In Vitro Ciclopirox Glucuronidation in Liver Microsomes from Humans and Various Experimental Animals.

BACKGROUND AND OBJECTIVE: Ciclopirox is a widely used antifungal drug, redisposition of which has drawn increasing attentions due to multiple promising activities. The drug undergoes extensive glucuronidation, which acts as a major obstacle in the ongoing novel application and still remains poorly understood. The current study aims to phenotype ciclopirox glucuronidation pathway and as well to decipher the related species differences. METHODS: Ciclopirox glucuronidation was investigated in liver microsomes from humans (HLM) and various experimental animals. Assays with recombinant uridine diphosphate glucuronosyltransferases (UGTs), enzyme kinetic analyses and selective inhibitors were used to determine the role of individual UGTs in ciclopirox glucuronidation. RESULTS: HLM is highly active in ciclopirox glucuronidation with Michaelis-Menten constant (Km), maximum velocity (Vmax), and intrinsic clearance (CLint) values of 139 µM, 7.89 nmol/min/mg, and 56 µL/min/mg, respectively. UGT1A9 displays by far the highest activity, whereas several other isoforms (UGT1A6, UGT1A7, and UGT1A8) catalyze formation of traced glucuronides. Further kinetic analysis demonstrates that UGT1A9 has a closed Km value (167 µM) to HLM. UGT1A9 selective inhibitor (magnolol) can potently inhibit ciclopirox glucuronidation in HLM with the IC50 value of 0.12 µM. The reaction displays remarkable differences across liver microsomes from mice, rats, cynomolgus monkey, minipig, and beagle dog, with the CLint values in the range of 26-369 µL/min/mg. In addition, ciclopirox glucuronidation activities of experimental animals' liver microsomes were less sensitive to magnolol than that of HLM. CONCLUSIONS: Ciclopirox glucuronidation displays remarkable species differences with UGT1A9 as a dominant contributor in humans. It is suggested that the pharmacological or toxicological effects of ciclopirox may be UGT1A9 and species dependent.

The top 100 most cited articles on mucopolysaccharidoses: a bibliometric analysis.

Background: Bibliometrics can trace general research trends in a particular field. Mucopolysaccharidoses (MPS), as a group of rare genetic diseases, seriously affect the quality of life of patients and their families. Scholars have devoted themselves to studying MPS's pathogenesis and treatment modalities and have published many papers. Therefore, we conducted a bibliometric and visual study of the top 100 most highly cited articles to provide researchers with an indication of the current state of research and potential directions in the field. Methods: The Web of Science Core Collection was searched for articles on MPS from 1 January 1900, to 8 November 2023, and the top 100 most cited articles were screened. The title, year of publication, institution, country, and first author of the articles were extracted and statistically analyzed using Microsoft Excel 2007. Keyword co-occurrence and collaborative networks were analyzed using VOSviewer 1.6.16. Results: A total of 9,273 articles were retrieved, and the top 100 most cited articles were filtered out. The articles were cited 18,790 times, with an annual average of 188 citations (122-507). Forty-two journals published these articles, with Molecular Genetics and Metabolism and Proceedings of the National Academy of Sciences of the United States being the most published journal (N = 8), followed by Pediatrics (N = 7), Blood (N = 6). The United States (N = 68), the UK (N = 25), and Germany (N = 20) were the top contributing countries. The Royal Manchester Children's Hospital (N = 20) and the University of North Carolina (N = 18) were the most contributing institutions. Muenzer J was the most prolific author (N = 14). Conclusion: We conducted a bibliometric and visual analysis of the top 100 cited articles in MPS. This study identifies the most influential articles currently available in the field of MPS, which provides a good basis for a better understanding of the disease and informs future research directions.

The exocyst subunit CsExo70B promotes both fruit length and disease resistance via regulating receptor kinase abundance at plasma membrane in cucumber.

Plant defence against pathogens generally occurs at the expense of growth and yield. Uncoupling the inverse relationship between growth and defence is of great importance for crop breeding, while the underlying genes and regulatory mechanisms remain largely elusive. The exocytosis complex was shown to play an important role in the trafficking of receptor kinases (RKs) to the plasma membrane (PM). Here, we found a Cucumis sativus exocytosis subunit Exo70B (CsExo70B) regulates the abundance of both development and defence RKs at the PM to promote fruit elongation and disease resistance in cucumber. Knockout of CsExo70B resulted in shorter fruit and susceptibility to pathogens. Mechanistically, CsExo70B associates with the developmental RK CsERECTA, which promotes fruit longitudinal growth in cucumber, and contributes to its accumulation at the PM. On the other side, CsExo70B confers to the spectrum resistance to pathogens in cucumber via a similar regulatory module of defence RKs. Moreover, CsExo70B overexpression lines showed an increased fruit yield as well as disease resistance. Collectively, our work reveals a regulatory mechanism that CsExo70B promotes both fruit elongation and disease resistance by maintaining appropriate RK levels at the PM and thus provides a possible strategy for superior cucumber breeding with high yield and robust pathogen resistance.

Mogroside V ameliorates broiler pulmonary inflammation via modulating lung microbiota and rectifying Th17/Treg dysregulation in lipopolysaccharides-induced lung injury.

The dysbiosis of lung microbiota and inflammatory factors play a crucial role in the occurrence of lipopolysaccharides (LPS)-induced lung injury. Recently, mogroside V (MGV) has received increasing attention due to its potential health benefits in pneumonia, but its complex mechanism needs further experimental elucidation. In this study, we established an LPS-induced chicken lung injury model to investigate the protective effect of MGV on LPS-induced acute lung injury in broiler and its related mechanisms. A total of 192 one-day-old white-finned broilers were randomly assigned into 4 groups with 6 replicates: 1) control group: basal diet (d 1-44), saline (d 43); 2) LPS group: basal diet (d 1-44), LPS (d 43); 3) MGV group: basal diet + 0.2% MGV (d 1-44), saline (d 43); 4) MGV-LPS group: basal diet + 0.2% MGV (d 1-44), LPS (d 43). The results showed that pathological examination showed that lung tissue inflammation infiltration was reduced after MGV treatment. In addition, MGV can promote the balance of Th17 and Treg cell cytokines, significantly inhibit the expression of proinflammatory cytokines (IL-1ß (P < 0.01), IL-6 (P < 0.001), IL-17F (P < 0.05)), and decrease immunosuppressive target expression (PD-L1 (P < 0.01), PD-1 (P < 0.001), RORα (P < 0.001)), activating the immune system. Furthermore, 16S rRNA sequencing analysis showed that MGV treatment could increase the abundance of beneficial bacteria in the lung and reduce the abundance of bacteria associated with inflammation. Generally, MGV intervention has a preventive effect on the pathological damage induced by lipopolysaccharides. Its mechanism is related to inhibiting the inflammatory response, regulating the Th17/Treg balance, and maintaining the stability of lung microbiota.

Clinical Characteristics and Current Status of Treatment for Recurrent Bladder Cancer after Surgeries on Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma (UTUC) is a relatively rare, but highly malignant, disease with an estimated annual incidence of 2 cases per 100,000 people. The main surgical treatment modalities for UTUC are radical nephroureterectomy (RNU) with bladder cuff resection. After surgery, intravesical recurrence (IVR) can occur in up to 47% of patients, and 75% of them present with non-muscle invasive bladder cancer (NMIBC). However, there are few studies focused on the diagnosis and treatment of postoperatively recurrent bladder cancer for patients with previous UTUC history (UTUC-BC), and many of the influencing factors are still controversial. In this article, we performed a narrative review of the recent literature, mainly summarizing the factors influencing postoperative IVR in patients with UTUC and discussing the subsequent prevention, monitoring, and treatment tools for it.

Study on Flow Characteristics of Working Medium in Microchannel Simulated by Porous Media Model.

As a phase change evaporator, a microchannel array heat exchanger is of great significance in the field of microscale heat dissipation. The performance of which strongly depends on the flow resistance, capillary force, and other factors. In order to improve the heat dissipation efficiency, it is necessary to perform an in-depth study of the characteristics of microchannel flow using numerical simulation. However, the current simulation model requires high computational cost and long simulation time. To solve this problem, this paper simplifies the numerical simulation of the rectangular parallel array microchannels by building the basic flow model based on the concept of porous media. In addition, we explore the effect of aspect-ratio (AR), hydraulic diameter, inlet velocity, and other parameters of fluid flow behavior inside the microchannels. Meanwhile, a user-defined function (UDF) is formulated to add the capillary force into the model to introduce capillary force into the porous media model. Through the above research, the paper establishes the porous media model for single-phase and gas-liquid two-phase flow, which acts as a simplification of microchannel array simulation without grossly affecting the results obtained. In addition, we designed and manufactured experiments using silicon-based microchannel heat exchangers with different-ratios, and combined with the visualization method to measure the performance of the device and compared them with simulation results. The theoretical model is verified through the suction experiment of array microchannel evaporator capillary core. The simplified model of microchannel array significantly saves the computational cost and time, and provides guidance for the related experimental researches.

Comparative cytotoxic effects of five commonly used triazole alcohol fungicides on human cells of different tissue types.

The widespread application of triazole fungicides makes people attach great concern over its adverse effects in mammalian. In this paper, cytotoxic effects of triazole alcohol fungicides (TAFs) were assessed on human HeLa, A549, HCT116 and K562 cells, and the potential mechanism of TAFs cytotoxicity was studied preliminarily. Results showed that TAFs had cytotoxicity on human cells with different level and cytotoxic selectivity. TAFs cytotoxicity was resonated with a typical hormetic biphasic dose action that produced a complex pattern of stimulatory or inhibitory effects on cell viability. Among the five TAFs, diniconazole revealed a widest range of cytotoxicity to inhibit the viability of the adherent and the suspension cells, causing HeLa cells shrinkage, A549 cells shrunken, and K562 cells collapse, and showed stronger cytotoxicity than hexaconazole. Moreover, the involvement of ROS generation in the cytotoxicity of TAFs on human cells was observed, and the apoptosis of HeLa cells and the formation of apoptotic body in K562 cells induced by diniconazole were characterized. The results indicated the cytotoxicity of TAFs with different structures on human cells was depended on their own property and cell specificity, K562 cells were the most susceptible to TAFs and diniconazole was the strongest toxic.

Design of Rugby-Like GeO2 Grown on Carbon Cloth as a Flexible Anode for High-Performance Lithium-Ion Batteries.

The new demands for energy storage systems have been placed with demands for flexible wearable electronics. Herein, rugby-like GeO2 nanoparticles (NPs) have been directly grown on carbon cloth (GeO2 NPs/CC) through a one-step hydrolysis process at room temperature, which can be used as a self-supporting flexible anode for lithium ion battery (LIBs). The rugby-like GeO2 NPs/CC showed an improved lithium-storage performance with features of high reversible capacity ~2000 mA·h·g-1 even after 100 cycles and good cycling stability. Besides, its initial coulomb efficiency (79.1%) was also enhanced compared to that of some reported GeO2-based materials.