Human UDP-glucuronosyltransferase 1As catalyze aristolochic acid D O-glucuronidation to form a lesser nephrotoxic glucuronide.

ETHNOPHARMACOLOGICAL RELEVANCE: Aristolochic acids (AAs) are naturally occurring nitro phenanthrene carboxylic acids primarily found in plants of the Aristolochiaceae family. Aristolochic acid D (AAD) is a major constituent in the roots and rhizomes of the Chinese herb Xixin (the roots and rhizomes of Asarum heterotropoides F. Schmidt), which is a key material for preparing a suite of marketed Chinese medicines. Structurally, AAD is nearly identical to the nephrotoxic aristolochic acid I (AAI), with an additional phenolic group at the C-6 site. Although the nephrotoxicity and metabolic pathways of AAI have been well-investigated, the metabolic pathway(s) of AAD in humans and the influence of AAD metabolism on its nephrotoxicity has not been investigated yet. AIM OF THE STUDY: To identify the major metabolites of AAD in human tissues and to characterize AAD O-glucuronidation kinetics in different enzyme sources, as well as to explore the influence of AAD O-glucuronidation on its nephrotoxicity. MATERIALS AND METHODS: The O-glucuronide of AAD was biosynthesized and its chemical structure was fully characterized by both 1H-NMR and 13C-NMR. Reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses were conducted to assess the crucial enzymes involved in AAD O-glucuronidation in humans. Docking simulations were performed to mimic the catalytic conformations of AAD in human UDP-glucuronosyltransferases (UGTs), while the predicted binding energies and distances between the deprotonated C-6 phenolic group of AAD and the glucuronyl moiety of UDPGA in each tested human UGT isoenzyme were measured. The mitochondrial membrane potentials (MMP) and reactive oxygen species (ROS) levels in HK-2 cells treated with either AAI, or AAD, or AAD O-glucuronide were tested, to elucidate the impact of O-glucuronidation on the nephrotoxicity of AAD. RESULTS: AAD could be rapidly metabolized in human liver and intestinal microsomes (HLM and HIM, respectively) to form a mono-glucuronide, which was purified and fully characterized as AAD-6-O-ß-D-glucuronide (AADG) by NMR. UGT1A1 was the predominant enzyme responsible for AAD-6-O-glucuronidation, while UGT1A9 contributed to a lesser extent. AAD-6-O-glucuronidation in HLM, HIM, UGT1A1 and UGT1A9 followed Michaelis-Menten kinetics, with the Km values of 4.27 µM, 9.05 µM, 3.87 µM, and 7.00 µM, respectively. Docking simulations suggested that AAD was accessible to the catalytic cavity of UGT1A1 or UGT1A9 and formed catalytic conformations. Further investigations showed that both AAI and AAD could trigger the elevated intracellular ROS levels and induce mitochondrial dysfunction and in HK-2 cells, but AADG was hardly to trigger ROS accumulation and mitochondrial dysfunction. CONCLUSION: Collectively, UGT1A-catalyzed AAD 6-O-glucuronidation represents a crucial detoxification pathway of this naturally occurring AAI analogs in humans, which is very different from that of AAI.

Bioactive tigliane diterpenoids from the latex of Euphorbia fischeriana.

Latex is a type of sticky endogenous fluids derived from diverse plants including Euphorbia fischeriana, and is of great scientific and commercial values. In the current study, it was demonstrated that the latex extracted from E. fischeriana strongly respelled the growth of cotton bollworm, Helicoverpa armigera. Using spectroscopic methods, HPLC, and GC-MS analyses, six aliphatic tigliane diterpenoids were isolated from the latex of E. fischeriana, among which three compounds (2, 3, and 5) were new. Two major compounds (1 and 4) exhibited remarkable antifeedant activity against H. armigera, with EC50 values at 2.59 and 15.32 µg/cm2, respectively. In addition, the quantification analysis of diterpenoids in different organs indicated that 4 was the most abundant constituent and was highly accumulated in the latex. Collectively, the current study highlighted that the diterpenoids in latex of E. fischeriana had a considerable antifeedant function against H. armigera, which might be employed for the future development of natural insecticides for organic farming.

Basilic vein transposition-radial artery fistula created using the no-touch technique
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OBJECTIVE: To compare the functions and complications of forearm basilic vein transposition-arteriovenous fistula (BVT-AVF) created using the no-touch technique with that of conventional radiocephalic arteriovenous fistula (RC-AVF). MATERIALS AND METHODS: The no-touch technique was used to created basilic vein transposition-radial artery fistula in 22 patients. Another 30 patients received surgeries for RC-AVF. The fistula functions and complications were compared between these two groups. RESULTS: The two groups did not differ significantly in the incidence of postoperative bleeding, limb swelling, infection, steal syndrome, fistula thrombosis, fistula aneurysm, fistula flow, fistula maturation time, Kt/v, and fistula median survival. CONCLUSION: Forearm BVT-AVF created by the no-touch technique is a good alternative access for patients in whom the standard arteriovenous fistula cannot be established.

Sustained low-efficiency diafiltration is superior to hemodialysis in promoting renal function recovery in elderly wasp sting victims with stage III acute kidney injury: a retrospective study.

Objective: To study the efficacy and safety of sustained low-efficiency diafiltration (SLEDf) versus hemodialysis (HD) for patients with wasp stings who developed stage III acute kidney injury (AKI). Methods: We retrospectively analyzed the clinical data of consecutive patients who developed AKI following wasp stings. All eligible patients received renal replacement therapy in combination with hemoperfusion. Thereafter, blood purification therapy and HD were performed with a volumetrically controlled machine and 1.7 m2 surface, Fresenius Polysulfone HD filter and SLEDf was undertaken with a volumetrically controlled machine and 1.3 m2 surface, Fresenius Polysulfone HD filter. Results: Forty patients developed stage III AKI following wasp stings, including 14 patients that received SLEDf and 26 patients underwent HD. Thirteen patients were aged less than 60 years and underwent HD (group I), 27 patients were aged at least 60 years, including 13 patients undergoing HD (group II) and 14 patients receiving SLEDf (group III). Groups I and II completed 150 and 162 sessions of HD, respectively, and group III completed 156 sessions of sustained low-efficiency blood purification therapy, including 50 sessions of SLEDf. The time to return to normal serum creatinine levels was 38.8 ± 2.7 days for group I, 47.2 ± 5.3 days for group II, and 39.2 ± 3.3 days for group III. A statistically significant difference was observed in time to normal serum creatinine levels among the three groups. Conclusion: Elderly wasp victims have more severe illness than younger wasp victims and SLEDf is safe and superior to HD in recovery of renal function of elderly wasp victims.

Evaluation on treatment of sustained low-efficiency hemodialysis against patients with multiple organ dysfunction syndrome following wasp stings.

BACKGROUND: To evaluate the treatment of sustained low-efficiency hemodialysis (SLED) against patients with multiple organ dysfunction syndrome (MODS) following wasp stings. METHODS: Clinical data of 35 patients with MODS following wasp stings were retrospectively analysed. These patients were divided into three groups according to the treatment strategy used: 1) hemodialysis (HD) group, 2) continuous veno-venous hemofiltration (CVVH)/HD group, and 3) SLED/HD group. The clinical parameters, treatment outcome, and safety findings were compared among the three groups. RESULTS: The recovery rate (76.92% vs 77.78% vs 91.67%, p = 0.621) and mortality rate (15.38% vs 11.11% vs 8.33%, p = 0.999) were similar among the three groups. When compared to the HD group, patients treated with CVVH/HD or SLED/HD required a shorter period of time to enter into polyuria stage [(24.7 ± 4.3) days vs (20.2 ± 4.7) days vs (18.2 ± 3.0) days, F = 9.11, p = 0.0007], and required a shorter time for serum creatinine to return to normal [(45.7 ± 13.4) days vs (33.1 ± 9.4) days vs (31.9 ± 9.8), F = 5.83, p = 0.0069]; while such parameters had no significant differences between SLED/HD group and CVVH/HD group. The adverse events of hypotension and arrhythmia were found in the HD group, while no adverse events were reported in the SLED/HD and CVVH/HD groups. There was no significant difference in the cost of blood purification treatment between the SLED/HD group and HD group. CONCLUSION: The use of SLED, CVVH and HD provided a comparable recovery and survival rates in patients with MODS secondary to wasp stings. Compared to HD, the use of SLED is recommended as a treatment strategy because of the efficacy on recover of renal function, satisfactory safety outcome, as well as the reasonable treatment cost.

Essentiality drives the orientation bias of bacterial genes in a continuous manner.

Studies had found that bacterial genes are preferentially located on the leading strands. Subsequently, the preferences of essential genes and highly expressed genes were compared by classifying all genes into four groups, which showed that the former has an exclusive influence on orientation. However, only some functional classes of essential genes have this orientation bias. Nevertheless, previous studies only performed comparative analyzes by differentiating the orientation bias extent of two types of genes. Thus, it is unclear whether the influence of essentiality on strand bias works continuously. Herein, we found a significant correlation between essentiality and orientation bias extent in 19 of 21 analyzed bacterial genomes, based on quantitative measurement of gene essentiality (or fitness). The correlation coefficient was much higher than that derived from binary essentiality measures (essential or non-essential). This suggested that genes with relatively lower essentiality, i.e., conditionally essential genes, also have some orientation bias, although it is weaker than that of absolutely essential genes. The results demonstrated the continuous influence of essentiality on orientation bias and provided details on this visible structural feature of bacterial genomes. It also proved that Geptop and IFIM could serve as useful resources of bacterial gene essentiality, particularly for quantitative analysis.

IFIM: a database of integrated fitness information for microbial genes.

Knowledge of an organism's fitness for survival is important for a complete understanding of microbial genetics and effective drug design. Current essential gene databases provide only binary essentiality data from genome-wide experiments. We therefore developed a new database that Integrates quantitative Fitness Information for Microbial genes (IFIM). The IFIM database currently contains data from 16 experiments and 2186 theoretical predictions. The highly significant correlation between the experiment-derived fitness data and our computational simulations demonstrated that the computer-generated predictions were often as reliable as the experimental data. The data in IFIM can be accessed easily, and the interface allows users to browse through the gene fitness information that it contains. IFIM is the first resource that allows easy access to fitness data of microbial genes. We believe this database will contribute to a better understanding of microbial genetics and will be useful in designing drugs to resist microbial pathogens, especially when experimental data are unavailable. Database URL: http://cefg.uestc.edu.cn/ifim/ or http://cefg.cn/ifim/

Nitrification characteristics of nitrobacteria immobilized in waterborne polyurethane in wastewater of corn-based ethanol fuel production.

A technology to achieve stable and high ammonia nitrogen removal rates for corn distillery wastewater (ethanol fuel production) treatment has been designed. The characteristics of nitrifying bacteria entrapped in a waterborne polyurethane (WPU) gel carrier were evaluated after acclimation. In the acclimation period, nitrification rates of WPU-immobilized nitrobacteria were monitored and polymerase chain reaction (PCR) was also carried out to investigate the change in ammonium-oxidizing bacteria. The results showed that the pellet nitrification rates increased from 21 to 228 mg-N/(L-pellet x hr) and the quantity of the ammonia oxidation bacteria increased substantially during the acclimation. A continuous ammonia removal experiment with the anaerobic pond effluent of a distillery wastewater system was conducted with immobilized nitrifying bacteria for 30 days using an 80 L airlift reactor with pellets at a fill ratio of 15% (V/V). Under the conditions of 75 mg/L influent ammonia, hydraulic retention time (HRT) of 3.7-5.6 hr, and dissolved oxygen (DO) of 4 mg/L, the effluent ammonia concentration was lower than 10 mg/L and the ammonia removal efficiency was 90%. While the highest ammonia removal rate, 162 mg-N/(L-pellet x hr), was observed when the HRT was 1.3 hr.