Cytochrome P450 Genes Research Articles

The variation of a cytochrome P450 gene, CYP6G4, drives the evolution of Musca domestica L. (Diptera: Muscidae) resistance to insecticides in China

Long term and excessive insecticide use has resulted in some environmental problems and especially, insecticide resistance evolution in insect pests. The variation of cytochrome P450 monooxygenases (P450s), associated with the metabolic detoxification of toxic xenobiotics, is often involved in insecticide resistance. Here, we found that the variation in a P450 gene, CYP6G4, is the most important driver of carbamates resistance in the house fly (Musca domestica). Deciphering the detailed molecular mechanisms of the insecticide resistance is critical for performing suitable insecticide resistance management strategies. Our research results revealed that the combination of amino acid mutations (110C-330E-360N/S, 110C-330E-360S) of CYP6G4 could improve the resistance to propoxur. The nucleotide variations in the promoter region of CYP6G4 significantly increased the luciferase activity by the reporter gene assays. Additionally, miR-281-1-5p was confirmed to post-transcriptionally down-regulate the expression of CYP6G4. These findings suggest that three independent mechanisms; amino acid mutations of the P450 protein, mutations in the promoter region and low expression of post-trans-regulatory factors, as the powerful strategies for the insect resistance to toxic compounds, play a crucial role in the evolutionary processes of insecticide resistance.

Identification of iron metabolism-related genes as diagnostic signatures in sepsis by blood transcriptomic analysis.

Iron metabolism is considered to play the principal role in sepsis, but the key iron metabolism-related genetic signatures are unclear. In this study, we analyzed and identified the genetic signatures related to the iron-metabolism in sepsis by using a bioinformatics analysis of four transcriptomic datasets from the GEO database. A total of 21 differentially expressed iron metabolism-related signatures were identified including 9 transporters, 8 enzymes, and 4 regulatory factors. Among them, lipocalin 2 was found to have the highest diagnostic value as its expression showed significant differences in all the comparisons including sepsis vs healthy controls, sepsis vs non-sepsis diseases, and mild forms vs severe forms of sepsis. Besides, the cytochrome P450 gene CYP1B1 also showed diagnostic values for sepsis from the non-sepsis diseases. The CYP4V2, LTF, and GCLM showed diagnostic values for distinguishing the severe forms from mild forms of sepsis. Our analysis identified 21 sepsis-associated iron metabolism-related genetic signatures, which may represent diagnostic and therapeutic biomarkers of sepsis, and will improve our understanding of the molecular mechanism underlying the occurrence of sepsis.

Multiple-P450 Gene Co-Up-Regulation in the Development of Permethrin Resistance in the House Fly, Musca domestica

This paper reports a study conducted at the whole transcriptome level to characterize the P450 genes involved in the development of pyrethroid resistance, utilizing expression profile analyses of 86 cytochrome P450 genes in house fly strains with different levels of resistance to pyrethroids/permethrin. Interactions among the up-regulated P450 genes and possible regulatory factors in different autosomes were examined in house fly lines with different combinations of autosomes from a resistant house fly strain, ALHF. Eleven P450 genes that were significantly up-regulated, with levels > 2-fold those in the resistant ALHF house flies, were in CYP families 4 and 6 and located on autosomes 1, 3 and 5. The expression of these P450 genes was regulated by trans- and/or cis-acting factors, especially on autosomes 1 and 2. An in vivo functional study indicated that the up-regulated P450 genes also conferred permethrin resistance in Drosophila melanogaster transgenic lines. An in vitro functional study confirmed that the up-regulated P450 genes are able to metabolize not only cis- and trans-permethrin, but also two metabolites of permethrin, PBalc and PBald. In silico homology modeling and the molecular docking methodology further support the metabolic capacity of these P450s for permethrin and substrates. Taken together, the findings of this study highlight the important function of multi-up-regulated P450 genes in the development of insecticide resistance in house flies.

Alzheimer's Precision Neurology: Epigenetics of Cytochrome P450 Genes in Circulating Cell-Free DNA for Disease Prediction and Mechanism.

Precision neurology combines high-throughput technologies and statistical modeling to identify novel disease pathways and predictive biomarkers in Alzheimer's disease (AD). Brain cytochrome P450 (CYP) genes are major regulators of cholesterol, sex hormone, and xenobiotic metabolism, and they could play important roles in neurodegenerative disorders. Increasing evidence suggests that epigenetic factors contribute to AD development. We evaluated cytosine ('CpG')-based DNA methylation changes in AD using circulating cell-free DNA (cfDNA), to which neuronal cells are known to contribute. We investigated CYP-based mechanisms for AD pathogenesis and epigenetic biomarkers for disease detection. We performed a case-control study using 25 patients with AD and 23 cognitively healthy controls using the cfDNA of CYP genes. We performed a logistic regression analysis using the MetaboAnalyst software computer program and a molecular pathway analysis based on epigenetically altered CYP genes using the Cytoscape program. We identified 130 significantly (false discovery rate correction q-value < 0.05) differentially methylated CpG sites within the CYP genes. The top two differentially methylated genes identified were CYP51A1 and CYP2S1. The significant molecular pathways that were perturbed in AD cfDNA were (i) androgen and estrogen biosynthesis and metabolism, (ii) C21 steroid hormone biosynthesis and metabolism, and (iii) arachidonic acid metabolism. Existing evidence suggests a potential role of each of these biochemical pathways in AD pathogenesis. Next, we randomly divided the study group into discovery and validation sub-sets, each consisting of patients with AD and control patients. Regression models for AD prediction based on CYP CpG methylation markers were developed in the discovery or training group and tested in the independent validation group. The CYP biomarkers achieved a high predictive accuracy. After a 10-fold cross-validation, the combination of cg17852385/cg23101118 + cg14355428/cg22536554 achieved an AUC (95% CI) of 0.928 (0.787~1.00), with 100% sensitivity and 92.3% specificity for AD detection in the discovery group. The performance remained high in the independent validation or test group, achieving an AUC (95% CI) of 0.942 (0.905~0.979) with a 90% sensitivity and specificity. Our findings suggest that the epigenetic modification of CYP genes may play an important role in AD pathogenesis and that circulating CYP-based cfDNA biomarkers have the potential to accurately and non-invasively detect AD.

P450-mediated resistance in Myzus persicae (Sulzer) (Hemiptera: Aphididae) reduces the efficacy of neonicotinoid seed treatments in Brassica napus.

The prophylactic use of seeds treated with neonicotinoid insecticides remains an important means of controlling aphid pests in canola (Brassica napus) crops in many countries. Yet, one of the most economically important aphid species worldwide, the peach potato aphid (Myzus persicae), has evolved mechanisms which confer resistance to neonicotinoids, including amplification of the cytochrome P450 gene, CYP6CY3. While CYP6CY3 amplification has been associated with low-level resistance to several neonicotinoids in laboratory acute toxicity bioassays, its impact on insecticide efficacy in the field remains unresolved. In this study, we investigated the impact of CYP6CY3 amplification on the ability of M. persicae to survive neonicotinoid exposure under laboratory and semi-field conditions. Three M. persicae clones, possessing different copy numbers of CYP6CY3, were shown to respond differently when exposed to the neonicotinoids, imidacloprid and thiamethoxam, in laboratory bioassays. Two clones, EastNaernup209 and Osborne171, displayed low levels of resistance (3-20-fold), which is consistent with previous studies. However, in a large-scale semi-field trial, both clones showed a surprising ability to survive and reproduce on B. napus seedlings grown from commercial rates of neonicotinoid-treated seed. In contrast, an insecticide-susceptible clone, of wild-type CYP6CY3 copy number, was unable to survive on seedlings treated in the same manner. Our findings suggest that amplification of CYP6CY3 in M. persicae clones substantially impairs the efficacy of neonicotinoid seed treatments when applied to B.napus. These findings highlight the potentially important real-world implications of resistances typically considered to be 'low level' as defined through laboratory bioassays. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Ectopic expression of MmCYP1A1, a mouse cytochrome P450 gene, positively regulates stress tolerance in apple calli and Arabidopsis.

Ectopic expression of MmCYP1A1 gene from Mus musculus in apple calli and Arabidopsis increased the levels of melatonin and 6-hydroxymelatonin, and improved their stress resistance. Melatonin occurs widely in organisms, playing a key regulatory role. CYP1A1 is a cytochrome P450 monooxygenase, involved in the melatonin metabolism, and is responsible for the synthesis of 6-hydroxymelatonin from melatonin. Melatonin and 6-hydroxymelatonin have strong antioxidant activities in animals. Here, we cloned MmCYP1A1 from Mus musculus and found that ectopic expression of MmCYP1A1 improved the levels of melatonin and 6-hydroxymelatonin in transgenic apple calli and Arabidopsis. Subsequently, we observed that MmCYP1A1 increased the tolerance of transgenic apple calli and Arabidopsis to osmotic stress simulated by polyethylene glycol 6000 (PEG 6000), as well as resistance of transgenic Arabidopsis to drought stress. Further, the number of lateral roots of MmCYP1A1 transgenic Arabidopsis were enhanced significantly after PEG 6000 treatment. The expression of MmCYP1A1 remarkably reduced malondialdehyde (MDA) content, electrolyte leakage, accumulation of H2O2 and O2- during stress treatment. Moreover, MmCYP1A1 enhanced stress tolerance in apple calli and Arabidopsis by increasing the expression levels of resistance genes. MmCYP1A1 also promoted stomatal closure in transgenic Arabidopsis to reduce leaf water loss during drought. Our results indicate that MmCYP1A1 plays a key role in plant stress tolerance, which may provide a reference for future plant stress tolerance studies.

Newly Identified Tree Shrew Cytochrome P450 2A13 is Expressed in Liver and Lung and Encodes a Functional Drug-Metabolizing Enzyme Similar to Dog Cytochrome P450 2A13 and Pig Cytochrome P450 2A19.

The tree shrew, a non-rodent primate-like species, is used in various fields of biomedical research, including hepatitis virus infection, myopia, depression, and toxicology. Recent genome analysis found that the numbers of cytochrome P450 (P450 or CYP) genes are similar in tree shrews and humans and their sequence identities are high. Although the P450s are a family of important drug-metabolizing enzymes, they have not yet been fully investigated in tree shrews. In the current study, tree shrew CYP2A13 cDNA was isolated from liver, and its characteristics were compared with those of pig, dog, and human CYP2As. Tree shrew CYP2A13 amino acid sequences were highly identical (87-92%) to the human CYP2As and contained sequence motifs characteristic of P450s. Phylogenetic analysis revealed that tree shrew CYP2A13 was more closely related to human CYP2As than to rat CYP2As, similar to dog and pig CYP2As. Among the tissue types analyzed, tree shrew CYP2A13 mRNA was preferentially expressed in liver and lung, similar to dog CYP2A13 mRNA, whereas dog CYP2A25 and pig CYP2A19 mRNAs were predominantly expressed in liver. Tree shrew liver microsomes and tree shrew CYP2A13 proteins heterologously expressed in Escherichia coli catalyzed coumarin 7-hydroxylation and phenacetin O-deethylation, just as human, dog, and pig CYP2A proteins and liver microsomes do. These results demonstrate that tree shrew CYP2A13 is expressed in liver and lung and encodes a functional drug-metabolizing enzyme. SIGNIFICANCE STATEMENT: Novel tree shrew cytochrome P450 2A13 (CYP2A13) was identified and characterized in comparison with human, dog, and pig CYP2As. Tree shrew CYP2A13 isolated from liver had high sequence identities and close phylogenetic relationships to its human homologs and was abundantly expressed in liver and lung at the mRNA level. Tree shrew CYP2A13 metabolized coumarin and phenacetin, human selective CYP2A6 and CYP2A13 substrates, respectively, similar to dog and pig CYP2As, and is a functional drug-metabolizing enzyme likely responsible for drug clearances.

The Chromosome-Level Genome of Hestina assimilis (Lepidoptera: Nymphalidae) Reveals the Evolution of Saprophagy-Related Genes in Brush-Footed Butterflies.

Most butterflies feed on nectar, while some saprophagous butterflies forage on various non-nectar foods. To date, little is known about the genomic and molecular shifts associated with the evolution of the saprophagous feeding strategy. Here, we assembled the high-quality chromosome-level genome of Hestina assimilis to explore its saprophagous molecular and genetic mechanisms. This chromosome-level genome of H. assimilis is 412.82 Mb, with a scaffold N50 of 15.70 Mb. In total, 98.11% of contigs were anchored to 30 chromosomes. Compared with H. assimilis and other Nymphalidae butterflies, the genes of metabolism and detoxification experienced expansions. We annotated 80 cytochrome P450 (CYP) genes in the H. assimilis genome, among which genes belonging to the CYP4 subfamily were significantly expanded (p < 0.01). These P450 genes were unevenly distributed and mainly concentrated on chromosomes 6-9. We identified 33 olfactory receptor (OR), 20 odorant-binding protein (OBP), and six gustatory receptor (GR) genes in the H. assimilis genome, which were fewer than in the nectarivorous Danaus plexippus. A decreased number of OBP, OR, and GR genes implied that H. assimilis should resort less to olfaction and gustation than their nectarivorous counterparts, which need highly specialized olfactory and gustatory functions. Moreover, we found one site under positive selection occurred in residue 996 (phenylalanine) of GR genes exclusive to H. assimilis, which is conservative in most lineages. Our study provides support for the adaptive evolution of feeding habits in butterflies.

Identification and characterization of pathogenicity-related genes of Rhizoctonia solani AG3 during tobacco infection.

Tobacco target spot disease is caused by a ubiquitous soil-borne phytopathogen Rhizoctonia solani; the pathogenic mechanisms underlying the effects of R. solani remain unclear. Deeper understanding of the functional responses to R. solani during host plant infection would help identify the molecular mechanisms essential for successful host invasion. In this study, we performed global transcriptional analysis of R. solani during various stages (12, 24, 48, 72, 96, and 120h) of tobacco infection via an RNA sequencing method, while utilizing the pathosystem model R. solani AG3-tobacco (Nicotiana tabacum L.). After R. solani inoculation, the number of differentially expressed genes of R. solani differed at the various time points. Moreover, several gene ontology and Kyoto encyclopedia of genes and genomes pathways were unique in different infection stages, especially with respect to the genes involved in plant cell wall degradation and catalysis of biotransformation reactions, such as the pectin metabolic process and pectin catabolic process. The overexpressing-PD8 N. benthamiana plants enhanced the susceptibility to R. solani. In addition, we found that large amounts of reactive oxygen species (ROS) were generated in tobacco after infected by R. solani. R. solani encoding FAD/NAD binding oxidoreductase and peroxidase gene family to eliminating ROS and counteract oxidative stress. Moreover, Perox3 was validated that can enhance the ability of scavenging ROS by co-injecting. Overall, our findings show that pectin-degrading enzymes and cytochrome P450 genes are critical for plant infection. These results provide comprehensive insights into R. solani AG3 transcriptome responses during tobacco invasion.

Integration of meta-analysis, machine learning and systems biology approach for investigating the transcriptomic response to drought stress in Populus species

In Populus, drought is a major problem affecting plant growth and development which can be closely reflected by corresponding transcriptomic changes. Nevertheless, how these changes in Populus are not fully understood. Here, we first used meta-analysis and machine learning methods to identify water stress-responsive genes and then performed a systematic approach to discover important gene networks. Our analysis revealed that large transcriptional variations occur during drought stress. These changes were more associated with the response to stress, cellular catabolic process, metabolic pathways, and hormone-related genes. The differential gene coexpression analysis highlighted two acetyltransferase NATA1-like and putative cytochrome P450 genes that have a special contribution in response to drought stress. In particular, the findings showed that MYBs and MAPKs have a prominent role in the drought stress response that could be considered to improve the drought tolerance of Populus. We also suggest ARF2-like and PYL4-like genes as potential markers for use in breeding programs. This study provides a better understanding of how Populus responses to drought that could be useful for improving tolerance to stress in Populus.

Transcriptome Analysis of CYP450 Family Members in Fritillaria cirrhosa D. Don and Profiling of Key CYP450s Related to Isosteroidal Alkaloid Biosynthesis.

Fritillaria cirrhosa D. Don (known as Chuan-Bei-Mu in Chinese) can synthesize isosteroidal alkaloids (ISA) with excellent medicinal value, and its bulb has become an indispensable ingredient in many patented drugs. Members of the cytochrome P450 (CYP450) gene superfamily have been shown to play essential roles in regulating steroidal alkaloids biosynthesis. However, little information is available on the P450s in F. cirrhosa. Here, we performed full-length transcriptome analysis and discovered 48 CYP450 genes belonging to 10 clans, 25 families, and 46 subfamilies. By combining phylogenetic trees, gene expression, and key F. cirrhosa ISA content analysis, we presumably identify seven FcCYP candidate genes, which may be hydroxylases active at the C-22, C-23, or C-26 positions in the late stages of ISA biosynthesis. The transcript expression levels of seven FcCYP candidate genes were positively correlated with the accumulation of three major alkaloids in bulbs of different ages. These data suggest that the candidate genes are most likely to be associated with ISA biosynthesis. Finally, the subcellular localization prediction of FcCYPs and transient expression analysis within Nicotiana benthamiana showed that the FcCYPs were mainly localized in the chloroplast. This study presents a systematic analysis of the CYP450 gene family in F. cirrhosa and provides a foundation for further functional characterization of the CYPs involved in ISA biosynthesis.

Comprehensive in vitro and in silico assessments of metabolic capabilities of 24 genomic variants of CYP2C19 using two different substrates.

Introduction: Most hepatically cleared drugs are metabolized by cytochromes P450 (CYPs), and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide curated clinical references for CYPs to apply individual genome data for optimized drug therapy. However, incorporating novel pharmacogenetic variants into guidelines takes considerable time. Methods: We comprehensively assessed the drug metabolizing capabilities of CYP2C19 variants discovered through population sequencing of two substrates, S-mephenytoin and omeprazole. Results: Based on established functional assays, 75% (18/24) of the variants not yet described in Pharmacogene Variation (PharmVar) had significantly altered drug metabolizing capabilities. Of them, seven variants with inappreciable protein expression were evaluated as protein damaging by all three in silico prediction algorithms, Sorting intolerant from tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Combined annotation dependent depletion (CADD). The five variants with decreased metabolic capability (<50%) of wild type for either substrates were evaluated as protein damaging by all three in silico prediction algorithms, except CADD exact score of NM_000769.4:c.593T>C that was 19.68 (<20.0). In the crystal structure of the five polymorphic proteins, each altered residue of all those proteins was observed to affect the key structures of drug binding specificity. We also identified polymorphic proteins indicating different tendencies of metabolic capability between the two substrates (5/24). Discussion: Therefore, we propose a methodology that combines in silico prediction algorithms and functional assays on polymorphic CYPs with multiple substrates to evaluate the changes in the metabolism of all possible genomic variants in CYP genes. The approach would reinforce existing guidelines and provide information for prescribing appropriate medicines for individual patients.

Tomato Chlorosis Virus (ToCV) Infection Induced the Resistance of Bemisia tabaci to Two Insecticides: Pyrethroids and Flupyradifurone

Insect vectors and insect-borne plant viruses seriously endanger the safety of agricultural production. An insecticide is one of the main methods to prevent insect-borne virus transmission. However, the curious relationship between the resistance of insect vectors and arboviruses has been less studied. In this study, the effect of Tomato chlorosis virus (ToCV) on the insecticide resistance of Bemisia tabaci MED was studied. It was found that the detoxification cytochrome P450, glutathione S-transferase, and carboxylesterase-related genes in ToCV-infected B. tabaci were upregulated. The activity of the three detoxification enzymes all increased at the same time, after 48 h of virus acquisition, with the activity of carboxylesterase being the most pronounced. It was found that cytochrome P450 and glutathione S-transferase activity was the least. ToCV led to the reduced sensitivity of B. tabaci MED to pyrethroids and flupyradifurone. Therefore, it was proven that the insect-borne plant virus ToCV shows the possibility of enhancing insect-borne insecticide resistance.

Association of CYP3A5*3, CYP3A4*18 & CYP2B6*6 polymorphisms with imatinib treatment outcome in Azerbaijani chronic myeloid leukaemia patients.

Imatinib mesylate (IM) is a reliable first line treatment for chronic myeloid leukaemia (CML). Nevertheless, despite promising results, a considerable proportion of patients develop resistance to the drug. Cytochrome P450 (CYP) enzymes play a crucial role in IM metabolism. Thus, point mutations in CYP genes may modify IM enzyme activity resulting in insufficient treatment response. This investigation was aimed to identify the functional impact of CYP3A5*3, CYP3A4*18 and CYP2B6*6 polymorphisms on the IM response in patients with CML in Azerbaijan. Genotyping of CYP3A5*3, CYP3A4*18 and CYP2B6*6 was performed in 153 patients (102 IM non-responders and 51 IM responders) with CML by the PCR-restriction fragment length polymorphism (RFLP) assays. The odds ratios (ORs) with 95 per cent confidence intervals (CIs) were applied to assess the association between allelic variants and IM therapy outcome. The results were validated by sequencing. The frequency of the CYP3A4*18 allele was considerably lower in the responder's group (97.1 vs. 100%; P=0.036). For CYP3A5*3, the allelic frequency was slightly higher among the IM responders (100 vs. 99.02%) with no significant difference. Although patients heterozygous (TC) for CYP2B6*6 demonstrated a higher risk of acquiring resistance (OR 1.04; 95% CI: 0.492-2.218), differences were not significant (P=0.909). In addition, the homozygous genotype (TT) demonstrated a lower risk of unresponsiveness (OR 0.72; 95% CI: 0.283-1.836), but associations were not significant (P=0.491). Our results demonstrated that CYP3A4*18 was significantly associated with IM treatment response in patients with CML in Azerbaijan, whereas rather common CYP3A5*3 was identified to have no such association.

Cytochrome P450 gene and pediatric epilepsy: An observational study

Cytochrome P450 gene and pediatric epilepsy: An observational study

Biochanin A in murine Schistosoma mansoni infection: effects on inflammation, oxidative stress and fibrosis.

Biochanin A (BCA) is a multifunctional natural compound that possesses anti-infective, anti-inflammatory, anti-oxidative and hepatoprotective effects. The aim of the study was to assess the therapeutic efficacy of BCA on Schistosoma mansoni-infected mice. Fifty mice were divided into six different groups as non-infected, non-infected BCA-treated, infected untreated, early infected BCA-treated (seven days post-infection (dpi)), late infected BCA-treated 60 dpi and infected praziquantel (PZQ)-treated groups. Parasitological, histopathological examination and immunohistochemical staining of transforming growth factor (TGF)-β, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) were investigated in liver sections. Cytochrome P450 (CYP450) gene expression of S. mansoni was evaluated by quantitative real-time polymerase chain reaction (RT-qPCR). A single dose of BCA significantly reduced worm burden in early (82.14%) and late infection (77.74%), mean tissue egg load in early (7.27 ± 0.495) and late BCA administration (7.63 ± 0.435) and decreased granuloma size. CYP450 mRNA expression was significantly reduced in early BCA treatment as compared to late treatment which emphasizes that early administration of BCA had more pronounced effects on worms than late administration. Both early and late BCA administration led to significant reduction in inflammatory cytokines as TGF and iNOS. Although the reduction of TGF and iNOS in BCA-treated mice was superior to PZQ, no statistically significant differences were noted. However, a significant downregulation of COX2 was noted in hepatocytes as compared to both infected control and PZQ-treated mice. BCA has schistosomicidal, anti-inflammatory, antioxidant and anti-fibrotic effects and could be regarded as a potential drug in schistosomiasis treatment.

Garcinia mangostana pericarp and α-mangostin normalized the expression of colonic and renal cytochrome P450 genes and abated the expression of renal inflammatory genes in dextran sulfate sodium-induced ulcerative colitis in mice

Garcinia mangostana pericarp and α-mangostin normalized the expression of colonic and renal cytochrome P450 genes and abated the expression of renal inflammatory genes in dextran sulfate sodium-induced ulcerative colitis in mice

Bioinformatics-guided discovery of biaryl-linked lasso peptides.

Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) that feature an isopeptide bond and a distinct lariat fold. A growing number of secondary modifications have been described that further decorate lasso peptide scaffolds. Using genome mining, we have discovered a pair of lasso peptide biosynthetic gene clusters (BGCs) that include cytochrome P450 genes. Using mass spectrometry, stable isotope incorporation, and extensive 2D-NMR spectrometry, we report the structural characterization of two unique examples of (C-N) biaryl-linked lasso peptides. Nocapeptin A, from Nocardia terpenica, is tailored with a Trp-Tyr crosslink, while longipepetin A, from Longimycelium tulufanense, features a Trp-Trp linkage. Besides the unusual bicyclic frame, a Met of longipepetin A undergoes S-methylation to yield a trivalent sulfonium, a heretofore unprecedented RiPP modification. A bioinformatic survey revealed additional lasso peptide BGCs containing P450 enzymes which await future characterization. Lastly, nocapeptin A bioactivity was assessed against a panel of human and bacterial cell lines with modest growth-suppression activity detected towards Micrococcus luteus.

Clinical relevance of pharmacogenetic testing of cytochrome P450 gene (CYP2C19) polymorphisms to personalize the selection of proton pump inhibitors

Clinical relevance of pharmacogenetic testing of cytochrome P450 gene (CYP2C19) polymorphisms to personalize the selection of proton pump inhibitors

CYP2C8 and CYP2J2 gene variations increase the risk of hypertensive intracerebral hemorrhage

PurposeMany studies have shown that cytochrome P450 (CYP) gene polymorphisms are usually associated with an increased risk of cardiovascular and cerebrovascular diseases. To explore the association of CYP2C8 and CYP2J2 gene polymorphisms with hypertensive intracerebral hemorrhage (HICH) in the Han Chinese population. MethodsForty HICH patients and 40 control subjects were recruited for this study. Two single nucleotide polymorphisms (SNP) (rs1058932, rs2275622) in the CYP2C8 gene and two SNPs (rs2271800, rs1155002) in the CYP2J2 gene were selected for genotyping by direct sequencing. Statistical analysis was applied to examine the effect of genetic variation on HICH. ResultsWe found that variant alleles of CYP2C8 rs1058932 (A) and rs2275622 (C) were both significantly associated with HICH, especially in females. We also found significant associations of CYP2C8 rs1058932 (A) and rs2275622 (C) variant alleles with poor outcomes in HICH patients, especially in males. ConclusionsCYP2C8 gene polymorphisms might increase the risk of HICH in the Han Chinese population and might lead to poor outcomes. This finding adds to the body of literature supporting novel therapeutic strategies for HICH.