ACS Applied Bio Materials
·
2020
·
IF 0
Xiaojun He,Ziman Zheng,Feifan Zhang,Chuchu Xu,Wei Xu,Lisong Ye,Xiaoshuai Sun,Zhan Zhou,Jianliang Shen
Bioactive molecules play a vital role in the process of regulating the redox balance in the intracellular environment, especially in maintaining the function of organelles. To explore the association and function of bioactive molecules in organelles, it is essential to develop a chemosensor tool that uses multiresponse fluorescence signals to distinguish between and track two related bioactive molecules in organelles. However, the development of sensors with multiresponse functions is still a challenging task. Herein, we present a unique and practical single chemosensor (Mito-CTC) that can monitor HClO (as an oxidative substance) and H2S (as a reductive substance) in mitochondria (organelle targeting) with multiresponse fluorescence signals. The response of the sensor to HClO and H2S changes from red to green and blue channel emission simultaneously, respectively, thereby providing a specific signal response to reductive/oxidative substances in the mitochondria. Using a single chemosensor, we have realized multichannel bioimaging of the exogenous and endogenous HClO and H2S in cellular mitochondria. Additionally, the excellent properties of the sensor Mito-CTC can be used to reveal the relationship between HClO and H2S in mitochondria. Meanwhile, Mito-CTC has been endowed with the ability to image in bacteria and zebrafish attributed to the good permeability and low cytotoxicity. Expectantly, drug-induced liver injury (DILI) caused by fluoxetine (an antidepressant drug) and the degree of drug-induced toxicity to the liver were evaluated using Mito-CTC through discriminating and imaging HClO, indicating that Mito-CTC has the potential function of evaluating the toxicity of the drug to the liver.
研究领域:
生物化学
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医学影像
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药理学
✓ 已验证
DOI
PubMed
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2025
·Vol. 82
·期 1
·1-16
·
IF 6.2
Zhao Xueqin,Li Yuanhao,Yang Liu,Chen Xi,Zhang Jialong,Chen Tong,Wang Haoqi,Li Fei,Cheng Chen,Wu Jingjing,Cong Jingjing,Yin Wenwei,Li Jing,Wang Xuefu
Acetaminophen (APAP) overdose induces acute liver injury and represents the most frequent cause of drug-induced liver injury worldwide. Macrophage-mediated inflammation plays detrimental roles during the early stage of liver injury. However, the potential targets regulating inflammation to improve drug-induced liver injury remains undefined. In this study, we reported that G protein-coupled receptor 35 (GPR35) improves drug-induced liver injury by blocking macrophage-mediated inflammation via the Gαs-cyclic AMP-protein kinase A (Gαs-cAMP-PKA) pathway. The ablation of GPR35 exacerbates APAP-induced liver injury, characterized by higher levels of alanine aminotransferase and aspartate aminotransferase in sera, larger damaged areas, and increased levels of pro-inflammatory cytokines. More hepatic macrophages appeared in the inflamed liver of mice with GPR35 deficiency. In contrast, the agonists of GPR35 alleviated APAP-induced liver injury. The depletion of macrophages abolished GPR35-mediated protection. Mechanistically, GPR35 ablation facilitated the activation of pro-inflammatory AKT, MAPK, and NF-κB signaling pathways at the downstream of Toll-like receptors in macrophages. GPR35 agonists activated Gαs-cAMP-PKA signaling to inhibit the activation of these pro-inflammatory signaling pathways and then suppress the inflammatory response in macrophages. Thus, our findings demonstrate that GPR35 prevents drug-induced liver injury by blocking macrophage-mediated inflammation via the Gαs-cAMP-PKA pathway, indicating that GPR35 is a potential target for the development of novel medicines that control drug-induced liver injury.
研究领域:
药理学
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肝脏病学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Non-coding RNA Research
·
2024
·
IF 5.9
Zixuan Yang,Lei Shi,Minhui Zheng,Minbo Hou,Mengdi Zhou,Naying Su,Hui Lang,Liyuan Zhao,Mengyun Gu,Naping Tang,Yan Chang
Background Drug-induced liver injury (DILI) is a leading cause of drug development failures during clinical trials and post-market introduction. Current biomarkers, such as ALT and AST, lack the necessary specificity and sensitivity needed for accurate detection. Exosomes, which protect LncRNAs from RNase degradation, could provide reliable and easily accessible options for biomarkers. Materials and methods RNA-sequencing was used to identify differentially expressed LncRNAs (DE-LncRNAs), followed by isolation of LncRNAs from plasma exosomes in this study. Exosome characterization was conducted by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB). Bioinformatics analysis included functional enrichment and co-expression network analysis. Five rat models were established, and quantitative real-time PCR was used to verify the specificity and sensitivity of two candidate exosomal LncRNAs. Results The APAP-induced hepatocellular injury model was successfully established for RNA-sequencing, leading to the identification of several differentially expressed exosomal LncRNAs. Eight upregulated exosomal DE-LncRNAs were selected for validation. Among them, NONRATT018001.2 (p < 0.05) and MSTRG.73954.4 (p < 0.05) exhibited a more than 2-fold increase in expression levels. In hepatocellular injury and intrahepatic cholestasis models, both NONRATT018001.2 and MSTRG.73954.4 showed earlier increases compared to serum biomarkers ALT and AST. However, no histological changes were observed until the final time point. In the fatty liver model, NONRATT018001.2 and MSTRG.73954.4 increased earlier than ALT and AST at 21 days. By the 7th day, minor steatosis was evident in liver tissue, while the expression levels of the two candidate exosomal LncRNAs exceeded 2 and 4 times, respectively. In the hepatic fibrosis model, NONRATT018001.2 and MSTRG.73954.4 showed increases at every time point. By the 49th day, hepatocellular necrosis and fibrosis were observed in the liver tissue, with NONRATT018001.2 showing an increase of more than 8 times. The specificity of the identified exosomal DE-LncRNAs was verified using a myocardial injury model and they showed no significant differences between the case and control groups. Conclusion NONRATT018001.2 and MSTRG.73954.4 hold potential as biomarkers for distinguishing different types of organ injury induced by drugs, particularly enabling early prediction of liver injury. Further experiments, such as siRNA interference or gene knockout, are warranted to explore the underlying mechanisms of these LncRNAs.
研究领域:
分子生物学
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肝脏病学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2025
·
IF 4.6
Han-Yang Zou,Zhao-Chen Wang,Xiao-Hui Liu,Yi-Fan Du,Xiao-Qun Cao,Jizhen Shang,Shi-Li Shen,Xiao-Fan Zhang
Mitochondria play a critical role in providing energy to maintain cellular physiological functions. The viscosity in mitochondria is one of the important indicators of mitochondrial microenvironment. When mitochondrial viscosity increases, it often indicates the occurrence or development of certain diseases. Herein, a series of near-infrared (NIR) fluorescent probes (ZHY-1 ∼ 4) were developed to detect viscosity changes. After screening, we selected ZHY-2 for cellular imaging, since it had the largest fluorescence intensity enhancement (222 times) in response to viscosity compared to the other probes (ZHY-1, ZHY-3, ZHY-4). In addition, ZHY-2 responded to viscosity specifically, and was not affected by pH and other biological species. Also, the probe ZHY-2 had good biocompatibility and mitochondria-targeting ability. It has been applied to measure viscosity changes after stimulation of nystatin and rapamycin. Finally, using probe ZHY-2, we have achieved the real-time fluorescence imaging of viscosity during starvation, as well as in drug-induced liver injury mice.
研究领域:
生物化学
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医学影像
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Sitian Liu,Zihan Wang,Xinyi Chen,Mingying Han,Jie Xu,Ting Li,Liu Yu,Maoyu Qin,Meng Long,Mingchuan Li,Hongwu Zhang,Yanbing Li,Ling Wang,Wenhua Huang,Yaobin Wu
Cardiac safety assessments are significant in drug discovery, as drug-induced cardiotoxicity (DIC) is the primary cause of drug attrition. Despite heart-on-a-chip (HoC) technology becoming an increasingly popular tool for evaluating DIC, its development remains a challenge owing to the anisotropic cardiac structure of the native myocardium. Herein, an anisotropic multiscale cardiac scaffold is presented via a hybrid biofabrication method by combining 3D printing with electrospinning technology, where the 3D-printed micrometer-scale scaffold frames enable mimicking the interwoven myocardium anatomical structure and the branched-aligned electrospun nanofibers network is able to directionally guide cellular arrangements. The in vitro 3D bioengineered cardiac tissues are then fabricated by encapsulating three-layer multiscale scaffolds within a photocurable methacrylated gelatin hydrogel shell. It is demonstrated that such an anisotropic multiscale structure could contribute to enhancing cardiomyocyte maturation and synchronous beating behavior. More attractively, with the integration of 3D bioengineered cardiac tissues and a self-designed microfluidic perfusion system, a 3D anisotropic HoC platform is established for evaluating DIC and cardioprotective efficacy. Collectively, these results indicate that the HoC model developed by integrating the 3D bioengineered cardiac tissues could effectively recapitulate the clinical manifestations, thereby highlighting their efficacy as a valuable preclinical platform for testing drug efficacy and cardiotoxicity.
研究领域:
生物医学工程
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药理学
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组织工程
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2025
·
IF 6
Weitao Xing,Kaili Yang,Yonglong Zhu,Xinyi Li,Yan Zhang,Linxia Guo,Jing-Yuan Ge,Yang Bai,Zhongyan Chen
Background Carboxylesterase (CE) is an important enzyme that mainly exists in liver cells and can catalyze the hydrolysis of esters in a variety of pharmaceuticals and xenobiotics. Real-time and non-invasive imaging of CE is of great significance for the study of CE-related metabolic diseases. Although fluorescence sensing technology is considered a promising candidate, the slow response rate (> 60 min), low sensitivity, and short emission wavelength (<650 nm) of most CE probes limit their practical application. Therefore, it is significant and urgent to develop novel fluorescent probes for the rapid diagnosis of CE-related diseases. Results Herein, a near-infrared fluorescent probe, CF 3 -BDP-CE , has been developed by introducing acetyl as the CE recognition unit into the fluorophore meso -trifluoromethyl-BODIP for the detection of CE. CF 3 -BDP-CE exhibited a remarkable fluorescence enhancement at 690 nm for CE with a limit of detection of 7.9 × 10 −4 U/mL. Importantly, the fast response kinetics (within 3 min) make CF 3 -BDP-CE superior to most reported probes. The emission turn-on mechanism was confirmed by theoretical calculation, revealing that after the hydrolysis of CF 3 -BDP-CE , the intramolecular charge transfer process leads to strong fluorescence. Furthermore, CF 3 -BDP-CE has been successfully applied to real-time imaging of endogenous CE changes in living cells and to imaging CE activity differences between tumor and normal cells. In addition, CF 3 -BDP-CE has been successfully used to track CE abnormalities in acetaminophen-induced liver injury model mice. Significance A NIR fluorescent probe CF 3 -BDP-CE was developed to effectively track the dynamic change of CE fluctuation in living cells and mice, with potential applications in the diagnosis of CE-related diseases.
研究领域:
生物化学
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医学诊断
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分子影像学
✓ 已验证
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2020
·
IF 7.1
Wen-Li Jiang,Wen-Xin Wang,Juan Liu,Yongfei Li,Chun-Yan Li
Hydrogen peroxide (H 2 O 2 ), as one of important reactive oxygen species (ROS), can be endogenously produced in the liver, and used as a biomarker for predicting drug-induced liver injury (DILI). So, it is important to construct an efficient method for monitoring H 2 O 2 in the liver to assess DILI. Herein, a hepatocyte-targeted fluorescent probe (GCP) for ratiometric detection of H 2 O 2 is developed. GCP consists of two main parts: coumarin-pyran-based fluorophore and galactose-based hepatocyte-targetable group. The probe itself shows near-infrared (NIR) emission owing to its extended π-conjugation. Meanwhile, a large emission shift from 706 to 482 nm (224 nm) is observed after the reaction with H 2 O 2 . Taking advantage of the spectroscopic property, GCP exhibits high sensitivity toward H 2 O 2 with 19-fold fluorescence ratio enhancement and is highly selective over other ROS. Moreover, the probe possesses a good hepatocyte-targeting ability and is applied for ratiometric monitoring endogenous H 2 O 2 in HepG2 cells. Furthermore, the probe can trace H 2 O 2 level during DILI in HepG2 cells. Most importantly, GCP can locate in the liver of zebrafish and detect H 2 O 2 level in the liver during DILI, which will be a potentially useful tool to assess DILI.
研究领域:
生物化学
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医学诊断
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分子影像学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Shuliang Song,Xiao Zhang,Lei Cui,Yan Wang,Xiao Tian,Ke Wang,Kai Ji
Malignant tumors contribute significantly to human mortality. Chemotherapy is a commonly used treatment for tumors. However, due to the low selectivity of chemotherapeutic drugs, immune cells can be damaged during antitumor treatment, resulting in toxicity. Lipopolysaccharide (LPS) can stimulate immune cells to respond to foreign substances. Here, we found that 10 ng/mL LPS could induce tolerance to antitumor drugs in macrophages without altering the effect of the drugs on tumor cells. Differentially expressed genes (DEGs) were identified between cells before and after LPS administration using transcriptome sequencing and found to be mainly associated with ATP-binding cassette (ABC)-resistant transporters and glutathione S-transferase (GST). LPS was shown by qRT-PCR and western blotting to promote the expression of ABCC1, GSTT1, and GSTP1 by 38.3 %, 194.8 %, and 27.0 %. Furthermore, three inhibitors (inhibitors of GST, glutathione synthesis, and ABCC1) were used for further investigation, showing that these inhibitors reduced macrophage survival rates by 44.0 %, 52.3 %, and 43.3 %, while the intracellular adriamycin content increased by 28.9 %, 42.9 %, and 51.3 %, respectively. These findings suggest that the protective mechanism of LPS on macrophages is associated with increased GST activity, the consumption of glutathione, and increased expression of ABCC1 protein. Therefore, LPS has a potential role in enhancing immunity.
研究领域:
肿瘤学
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免疫学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2014
·
IF 2.829
Tingting Wang,Ying Feng,Xiaohan Jin,Xuxin Fan,Jacques Crommen,Zhengjin Jiang
Drug-induced phospholipidosis (PLD) is a storage disorder of lysosomes characterized by the excessive accumulation of phospholipids as a result of improper medical treatments. Although few evidences have supported that PLD can induce significant pathological consequences, this potential toxicity indeed can put off the drug discovery process. In this research, a high-throughput liposome electrokinetic chromatography (LEKC) method was validated to evaluate the PLD risk of drug candidates by screening drug-phospholipid interaction, which correlates to the phospholipidosis inducing risk. A statistical analysis based on the Spearman's correlation test showed that the retention factors (log k) of the tested drugs in the LEKC system and the literature reported in vivo and in vitro PLD data were highly correlated. In order to investigate the predictability of LEKC, the effect of liposome composition such as the molar ratio of phospholipids and the addition of cholesterol were also discussed in this study. The results indicated that the LEKC method could offer a fast, reliable and cost-effective screening tool for early prediction of the PLD inducing potential of drug candidates.
研究领域:
药理学
·
毒理学
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOSENSORS & BIOELECTRONICS
·
2017
·
IF 7.78
Jin Peng,Xianfeng Hou,Fang Zeng,Shuizhu Wu
Drug-induced organ damages have been considered as a grave problem regarding public health; hence effective method for in vivo detection of drug-induced organ damages is of great significance. Herein we developed a ratiometric fluorescent nanoprobe (NPs-A), which was prepared by loading the probe molecules into phospholipid bilayer, for assaying hydrogen peroxide (H 2 O 2 , an organ damage biomarker) level in vivo. The photophysical behavior of the probe molecule depends on the electron-withdrawing ability of the group at the 6- position of anthracene ring, on which the recognition moiety for hydrogen peroxide (dicarbonyl coupled with nitrophenyl, referred to as nitrophenyl-dicarbonyl) was introduced. Upon the reaction of the probe with H 2 O 2 , nitrophenyl-dicarbonyl group transforms into carboxyl group, and due to the variation of the electron-withdrawing ability of the 6th substituent , the fluorescent properties of the probe molecule alters accordingly, thus ensuring the ratiometric detection for H 2 O 2 with high selectivity with the detection limit of 0.49 μM. In addition, the nanoprobe (NPs-A) was applied for cell and in vivo imaging applications; and the results indicate that it can detect and track the level of H 2 O 2 in living cells and to monitor and spatially map endogenous H 2 O 2 levels in a drug-induced organ damage model of zebrafish.
研究领域:
生物医学工程
·
分析化学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2024
·
IF 4.3
Yongquan Wu,Shufen Pan,Yuting Han,Yanyan Tang,Qinglin Chen,Qingchun Lan
Bisulfite (HSO 3 − ) plays an important role in life activities. Abnormal content of HSO 3 − may cause cardiovascular, cancer and other diseases. Frequency upconverted luminescent (FUCL) probes are a class of anti-Stokes luminescent materials with long-wavelength excitation and short-wavelength emission properties, which offer advantages in a range of applications due to their higher sensitivity and photostability. In addition, FUCL imaging has the advantages of high tissue penetration depth and low photo-damage, thus, it is more suitable for fluorescence imaging. In this work, a FUCL probe based on an xanthene fluorophore was designed and synthesised to detect HSO 3 − . The Probe PT-1 could respond to HSO 3 − and had high selectivity and sensitivity. It also exhibited a quenched FUCL signal. The detection limit of FUCL concerning HSO 3 − was 43 nM (λ ex = 730 nm), which is half the detection limit achieved under traditional excitation (93 nM, λ ex = 643 nm). Cell fluorescence imaging showed that PT-1 could effectively target mitochondria and monitor endogenous/exogenous HSO 3 − in living cells. More importantly, PT-1 was successfully used to monitor the level of HSO 3 − in mice with drug-induced liver injury through FUCL imaging.
研究领域:
生物化学
·
医学影像
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHIC SCIENCE
·
2016
·Vol. 55
·期 1
·60-68
·
IF 1.32
Gu Liqiang,Shi Huiyan,Zhang Ruowen,Wei Zhe,Bi Kai-Shun,Chen Xiao-Hui
In clinical diagnosis, serum creatinine (CR) was commonly used as the routine markers for the evaluation of kidney injury. To investigate the specific and sensitive nephrotoxicity biomarkers in different drug-induced kidney injury (DKI) models, receiver operating characteristic (ROC) analysis was applied in this study. The quantification data were acquired by the LC–MS determination. Histopathology results showed that different kinds of kidney injuries were observed in different DKI models (gentamycin, cisplatin, methotrexate and amphotericin B models), indicating the injuries might be caused by different mechanisms. Then, five typical biomarkers were simultaneously determined by a newly developed and validated LC–MS method. Uric acid, CR, hippuric acid, 3-indoxyl sulfate and phenaceturic acid were separated by an Apollo C18 column and a methanol/water (5 mM ammonium acetate) gradient program. The prepared calibration curves showed good linearity with regression coefficients all above 0.9927. Of all the analytes, the precision were below 9.9% and the accuracy were from −10.3% to 9.2%. ROC results showed that different nephrotoxicity biomarkers were specific in different DKI models. The changes of different biomarkers might be induced by different nephrotoxic mechanisms in the DKI models. These specific and sensitive biomarkers in combination with serum CR are promising in the clinical diagnosis of DKI.
研究领域:
毒理学
·
临床医学
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）