查找使用阿拉丁产品的科研文献

Hyaluronic acid-modified cationic nanoparticles overcome enzyme CYP1B1-mediated breast cancer multidrug resistance

Jun Zhang,Jia Song,Xiao Liang,Yunzhi Yin,Tiantian Zuo,Daijie Chen,Qi Shen

Aim: Enzyme CYP1B1 (CYP1B1) is usually overexpressed in multidrug resistance (MDR) breast cancer cells, which could metabolically inactivate docetaxel (DTX). Materials & methods: The cationic core–shell nanoparticles (hyaluronic acid/polyethyleneimine nanoparticles [HA/PEI NPs]) modified with hyaluronic acid (HA) were developed and coloaded with DTX and α-napthtoflavone (ANF, a CYP1B1 inhibitor) to overcome MDR in breast cancer induced by CYP1B1. Physicochemical characterization, MDR reversing effect in vitro and pharmacokinetics in vivo of HA/PEI NPs were evaluated. Results: The HA/PEI NPs exhibited spherical morphology with size of (193.6 ± 3.1) nm. The HA/PEI NPs could reverse MDR effectively by downregulating the expression of CYP1B1. The HA/PEI NPs improved the bioavailability of DTX. Conclusion: The HA/PEI NPs might be a promising strategy to overcome CYP1B1-mediated breast cancer MDR.

Colistin Induces Oxidative Stress and Apoptotic Cell Death through the Activation of the AhR/CYP1A1 Pathway in PC12 Cells

Baofu Xie,Yue Liu,Chunhong Chen,Tony Velkov,Shusheng Tang,Jianzhong Shen,Chongshan Dai

Colistin is commonly regarded as the “last-resort” antibiotic for combating life-threatening infections caused by multidrug-resistant (MDR) gram-negative bacteria. Neurotoxicity is a potential adverse event associated with colistin application in clinical settings, yet the exact molecular mechanisms remain unclear. This study examined the detrimental impact of colistin exposure on PC12 cells and the associated molecular mechanisms. Colistin treatment at concentrations of 0–400 μM decreased cell viability and induced apoptotic cell death in both time- and concentration-dependent manners. Exposure to colistin triggered the production of reactive oxygen species (ROS) and caused oxidative stress damage in PC12 cells. N-acetylcysteine (NAC) supplementation partially mitigated the cytotoxic and apoptotic outcomes of colistin. Evidence of mitochondrial dysfunction was observed through the dissipation of membrane potential. Additionally, colistin treatment upregulated the expression of AhR and CYP1A1 mRNAs in PC12 cells. Pharmacological inhibition of AhR (e.g., using α-naphthoflavone) or intervention with the CYP1A1 gene significantly decreased the production of ROS induced by colistin, subsequently lowering caspase activation and cell apoptosis. In conclusion, our findings demonstrate, for the first time, that the activation of the AhR/CYP1A1 pathway contributes partially to colistin-induced oxidative stress and apoptosis, offering insights into the cytotoxic effects of colistin.

Antimicrobial Activity, Preliminary Safety, and Pharmacokinetics Assessment of 2–3: A Pleuromutilin-Derived Compound

Feifei Zhao,Yizhen Zhu,Lingxiang Mao,Honghao Huang,Wei Wei,Qiangcheng Deng,Youzhi Tang,Ning Han,Zhenling Zeng

Staphylococcus aureus poses a global threat to livestock health and public health security, necessitating a novel antibiotic. Pleuromutilin, a natural antibiotic, has served as a promising foundation for developing new antibacterial agents through structural modification. This study aims to evaluate the antibacterial potential, safety, and pharmacokinetic profile of a novel pleuromutilin derivative 2-3 (22-[2-(L-prolylamino)phenylsulfanyl]-22-deoxypleuromutilin). The compound 2–3 exhibited potent antibacterial activity (MIC = 0.25 μg/mL), concentration-dependent bactericidal effects, and prolonged post-antibiotic effects (PAEs). Safety assessments revealed low cytotoxicity (CC50 = 62.63 μg/mL) and no observable hemolytic activity. In vitro metabolic studies indicated species-dependent clearance, primarily mediated by CYP3A4. Pharmacokinetic in rats showed rapid absorption and elimination, with oral and intramuscular bioavailability of 16.03% ± 8.82% and 53.36% ± 12.27%, respectively. Notably, 2–3 demonstrated superior efficacy over tiamulin in a neutropenic murine thigh infection model. Molecular docking revealed a stronger binding free energy between 2–3 and the 50S ribosomal subunit compared to tiamulin. Collectively, these results highlight 2–3 as a promising clinical candidate against S. aureus infections, characterized by enhanced efficacy and a favorable safety profile.

CYP-mediated metabolic divergence underpins oxoglaucine selectivity: Detoxification in healthy hepatocytes versus mitochondrial apoptosis in hepatocellular carcinoma

Pinzheng Li,Hengbin Zhang,Yingchun Chen,Shuanghui Lu,Huidi Jiang,Su Zeng,Hui Zhou

Oxoglaucine (OXO), an aporphine alkaloid derived from Corydalis yanhusuo , exhibits a broad spectrum of pharmacological activities, including antiviral, antifungal, antiplatelet, and anti-hepatic fibrosis effects, with particularly promising anticancer potential. In this study, we systematically investigated the hepatotoxicity profile and underlying mechanisms of OXO using in vitro models. Dose–response assays revealed that while OXO induced significant cytotoxicity in hepatocytes, primary hepatocytes exhibited markedly reduced sensitivity compared to hepatocellular carcinoma cells at therapeutically relevant concentrations. Mechanistic studies in mouse primary hepatocytes and human primary hepatocytes attributed this selective cytotoxicity to differential cytochrome P450 (CYP) enzyme expression. This finding was functionally validated by the observation that co-treatment with the broad-spectrum CYP inhibitor aminobenzotriazole (ABT) enhanced OXO-induced toxicity in mouse primary hepatocytes and human primary hepatocytes. Regarding its mechanism of toxicity, OXO induced marked cytotoxicity in the HepG2 cell line by triggering mitochondrial-mediated apoptosis, as evidenced by a decreased Bcl-2/Bax ratio, cytochrome C release, Caspase-3 activation, and S-phase cell cycle arrest. Collectively, our findings in HepG2 cells and primary hepatocytes elucidate the role of CYP-mediated metabolism in the selective cytotoxicity of OXO. These findings not only provide crucial mechanistic insights but also support the further development of OXO as a promising candidate for preclinical and clinical evaluation in hepatocellular carcinoma.

Cytochrome P450-Mediated Detoxification and NF-κB/NLRP3 Pathway-Driven Hepatotoxicity of Emodin: Multiomics and laboratory evidence

Lili Wu,Siyu Chen,Qiyuan Yang,Xing Li,Lingyan Liu,Shengjun Ji,Shuaiyuan Tang,Sihui Zhang,Yan Wang,Runzhi Chen,Zhikun Zhan

Emodin, a bioactive compound abundant in Chinese medicinal herbs, possesses broad therapeutic potential but raises safety concerns due to conflicting reports of hepatotoxicity. This study investigated the toxicological mechanisms underlying emodin-induced liver injury. Emodin (25-100 μM) elicited dose-dependent cytotoxicity in HepG2 cells, with the cytochrome P450 (CYP) enzymes CYP1A2 and CYP3A4 identified as the primary enzymes metabolizing emodin into hydroxylated products (M1-M3). The comparative cytotoxicity assay of emodin and its metabolites in HepG2 cells indicated that CYP-mediated metabolism functions as a critical detoxification pathway. Moreover, inhibition of CYP with 1-aminobenzotriazole (ABT, 500 μM) markedly enhanced emodin (12.5-100 μM) cytotoxicity in HepG2 cells. Similarly, ABT (50 mg/kg) markedly exacerbated emodin (400 mg/kg)-induced hepatotoxicity in mice following three weeks of co-administration. Transcriptomic profiling and validation experiments demonstrated that activation of the NF-κB/NLRP3 signaling axis contributes to emodin-induced hepatic injury. Metabolomic analyses further revealed perturbations in key pathways, including lipopolysaccharide (LPS) biosynthesis, sphingolipid metabolism, and cholesterol metabolism. Integrated multi-omics analysis identified a significant positive correlation between these metabolites (LPS, sphingosine, cholesterol) and NF-κB/NLRP3 pathway genes. These findings suggest that emodin-mediated upregulation of LPS, sphingosine, and cholesterol activates the NF-κB/NLRP3 pathway, subsequently triggering hepatic injury. Collectively, this study delineates the metabolic detoxification routes of emodin and provides mechanistic insight into its hepatotoxic potential.

Metabolic degradation of lentinan in liver mediated by CYP450 enzymes and epoxide hydrolase

Ziming Zheng,Yu Zhang,Yuxuan Liu,Jinglin Wang,Zheng Cui,Xianglin Pan,Yan Liu,Wenqi Tang,Kaiping Wang

Lentinan (LNT), a typical triple helix β-glucan, has been widely used as drug and biomaterial. However, its pharmacokinetics in vivo is rarely reported, which severely limits its further development and application. The aim of this study is to establish a sensitive method for detecting LNT in biosamples and to evaluate the plasma level, tissue distribution and metabolic degradation of LNT in rats. 5-([4,6-Dichlorotriazin-2-yl] amino) fluorescein (DTAF) was labelled to LNT. After purification and identification, FLNT was intravenously administered to rats at dose of 32 mg/kg. LNT was predominantly incorporated into the liver and liver microsomes were used to study the degradation mechanism of LNT in the liver. The results showed that two cytochrome P450 (CYP450) enzymes subtypes (CYP2D6 and CYP2C9), as well as epoxide hydrolase, were involved in the metabolic degradation of LNT. These findings provide a pharmacokinetic reference for further study and application of LNT and other β-glucans.

Nitidine Chloride–Induced CYP1 Enzyme Inhibition and Alteration of Estradiol Metabolism

Xu Mao,Jian Wang,Qian Wang,Lan Yang,Yilin Li,Hao Lin,Ying Peng,Jiang Zheng

The cytochrome P450 (P450) 1 family is an important phase I enzyme involved in carcinogen activation. Nitidine chloride (NC) is a pharmacologically active alkaloid with polyaromatic hydrocarbon found in the roots of Zanthoxylum nitidum (Roxb.) DC, a traditional medicinal herb widely used in China. We examined the inhibitory effects of NC on CYP1A1, 1B1, and 1A2. NC significantly inhibited CYP1A1- and 1B1-catalyzed ethoxyresorufin O-deethylation activity (IC50 = 0.28 ± 0.06 and 0.32 ± 0.02 μM, respectively) in a concentration-dependent manner, but only showed slight inhibition of CYP1A2 activity (IC50 > 50 μM). Kinetic analysis revealed that NC competitively inhibited CYP1B1 with a Ki value of 0.47 ± 0.05 μM, whereas NC caused a mixed type of inhibition on CYP1A1 with Ki and KI values of 0.14 ± 0.04 and 0.19 ± 0.09 μM, respectively. The observed enzyme inhibition neither required NADPH nor revealed time dependency. Molecular docking manifested the generation of strong hydrogen-bonding interactions of Ser116 in CYP1A1 and Ser127 in CYP1B1 with methoxy moiety of NC. Additionally, NC-induced alteration of estradiol (E2) metabolism was also investigated in the present study. Hydroxyestradiols, including 2-hydroxyestradiol [(2-OHE2) nontoxic] and 4-hydroxyestradiol [(4-OHE2) genotoxic] generated in recombinant enzyme incubation systems and cultured MCF-7 cells were analyzed, and NC was found to preferentially inhibit the nontoxic 2-hydroxylation activity of E2 mediated by CYP1A1. In conclusion, NC was a mixed type inhibitor of CYP1A1 and a competitive inhibitor of CYP1B1. The remarkable inhibition on E2 2-hydroxylation might increase the risk of 4-OHE2–induced genotoxicity.

Pharmacokinetics and pharmacodynamics analysis of XQ-1H and its combination therapy with clopidogrel on cerebral ischemic reperfusion injury in rats

Bayarmaa Khadankhuu,Yuxiang Fei,Dan Xu,Yingchao Li,Kai Hou,Fengyang Li,Weirong Fang,Xijing Chen,Yunman Li

Ischemic stroke is the main cause of disability and mortality worldwide. 10-O-(N N-dimethylaminoethyl)-ginkgolide B methane-sulfonate (XQ-1 H) is a novel drug based on the remedial approach for ischemic stroke. Clopidogrel, a widely used anti-platelet drug, is often co-prescribed in the clinic. In this study, we established an UPLC-MS/MS spectrometry method for the determination of XQ-1H and investigated the pharmacokinetic effect of clopidogrel on XQ-1H in rats subjected to middle cerebral artery occlusion (MCAO). Meanwhile, the anti-apoptotic and neuroprotective effects of XQ-1H and its combination with clopidogrel were also studied. The results revealed that XQ-1H and its combination with clopidogrel abridged brain infarct volume, cerebral edema and alleviated neurological dysfunction caused by cerebral ischemic reperfusion injury. Further study demonstrated that XQ-1H combined with clopidogrel lessened TUNEL positive cells, up-regulated bcl-2 expression notably and down-regulated bax expression as compared to both XQ-1H and clopidogrel individually. In addition, a rapid, sensitive UPLC-MS/MS method was developed to quantify the concentration of XQ-1H in MCAO/R rats. Our pharmacokinetic results showed that clopidogrel significantly increased the exposure of XQ-1H, increased the peak plasma concentration (C max ), area under the curve (AUC) and slowed elimination of XQ-1H in the co-administered group. Besides, for further exploring which CYP450 isoforms are involved in the XQ-1H metabolism, XQ-1H was incubated in human liver microsomes (HLMs) system with or without P450 isoform-selective inhibitors. Our results revealed that clopidogrel altered pharmacokinetics of XQ-1H potentially and subsequently enhanced the pharmacological effect of XQ-1H. Moreover, XQ-1H could be applied as an efficacious neuroprotective agent for ischemic stroke because of its considerable effect on averting neuronal apoptosis.

Human microsomal cyttrochrome P450-mediated reduction of oxysophocarpine, an active and highly toxic constituent derived from Sophora flavescens species, and its intestinal absorption and metabolism in rat

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.

Metabolism of the anthelmintic drug niclosamide by cytochrome P450 enzymes and UDP-glucuronosyltransferases: metabolite elucidation and main contributions from CYP1A2 and UGT1A1

Danyi Lu,Zhiguo Ma,Tianpeng Zhang,Xingwang Zhang,Baojian Wu

Bile Duct Ligation Upregulates Expression and Function of L-Amino Acid Transporter 1 at Blood–Brain Barrier of Rats via Activation of Aryl Hydrocarbon Receptor by Bilirubin

Xiaoke Zheng,Hanyu Yang,Lan Qin,Siqian Wang,Lei Xie,Lu Yang,Weimin Kong,Liang Zhu,Li Liu,Xiaodong Liu

Liver failure is associated with increased levels of brain aromatic amino acids (AAAs), whose transport across the blood–brain barrier (BBB) is mainly mediated by L-amino acid transporter 1 (LAT1). We aimed to investigate whether liver failure induced by bile duct ligation (BDL) increases levels of brain AAAs by affecting the expression and function of LAT1. The LAT1 function was assessed using the brain distribution of gabapentin. It was found that BDL significantly increased levels of gabapentin, phenylalanine, and tryptophan in the cortex, hippocampus, and striatum of rats, and upregulated the expression of total LAT1 protein in hippocampus and striatum as well as cortex membrane LAT1 protein. HCMEC/D3 served as in vitro BBB model, and the data showed that both the serum of BDL rats and bilirubin induced LAT1 expression and function, while bilirubin oxidase almost abolished the upregulation of LAT1 protein by bilirubin and the serum of BDL rats. The enhanced function and expression of LAT1 were also observed in the hippocampus and striatum of hyperbilirubinemia rats. Both aryl hydrocarbon receptor (AhR) antagonist α-naphthoflavone and AhR silencing obviously attenuated the upregulation of LAT1 protein by bilirubin or omeprazole. This study provides the first evidence that BDL upregulates LAT1 at the rat BBB, attributed to the activation of AhR by the increased plasma bilirubin. The results highlight the mechanisms causing BDL-increased levels of brain AAAs and their physiological significance.Keywords:L-amino acid transporter;blood–brain barrier;liver failure;unconjugated bilirubin;aryl hydrocarbon receptor

Chlorine disinfection byproduct of diazepam affects nervous system function and possesses gender-related difference in zebrafish

Xiaole Zhao,Xiaoyong Huang,Wenjing Peng,Muke Han,Xin Zhang,Kui Zhu,Bing Shao

Chlorinated disinfection byproducts in water posed potential health threat to humans. Nowadays, chlorinated derivatives of diazepam were ubiquitously detected in drinking water. Among these derivatives, 2-methylamino-5-chlorobenzophenone (MACB) was capable of penetrating the blood-brain barrier (BBB) and induced microglial phagocytosis of neurons in zebrafish. However, little is known about the MACB metabolism in vivo. Here, we determined the metabolism of MACB in zebrafish and microglia cell model. We found that MACB mainly disrupted the metabolism of branched-chain amino acids (Leu, Ile and Val) in zebrafish model and gamma-aminobutyric acid (GABA) pathway-related amino acids in microglia model. Additionally, we demonstrated that MACB can be metabolized by the mixed-function oxidase CYP1A2 enzyme which could be inhibited by estrogen causing the gender-difference in the accumulation of MACB in vivo. These results indicated that MACB perturbed metabolism and induced neurological disorders, particularly in the female zebrafish.