Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative ...metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1-3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.
Iron-sulfur clusters are essential cofactors found in all kingdoms of life and play essential roles in fundamental processes, including but not limited to respiration, photosynthesis, and nitrogen ...fixation. The chemistry of iron-sulfur clusters makes them ideal for sensing various redox environmental signals, while the physics of iron-sulfur clusters and its host proteins have been long overlooked. One such protein, MagR, has been proposed as a putative animal magnetoreceptor. It forms a rod-like complex with cryptochromes (Cry) and possesses intrinsic magnetic moment. However, the magnetism modulation of MagR remains unknown. Here in this study, iron-sulfur cluster binding in MagR has been characterized. Three conserved cysteines of MagR play different roles in iron-sulfur cluster binding. Two forms of iron-sulfur clusters binding have been identified in pigeon MagR and showed different magnetic properties: 3Fe-4S-MagR appears to be superparamagnetic and has saturation magnetization at 5 K but 2Fe-2S-MagR is paramagnetic. While at 300 K, 2Fe-2S-MagR is diamagnetic but 3Fe-4S-MagR is paramagnetic. Together, the different types of iron-sulfur cluster binding in MagR attribute distinguished magnetic properties, which may provide a fascinating mechanism for animals to modulate the sensitivity in magnetic sensing.
Jasmonate ZIM-domain (JAZ) proteins, which act as negative regulators in the jasmonic acid (JA) signalling pathway, have significant implications for plant development and response to abiotic stress. ...Through a comprehensive genome-wide analysis, a total of 20 members of the JAZ gene family specific to alfalfa were identified in its genome. Phylogenetic analysis divided these 20 MsJAZ genes into five subgroups. Gene structure analysis, protein motif analysis, and 3D protein structure analysis revealed that alfalfa JAZ genes in the same evolutionary branch share similar exon-intron, motif, and 3D structure compositions. Eight segmental duplication events were identified among these 20 MsJAZ genes through collinearity analysis. Among the 32 chromosomes of the autotetraploid cultivated alfalfa, there were 20 MsJAZ genes distributed on 17 chromosomes. Extensive stress-related cis-acting elements were detected in the upstream sequences of MsJAZ genes, suggesting that their response to stress has an underlying function. Furthermore, the expression levels of MsJAZ genes were examined across various tissues and under the influence of salt stress conditions, revealing tissue-specific expression and regulation by salt stress. Through RT-qPCR experiments, it was discovered that the relative expression levels of these six MsJAZ genes increased under salt stress. In summary, our study represents the first comprehensive identification and analysis of the JAZ gene family in alfalfa. These results provide important information for exploring the mechanism of JAZ genes in alfalfa salt tolerance and identifying candidate genes for improving the salt tolerance of autotetraploid cultivated alfalfa via genetic engineering in the future.
Hierarchically structured nitrogen‐doped carbon nanotube (NCNT) composites, with copper (Cu) nanoparticles embedded uniformly within the nanotube walls and cobalt oxide (CoxOy) nanoparticles ...decorated on the nanotube surfaces, are fabricated via a combinational process. This process involves the growth of Cu embedded CNTs by low‐ and high‐temperature chemical vapor deposition, post‐treatment with ammonia for nitrogen doping of these CNTs, precipitation‐assisted separation of NCNTs from cobalt nitrate aqueous solution, and finally thermal annealing for CoxOy decoration. Theoretical calculations show that interaction of Cu nanoparticles with CNT walls can effectively decrease the work function of CNT surfaces and improve adsorption of hydroxyl ions onto the CNT surfaces. Thus, the activities of the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) are significantly enhanced. Because of this benefit, further nitrogen doping, and synergistic coupling between CoxOy and NCNTs, Cu@NCNT/CoxOy composites exhibit ORR activity comparable to that of commercial Pt/C catalysts and high OER activity (outperforming that of IrO2 catalysts). More importantly, the composites display superior long‐term stability for both ORR and OER. This simple but general synthesis protocol can be extended to design and synthesis of other metal/metal oxide systems for fabrication of high‐performance carbon‐based electrocatalysts with multifunctional catalytic activities.
Nitrogen‐doped carbon nanotubes (NCNTs), with copper (Cu) nanoparticles embedded uniformly within their walls and cobalt oxide (CoxOy) nanoparticles decorated on their surfaces, are controllably synthesized via a rationally designed multistep procedure. The resultant Cu@NCNT/CoxOy composites exhibit electrocatalytic activity comparable to that of commercial Pt/C catalysts for the oxygen reduction reaction and activity higher than that of IrO2 catalysts for the oxygen evolution reaction.
The neurobehavioral effects of paternal smoking and nicotine use have not been widely reported. In the present study, nicotine exposure induced depression in the paternal generation, but reduced ...depression and promoted hyperactivity in F1 offspring. While this intergenerational effect was not passed down to the F2 generation. Further studies revealed that nicotine induced the down-regulation of mmu-miR-15b expression due to hyper-methylation in the CpG island shore region of mmu-miR-15b in both the spermatozoa of F0 mice and the brains of F1 mice. As the target gene of mmu-miR-15b, Wnt4 expression was elevated in the thalamus of F1 mice due to the inheritance of DNA methylation patterns from the paternal generation. Furthermore, the increased expression of Wnt4 elevated the phosphorylation level of its downstream protein GSK-3 through the canonical WNT4 pathway which involved in the behavioral alterations observed in F1 mice. Moreover, in vivo stereotaxic brain injections were used to induce the overexpression of mmu-miR-15b and WNT4 and confirm the neurobehavioral effects in vitro. The behavioral phenotype of the F1 mice resulting from paternal nicotine exposure could be attenuated by viral manipulation of mmu-miR-15b in the thalamus.
Alfalfa (
) is an important leguminous forage, known as the "The Queen of Forages". Abiotic stress seriously limits the growth and development of alfalfa, and improving the yield and quality has ...become an important research area. However, little is known about the Msr (methionine sulfoxide reductase) gene family in alfalfa. In this study, 15
genes were identified through examining the genome of the alfalfa "Xinjiang DaYe". The MsMsr genes differ in gene structure and conserved protein motifs. Many cis-acting regulatory elements related to the stress response were found in the promoter regions of these genes. In addition, a transcriptional analysis and qRT-PCR (quantitative reverse transcription PCR) showed that
genes show expression changes in response to abiotic stress in various tissues. Overall, our results suggest that
genes play an important role in the response to abiotic stress for alfalfa.
•Nicotine decreases mice serum testosterone by triggering testicular autophagy instead of apoptosis via TCL1-mTOR-autophagy pathway in Leydig cells.•This study is among the first to use ...bioinformatics in the reproductive research area to draw the relationship between nicotine and testicular autophagy.•This work as determined the relationship between nicotine and changes of testosterone concentrations in mouse sera on a molecular level.•It was also found that the TCL1 promoter is methylated consequent to a cascade pathway induced by the presence of nicotine.
A new report has shown that nicotine exposure can decrease serum testosterone by apoptosis in Leydig cells; however, in our previous studies, we have almost never observed apoptosis there. The purpose of this study is to ensure whether apoptosis or autophagy in Leydig cells occurred. Our results confirmed again that the concentration of testosterone in the sera of nicotine-treated mice statistically decreased (P < 0.05). Furthermore, the data of single cell transcriptome indicated that the expression of autophagy-related genes was increased after nicotine exposure. Likewise, chemical and immune-histological staining demonstrated that autophagy of the Leydig cells increased after nicotine treatment rather than apoptosis. Apoptosis mainly exists in spermatids. Further, the expression of autophagy-related genes, such as Beclin1 and LC3, were up-regulated after nicotine exposure (P < 0.05). Additionally, the data of transmission electron microscopy showed more autophagosomes in the Leydig cells of the nicotine-exposed groups than the cells of the control groups. Moreover, immunofluorescent staining of LC3 in the TM3 Leydig cell line indicated that rapamycin and nicotine exposure up-regulates the autophagy phenotype/process and down-regulates their testosterone synthesis. In addition, the methylation level of the promoter region of TCL1 is increased in the nicotine-treated group compared to the control group, consequently decreasing the expression of TCL1. In conclusion, the autophagy in Leydig cells induced by nicotine, which is set by the hyper-methylation of the TCL1 promoter region via the TCL1-mTOR-autophagy signaling pathway.
Biotransformation of organophosphorus flame retardants (OPFRs) mediated by cytochrome P450 enzymes (CYPs) has a potential correlation with their toxicological effects on humans. In this work, we ...employed five typical OPFRs including tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(1-chloro-2-propyl) phosphate (TCIPP), tri(2-chloroethyl) phosphate (TCEP), triethyl phosphate (TEP), and 2-ethylhexyl diphenyl phosphate (EHDPHP), and performed density functional theory (DFT) calculations to clarify the CYP-catalyzed biotransformation of five OPFRs to their diester metabolites. The DFT results show that the reaction mechanism consists of Cα-hydroxylation and O-dealkylation steps, and the biotransformation activities of five OPFRs may follow the order of TCEP ≈ TEP ≈ EHDPHP > TCIPP > TDCIPP. We further performed molecular dynamics (MD) simulations to unravel the binding interactions of five OPFRs in the CYP3A4 isoform. Binding mode analyses demonstrate that CYP3A4-mediated metabolism of TDCIPP, TCIPP, TCEP, and TEP can produce the diester metabolites, while EHDPHP metabolism may generate para-hydroxyEHDPHP as the primary metabolite. Moreover, the EHDPHP and TDCIPP have higher binding potential to CYP3A4 than TCIPP, TCEP, and TEP. This work reports the biotransformation profiles and binding features of five OPFRs in CYP, which can provide meaningful clues for the further studies of the metabolic fates of OPFRs and toxicological effects associated with the relevant metabolites.
Zwitterionic sulfobetaine-based monolithic stationary phases have attracted increasing attention for their use in hydrophilic interaction chromatography. In this study, a novel hydrophilic polymeric ...monolith was fabricated through photo-initiated copolymerization of 3-(3-vinyl-1-imidazolio)-1-propanesulfonate (SBVI) with pentaerythritol triacrylate using methanol and tetrahydrofuran as the porogenic system. Notably, the duration for the preparation of this novel monolith was as little as 5 min, which was significantly shorter than that required for previously reported sulfobetaine-based monoliths prepared via conventional thermally initiated copolymerization. Moreover, these monoliths showed good morphology, permeability, porosity (62.4%), mechanical strength (over 15 MPa), column efficiency (51,230 plates/m), and reproducibility (relative standard deviations for all analytes were lower than 4.6%). Mechanistic studies indicated that strong hydrophilic and negative electrostatic interactions might be responsible for the retention of polar analytes on the zwitterionic SBVI-based monolith. In particular, the resulting monolith exhibited good anti-protein adhesion ability and low nonspecific protein adsorption. These excellent features seem to favor its application in bioanalysis. Therefore, the novel zwitterionic sulfobetaine-based monolith was successfully employed for the highly selective separation of small bioactive compounds and the efficient enrichment of N-glycopeptides from complex samples. In this study, we prepared a novel zwitterionic sulfobetaine-based monolith with good performance and developed a simpler and faster method for preparation of zwitterionic monoliths.
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•A SBVI modified monolith was fabricated within 5 min.•The monolith exhibited good selectivity for the separation of bioactive compounds.•The SBVI-based monolith exhibited excellent anti-protein adsorption ability.•The SBVI-based monolith exhibited good enrichment capacity for N-glycopeptides in biological samples.
Branched and multi‐generation branched architectures of silicon nanotubes (SiNTs) and metal nanowires (NWs), built via filling the branched and multi‐generation‐branched nanochannels of anodic ...aluminum oxide (AAO) templates by pyrolysis of silane and electrodeposition of metals, are reported. The AAO templates with branched and multi‐generation‐branched nanochannels are created by sequentially reducing the applied anodizing voltage multiple times during the anodization of aluminum. The desired total generation number of branching can be controlled by the times of voltage reduction during the anodization; while each generation of branching is controlled in terms of branching number, diameter and length. The approach allows precise control over the complexity of the SiNTs and metal NWs with several levels of junctions and branching that have potentials in nanoelectronics, nanomagnetism and nanosystems.
Branched and multi‐generation‐branched silicon nanotubes and metal (Au and Ni) nanowires have been achieved by filling the branched and multi‐generation‐branched nanochannels of the anodic aluminum oxide templates, which are created by sequentially reducing the applied anodizing voltage multiple times during the anodization of aluminum.
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