The major histocompatibility complex (MHC) genes are the most polymorphic genes in vertebrates, and their proteins play a critical role in adaptive immunity for defense against a variety of pathogens. MHC diversity was lost in many species after experiencing a decline in size. To understand the variation and evolution of MHC genes in the Siberian ibex, Capra sibirica, which has undergone a population decline, we analyzed the variation of the second exon of MHC class II DRB genes in samples collected from five geographic localities in Xinjiang, China, that belong to three diverged mitochondrial clades. Consequently, we identified a total of 26 putative functional alleles (PFAs) with 260 bp in length from 43 individuals, and found one (for 27 individuals) to three (for 5 individuals) PFAs per individual, indicating the presence of one or two DRB loci per haploid genome. The Casi-DRB1*16 was the most frequently occurring PFA, Casi-DRB1*22 was found in only seven individuals, 14 PFAs occurred once, 7 PFAs twice, implying high frequency of rare PFAs. Interestingly, more than half (15) of the PFAs were specific to clade I, only two and three PFAs were specific to clades II and III, respectively. So, we assume that the polygamy and sexual segregation nature of this species likely contributed to the allelic diversity of DRB genes. Genetic diversity indices showed that PFAs of clade II were lower in nucleotide, amino acid, and supertype diversity compared to those of the other two clades. The pattern of allele sharing and FST values between the three clades was to some extent in agreement with the pattern observed in mitochondrial DNA divergence. In addition, recombination analyses revealed no evidence for significant signatures of recombination events. Alleles shared by clades III and the other two clades diverged 6 million years ago, and systematic neighbor grids showed Trans-species polymorphism. Together with the PAML and MEME analyses, the results indicated that the DRB gene in C. sibirica evolved under balancing and positive selection. However, by comparison, it can be clearly seen that different populations were under different selective pressures. Our results are valuable in understanding the diversity and evolution of the DRB gene in a mountain living C. sibirica and in making decisions on future long-term protection strategies.
Fluorocarbons , Polymorphism, Genetic , Humans , Animals , Exons , Goats/genetics , Demography , Phylogeny , Alleles , Genetic Variation
Maternal lineages of mitochondrial DNA (mtDNA) are recognized as important components of intra and interspecific biodiversity and help us to disclose the phylogeny and divergence times of many taxa. Species of the genus Capra are canonical mountain dwellers. Among these is the Siberian ibex (Capra sibirica), which is regarded as a relic species whose intraspecific classification has been controversial so far. We collected 58 samples in Xinjiang, China, and analyzed the mtDNA genes to shed light on the intraspecific relationships of the C. sibirica populations and estimate the divergence time. Intriguingly, we found that the mtDNA sequences of C. sibirica split into two main lineages in both phylogenetic and network analyses: the Southern lineage, sister to Capra falconeri, consisting of samples from Ulugqat, Kagilik (both in Xinjiang), India, and Tajikistan; and the Northern lineage further divided into four monophyletic clades A-D corresponding to their geographic origins. Samples from Urumqi, Sawan, and Arturk formed a distinct monophyletic clade C within the Northern lineage. The genetic distance between the C. sibirica clades ranges from 3.0 to 8.6%, with values of F ST between 0.839 and 0.960, indicating notable genetic differentiation. The split of the genus Capra occurred approximately 6.75 Mya during the late Miocene. The Northern lineage diverged around 5.88 Mya, followed by the divergence of Clades A-D from 3.30 to 1.92 Mya during the late Pliocene and early Pleistocene. The radiation between the Southern lineage and C. falconeri occurred at 2.29 Mya during the early Pleistocene. Our results highlight the importance of extensive sampling when relating to genetic studies of alpine mammals and call for further genomic studies to draw definitive conclusions.
Nowadays, considerable efforts have been extensively devoted to explore a general strategy for improving the color uniformity and thermal stability of phosphors, which is vital for its applications in health and comfort lighting. In this study, the SrSi2O2N2:Eu2+/g-C3N4 composites were successfully prepared via a facile and effective solid-state method to improve their photoluminescence properties and thermal stability. The coupling microstructure and chemical composition of the composites were demonstrated by high-resolution transmission electron microscopy (HRTEM) and EDS line-scanning analyses. Notably, the dual emissions at â¼460 nm (blue) and â¼520 nm (green) were observed for the SrSi2O2N2:Eu2+/g-C3N4 composite under near-ultraviolet (NUV) excitation, attributed to the g-C3N4 and 5d-4f transition of Eu2+ ions, respectively. The coupling structure will be beneficial to the color uniformity of the blue/green emitting light. Further, SrSi2O2N2:Eu2+/g-C3N4 composites exhibited a similar photoluminescence intensity compared with the SrSi2O2N2:Eu2+ phosphor even after thermal treatment at 500 °C for 2 h due to the protection of g-C3N4. The decreased decay time (1798.3 ns) of green emission for SSON/CN compared with SSON phosphor (1835.5 ns) indicated that the coupling structure suppressed the non-radiative transition and improved photoluminescence properties and thermal stability. This work provides a facile strategy to construct SrSi2O2N2:Eu2+/g-C3N4 composites with coupling structure for improved color uniformity and thermal stability.
Objective: Holistic care is a key element in nursing care. Aiming at the heterogeneous disease of cerebral palsy, researchers focused on children with cerebral palsy who received transnasal transplantation of neural stem cells as a specific group. Based on establishing a multidisciplinary team, comprehensive care is carried out for this type of patient during the perioperative period to improve the effectiveness and safety of clinical research and increase the comfort of children. Methods: Between January 2018 and June 2023, 22 children with cerebral palsy underwent three transnasal transplants of neural stem cells. Results: No adverse reactions related to immune rejection were observed in the 22 children during hospitalization and follow-up. All children tolerated the treatment well, and the treatment was superior. One child developed nausea and vomiting after sedation; three had a small amount of bleeding of nasal mucosa after transplantation. Two children had a low fever (≤38.5°C), and one had a change in the type and frequency of complex partial seizures. Moreover, 3 children experienced patch shedding within 4â h of patch implantation into the nasal cavity. Conclusion: The project team adopted nasal stem cell transplantation technology. Based on the characteristics of transnasal transplantation of neural stem cells in the treatment of neurological diseases in children, a comprehensive and novel holistic care plan is proposed. It is of great significance to guide caregivers of children to complete proper care, further improve the safety and effectiveness of treatment, and reduce the occurrence of complications.
PURPOSE: Rivaroxaban, an oral anticoagulant, undergoes the metabolism mediated by human cytochrome P450 (CYP). The present study is to quantitatively analyze and compare the contributions of multiple CYPs in the metabolism of rivaroxaban to provide new information for medication safety. METHODS: The metabolic stability of rivaroxaban in the presence of human liver microsomes (HLMs) and recombinant CYPs was systematically evaluated to estimate the participation of various CYP isoforms. Furthermore, the catalytic efficiency of CYP isoforms was compared via metabolic kinetic studies of rivaroxaban with recombinant CYP isoenzymes, as well as via CYP-specific inhibitory studies. Additionally, docking simulations were used to illustrate molecular interactions. RESULTS: Multiple CYP isoforms were involved in the hydroxylation of rivaroxaban, with decreasing catalytic rates as follows: CYP2J2 > 3A4 > 2D6 > 4F3 > 1A1 > 3A5 > 3A7 > 2A6 > 2E1 > 2C9 > 2C19. Among the CYPs, 2J2, 3A4, 2D6, and 4F3 were the four major isoforms responsible for rivaroxaban metabolism. Notably, the intrinsic clearance of rivaroxaban catalyzed by CYP2J2 was nearly 39-, 64-, and 100-fold that catalyzed by CYP3A4, 2D6, and 4F3, respectively. In addition, rivaroxaban hydroxylation was inhibited by 41.1% in the presence of the CYP2J2-specific inhibitor danazol, which was comparable to the inhibition rate of 43.3% by the CYP3A-specific inhibitor ketoconazole in mixed HLMs. Furthermore, molecular simulations showed that rivaroxaban is principally bound to CYP2J2 by π-alkyl bonds, carbon-hydrogen bonds, and alkyl interactions. CONCLUSION: CYP2J2 dominated the hydroxylation of rivaroxaban, which may provide new insight into clinical drug interactions involving rivaroxaban.
Cytochrome P-450 CYP2J2/metabolism , Factor Xa Inhibitors/pharmacokinetics , Microsomes, Liver/metabolism , Rivaroxaban/pharmacokinetics , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Danazol/pharmacology , Drug Interactions , Humans , Isoenzymes , Microsomes, Liver/enzymology , Molecular Docking Simulation
Design and fabrication of bifunctional efficient and durable noble-metal-free electrocatalyst for hydrogen and oxygen evolution is highly desirable and challenging for overall water splitting. Herein, a novel hybrid nanostructure with Ni2P/CoP nanoparticles decorated on a porous N-doped fullerene nanorod (p-NFNR@Ni-Co-P) was developed as a bifunctional electrocatalyst. Benefiting from the electric current collector (ECC) effect of FNR for the active Ni2P/CoP nanoparticles, the p-NFNR@Ni-Co-P exhibited outstanding electrocatalytic performance for overall water splitting in alkaline medium. To deliver a current density of 10 mA cm-2, the electrolytic cell assembled by p-NFNR@Ni-Co-P merely required a potential as low as 1.62 V, superior to the benchmark noble-metal-based electrocatalyst. Experimental and theoretical results demonstrated that the surface engineered FNR serving as an ECC played a critical role in accelerating the charge transfer during the electrocatalytic reaction. The present work paves the way for fullerene nanostructures in the realm of energy conversion and storage.
The 2019 novel coronavirus (SARS-CoV-2) has spread rapidly worldwide and was declared a pandemic by the WHO in March 2020. The evolution of SARS-CoV-2, either in its natural reservoir or in the human population, is still unclear, but this knowledge is essential for effective prevention and control. We propose a new framework to systematically identify recombination events, excluding those due to noise and convergent evolution. We found that several recombination events occurred for SARS-CoV-2 before its transfer to humans, including a more recent recombination event in the receptor-binding domain. We also constructed a probabilistic mutation network to explore the diversity and evolution of SARS-CoV-2 after human infection. Clustering results show that the novel coronavirus has diverged into several clusters that cocirculate over time in various regions and that several mutations across the genome are fixed during transmission throughout the human population, including D614G in the S gene and two accompanied mutations in ORF1ab. Together, these findings suggest that SARS-CoV-2 experienced a complicated evolution process in the natural environment and point to its continuous adaptation to humans. The new framework proposed in this study can help our understanding of and response to other emerging pathogens.
Evolution, Molecular , Recombination, Genetic , SARS-CoV-2/genetics , COVID-19/virology , Humans , Phylogeny , Reproducibility of Results
BACKGROUND: The novel COVID-19 disease has spread worldwide, resulting in a new pandemic. The Chinese government implemented strong intervention measures in the early stage of the epidemic, including strict travel bans and social distancing policies. Prioritizing the analysis of different contributing factors to outbreak outcomes is important for the precise prevention and control of infectious diseases. We proposed a novel framework for resolving this issue and applied it to data from China. OBJECTIVE: This study aimed to systematically identify national-level and city-level contributing factors to the control of COVID-19 in China. METHODS: Daily COVID-19 case data and related multidimensional data, including travel-related, medical, socioeconomic, environmental, and influenza-like illness factors, from 343 cities in China were collected. A correlation analysis and interpretable machine learning algorithm were used to evaluate the quantitative contribution of factors to new cases and COVID-19 growth rates during the epidemic period (ie, January 17 to February 29, 2020). RESULTS: Many factors correlated with the spread of COVID-19 in China. Travel-related population movement was the main contributing factor for new cases and COVID-19 growth rates in China, and its contributions were as high as 77% and 41%, respectively. There was a clear lag effect for travel-related factors (previous vs current week: new cases, 45% vs 32%; COVID-19 growth rates, 21% vs 20%). Travel from non-Wuhan regions was the single factor with the most significant impact on COVID-19 growth rates (contribution: new cases, 12%; COVID-19 growth rate, 26%), and its contribution could not be ignored. City flow, a measure of outbreak control strength, contributed 16% and 7% to new cases and COVID-19 growth rates, respectively. Socioeconomic factors also played important roles in COVID-19 growth rates in China (contribution, 28%). Other factors, including medical, environmental, and influenza-like illness factors, also contributed to new cases and COVID-19 growth rates in China. Based on our analysis of individual cities, compared to Beijing, population flow from Wuhan and internal flow within Wenzhou were driving factors for increasing the number of new cases in Wenzhou. For Chongqing, the main contributing factor for new cases was population flow from Hubei, beyond Wuhan. The high COVID-19 growth rates in Wenzhou were driven by population-related factors. CONCLUSIONS: Many factors contributed to the COVID-19 outbreak outcomes in China. The differential effects of various factors, including specific city-level factors, emphasize the importance of precise, targeted strategies for controlling the COVID-19 outbreak and future infectious disease outbreaks.
COVID-19/epidemiology , Disease Outbreaks/statistics & numerical data , China/epidemiology , Factor Analysis, Statistical , Humans
PFASs are highly persistent in both natural and living environment, and pose a significant risk for wildlife and human beings. The present study was carried out to determine the inhibitory behaviours of fourteen PFASs on metabolic activity of two major isoforms of carboxylesterases (CES). The probe substrates 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) for CES1 and fluorescein diacetate (FD) for CES2 were utilized to determine the inhibitory potentials of PFASs on CES in vitro. The results demonstrated that perfluorododecanoic acid (PFDoA), perfluorotetradecanoic acid (PFTA) and perfluorooctadecanoic acid (PFOcDA) strongly inhibited CES1 and CES2. The half inhibition concentration (IC50) value of PFDoA, PFTA and PFOcDA for CES1 inhibition was 10.6 µM, 13.4 µM and 12.6 µM, respectively. The IC50 for the inhibition of PFDoA, PFTA and PFOcDA towards CES2 were calculated to be 9.56 µM, 17.2 µM and 8.73 µM, respectively. PFDoA, PFTA and PFOcDA exhibited noncompetitive inhibition towards both CES1 and CES2. The inhibition kinetics parameters (Ki) were 27.7 µM, 26.9 µM, 11.9 µM, 4.04 µM, 29.1 µM, 27.4 µM for PFDoA-CES1, PFTA-CES1, PFOcDA-CES1, PFDoA-CES2, PFTA-CES2, PFOcDA-CES2, respectively. In vitro-in vivo extrapolation (IVIVE) predicted that when the plasma concentrations of PFDoA, PFTA and PFOcDA were greater than 2.77 µM, 2.69 µM and 1.19 µM, respectively, it might interfere with the metabolic reaction catalyzed by CES1 in vivo; when the plasma concentrations of PFDoA, PFTA and PFOcDA were greater than 0.40 µM, 2.91 µM, 2.74 µM, it might interfere with the metabolic reaction catalyzed by CES2 in vivo. Molecular docking was used to explore the interactions between PFASs and CES. In conclusion, PFASs were found to cause inhibitory effects on CES in vitro, and this finding would provide an important experimental basis for further in vivo testing of PFASs focused on CES inhibition endpoints.
Carboxylesterase , Carboxylic Ester Hydrolases , Humans , Molecular Docking Simulation , Protein Isoforms
UDP-glucuronosyltransferases (UGTs) and ß-glucuronidase (GUS) catalyze entirely distinct metabolism reactions. UGTs are responsible for the glucuronidation of a variety of drugs, endogenous and environmental chemicals, whereas GUS hydrolyzes glucuronides and liberates the parent substrates. Information on the overlap of ligand selectivity between UGT and GUS is essential for exploring the pharmacological or toxicological effects of the inhibitors of these two metabolic enzymes. This study is conducted to test whether UGTs and GUS share common ligands, by investigating the inhibitory effects towards E. coli GUS by a series of UGT typical substrates and inhibitors. Results showed that three typical ligands of UGTs, including two specific substrates (estradiol and trifluoperazine, E2 and TFP) and one selective inhibitor (magnolol, Mag), can inhibit the activity of GUS. Kinetic assays indicated that all the three UGT specific chemicals displayed competitive inhibition, with K i values of 31.4 (E2), 56.9 (TFP), and 16.6 µM (Mag). Docking studies further revealed that the three chemicals can enter the active sites of GUS by forming contacts with residues Glu-413, Trp-549, Asp-163, Tyr-472, Arg-562, or bound water. Our study indicates that ligand selectivity overlaps between UGTs and GUS, and some chemicals can act as co-inhibitors of these two metabolic enzymes. The pharmacological or toxicological effects of those co-inhibitors require further investigations.
The design and fabrication of intricate hollow architectures as cost-effective and dual-function electrocatalyst for water and urea electrolysis is of vital importance to the energy and environment issues. Herein, a facile solvothermal strategy for construction of Prussian-blue analogue (PBA) hollow cages with an open framework was developed. The as-obtained CoFe and NiFe hollow cages (CFHC and NFHC) can be directly utilized as electrocatalysts towards oxygen evolution reaction (OER) and urea oxidation reaction (UOR) with superior catalytic performance (lower electrolysis potential, faster reaction kinetics and long-term durability) compared to their parent solid precursors (CFC and NFC) and even the commercial noble metal-based catalyst. Impressively, to drive a current density of 10 mA cm-2 in alkaline solution, the CFHC catalyst required an overpotential of merely 330 mV, 21.99% lower than that of the solid CFC precursor (423 mV) at the same condition. Meanwhile, the NFHC catalyst could deliver a current density as high as 100 mA cm-2 for the urea oxidation electrolysis at a potential of only 1.40 V, 24.32% lower than that of the solid NFC precursor (1.85 V). This work provides a new platform to construct intricate hollow structures as promising nano-materials for the application in energy conversion and storage.
Luminescent carbon quantum dots (CQDs) represent a new form of nanocarbon materials which have gained widespread attention in recent years, especially in chemical sensor, bioimaging, nanomedicine, solar cells, light-emitting diode (LED), and electrocatalysis. CQDs can be prepared simply and inexpensively by multiple techniques, such as the arc-discharge method, microwave pyrolysis, hydrothermal method, and electrochemical synthesis. CQDs show excellent physical and chemical properties like high crystallization, good dispersibility, photoluminescence properties. In particular, the small size, superconductivity, and rapid electron transfer of CQDs endow the CQDs-based composite with improved electric conductivity and catalytic activity. Besides, CQDs have abundant functional groups on the surface which could facilitate the preparation of multi-component electrical active catalysts. The interactions inside these multi-component catalysts may further enhance the catalytic performance by promoting charge transfer which plays an important role in electrochemistry. Most recent researches on CQDs have focused on their fluorescence characteristics and photocatalytic properties. This review will summarize the primary advances of CQDs in the synthetic methods, excellent physical and electronic properties, and application in electrocatalysis, including oxygen reduction reaction (ORR), oxygen evolution reaction (OER), hydrogen evolution reduction (HER), and CO2 reduction reaction (CO2RR).
Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1-14) and four known analogues (15-18) from Alisma orientale, and finally constructed a small library of protostane-type triterpenoids (1-70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC50â¯=â¯90â¯nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology.
Biological Products/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Terpenes/pharmacology , Alisma/chemistry , Biological Products/chemistry , Biological Products/isolation & purification , Cells, Cultured , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Molecular Docking Simulation , Molecular Structure , Mutagenesis, Site-Directed , Receptors, Cytoplasmic and Nuclear/genetics , Structure-Activity Relationship , Terpenes/chemistry , Terpenes/isolation & purification
The application of boronic acid affinity chromatography to glycoprotein/glycopeptide enrichment is increasingly maturing. The enrichment selectivity, biocompatibility, and facile operation protocol are key aspects in efficient enrichment methods. In this work, a novel triazo-cyanide boronic acid functionalized material (TCNBA) was prepared using triazo-cyanide click chemistry. The TCNBA was proved to be successfully synthesized through infrared ray (IR) characterization. Subsequently, the glycopeptide/glycoprotein enrichment selectivity of the TCNBA was evaluated. Matrix-assisted laser desorption/ionization time-of-flight mass (MALDI-TOF MS) was employed for the glycopeptide enrichment selectivity evaluation. Taking the digestion of horseradish peroxidase (HRP) and immunoglobulin G (IgG) as samples, 13 and 11 glycopeptides could be characterized with improved signals after TCNBA enrichment, respectively. High abundance non-glycopeptides could be removed effectively from the eluting fraction. This result indicates the high glycopeptide enrichment selectivity of TCNBA. In addition, a mixture of HRP and bovine serum albumin (BSA) enzymatic solution (1:10, amount of substance ratio) was utilized as a sample, and five glycopeptide signals could be identified following enrichment. To evaluate the glycoprotein enrichment selectivity, sodium salt-polyacrylamide gel electrophoresis (SDS-PAGE) was adopted as an evaluation method. Mixtures of HRP, IgG, BSA, and ribonuclease B (RNaseB) proteins were employed as samples, and the results demonstrated that TCNBA had a high glycoprotein enrichment selectivity. The application of TCNBA to the analysis of a real biosample was also evaluated using human plasma. The results indicated the TCNBA could be utilized in large-scale glycoprotein analysis.
Boronic Acids/chemistry , Click Chemistry , Cyanides/chemistry , Glycopeptides/isolation & purification , Glycoproteins/isolation & purification , Silica Gel/chemistry , Humans , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Horseradish peroxidase (HRP) and laccase are well known oxidases, which have been widely applied for the biosynthesis of organic compounds. In the present work, flavone analogues as an important type of bioactive natural product could be oxidized by HRP or laccase, which afforded dimeric and oxidative flavones. All of the flavone analogues usually possessing phenolic groups could be transformed using HRP. However, only flavonols, isoflavones and chalcones with phenolic groups and dihydroxylflavones were effective substrates of laccase. The radical reaction mechanism with the B-ring of flavone analogues as the radical reaction trigger was proposed for the oxidation of flavones. In silico molecular docking analyses for assaying the interaction between flavone analogues and oxidases indicated that the phenolic groups at the B rings of flavones docked into the HEME active pocket of HRP well. Kinetic behaviors of the oxidation for various flavone analogues mediated by HRP or laccase displayed Hill and substrate inhibition kinetic models. Therefore, in the present work, the oxidation of various flavone analogues mediated by HRP or laccase has been successfully characterized, which would be helpful for the preparation of flavone derivatives.
Regenerative medicine has a high demand for the development of scaffold materials combined with other osteogenic inducers to generate bioactive composite materials for bone replacement therapies. Previously, we reported that wedelolactone promoted osteoblastogenesis of bone marrow mesenchymal stem cells (BMSCs). In this study, the effect of hydroxyapatites (HAps), bone composite materials we prepared, and the combined effect of wedelolactone and HAps on osteoblastogenesis differentiation was first evaluated. Three kinds of HAps constructed by a rod-like shape with particle size of 25 nm (HAp-1), 37 nm (HAp-2), and 33 nm (HAp-3) did not affect BMSC survival, but induced activity of alkaline phosphatase(ALP), a marker enzyme for osteoblastogenesis. HAp-1 treatment resulted in a more significant increase in the number of ALP staining-positive BMSC, and maintained an extended time for the increased number of ALP staining-positive BMSC. Moreover, HAp-1 combined with wedelolactone induced a higher ALP activity for a longer time than HAp-2 and HAp-3, and also increased the bone mineralization level. Osteoblastogenesis-related marker genes expression including osteorix, osteocalcin, and runx2 were increased after BMSC were treated with HAp-1 for 6 days. Although three kinds of HAps treatment for 9 days increased osteorix mRNA expression, osteocalcin, and runx2 mRNA expression levels were upregulated only by HAp-1. Similarly, only HAp-1 enhanced wedelolactone-induced osteocalcin, osteorix, and runx2 mRNA expression after 9 days treatment. Together, these results suggested that HAps with different sizes generated different effect on osteoblastogenesis. HAp-1 combined with wedelolacone can exert an enhanced effect on osteoblastogenesis, which has potential for treating osteoporosis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 145-153, 2019.
Bone Marrow Cells/metabolism , Cell Differentiation/drug effects , Coumarins , Durapatite , Mesenchymal Stem Cells/metabolism , Nanoparticles/chemistry , Osteoblasts/metabolism , Animals , Bone Marrow Cells/cytology , Coumarins/chemistry , Coumarins/pharmacology , Durapatite/chemistry , Durapatite/pharmacology , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred BALB C , Osteoblasts/cytology
Cytochrome P450 2J2 (CYP2J2), a key enzyme responsible for oxidative metabolism of various xenobiotics and endogenous compounds, participates in a diverse array of physiological and pathological processes in humans. Its biological role in tumorigenesis and cancer diagnosis remains poorly understood, owing to the lack of molecular tools suitable for real-time monitoring CYP2J2 in complex biological systems. Using molecular design principles, we were able to modify the distance between the catalytic unit and metabolic recognition moiety, allowing us to develop a CYP2J2 selective fluorescent probe using a near-infrared fluorophore ( E)-2-(2-(6-hydroxy-2, 3-dihydro-1 H-xanthen-4-yl)vinyl)-3,3-dimethyl-1-propyl-3 H-indol-1-ium iodide (HXPI). To improve the reactivity and isoform specificity, a self-immolative linker was introduced to the HXPI derivatives in order to better fit the narrow substrate channel of CYP2J2, the modification effectively shortened the spatial distance between the metabolic moiety ( O-alkyl group) and catalytic center of CYP2J2. After screening a panel of O-alkylated HXPI derivatives, BnXPI displayed the best combination of specificity, sensitivity and applicability for detecting CYP2J2 in vitro and in vivo. Upon O-demethylation by CYP2J2, a self-immolative reaction occurred spontaneously via 1,6-elimination of p-hydroxybenzyl resulting in the release of HXPI. Allowing BnXPI to be successfully used to monitor CYP2J2 activity in real-time for various living systems including cells, tumor tissues, and tumor-bearing animals. In summary, our practical strategy could help the development of a highly specific and broadly applicable tool for monitoring CYP2J2, which offers great promise for exploring the biological functions of CYP2J2 in tumorigenesis.
Cytochrome P-450 Enzyme System/analysis , Fluorescent Dyes/chemistry , Xanthenes/chemistry , Animals , Cell Line, Tumor , Cytochrome P-450 CYP2J2 , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/metabolism , Humans , Leukemia/diagnostic imaging , Lymphoma/diagnostic imaging , Mice, Nude , Microscopy, Confocal/methods , Microscopy, Fluorescence/methods , Microsomes, Liver/metabolism , Molecular Docking Simulation , Neovascularization, Pathologic/diagnostic imaging , Protein Binding , Xanthenes/chemical synthesis , Xanthenes/metabolism
Europium(ii)-doped phosphate cyan@red-emitting phosphors with highly dispersed luminescence centers were developed for the first time by using the deposition-precipitation method. Amazingly, when excited by near-ultraviolet light, the single phosphor generated warm white light with an adjustable correlated colour temperature (4000-2500 K) and high colour-rendering index (Ra â¼ 90).
