JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2023
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IF 3.4
Jinhua Li,Namrta Choudhry,Gang Lv,Naganna Nimishetti,Mallu Chenna Reddy,Hong Liu,Thaddeus D. Allen,Jing Zhang,Dun Yang
This study investigated the metabolism of LXY18, a quinolone-based compound that suppresses tumorigenesis by blocking AURKB localization. Metabolite profiling of LXY18 in liver microsomes from six species and human S9 fractions revealed that LXY18 undergoes various conserved metabolic reactions , such as N-hydroxylation, N-oxygenation, O-dealkylation, and hydrolysis, resulting in ten metabolites. These metabolites were produced through a combination of CYP450 enzymes, and non-CYP450 enzymes including CES1 , and AO . Two metabolites, M1 and M2 were authenticated by chemically synthesized standards. M1 was the hydrolyzed product catalyzed by CES1 whereas M2 was a mono-N-oxidative derivative catalyzed by a CYP450 enzyme. AO was identified as the enzyme responsible for the formation of M3 with the help of AO-specific inhibitors and LXY18 analogs, 5b and 5c. M1 was the intermediate of LXY18 to produce M7, M8, M9, and M10. LXY18 potently inhibited 2C19 with an IC 50 of 290 nM but had a negligible impact on the other CYP450s, indicating a low risk of drug-drug interaction. Altogether, the study provides valuable insights into the metabolic process of LXY18 and its suitability as a drug candidate. The data generated serves as a significant reference point for conducting further safety assessments and optimizing drug development .
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ACS Biomaterials Science & Engineering
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2020
·
IF 4.152
Zongjun Liu,Peng Wan,Zhao Liu,Mingxin Yang,ShanShan Li,You Wang,Yang Gan
Reactive oxygen species (ROS) as one kind of oxygen-dependent toxic free radical has been widely adopted in ROS-mediated therapies (RMT). However, two shackles, known as tumor hypoxia and high intratumor glutathione (GSH) levels, respectively, limit RMT as the former prevents ROS from generating, while the latter scavenges the ROS generated. Herein, we developed a novel nanoplatform to simultaneously overcome the two shackles by facile preparation of mesoporous carbon nanospheres (MCNs) with AIBI and raloxifene loaded inside as an initiator and inhibitor, respectively, and phase-change materials (PCMs) capped outside as gatekeepers. Upon 808 nm NIR light irradiation, the photothermal effect of MCNs melted PCMs causing the loaded AIBI and raloxifene to be released, during which the AIBI was further decomposed into oxygen-irrelevant radicals to kill cancer cells, while the raloxifene suppressed GSH synthesis, synergistically enabling an enhanced photonic thermodynamic cancer therapy.
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PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
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IF 4.2
Zhengsheng Mao,Youjia Yu,Gen Ba,Hongmei Zhao,Qifang Shi,Yue Cao,Weiran Xie,Jinsong Zhang,Hao Sun,Feng Chen
Diquat (DQ) poisoning has garnered attention in recent years, primarily due to the rising incidence of cases worldwide, coupled with the absence of a viable antidote for its treatment. Despite the fact that diquat monopyridone (DQ-M) has been identified as a significant metabolite of DQ, the enzyme responsible for its formation remains unknown. In this study, we have identified aldehyde oxidase (AOX) as a vital enzyme involved in DQ oxidative metabolism . The metabolism of DQ to DQ-M was significantly inhibited by AOX inhibitors including raloxifene and hydralazine . The source of oxygen incorporated into DQ-M was proved to be from water through a H2 18 O incubation experiment which further corroborated DQ-M formation via AOX metabolism. The product of DQ-M in vitro generated by fresh rat tissues co-incubation was consistent with its AOX expression. The result of the molecular docking analysis of DQ and AOX protein showed that DQ is capable of binding to AOX. Furthermore, the cytotoxicity of DQ was significantly higher than DQ-M at the same concentration tested in six cell types. This work is the first to uncover the involvement of aldehyde oxidase, a non-cytochrome P450 enzyme, in the oxidative metabolic pathway of diquat, thus providing a potential target for the development of detoxification treatment.
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JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Ruonan He,Junyi Yang,Shengjie Yuan,Ling Chen,Hongqiang Ren,Bing Wu
Real-time monitoring of estrogenic activity in the aquatic environment is a challenging task. Current biosensors face difficulties due to their limited response speed and environmental tolerance, especially for detecting wastewater, the major source of estrogenic compounds in aquatic environments. To address these difficulties, this study developed a single fluorescent protein (FP) -based whole-cell bacterial biosensor named ER-Light, which was achieved by inserting the sensing domain of the estrogen receptor (ER) into the FP Citrine and expressing it in the periplasm of Escherichia coli . As designed, ER-Light enables the detection of net estrogenic activity in mixtures, represented by estradiol equivalent concentration (EEQ). ER-Light detects EEQ in 40 s with a detection limit of 4.55 × 10 −7 μM and a maximum working range of 1.1 × 10 −4 μM, demonstrating sufficient response speed, sensitivity, and working range. In addition, the ER-Light can survive and tolerate wastewater effluent. Satisfactory recoveries (91.0 % to 102.1 %) eliminated concerns about the matrix effect of wastewater. EEQs (Not detected-2.9 ×10 −5 µM) measured by ER-Light from the effluent of 9 wastewater treatment plants validate its practicality in detecting wastewater. This is the first attempt to integrate ER into FP-based biosensors for environment monitoring. Our findings provide valuable design rules for real-time detection of bioactivity effects in the environment, contributing to the safeguarding of ecological and human health.
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REPRODUCTIVE TOXICOLOGY
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2025
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IF 2.8
Shiling Chen,Xiuying Lin,Lei Liu,Jianhua Fu,Xiaodan Lu,Chunxue Niu,Qilai Wang,HaiFeng Wei,Mengxue Wu,Munan Sun,Lixin Cao,Xuguang Mi,Yanqiu Fang
Estrogen plays a central role in promoting endometrial thickening during the menstrual cycle. In patients with a thin endometrium, endometrial cells exhibit reduced sensitivity to estrogen, contributing to female infertility. We established an endometrial stromal cell damage model using the estrogen antagonist raloxifene (RAL) and investigated the role and underlying mechanism of human umbilical cord mesenchymal stem cell–derived exosomes (hUCMSC-EXO) in repairing RAL-induced damage in human endometrial stromal cells (hEndoSCs). In this study, hEndoSCs were treated with RAL and subsequently cultured with hUCMSC-EXO. The results showed that hUCMSC-EXO restored the proliferative capacity of hEndoSCs, decreased endogenous reactive oxygen species production, and increased mitochondrial membrane potential. Mechanistic analysis indicated that hUCMSC-EXO activated intracellular autophagy, and that autophagy inhibition reversed the protective effects of hUCMSC-EXO on hEndoSCs. These findings suggest that hUCMSC-EXO may ameliorate endometrial injury associated with estrogen insensitivity.
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American Journal of Translational Research
·
2025
·Vol. 17
·期 7
·5081
·
IF 1.6
Pengyu Huang,Suhua Jiang,Beihong Zheng,Yun Fu,Wenqiang You,Haiyan Li
Objective: To evaluate the therapeutic outcomes of combining ethinylestradiol-cyproterone acetate (EE-CPA) with raloxifene in the management of polycystic ovary syndrome (PCOS)-associated infertility. Methods: The study included 115 women diagnosed with PCOS-associated infertility, admitted between January 2021 and January 2025. The participants were divided into two groups: 55 women receiving raloxifene monotherapy (control group) and 60 treated with EE-CPA plus raloxifene (observation group). The following were assessed: therapeutic effectiveness, adverse drug reactions (abdominal/pelvic pain, nausea/vomiting, body weight fluctuations, and breast tenderness), metabolic markers (fasting plasma glucose [FPG], fasting serum insulin [FINS], and homeostasis model assessment of insulin resistance [HOMA-IR]), sex hormones (estradiol [E2], follicle-stimulating hormone [FSH], and luteinizing hormone [LH]), ovarian function (ovarian volume and endometrial thickness), endometrial receptivity (resistance index [RI] and pulsatility index [PI]), and pregnancy outcomes (ovulation, miscarriage, and clinical pregnancy). Results: The combination therapy showed superior outcomes, including enhanced overall effectiveness, increased ovulation and pregnancy rates, and a reduced miscarriage rate (all P>0.05). No significant differences in adverse drug reactions were found between the two groups (P>0.05). After treatment, the observation group showed greater improvements in metabolic markers, FSH, LH, ovarian volume, RI, and PI (all P>0.05). Additionally, E2 levels and endometrial thickness were more significantly enhanced in the observation group compared to the control group (all P>0.05). Conclusions: The combination of EE-CPA and raloxifene is highly effective in managing PCOS-associated infertility, improving therapeutic outcomes without significantly increasing adverse effects. It also leads to notable improvements in metabolism, sex hormones, ovarian function, and endometrial receptivity, ultimately enhancing pregnancy outcomes.
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