g demonstrated dose-dependent antithrombotic efficacy. Therefore, these results supported that compound 44g could be a potential and efficacious agent for the treatment of thrombotic diseases.

Switching a Xanthine Oxidase Inhibitor to a Dual-Target Antagonist of P2Y1 and P2Y12 as an Oral Antiplatelet Agent with a Wider Therapeutic Window in Rats than Ticagrelor.

ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y1 and P2Y12 on the platelet. The clinical effectiveness of inhibiting P2Y12 has been well established, and preclinical studies indicated that the inhibition of P2Y1 could provide equivalent antithrombotic efficacy as P2Y12 antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1H-imidazole scaffold of our previously reported xanthine oxidase inhibitor WSJ-557, we first achieved the transition from the xanthine oxidase inhibitors to dual-target antagonists against P2Y1 and P2Y12. We described the structure-activity relationships of the 2-phenyl-1H-imidazole compounds, which led to the identification of the most potent antiplatelet agents, 24w and 25w, both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that 24w demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that 24w and 25w could be promising drug candidates.

Targeting the subpocket in xanthine oxidase: Design, synthesis, and biological evaluation of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives.

Xanthine oxidase is an important target for the treatment of hyperuricemia, gout and other related diseases. Analysis of the high-resolution structure of xanthine oxidase with febuxostat identified the existence of a subpocket formed by the residues Leu648, Asn768, Lys771, Leu1014 and Pro1076. In this study, we designed and synthesized a series of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives (8a-8z) with a tetrazole group targeting this subpocket of the xanthine oxidase active site, and they were further evaluated for their inhibitory potency against xanthine oxidase in vitro. The results showed that all the tested compounds (8a-8z) exhibited an apparent xanthine oxidase inhibitory potency, with IC50 values ranging from 0.0288 µM to 0.629 µM. Among them, compound 8u emerged as the most potent xanthine oxidase inhibitor, with an IC50 value of 0.0288 µM, which was comparable to febuxostat (IC50 = 0.0236 µM). The structure-activity relationship results revealed that the hydrophobic group at the 4'-position was indispensable for the inhibitory potency in vitro against xanthine oxidase. A Lineweaver-Burk plot revealed that the representative compound 8u acted as a mixed-type inhibitor for xanthine oxidase. Furthermore, molecular modeling studies were performed to gain insights into the binding mode of 8u with xanthine oxidase and suggested that the tetrazole group of the phenyl unit was accommodated in the subpocket, as expected. Moreover, a potassium oxonate-induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 8u, and the result demonstrated that compound 8u could effectively reduce serum uric acid levels at an oral dose of 5 mg/kg. In addition, acute oral toxicity study in mice indicated that compound 8u was nontoxic and tolerated at a dose up to 2000 mg/kg. Thus, compound 8u could be a potential and efficacious agent in treatment of hyperuricemia with low toxicity.