Natural Products and Bioprospecting
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2024
·Vol. 14
·期 1
·1-21
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IF 4.8
Lu Jindi,Liang Weimin,Hu Yiwei,Zhang Xi,Yu Ping,Cai Meiqun,Xie Danni,Zhou Qiong,Zhou Xuefeng,Liu Yonghong,Wang Junfeng,Guo Jiayin,Tang Lan
N -Hydroxyapiosporamide ( N -hydap), a marine product derived from a sponge-associated fungus, has shown promising inhibitory effects on small cell lung cancer (SCLC). However, there is limited understanding of its metabolic pathways and characteristics. This study explored the in vitro metabolic profiles of N -hydap in human recombinant cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs), as well as human/rat/mice microsomes, and also the pharmacokinetic properties by HPLC–MS/MS. Additionally, the cocktail probe method was used to investigate the potential to create drug-drug interactions (DDIs). N -Hydap was metabolically unstable in various microsomes after 1 h, with about 50% and 70% of it being eliminated by CYPs and UGTs, respectively. UGT1A3 was the main enzyme involved in glucuronidation (over 80%), making glucuronide the primary metabolite. Despite low bioavailability (0.024%), N -hydap exhibited a higher distribution in the lungs (26.26%), accounting for its efficacy against SCLC. Administering N -hydap to mice at normal doses via gavage did not result in significant toxicity. Furthermore, N -hydap was found to affect the catalytic activity of drug metabolic enzymes (DMEs), particularly increasing the activity of UGT1A3, suggesting potential for DDIs. Understanding the metabolic pathways and properties of N -hydap should improve our knowledge of its drug efficacy, toxicity, and potential for DDIs. Graphical Abstract
研究领域:
药理学
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肿瘤学
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毒理学
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海洋生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Ligui Wu,Hao Luo,Jingcheng Xu,Ling Yu,Jiangtao Xiong,Yizhi Liu,Xiangfeng Huang,Xiaoming Zou
The extensive use of antidiabetic drugs (ADDs) and their detection in high concentrations in the environment have been extensively documented. However, the mechanism of ADDs dissipation in aquatic environments is still not well understood. This study thoroughly investigates the dissipation behavior of ADDs and the underlying mechanisms in the aerobic activated sludge system. The results indicate that the removal efficiencies of ADDs range from 3.98% to 100% within 48 h, largely due to the biodegradation process. Additionally, the gene expression of cytochrome P450 (CYP450) is shown to be significantly upregulated in most ADDs-polluted samples (P < 0.05), indicating the vital role of CYP450 enzymes in the biodegradation of ADDs. Enzyme inhibition experiments validated this hypothesis. Moreover, molecular docking and simulation results indicate that a strong correlation between the biodegradation of ADDs and the interactions between ADDs and CYP450 (E binding ). The differences in dissipation behavior among the tested ADDs are possibly due to their electrophilic characteristics. Overall, this study makes the initial contribution to a more profound comprehension of the crucial function of CYP450 enzymes in the dissipation behavior of ADDs in a typical aquatic environment. Environmental Implication This work underscores the role of CYP450 enzymes in the biodegradation of antidiabetic drugs (ADDs). While removal efficiencies vary widely, the biodegradation process can lead to the formation of degradation products potentially more toxic than the original compounds. This points to a critical need for advanced wastewater treatment technologies capable of addressing not only the removal of ADDs but also the mitigation of their toxic byproducts. The study's findings emphasize the importance of understanding the specific mechanisms of pharmaceutical pollution, which is essential for protecting aquatic ecosystems and, by extension, human health from the unintended consequences of widespread pharmaceutical use.
研究领域:
环境科学
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生物技术
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
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2015
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IF 2.345
Lili Wu,Wanping Zhong,Junjin Liu,Weichao Han,Shilong Zhong,Qiang Wei,Shuwen Liu,Lan Tang
Oxysophocarpine (OSC), an active and toxic quinolizidine alkaloid, is highly valued in Sophora flavescens Ait. and Subprostrate sophora Root. OSC is used to treat inflammation and hepatitis for thousands of years in China. This study aims to investigate the CYP450-mediated reduction responsible for metabolizing OSC and to evaluate the absorption and metabolism of OSC in rat in situ. Four metabolites were identified, with sophocarpine (SC) as the major metabolite. SC formation was rapid in human and rat liver microsomes (HLMs and RLMs, respectively). The reduction rates in the liver are two fold higher than in the intestine, both in humans and rats. In HLMs, inhibitors of CYP2C9 , 3A4/5, 2D6, and 2B6 had strong inhibitory effects on SC formation. Meanwhile, inhibitors of CYP3A and CYP2D6 had significant inhibition on SC formation in RLMs. Human recombinant CYP3A4/5, 2B6, 2D6, and 2C9 contributed significantly to SC production. The permeability in rat intestine and the excretion rates of metabolites were highest in the duodenum (p < 0.05), and the absorbed amount of OSC in duodenum and jejunum was concentration-dependent. The metabolism could be significantly decreased by CYP3A inhibitor ketoconazole. In conclusion, the liver was the main organ responsible for OSC metabolism. First-pass metabolism via CYP3A4/5, 2B6, 2D6, and 2C9 may be the main reason for the poor OSC bioavailability.
研究领域:
药理学
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毒理学
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中药学
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产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2022
·
IF 4.966
Bin Liu,Hui Chen
Bark beetles rely on detoxifying enzymes to resist the defensive oleoresin terpenes of the host tree. Insect cytochrome P450 (CYPs) plays a key role in the detoxification of plant allelochemicals and pesticides. CYP6 family is unique to Insecta, and its biochemical function is basically related to catabolize heterologous substances. In this study, two Dendroctonus armandi CYP6 genes, CYP6DF1 and CYP6DJ2, were characterized. Spatiotemporal expression profiling revealed that CYP6DF1 and CYP6DJ2 expressions were higher in larvae and adult stages of D. armandi than in egg and pupae stages, and that two genes predominantly expressed in brain , midgut, fat body, or Malpighian tubules . Moreover, CYP6DF1 and CYP6DJ2 expressions were significantly induced after exposure to (+)- α -pinene. Importantly, silencing CYP6DF1 and CYP6DJ2 significantly inhibited the CYP activity and increased the mortality in the adults fumigated with (+)- α -pinene. Additionally, piperonyl butoxide exposure to adults also increase the sensitivity after treatment with (+)- α -pinene, which led to a significant reduction of the CYP activity, resulting a significant increase in adult mortality. These results suggest that the CYP6 family plays a key role in determining the susceptibility of D. armandi to (+)- α -pinene, which may have implications for the development of novel therapeutics to control this important pest.
研究领域:
昆虫学
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生物化学
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分子生物学
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害虫管理
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DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2025
·
IF 4
Bing Bai,Huan-Juan Zhao,Bo-Kun Wang,Yu-Ting Li,Ping Gao,Yun-Tong Lv,Xue-Qing Yang
During long-term plant-insect interactions, plants have evolved diverse plant secondary metabolites (PSMs) as defenses against herbivory, while insects have developed sophisticated detoxification mechanisms to neutralize these compounds. Invasive and native herbivorous species may employ distinct metabolic strategies to cope with PSMs, a phenomenon that remains incompletely characterized. Here, we report the differential detoxification strategies of two closely related fruit borers, the invasive Cydia pomonella and the native Grapholita molesta , which exhibit interspecific competition, in response to quercetin stress—a flavonoid present in their host fruits. C. pomonella requires more generations to adapt 70 μg/g quercetin, indicating differential tolerance to flavonoid toxicity. Metabolic profiling shows G. molesta primarily detoxifies quercetin mainly via synergistic cytochrome P450 (P450) and transmembrane transport, whereas C. pomonella shifts from transport to a predominant role of oxidation over time. Given that C. pomonella was not pre-adapted to high quercetin stress in its native habitat, its constitutive defense system was likely suppressed under quercetin exposure. This species compensated by upregulating ATP-binding cassette (ABC) transporter-mediated excretion, as evidenced by HPLC quantification which indicated that the fecal quercetin content exceeded 50 % of the administered dose. Correlation analysis suggests that C. pomonella employs a biphasic detoxification: initial short-term dominated by ABC transporter activity, followed by a long-term reliance on P450-mediated metabolism. Conversely, G.molesta primarily utilizes a synergistic enzymatic detoxification system involving multiple enzymes. These findings elucidate divergent adaptive mechanisms to quercetin stress in the two fruit borers and enhance understanding of herbivorous insect-plant co-evolution and the interspecific interactions between invasive and native pest species.
研究领域:
昆虫学
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植物-昆虫互作
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生态适应
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生化毒理学
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入侵物种生物学
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产品关联
DOI
PubMed
高影响因子
BIOPHARMACEUTICS & DRUG DISPOSITION
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2025
·
IF 2
Jiao Li,Jinzhen Wang,Benlu Zhong,Fan Wu,Weihong Yin,Siwen Wang,Xueying Yan,Mingyu Cui
Curcuminoids (CURs), natural polyphenols, are often combined with atorvastatin to treat hyperlipidemia. In order to assess the safety of combination, the effect of CURs on Cytochrome P450 (CYP) 3A2 activity in rats was investigated. Additionally, the effect of CURs on pharmacokinetics and pharmacodynamics of atorvastatin in rats was evaluated. The effect of CURs on CYP3A2 activity was studied using the probe drug method (dapsone as a probe drug). Pharmacokinetic parameters of atorvastatin with or without CURs were calculated to evaluate herb-drug interactions (HDIs). The effect of CURs on pharmacodynamics of atorvastatin was investigated by blood lipid, oxidative stress, aminotransferases, inflammatory factors and liver histopathology. C max , AUC, and t 1/2 of dapsone in CURs group significantly increased ( p < 0.05). C max , AUC, and t 1/2 of atorvastatin in combination group significantly increased both in normal and hyperlipidemia rats ( p < 0.01). Pharmacodynamics indexes of all treatment groups were significantly improved. There was no significant difference between AC group and combination group except HDL-C, SOD and liver index. In conclusion, CURs combined with atorvastatin could not effectively enhance the lipid-lowering effect or alleviate liver damage. However, CURs could inhibit CYP3A2 activity in rats and increase plasma exposure of atorvastatin, which might increase the risk of HDIs. The findings provided new insight into the combination of CURs and atorvastatin in treating hyperlipidemia.
研究领域:
药理学
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药学
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生物化学
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分子生物学
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临床医学
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产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2021
·
IF 3.963
Jie Chen,Xin Hao,Buyong Wang,Ling Ma
Bursaphelenchus xylophilus is one of the most dangerous forest pathogens in the world, causing devastating pine forest deaths with considerable economic losses. In this study, we investigated the B. xylophilus RNA sequence responses of two different concentrations of levamisole hydrochloride (LH). We observed that body-wall muscle twitching, paralysis and, ultimately, death. 2.5 mg/ml and 3.5 mg/ml LH have toxicological effects on B. xylophilus , with mortality increasing significantly with concentration ( p < 0.05). RNA sequencing, differential gene expression analysis, and cluster analysis were performed, and 336, 384, 6 genes with significant variance in expression were identified. Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the 12 intersecting genes revealed that these genes are mostly involved in metabolism of xenobiotics and have essential roles in drug sensitivity. Through the trend analysis of DEGs, it was divided into 8 modules, and the significant modules were selected to construct the co-expression network as the central genes of the drug metabolism-cytochrome P450 pathway (ko00982) and metabolism of xenobiotics by cytochrome P450 (ko00980). Eight highly related genes were identified, including cuticle collagen, cystathionine beta-synthase, endochitinase, pyruvate dehydrogenase E1 component subunit beta , aldehyde dehydrogenase , lipase , and zinc metalloproteinase . The expression levels of these genes were upregulated significantly at low concentrations and were significantly related to the resistance of B. xylophilus to LH. This study shows that B. xylophilus gene family expansions occurred in xenobiotic detoxification pathways through gene expression and potential horizontal correlated gene transfer with LH and helps to elucidate LH lethality and the evolutionary mechanisms underlying the adaptations of B. xylophilus to the environment. These results contributing to our understanding of B. xylophilus under LH and provide a data platform to providing a basis for its control.
研究领域:
分子生物学
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基因组学
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转录组学
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线虫学
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药物基因组学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
·
IF 12.2
Shiye Zhu,Anwei Chen,Jiale Zhang,Si Luo,Jizhao Yang,Youzheng Chai,Jianhua Zeng,Ma Bai,Zhenghang Yang,Gen Lu
Fungi play vital roles in the fate of organic pollutants, particularly when interacting with minerals in aquatic and soil environments. Mechanisms by which fungi may mitigate pollutions in fungus-mineral interactions are still unclear. Inspired by biogeochemical cycling, we constructed a range of co-culture systems to investigate synergistic effects of the white-rot fungus Phanerochaete chrysosporium and the iron-bearing mineral siderite on thiamethoxam (THX) transformation, a common neonicotinoid pesticide. Co-culturing with siderite significantly enhanced THX transformation during the initial 10 days with a dose effect, achieving 86 % removal within 25 days. Fungi could affect siderite’s dissolution, transformation, and precipitation through their biological activities. These interactions triggered physiological adaptation and resilience in fungi. Siderite could enhance the activity of fungal ligninolytic enzymes and cytochrome P450, facilitating biotransformation. Genes expression related to growth, energy metabolism, and oxidative stress response upregulated, enhancing fungal resilience to THX. The primary THX degradation pathways included nitro-reduction, C-N cleavage, and de-chlorination. Molecular dynamics simulations provided insights into catalytic mechanisms of enzyme-THX interactions. Together, siderite could act as natural enhancers that endowed fungi to resist physical and chemical stresses in environments, providing insights into contaminants attenuation, fungal biomineralization, and the coevolution of the Earth's lithosphere and biosphere.
研究领域:
环境科学
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微生物学
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生物技术
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分子生物学
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生物地球化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
·
IF 12.2
Shouchun Xiao,Jingna Cui,Jiaxing Yang,Haonan Hou,Jianing Yao,Xiaoran Ma,Li Zheng,Fanrong Zhao,Xueke Liu,Donghui Liu,Zhiqiang Zhou,Peng Wang
Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R -famoxadone was 1.5 times more toxic to HepG2 cells than S -famoxadone. R -famoxadone induced more pronounced ferroptosis compared to S -famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R -famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R -famoxadone in mice was six times higher than that of S -famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19, and CYP2E1 for R -famoxadone caused its preferential accumulation. Overall, R -famoxadone poses a higher risk than S -famoxadone due to its greater cytotoxicity and persistence. This study provides the first evidence of ferroptosis-induced stereoselective toxicity, offering insights for the comprehensive health risk assessment of chiral famoxadone and valuable references for the application of high-efficiency, low-risk pesticide enantiomers.
研究领域:
毒理学
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药理学
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分子生物学
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环境科学
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DOI
PubMed
高影响因子
NATURE
·
2025
·
IF 48.5
Zhu Bao,Zhang Yanjun,Gao Rong,Wu Zhihua,Zhang Wei,Zhang Chao,Zhang Penghong,Ye Can,Yao Linbo,Jin Ying,Mao Hui,Tou Peiyao,Huang Peng,Zhao Jiangzhe,Zhao Qiao,Liu Chang-Jun,Zhang Kewei
Salicylic acid (SA) is a pivotal phytohormone for plant responses to biotic and abiotic stresses. Plants have evolved two pathways to produce SA: the isochorismate synthase and phenylalanine ammonia lyase (PAL) pathways 1 . Whereas the isochorismate synthase pathway has been fully identified 2 , 3 , 4 , the PAL pathway remains incomplete. Here we report the full characterization of the PAL pathway for SA biosynthesis via functional analysis of rice ( Oryza sativa ) SA-DEFICIENT GENE 1 ( OSD1 ) to OSD4 . The cinnamoyl-coenzyme A (CoA) ligase OSD1 catalyses the conversion of trans -cinnamic acid to cinnamoyl-CoA, which is subsequently transformed to benzoyl-CoA via the β-oxidative pathway in peroxisomes. The resulting benzoyl-CoA is further converted to benzyl benzoate by the peroxisomal benzoyltransferase OSD2. Benzyl benzoate is subsequently hydroxylated to benzyl salicylate by the endoplasmic reticulum membrane-resident cytochrome P450 OSD3, which is ultimately hydrolysed to salicylic acid by the cytoplasmic carboxylesterase OSD4. Evolutionary analyses reveal that the PAL pathway was first assembled before the divergence of gymnosperms and has been conserved in most seed plants. Activation of the PAL pathway in rice significantly enhances salicylic acid levels and plant immunity. Completion of the PAL pathway provides critical insights into the primary salicylic acid biosynthetic pathway across plant species and offers a precise target for modulating crop immunity.
研究领域:
植物学
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生物化学
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分子生物学
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遗传学
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农学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2019
·
IF 5.108
Fuwen Liu,Ying Zhang,Meng Zhang,Qishi Luo,Xue Cao,Changzheng Cui,Kuangfei Lin,Kai Huang
The widespread use of tetrabromobisphenol A (TBBPA) in industries has resulted in its frequent detection in environmental matrices, and the mechanisms of its associated hazards need further investigation. In this study, the nematode Caenorhabditis elegans (C. elegans) was exposed to environmentally relevant concentrations of TBBPA (0, 0.1, 1, 10, 100, 200 μg/L) to determine its effects. At TBBPA concentrations above 1 μg/L, the number of head thrashes, as the most sensitive physiological indicator, decreased significantly. Using the Illumina HiSeq™ 2000 sequencer, differentially expressed genes (DEGs) were determined, and 52 were down regulated and 105 were up regulated in the 200 μg/L TBBPA treatment group versus the control group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database analysis demonstrated that dorso-ventral axis formation is related to neurotoxicity; metabolism of xenobiotics by Cytochrome P450 (CYP450) and glutathione-S-transferase (GST) was found to be the vital metabolic mechanisms and were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). GST was ascribed to the augmentation because mutations in cyp-13A7 were constrained under TBBPA exposure. Additionally, oxidative stress indicators accumulated in a dose-dependent relationship. These results will help understand the molecular basis for TBBPA-induced toxicity in C. elegans and open novel avenues for facilitating the exploration of more efficient strategies against TBBPA toxicity.
研究领域:
环境毒理学
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分子生物学
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基因组学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF NUTRITION
·
2021
·Vol. 61
·期 1
·115-126
·
IF 5.619
Yan Xin,Liu Xiaoyun,Wang Yu,Ren Xueyang,Ma Jiamu,Song Ruolan,Wang Xiuhuan,Dong Ying,Fan Qiqi,Wei Jing,Yu Axiang,Sui Hong,She Gaimei
Purpose Alcoholic liver disease (ALD) is a major health issue globally. In addition to pharmacotherapy, dietary support is also regarded as reliable strategy for ALD management. As a widely distributed natural constituent within edible plants, the present study aims to investigate the hepatoprotective effects of ursolic acid (UA) against ALD and also to deepen insights into the underlying targets and mechanisms comprehensively. Methods The hepatoprotective activity of UA against chronic alcohol-induced liver injury was investigated on Lieber–DeCarli liquid diet-based mouse model. In-depth RNA-seq transcriptomics and TMT-based proteomics analyses were conducted in parallel. Data integration as well as bioinformatics analysis were also performed to unravel the targets and mechanisms associated with the hepatoprotective activity of UA intake against alcoholic liver injury comprehensively. Results The serum biomarkers and pathological characteristics indicated the hepatoprotective effects of UA intake on alcoholic liver injury. 567 target genes and 377 target proteins related to the hepatoprotective activity of UA were identified in transcriptomics and proteomics analysis respectively, most of which were associated with function of cellular process, cell part and binding. After data integration, 56 co-regulated targets, including ADH4, CYP450 enzymes, NQO1, apolipoproteins, glutathione–S–transferase, etc. which were consistently modulated on both mRNA and protein levels were identified. These co-regulated targets were found to be correlated with 70 KEGG pathways led by carcinogenesis, retinol metabolism and CYP450 metabolism pathways. Conclusion UA intake ameliorated chronic alcohol-induced liver injury. Given the role of the co-regulated targets in ALD and the bioinformatics analysis results, CYP450-, glutathione and redox homeostasis-dependent antioxidation, promotion of lipid transport, and restoration of ethanol metabolic capacity are the potentially underlying mechanisms. This information will further deepen our insights into the hepatoprotective effects of UA-rich edible plants, and provide us valuable instruction for ALD management.
研究领域:
药理学
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分子生物学
·
肝病学
·
营养基因组学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）