Identification and interspecies characterization of UDP-glucuronosyltransferase isoforms catalyzing acacetin glucuronidation using recombinant UGT enzymes and microsomes

Objective: To explore the glucuronic acid metabolism of acacetin in human liver and intestinal microsomes to better characterize human uridine 5′-diphospho (UDP)-glucuronosyltransferase (UGT) isoforms. In addition, interspecies comparisons were performed to identify the most appropriate experimental animal model for an in vivo study. Methods: Liquid chromatography tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) were used to confirm the successful biosynthesis of acacetin-7-O-glucuronide. Human isoforms of UGT and isozyme-specific chemical inhibitors were used for recombinant assays. Acacetin glucuronidation kinetics were assessed by combining acacetin with recombinant human UGT isoforms or with microsomes from humans or experimental animals. Kinetic differences between species were assessed in vitro using the same approach. Results: We identified multiple UGT isoforms that facilitated acacetin glucuronidation, and found that UGT1A1 was the major isoform that catalyzed this process. Acacetin-7-O-glucuronide formation exhibited clear substrate inhibition kinetics when combined with recombinant UGTs or with liver/intestinal microsomes derived from humans, monkeys, rats, mice, dogs, or pigs. Intrinsic metabolic clearance values of human intestinal microsomes were two-fold greater than those of human liver microsomes. Among the evaluated species, the Km value of dog microsomes (0.86 μM) was greatest in acacetin glucuronidation, while mice exhibited the highest CLint value, 5.05 mL/min/mg. The CLint values of microsomes derived from monkeys and minipigs were 1.99 mL/min/mg and 2.12 mL/min/mg, respectively, exhibiting similar intrinsic metabolic clearance activity to that observed in humans. Conclusion: Monkey may represent a suitable model for experimental studies of acacetin pharmacokinetics owing to a high sequence homology of UGT1A1 and similar UGT1A1 glucuronidation activity to humans. Keywords: Acacetin, UDP-glucuronosyltransferases, Human liver microsomes, Glucuronidation, Species difference

Mapping the knowledge of international Chinese medicines treatment on type 2 diabetes: A biblimetrical study

Objective: To uncover and identify the hot topic and frontier of Chinese medicines treatment of type 2 diabetes mellitus (T2DM). Methods: Web of Science TM was searched for published articles for Chinese medicines treatment of T2DM ranging from January 1st, 2002 to July 6th, 2016. Knowledge maps of the international Chinese medicines treatment of T2DM are visualized by using document co-occurrence analysis and word frequency analysis (Institution and Journal), co-citation clustering analysis (Co-reference), keyword co-occurrence clustering analysis with CiteSpac III, a tool of scientometrics. Results: Universidad Nacional Autonoma de Mexico is the institution with the highest number of published papers that had been cited in this field, while China has four institutions among the top 10. The journal of the highest frequency of co-cited journal was Diabetes Care, a core one in the field. Keywords co-occurrence network was composed of 185 nodes, 541 lines, and divided into 10 clusters. Co-citation network of co-reference was composed of 407 nodes, 1199 lines, and divided into 20 clusters. Using Chinese medicine to improve insulin resistance and Chinese medicine research on blood glucose control are the hot topics. The frontier contains two aspects: new drugs development and application of intestinal insulin treatment and development and use of traditional Chinese medicine antidiabetic plants. Conclusion: Institutions from China still plays a major role in TCM-focused T2DM studies. The effect of TCM herbs on insulin resistance is the hot topic of the domain. Developing new TCM herbal medicine that regulates incretin effect is the domain frontier. Research on the Chinese medicines treatment of T2DM needs more high-quality evidence to support, and its mechanism requires further exploration

Searching for the subatomic swirls in the CuCu and CuAu collisions

Recently the STAR Collaboration reported measurement of the “subatomic swirls”, that is, the most vortical fluid flow structures in the quark–gluon plasma produced via the AuAu collisions at the Relativistic Heavy Ion Collider (RHIC). This result has attracted significant interest and generated wide enthusiasm. For such an important finding, it is crucial to look for additional evidences of confirmation and to critically test the current interpretation of the global polarization measurement. We suggest that the CuCu and CuAu colliding systems at RHIC provide such opportunity. Interestingly, our calculations reveal that the fluid vorticity in the CuCu or CuAu collision is comparable to that in the AuAu collision. We find the computed Λ hyperon polarization effect is stronger in the CuCu and CuAu systems than the AuAu system at the same collisional beam energy and centrality class, with an interesting hierarchy CuCu > CuAu > AuAu due to interplay between Λ production timing and the time evolution of the vorticity. These predictions can be readily tested by experimental data

Evidence based on Mendelian randomization: Causal relationship between mitochondrial biological function and lung cancer and its subtypes

Objective: This study aimed to investigate the causal relationship between mitochondrial biological function and lung cancer, including its subtypes, via MR. Methods: SNPs significantly associated with lung cancer and its subtypes were employed as instrumental variables. MR-Egger regression, simple mode, weighted mode, simple median, and weighted median, were utilized to determine the causal relationship between the exposure factor and the occurrence of lung cancer and its subtypes. Results: NADH dehydrogenase (ubiquinone) flavoprotein 2 and transmembrane protein 70 were found to have a causal relationship with lung adenocarcinoma, acting as protective factors. The causal relationship between mitochondrial import inner membrane translocase subunit and NADH dehydrogenase (ubiquinone) iron-sulfur protein 4 and small-cell lung cancer was established as a risk factor. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8 exhibited a causal relationship with small-cell lung cancer, acting as a protective factor. Furthermore, NAD-dependent protein deacylase sirtuin-5 was causally linked to lung squamous cell carcinoma, serving as a protective factor. A funnel plot demonstrated the symmetrical distribution of the SNPs. Thew pleiotroy test (P > 0.05) and ''leave-one-out'' test validated the relative stability of the results. Conclusion: This study established a causal relationship between mitochondrial biological function and lung cancer, including its subtypes

Photocatalytic Oxidation of Acetone Over High Thermally Stable TiO2 Nanosheets With Exposed (001) Facets

Anatase TiO2 (A-TiO2) usually exhibits superior photocatalytic activity than rutile TiO2 (R-TiO2). However, the phase transformation from A-TiO2 to R-TiO2 will inevitably happens when the calcination temperature is up to 600°C, which hampers the practical applications of TiO2 photocatalysis in hyperthermal situations. In this paper, high energy faceted TiO2 nanosheets (TiO2-NSs) with super thermal stability was prepared by calcination of TiOF2 cubes. With increase in the calcination temperature from 300 to 600°C, TiOF2 transforms into TiO2 hollow nanoboxes (TiO2-HNBs) assembly from TiO2-NSs via Ostwald Rippening process. Almost all of the TiO2-HNBs are disassembled into discrete TiO2-NSs when calcination temperature is higher than 700°C. Phase transformation from A-TiO2 to R-TiO2 begins at 1000°C. Only when the calcination temperature is higher than 1200°C can all the TiO2-NSs transforms into R-TiO2. The 500°C-calcined sample (T500) exhibits the highest photoreactivity toward acetone oxidation possibly because of the production of high energy TiO2-NSs with exposed high energy (001) facets and the surface adsorbed fluorine. Surface oxygen vacancy, due to the heat-induced removal of surface adsorbed fluoride ions, is responsible for the high thermal stability of TiO2-NSs which are prepared by calcination of TiOF2 cubes

Inorganic Self-Assembled Bioactive Artificial Proto-Osteocells Inducing Bone Regeneration

Since the discovery of osteoinduction in the early 20th century, innovative biomaterials with osteoinductive potential have emerged as candidates for bone repair. Recently, artificial protocell models have demonstrated great potential for tissue regeneration. Herein, we developed artificial bioactive proto-osteocells by self-assembly of biodegradable biphasic-phosphate particles in the form of aqueous bone morphogenetic protein 2 (BMP2)-containing Pickering emulsions in corn oil to fulfill the release of BMP2 with controlled and local efficacy. These artificial proto-osteocells have the advantage of (1) being directly injected into the target location to avert reported side effects of BMP2, minimizing surgical complications, (2) exhibiting the capability of osteoinduction as shown in both in vitro and in vivo models, and (3) demonstrating calcific deposition locally by utilizing the biodegradable calcium phosphate shell. The efficiency of BMP2 within the artificial proto-osteocells showed 25 times greater bone-inducing potential when compared to the control. This study demonstrates for the first time a new strategy toward utilizing material-based artificial proto-osteocells to tackle medical issues in bone tissue repair and regeneration