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1
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Liu C, Zhang C, Wu H, Zhao Z, Wang Z, Zhang X, Yang J, Yu W, Lian Z, Gao M, Zhou L. The AKR1C1-CYP1B1-cAMP signaling axis controls tumorigenicity and ferroptosis susceptibility of extrahepatic cholangiocarcinoma. Cell Death Differ 2025; 32:506-520. [PMID: 39478199 PMCID: PMC11894074 DOI: 10.1038/s41418-024-01407-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/13/2024] [Accepted: 10/22/2024] [Indexed: 03/12/2025] Open
Abstract
Extrahepatic cholangiocarcinoma (ECC), a highly malignant type of cancer with increasing incidence, has a poor prognosis due to limited treatment options. Based on genomic analysis of ECC patient samples, here we report that aldo-keto reductase family 1 member C1 (AKR1C1) is highly expressed in human ECC tissues and closely associated with ECC progression and poor prognosis. Intriguingly, we show that inducible AKR1C1 knockdown triggers ECC cells to undergo ferroptosis. Mechanistically, AKR1C1 degrades the protein stability of the cytochrome P450 family member CYP1B1, a newly discovered mediator of ferroptosis, via ubiquitin-proteasomal degradation. Additionally, AKR1C1 decreases CYP1B1 mRNA level through the transcriptional factor aryl-hydrocarbon receptor (AHR). Furthermore, the AKR1C1-CYP1B1 axis modulates ferroptosis in ECC cells via the cAMP-PKA signaling pathway. Finally, in a xenograft mouse model of ECC, AKR1C1 depletion sensitizes cancer cells to ferroptosis and synergizes with ferroptosis inducers to suppress tumor growth. Therefore, the AKR1C1-CYP1B1-cAMP signaling axis is a promising therapeutic target for ECC treatment, especially in combination with ferroptosis inducers.
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Affiliation(s)
- Chang Liu
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Cheng Zhang
- Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Hongkun Wu
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhibin Zhao
- Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Zhenhua Wang
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiaomin Zhang
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jieli Yang
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Wenlong Yu
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
| | - Zhexiong Lian
- Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
| | - Minghui Gao
- The HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
| | - Lin Zhou
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China.
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2
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Quan T, Li R, Gao T. Role of Mitochondrial Dynamics in Skin Homeostasis: An Update. Int J Mol Sci 2025; 26:1803. [PMID: 40076431 PMCID: PMC11898645 DOI: 10.3390/ijms26051803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/07/2025] [Accepted: 02/09/2025] [Indexed: 03/14/2025] Open
Abstract
Skin aging is the most prominent phenotype of host aging and is the consequence of a combination of genes and environment. Improving skin aging is essential for maintaining the healthy physiological function of the skin and the mental health of the human body. Mitochondria are vital organelles that play important roles in cellular mechanisms, including energy production and free radical balance. However, mitochondrial metabolism, mitochondrial dynamics, biogenesis, and degradation processes vary greatly in various cells in the skin. It is well known that mitochondrial dysfunction can promote the aging and its associated diseases of the skin, resulting in the damage of skin physiology and the occurrence of skin pathology. In this review, we summarize the important role of mitochondria in various skin cells, review the cellular responses to vital steps in mitochondrial quality regulation, mitochondrial dynamics, mitochondrial biogenesis, and mitochondrial phagocytosis, and describe their importance and specific pathways in skin aging.
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Affiliation(s)
| | | | - Ting Gao
- College of Veterinary Medicine, China Agricultural University, Beijing 100083, China; (T.Q.); (R.L.)
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3
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Lin H, Li Z, Zeng T, Wang Y, Zhang L. The crucial involvement of gamma-Mangostin and CYP1B1 in the mechanism underlying the toxicity caused by cigarette smoke extract: In silico and in vitro insights. Toxicology 2025; 510:154016. [PMID: 39615578 DOI: 10.1016/j.tox.2024.154016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/05/2024] [Accepted: 11/24/2024] [Indexed: 12/13/2024]
Abstract
Cigarette smoke extracts (CSE) contain harmful substances that significantly contribute to respiratory conditions. Previous studies have primarily focused on the presence of carcinogens in CSE. However, it should be noted that other compounds may also synergistically contribute to a greater impact. This study proposes an innovative collaboration between natural products in CSE and carcinogens to enhance CSE-induced acute toxicity. Bioinformatics analysis coupled with experimental validation have elucidated the pivotal role of CYP1B1 in CSE-induced acute toxicity. Inhibitors targeting CYP1B1 have demonstrated preferential cytotoxicity towards cells exhibiting elevated levels of CYP1B1 expression. Afterwards, we conducted a virtual screening of the CSE composition database to identify a potential inhibitor for CYP1B1. After analyzing docking scores and complex interaction modes, γ-mangostin emerged as a highly promising CYP1B1 inhibitor. Molecular docking and dynamics were used to elucidate the complex structure formed between γ-mangostin and CYP1B1. Further investigations suggest that γ-mangostin can synergistically interact with carcinogens in CSE, causing cellular harm and contributing significantly to acute toxicity induced by CSE. Furthermore, γ-mangostin showed increased affinity towards CYP1B1 variants L432V and N453S, suggesting that organisms with these genetic variations may be more susceptible to cell damage caused by CSE. These new perspectives enhance our understanding of the mechanism behind acute toxicity associated with CSE and offer new possibilities for improving preventive measures and treatment strategies.
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Affiliation(s)
- Hao Lin
- State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Zijian Li
- State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Tao Zeng
- State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Ying Wang
- Innovation Institute for Artificial Intelligence in Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
| | - Lan Zhang
- Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China.
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4
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Luo J, Liang M, Ma T, Dong B, Jia L, Su M. Identification of angiogenesis-related subtypes and risk models for predicting the prognosis of gastric cancer patients. Comput Biol Chem 2024; 112:108174. [PMID: 39191168 DOI: 10.1016/j.compbiolchem.2024.108174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/02/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024]
Abstract
Gastric cancer (GC) is a leading cause of cancer-related mortality and is characterized by significant heterogeneity, highlighting the need for further studies aimed at personalized treatment strategies. Tumor angiogenesis is critical for tumor development and metastasis, yet its role in molecular subtyping and prognosis prediction remains underexplored. This study aims to identify angiogenesis-related subtypes and develop a prognostic model for GC patients. Using data from The Cancer Genome Atlas (TCGA), we performed consensus cluster analysis on differentially expressed angiogenesis-related genes (ARGs), identifying two patient subtypes with distinct survival outcomes. Differentially expressed genes between the subtypes were analyzed via Cox and LASSO regression, leading to the establishment of a subtype-based prognostic model using a machine learning algorithm. Patients were classified into high- and low-risk groups based on the risk score. Validation was performed using independent datasets (ICGC and GSE15459). We utilized a deconvolution algorithm to investigate the tumor immune microenvironment in different risk groups and conducted analyses on genetic profiling, sensitivity and combination of anti-tumor drug. Our study identified ten prognostic signature genes, enabling the calculation of a risk score to predict prognosis and overall survival. This provides critical data for stratified diagnosis and treatment upon patient admission, monitoring disease progression throughout the entire course, evaluating immunotherapy efficacy, and selecting personalized medications for GC patients.
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Affiliation(s)
- Jie Luo
- Department of Medical Affairs, Huanggang Central Hospital, Huanggang, China
| | - Mengyun Liang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Tengfei Ma
- Clinical Trial Centers, Huanggang Central Hospital, Huanggang, China; Huanggang Institute of Translational Medicine, Huanggang, China
| | - Bizhen Dong
- Huanggang Institute of Translational Medicine, Huanggang, China
| | - Liping Jia
- Department of Respiratory and Critical Care Medicine, Huanggang Central Hospital, Huanggang, China.
| | - Meifang Su
- Department of Hematopathology, Huanggang Central Hospital, Huanggang, China.
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5
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Lu J, Jin Z, Jin X, Chen W. Prognostic value and potential regulatory relationship of miR-200c-5p in colorectal cancer. J Biochem Mol Toxicol 2024; 38:e23770. [PMID: 39016041 DOI: 10.1002/jbt.23770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/23/2024] [Accepted: 07/05/2024] [Indexed: 07/18/2024]
Abstract
This study aimed to investigate the relationship and potential mechanisms of miR-200c-5p in colorectal cancer (CRC) progression. Differentially expressed miRNAs were screened using the TCGA database. Subsequently, univariate analysis was performed to identify CRC survival-related miRNAs. Survival and receiver operator characteristic curves were generated. The target genes of miR-200c-5p and the relevant signaling pathways or biological processes were predicted by the miRNet database and enrichment analyses. The miR-200c-5p expression was detected using quantitative reverse-transcription polymerase chain reaction, Cell Counting Kit-8, Transwell, and cell apoptosis experiments were performed to determine miR-200c-5p's impact on CRC cell viability, invasiveness, and apoptosis. Finally, we constructed a CRC mouse model with inhibited miR-200c-5p to evaluate its impact on tumors. miR-200c-5p was upregulated in CRC, implying a favorable prognosis. Gene set enrichment analysis revealed that miR-200c-5p may participate in signaling pathways such as the TGF-β signaling pathway, RIG-I-like receptor signaling pathway, renin-angiotensin system, and DNA replication. miR-200c-5p potentially targeted mRNAs, including KCNE4 and CYP1B1, exhibiting a negative correlation with their expression. Furthermore, these mRNAs may participate in biological processes like the regulation of intracellular transport, cAMP-dependent protein kinase regulatory activity, ubiquitin protein ligase binding, MHC class II protein complex binding, and regulation of apoptotic signaling pathway. Lastly, miR-200c-5p overexpression repressed the viability and invasiveness of CRC cells but promoted apoptosis. The tumor size, weight, and volume were significantly increased by inhibiting miR-200c-5p (p < 0.05). miR-200c-5p is upregulated in CRC, serving as a promising biomarker for predicting CRC prognosis.
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Affiliation(s)
- Jiying Lu
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Colorectal and Anal Surgery, The Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Zhekang Jin
- Department of Colorectal and Anal Surgery, The Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Xihan Jin
- Department of Colorectal and Anal Surgery, The Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Wenbin Chen
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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6
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Stute N, Koldehoff M. Lower overall survival in male patients with advanced disease undergoing allogeneic hematopoietic stem cell transplantation is associated with CYP1B1 Leu432Val polymorphism. Haematologica 2024; 109:799-808. [PMID: 37767566 PMCID: PMC10905095 DOI: 10.3324/haematol.2023.283649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic key enzyme involved in estrogen metabolism, steroid synthesis, and pro-carcinogen activation. In a single-center retrospective study, 382 patients who underwent allogeneic hematopoetic stem cell transplantation and their donors were genotyped for CYP1B1 C432G polymorphism by reverse transcription polymerase chain reaction. One hundred and sixty-nine patients (44%) were homozygous wild-type (wt) gene CC, 157 (41%) heterozygous CG and 56 (15%) homozygous gene mutated GG. Of interest, mutated CYP1B1 was more common in male (62%) than in female patients (48%) P=0.006, unlike in donors. Five-year estimate for overall survival (OS) was 58±4% (CC) versus 48±3% (CG and GG), P=0.048. Surprisingly, this difference was only evident in males (P=0.024): OS 58±6% versus 42±4%, whereas it was virtually absent in females. Importantly, this difference was only evident in male patients with advanced disease (AD) (n=118, P=0.002): OS 44±8% (CC) versus 32±6% (CG) versus 6±6% (GG), whereas it was virtually absent in male patients with early disease. One-year non-relapse mortality in male patients with AD was 8±4% (CC) versus 21±5% (CG) versus 50±12% (GG), P=0.002. Three-year relapse rate in male patients with AD was 31±7% (wt) versus 42±6% (mut), P=0.04. Multivariate analysis for OS in male patients with AD revealed CYP1B1 polymorphism as the only prognostic factor: RR 1.78, P=0.001. In conclusion, these results suggest that male patients with AD and mutant CYP1B1 polymorphism have lower OS after allogeneic hematopoetic stem cell transplantation due to a higher non-relapse mortality and a higher relapse rate.
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Affiliation(s)
- Norbert Stute
- Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany; Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Paracelsus Medical University, Salzburg
| | - Michael Koldehoff
- Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany; Department of Hygiene and Environmental Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Institute for Laboratory Medicine and Transfusion Medicine, Zotzô€€€Klimas, Düsseldorf.
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7
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Ruparelia KC, Zeka K, Beresford KJM, Wilsher NE, Potter GA, Androutsopoulos VP, Brucoli F, Arroo RRJ. CYP1-Activation and Anticancer Properties of Synthetic Methoxylated Resveratrol Analogues. Molecules 2024; 29:423. [PMID: 38257336 PMCID: PMC10818546 DOI: 10.3390/molecules29020423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/21/2023] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
Naturally occurring stilbenoids, such as the (E)-stilbenoid resveratrol and the (Z)-stilbenoid combretastatin A4, have been considered as promising lead compounds for the development of anticancer drugs. The antitumour properties of stilbenoids are known to be modulated by cytochrome P450 enzymes CYP1A1 and CYP1B1, which contribute to extrahepatic phase I xenobiotic and drug metabolism. Thirty-four methyl ether analogues of resveratrol were synthesised, and their anticancer properties were assessed, using the MTT cell proliferation assay on a panel of human breast cell lines. Breast tumour cell lines that express CYP1 were significantly more strongly affected by the resveratrol analogues than the cell lines that did not have CYP1 activity. Metabolism studies using isolated CYP1 enzymes provided further evidence that (E)-stilbenoids can be substrates for these enzymes. Structures of metabolic products were confirmed by comparison with synthetic standards and LC-MS co-elution studies. The most promising stilbenoid was (E)-4,3',4',5'-tetramethoxystilbene (DMU212). The compound itself showed low to moderate cytotoxicity, but upon CYP1-catalysed dealkylation, some highly cytotoxic metabolites were formed. Thus, DMU212 selectively affects proliferation of cells that express CYP1 enzymes.
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Affiliation(s)
- Ketan C. Ruparelia
- Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK; (K.C.R.); (K.J.M.B.); (N.E.W.); (R.R.J.A.)
| | - Keti Zeka
- Zayed Centre for Research into Rare Disease in Children, University College London, London WC1E 6BT, UK
| | - Kenneth J. M. Beresford
- Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK; (K.C.R.); (K.J.M.B.); (N.E.W.); (R.R.J.A.)
| | - Nicola E. Wilsher
- Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK; (K.C.R.); (K.J.M.B.); (N.E.W.); (R.R.J.A.)
| | - Gerry A. Potter
- Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK; (K.C.R.); (K.J.M.B.); (N.E.W.); (R.R.J.A.)
| | - Vasilis P. Androutsopoulos
- Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK; (K.C.R.); (K.J.M.B.); (N.E.W.); (R.R.J.A.)
| | - Federico Brucoli
- Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK; (K.C.R.); (K.J.M.B.); (N.E.W.); (R.R.J.A.)
| | - Randolph R. J. Arroo
- Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK; (K.C.R.); (K.J.M.B.); (N.E.W.); (R.R.J.A.)
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8
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Chen D, Li R, Shao Q, Wu Z, Cui J, Meng Q, Li S. Design and Synthesis of Novel Near-Infrared Fluorescence Probes Based on an Open Conformation of a Cytochrome P450 1B1 Complex for Molecular Imaging of Colorectal Tumors. J Med Chem 2023; 66:16032-16050. [PMID: 38031326 DOI: 10.1021/acs.jmedchem.3c01474] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
Abstract
Cytochrome P450 1B1 (CYP1B1) is induced during the early stage of cancer and is universally overexpressed in tumors. Thus, it was considered as a potential biomarker for the monitoring of cancer. In this study, we designed and synthesized CYP1B1-targeted near-infrared (NIR) fluorescence molecular probes based on the latest reported open conformation of the CYP1B1-α-naphthoflavone (ANF) complex. According to the architecture of the open channel, we introduced linkers and a Cy5.5 fragment at the 5' position of ANF derivatives with strong CYP1B1 inhibitory activity to obtain probes 19-21. Then, in vitro cell-based studies showed that the probes could be enriched in tumor cells by binding to CYP1B1. During in vivo and ex vivo imaging in a xenograft mouse model, probe 19 with the best binding affinity was proven to be able to identify tumor sites in both fluorescence imaging and photoacoustic imaging modes.
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Affiliation(s)
- Dongmei Chen
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Ruining Li
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Qi Shao
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Zhihao Wu
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Jiahua Cui
- School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Qingqing Meng
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Shaoshun Li
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
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9
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Cai J, Yi L, Xia Z, Huang X, Yang M, Zhao Z, Gao C, Yang H, Zhang J, Peng Z, Qiu D. Design, Synthesis, and Evaluation of 18F-Labeling CYP1B1 PET Tracer Based on 2-Phenylquinazolin. Bioorg Med Chem Lett 2023; 96:129533. [PMID: 37865282 DOI: 10.1016/j.bmcl.2023.129533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/27/2023] [Accepted: 10/18/2023] [Indexed: 10/23/2023]
Abstract
Cytochrome P450 (CYP)1B1 has been identified to be specifically overexpressed in several solid tumors, thus it's a potential target for the detection of tumors. Based on the 2-Phenylquinazolin CYP1B1 inhibitors, we designed and synthesized several positron emission computed tomography (PET) imaging probes targeting CYP1B1. Through IC50 determinations, most of these probes exhibited good affinity and selectivity to CYP1B1. Considering their affinity, solubility, and their 18F labeling methods, we chose compound 5c as the best candidate. The 18F radiolabeling of [18F] 5c was easy to handle with good radiolabeling yield and radiochemical purity. In vitro and in vivo stability study indicated that probe [18F]5c has good stability. In cell binding assay, [18F]5c could be specifically taken up by tumor cells, especially HCT-116 cells. Although the tumor-blood (T/B) and tumor-muscle (T/M) values and PET imaging results were unsatisfied, it is still possible to develop PET probes targeting CYP1B1 by structural modification on the basis of 5c in the future.
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Affiliation(s)
- Jiajing Cai
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Lan Yi
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Zhu Xia
- Department of Nuclear Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xinyue Huang
- College of Chemistry and Chemical Engineering, Chongqing University of Technology, Chongqing 400054, China
| | - Meixian Yang
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Zhenghuan Zhao
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Chenyang Gao
- Chongqing Yucai Secondary School, Chongqing 400050, China
| | - Hengyi Yang
- Chongqing Yucai Secondary School, Chongqing 400050, China
| | - Jiayuan Zhang
- Chongqing Yucai Secondary School, Chongqing 400050, China
| | - Zhiping Peng
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
| | - Dachuan Qiu
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
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10
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Lv MW, Zhang C, Ge J, Sun XH, Li JY, Li JL. Resveratrol protects against cadmium-induced cerebrum toxicity through modifications of the cytochrome P450 enzyme system in microsomes. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2023. [PMID: 37115015 DOI: 10.1002/jsfa.12668] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/14/2023]
Abstract
BACKGROUND Cadmium (Cd), known as a vital contaminant in the environment, penetrates the blood-brain barrier and accumulates in the cerebrum. Acute toxicosis of Cd, which leads to lethal cerebral edema, intracellular accumulation and cellular dysfunction, remains to be illuminated with regard to the exact molecular mechanism of cerebral toxicity. Resveratrol (RES), present in the edible portions of numerous plants, is a simply acquirable and correspondingly less toxic natural compound with neuroprotective potential, which provides some theoretical bases for antagonizing Cd-induced cerebral toxicity. RESULTS This work was executed to research the protective effects of RES against Cd-induced toxicity in chicken cerebrum. Markedly, these lesions were increased in the Cd group, which also exhibited a thinner cortex, reduced granule cells, vacuolar degeneration, and an enlarged medullary space in the cerebrum. Furthermore, Cd induced CYP450 enzyme metabolism disorders by disrupting the nuclear xenobiotic receptor response (NXRs), enabling the cerebrum to reduce the ability to metabolize exogenous substances, eventually leading to Cd accumulation. Meanwhile, accumulated Cd promoted oxidative damage and synergistically promoted the damage to neurons and glial cells. CONCLUSION RES initiated NXRs (especially for aromatic receptor and pregnancy alkane X receptor), decreasing the expression of CYP450 genes, changing the content of CYP450, maintaining CYP450 enzyme normal activities, and exerting antagonistic action against the Cd-induced abnormal response of nuclear receptors. These results suggest that the cerebrum toxicity caused by Cd was reduced by pretreatment with RES. © 2023 Society of Chemical Industry.
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Affiliation(s)
- Mei-Wei Lv
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, PR China
| | - Cong Zhang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, PR China
| | - Jing Ge
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, PR China
- College of Animal Science and Technology, Yangzhou University, Yangzhou, PR China
| | - Xiao-Han Sun
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, PR China
| | - Jin-Yang Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, PR China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, PR China
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, PR China
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, PR China
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11
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Wojtowicz K, Nowicki M. The characterization of the sensitive ovarian cancer cell lines A2780 and W1 in response to ovarian CAFs. Biochem Biophys Res Commun 2023; 662:1-7. [PMID: 37088000 DOI: 10.1016/j.bbrc.2023.04.059] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 04/25/2023]
Abstract
PURPOSE The cancer-associated fibroblasts (CAFs) are one of the most abundant components of the tumor microenvironment (TME). CAFs have been implicated in tumor progression, extracellular matrix (ECM) remodeling, and treatment resistance. Drug resistance is the primary limiting factor in achieving cures for patients with cancer, particularly ovarian cancer. Therefore, inhibiting CAFs can be an effective strategies for cancer treatment. In this research, we studied whether CAFs have an influence on drug-sensitive ovarian cancer cells to become more resistant. We examined the influence of CAFs on genes and proteins expression changes in sensitive ovarian cancer cells. We prepared a 3D co-culture to investigate the role of CAFs on cancer cell morphology. METHODS Here, we performed a detailed analysis of drug-sensitive ovarian cancer cell lines (A2780 and W1) and the influence of ovarian CAFs on the A2780 and W1 cells morphology, genes and proteins expression. The 2D and 3D cultures, genes expression analysis (TaqMan qPCR), and proteins expression (Western blot analysis) were assessed in this study. RESULTS We observed upregulation of ABCC5, CYP2C8, CYP2C9, and DHFR mRNA in cell lines supplemented by CAFs medium. We showed fibronectin overexpression and COL3A1 downregulation after supplementation with CAFs. Co-culturing with CAFs prevented the formation of spheroids in 3D conditions. CONCLUSION We demonstrated that the process of drug resistance in ovarian cancer cells is launched by CAFs. CAFs not only simulate cancer cells to produce drug transporters and specific enzymes production, but also remodel the TME to increase drug resistance. We believe that cancer progression and migration is due to the CAFs po-tumorigenic activity.
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Affiliation(s)
- Karolina Wojtowicz
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland.
| | - Michał Nowicki
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
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12
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Chen C, Yang Y, Guo Y, He J, Chen Z, Qiu S, Zhang Y, Ding H, Pan J, Pan Y. CYP1B1 inhibits ferroptosis and induces anti-PD-1 resistance by degrading ACSL4 in colorectal cancer. Cell Death Dis 2023; 14:271. [PMID: 37059712 PMCID: PMC10104818 DOI: 10.1038/s41419-023-05803-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/16/2023]
Abstract
Immune checkpoint blockade (ICB) is a promising treatment strategy for colorectal cancer (CRC) patients. However, most CRC patients do not response well to ICB therapy. Increasing evidence indicates that ferroptosis plays a critical role in immunotherapy. ICB efficacy may be enhanced by inducing tumor ferroptosis. Cytochrome P450 1B1 (CYP1B1) is a metabolic enzyme that participates in arachidonic acid metabolism. However, the role of CYP1B1 in ferroptosis remains unclear. In this study, we demonstrated that CYP1B1 derived 20-HETE activated the protein kinase C pathway to increase FBXO10 expression, which in turn promoted the ubiquitination and degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), ultimately inducing tumor cells resistance to ferroptosis. Furthermore, inhibiting CYP1B1 sensitized tumor cells to anti-PD-1 antibody in a mouce model. In addition, CYP1B1 expression was negatively correlated with ACSL4 expression, and high expression indicates poor prognosis in CRC. Taken together, our work identified CYP1B1 as a potential biomarker for enhancing anti-PD-1 therapy in CRC.
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Affiliation(s)
- Congcong Chen
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yabing Yang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yanguan Guo
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jiashuai He
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zuyang Chen
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Shenghui Qiu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yiran Zhang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Hui Ding
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Jinghua Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Yunlong Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes. Institute of Life and Health Engineering, Jinan University, Guangzhou, China.
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13
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Chen X, Zhao T, Du J, Guan X, Yu H, Wang D, Wang C, Meng Q, Yao J, Sun H, Liu K, Wu J. Comparative Inhibitory Effects of Natural Biflavones from Ginkgo against Human CYP1B1 in Recombinant Enzymes and MCF-7 Cells. PLANTA MEDICA 2023; 89:397-407. [PMID: 36064115 DOI: 10.1055/a-1936-4807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme overexpressed in many tumors and associated with angiogenesis. Ginkgetin, isoginkgetin, sciadopitysin, and amentoflavone, the primary biflavones found in Ginkgo biloba, have excellent anti-inflammatory and anti-tumor effects. However, the effect of biflavones on CYP1B1 activities remains unknown. In this study, 7-ethoxyresorufin O-deethylation (EROD) was used to characterize the activities of CYP1 families. The impacts of four ginkgo biflavones on CYP1B1 activity and the cellular protein expression of CYP1B1 were systematically investigated. The results showed that amentoflavone with six hydroxyl substituents exhibited the most potent selective inhibitory effect on CYP1B1 activity with IC50 of 0.054 µM in four biflavones. Sciadopitysin, with three hydroxyl and three methoxy substituents, had the weakest inhibitory activity against CYP1B1. Ginkgetin and isoginkgetin, both with four hydroxyl and two methoxy substituents, showed similar inhibitory intensity towards CYP1B1 with IC50 values of 0.289 and 0.211 µM, respectively. Kinetic analysis showed that ginkgetin and amentoflavone inhibited CYP1B1 in a non-competitive mode, whereas sciadopitysin and isoginkgetin induced competitive or mixed types of inhibition. Notably, four ginkgo biflavones were also confirmed to suppress the protein expressions of CYP1B1 and AhR in MCF-7. Furthermore, molecular docking studies indicated more hydrogen bonds formed between amentoflavone and CYP1B1, which might explain the strongest inhibitory action towards CYP1B1. In summary, these findings suggested that biflavones remarkably inhibited both the activity and protein expression of CYP1B1 and the inhibitory activities enhanced with the increasing hydroxyl substitution, providing new insights into the anti-tumor potentials of biflavones.
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Affiliation(s)
- Xiaodong Chen
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Tingting Zhao
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Jie Du
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xintong Guan
- College of Basic Medicine, Dalian Medical University, Dalian, China
| | - Hong Yu
- Department of Pharmacy, Dalian Municipal Women and Children's Medical Center, Liaoning Dalian, China
| | - Dalong Wang
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Changyuan Wang
- College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
| | - Qiang Meng
- College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
| | - Jialin Yao
- College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
| | - Huijun Sun
- College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
| | - Kexin Liu
- College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
| | - Jingjing Wu
- College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
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14
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Singh RD, Avadhesh A, Sharma G, Dholariya S, Shah RB, Goyal B, Gupta SC. Potential of Cytochrome P450, a Family of Xenobiotic Metabolizing Enzymes, in Cancer Therapy. Antioxid Redox Signal 2023; 38:853-876. [PMID: 36242099 DOI: 10.1089/ars.2022.0116] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Significance: Targeted cancer therapy with minimal off-target consequences has shown promise for some cancer types. Although cytochrome P450 (CYP) consists of 18 families, CYP1-4 families play key role in metabolizing xenobiotics and cancer drugs. This eventually affects the process of carcinogenesis, treatment outcomes, and cancer drug resistance. Differential overexpression of CYPs in transformed cells, together with phenotypic alterations in tumors, presents a potential for therapeutic intervention. Recent Advances: Recent advances in molecular tools and information technology have helped utilize CYPs as cancer targets. The precise expression in various tumors, X-ray crystal structures, improved understanding of the structure-activity relationship, and new approaches in the development of prodrugs have supported the ongoing efforts to develop CYP-based drugs with a better therapeutic index. Critical Issues: Narrow therapeutic index, off-target effects, drug resistance, and tumor heterogeneity limit the benefits of CYP-based conventional cancer therapies. In this review, we address the CYP1-4 families as druggable targets in cancer. An emphasis is given to the CYP expression, function, and the possible mechanisms that drive expression and activity in normal and transformed tissues. The strategies that inhibit or activate CYPs for therapeutic benefits are also discussed. Future Directions: Efforts are needed to develop more selective tools that will help comprehend molecular and metabolic alterations in tumor tissues with biological end-points in relation to CYPs. This will eventually translate to developing more specific CYP inhibitors/inducers. Antioxid. Redox Signal. 38, 853-876.
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Affiliation(s)
- Ragini D Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot, India
| | - Avadhesh Avadhesh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Gaurav Sharma
- Department of Physiology, All India Institute of Medical Sciences, Rajkot, India
| | - Sagar Dholariya
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot, India
| | - Rima B Shah
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, India
| | - Bela Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, India
| | - Subash Chandra Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
- Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, India
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15
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Sharma H, Raju B, Narendra G, Kumar M, Verma H, Sharma B, Tung GK, Kumar Jain S, Brás NF, Silakari O. In silico guided designing of optimized benzochalcones derivatives as potent CYP1B1 inhibitors: An integrated in vitro and ONIOM study. J Mol Graph Model 2023; 119:108390. [PMID: 36502606 DOI: 10.1016/j.jmgm.2022.108390] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 12/03/2022]
Abstract
Cytochrome P4501B1 (CYP1B1) is reported to be overexpressed in various malignancies including ovarian, lung, lymph, and breast cancers. The overexpression of this enzyme is accountable for the biotransformation-based inactivation of some anti-cancer drugs i.e. Docetaxel, Paclitaxel, and Cisplatin. To circumvent solutions to this issue, the current study reports some optimized derivatives of benzochalcone as selective CYP1B1 inhibitors. The optimized derivatives were screened using some structure-based drug-designing approaches including molecular docking and molecular dynamics. The implemented approaches revealed that all the designed molecules demonstrated not only essential interactions with key amino acid residues but also maintained stability within the active site of CYP1B1. Furthermore, to validate the in-silico results and develop a SAR, the designed molecules were subsequently synthesized and tested for their ability to selectively inhibit CYP1B1 over CYP1A1 using well established EROD assay. This assay results suggested that compounds 1(c), 1(d), and 1(e) are eightfold more selective CYP1B1 inhibitors over CYP1A1 with IC50 values ranging from 0.06 to 0.09 μM respectively. Among these, compound 1(d) manifested potent inhibitory activity i.e. IC50 of 0.06 μM with 24 folds selectivity over 1A1. To have a better insight into the binding pattern of 1(d) within CYP1B1 and precisely compute binding affinity for 1(d)-CYP1B1 complex, one of the advanced QM/MM approaches i.e. ONIOM has been implemented. Where 1(d)-CYP1B1 complex conferred comparable binding affinity in terms of ΔG (kcal/mol) with that of ANF-CYP1B1 complex. This research could provide a suitable starting point for the development of more potent multi-functional compounds with CYP1B1 inhibitory activity.
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Affiliation(s)
- Himani Sharma
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India
| | - Baddipadige Raju
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India
| | - Gera Narendra
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India
| | - Manoj Kumar
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India
| | - Himanshu Verma
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India
| | - Bhavna Sharma
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India
| | - Gurleen Kaur Tung
- Center for Basic and Translational Research in Health Sciences, Guru Nanak Dev University, Amritsar, India
| | - Subheet Kumar Jain
- Center for Basic and Translational Research in Health Sciences, Guru Nanak Dev University, Amritsar, India
| | - Natércia F Brás
- LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007, Porto, Portugal
| | - Om Silakari
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India.
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16
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Yi L, Huang X, Yang M, Cai J, Jia J, Peng Z, Zhao Z, Yang F, Qiu D. A new class of CYP1B1 inhibitors derived from bentranil. Bioorg Med Chem Lett 2023; 80:129112. [PMID: 36565966 DOI: 10.1016/j.bmcl.2022.129112] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/15/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
Cytochrome P450 1B1 (CYP1B1) is highly expressed in a variety of tumors and implicated to drug resistance. More and more researches have suggested that CYP1B1 is a new target for cancer prevention and therapy. Various CYP1B1 inhibitors with a rigid polycyclic skeleton have been developed, such as flavonoids, trans-stilbenes, and quinazolines. To obtain a new class of CYP1B1 inhibitors, we designed and synthesized a series of bentranil analogues, moreover, IC50 determinations were performed for CYP1B1 inhibition of five of these compounds and found that 6o and 6q were the best inhibitors, with IC50 values in the nM range. The selectivity index (SI) of CYP1B1 over CYP1A1 and CYP1A2 was 30-fold higher than that of α-naphthoflavone (ANF). The molecular docking results showed that compound 6q fitted better into the CYP1B1 binding site than other compounds, which was consistent with our experimental results. On the basis of 6o and 6q, it is expected to develop CYP1B1 inhibitors with stronger affinity, higher selectivity and better solubility.
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Affiliation(s)
- Lan Yi
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Xinyue Huang
- College of Chemistry and Chemical Engineering, Chongqing University of Technology, Chongqing 400054, China
| | - Meixian Yang
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Jiajing Cai
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Jianhua Jia
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Zhiping Peng
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Zhenghuan Zhao
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Fengyuan Yang
- School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, Chongqing 400044, China.
| | - Dachuan Qiu
- Department of Radiation Medicine, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
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17
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Zhang J, Wang Y, Yuan B, Qin H, Wang Y, Yu H, Teng X, Yang Y, Zou J, Zhang M, Huang W, Wang Y. Identifying key transcription factors and immune infiltration in non-small-cell lung cancer using weighted correlation network and Cox regression analyses. Front Oncol 2023; 13:1112020. [PMID: 37197420 PMCID: PMC10183566 DOI: 10.3389/fonc.2023.1112020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/12/2023] [Indexed: 05/19/2023] Open
Abstract
Introduction Lung cancer is one of the most common cancers and a significant cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases. Therefore, it is crucial to identify effective diagnostic and therapeutic methods. In addition, transcription factors are essential for eukaryotic cells to regulate their gene expression, and aberrant expression transcription factors are an important step in the process of oncogenesis in NSCLC. Methods Differentially expressed transcription factors between NSCLC and normal tissues by analyzing mRNA profiling from The Cancer Genome Atlas (TCGA) database program were identified. Weighted correlation network analysis (WGCNA) and line plot of least absolute shrinkage and selection operator (LASSO) were performed to find prognosis-related transcription factors. The cellular functions of transcription factors were performed by 5-ethynyl-2'-deoxyuridine (EdU) assay, wound healing assay, cell invasion assay in lung cancer cells. Results We identified 725 differentially expressed transcription factors between NSCLC and normal tissues. Three highly related modules for survival were discovered, and transcription factors highly associated with survival were obtained by using WGCNA. Then line plot of LASSO was applied to screen transcription factors related to prognosis and build a prognostic model. Consequently, SETDB2, SNAI3, SCML4, and ZNF540 were identified as prognosis-related transcription factors and validated in multiple databases. The low expression of these hub genes in NSCLC was associated with poor prognosis. The deletions of both SETDB2 and SNAI3 were found to promote proliferation, invasion, and stemness in lung cancer cells. Furthermore, there were significant differences in the proportions of 22 immune cells between the high- and low-score groups. Discussion Therefore, our study identified the transcription factors involved in regulating NSCLC, and we constructed a panel for the prediction of prognosis and immune infiltration to inform the clinical application of transcription factor analysis in the prevention and treatment of NSCLC.
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Affiliation(s)
- Jingyao Zhang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yinuo Wang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Baowen Yuan
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hao Qin
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong Wang
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hefen Yu
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xu Teng
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yunkai Yang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Zou
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Zhang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Huang
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Wei Huang, ; Yan Wang,
| | - Yan Wang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Wei Huang, ; Yan Wang,
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18
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Yuan B, Liu G, Dai Z, Wang L, Lin B, Zhang J. CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers (Basel) 2022; 14:cancers14225641. [PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1) is a critical metabolic enzyme of melatonin. Although melatonin has been identified to exhibit tumor suppressing activity, the role and mechanism of the clinical and immunological characteristics of CYP1B1 in cancer remain unclear. METHODS In this study, RNA expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) across 33 solid tumors. The expression, survival, immune subtype, molecular subtype, tumor mutation burden (TMB), microsatellite instability (MSI), biological pathways, and function in vitro and vivo were evaluated. The predictive value of CYP1B1 in immune cohorts was further explored. RESULTS We found the dysregulated expression of CYP1B1 was associated with the clinical stage and tumor grade. Immunological correlation analysis showed CYP1B1 was positively correlated with the infiltration of lymphocyte, immunomodulator, chemokine, receptor, and cancer-associated fibroblasts (CAFs) in most cancer. Meanwhile, CYP1B1 was involved in immune subtype and molecular subtype, and was connected with TMB, MSI, neoantigen, the activation of multiple melatonergic and immune-related pathways, and therapeutic resistance. CONCLUSIONS Together, this study comprehensively revealed the role and mechanism of CYP1B1 and explored the significant association between CYP1B1 expression and immune activity. These findings provide a promising predictor and molecular target for clinical immune treatment.
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Affiliation(s)
- Benchao Yuan
- Department of Oncology and Hematology, The Sixth People’s Hospital of Huizhou City, Huiyang Hospital Affiliated to Southern Medical University, Huizhou 516003, China
| | - Guihong Liu
- Department of Radiation Oncology, Dongguan Tungwah Hospital, Dongguan 523120, China
| | - Zili Dai
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou 510095, China
| | - Li Wang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou 510095, China
| | - Baisheng Lin
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou 510095, China
| | - Jian Zhang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou 510095, China
- Guangzhou Medical University, Guangzhou 511495, China
- Correspondence: ; Tel./Fax: +86-020-66673666
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19
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Karthika C, Najda A, Klepacka J, Zehravi M, Akter R, Akhtar MF, Saleem A, Al-Shaeri M, Mondal B, Ashraf GM, Tagde P, Ramproshad S, Ahmad Z, Khan FS, Rahman MH. Involvement of Resveratrol against Brain Cancer: A Combination Strategy with a Pharmaceutical Approach. Molecules 2022; 27:4663. [PMID: 35889532 PMCID: PMC9320031 DOI: 10.3390/molecules27144663] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/15/2022] [Accepted: 07/18/2022] [Indexed: 11/25/2022] Open
Abstract
A brain tumor (BT) is a condition in which there is growth or uncontrolled development of the brain cells, which usually goes unrecognized or is diagnosed at the later stages. Since the mechanism behind BT is not clear, and the various physiological conditions are difficult to diagnose, the success rate of BT is not very high. This is the central issue faced during drug development and clinical trials with almost all types of neurodegenerative disorders. In the first part of this review, we focus on the concept of brain tumors, their barriers, and the types of delivery possible to target the brain cells. Although various treatment methods are available, they all have side effects or toxic effects. Hence, in the second part, a correlation was made between the use of resveratrol, a potent antioxidant, and its advantages for brain diseases. The relationship between brain disease and the blood-brain barrier, multi-drug resistance, and the use of nanomedicine for treating brain disorders is also mentioned. In short, a hypothetical concept is given with a background investigation into the use of combination therapy with resveratrol as an active ingredient, the possible drug delivery, and its formulation-based approach.
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Affiliation(s)
- Chenmala Karthika
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty 643001, India;
| | - Agnieszka Najda
- Department of Vegetable and Herbal Crops, University of Life Science in Lublin, Doświadczalna Street 51A, 20280 Lublin, Poland
| | - Joanna Klepacka
- Department of Commodity Science and Food Analysis, Faculty of Food Science, University of Warmia and Mazury in Olsztyn, Oczapowskiego 2, 10719 Olsztyn, Poland;
| | - Mehrukh Zehravi
- Department of Clinical Pharmacy Girls Section, Prince Sattam Bin Abdul Aziz University, Alkharj 11942, Saudi Arabia;
| | - Rokeya Akter
- Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea;
| | - Muhammad Furqan Akhtar
- Riphah Institute of Pharmaceutical Sciences, Lahore Campus, Riphah International University, Lahore 54950, Pakistan;
| | - Ammara Saleem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad 38000, Pakistan;
| | - Majed Al-Shaeri
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Banani Mondal
- Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj 1400, Bangladesh; (B.M.); (S.R.)
| | - Ghulam Md. Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Priti Tagde
- Amity Institute of Pharmacy, Amity University, Noida 201301, India;
| | - Sarker Ramproshad
- Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj 1400, Bangladesh; (B.M.); (S.R.)
| | - Zubair Ahmad
- Unit of Bee Research and Honey Production, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia;
- Biology Department, College of Arts and Sciences, Dehran Al-Junub, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia;
| | - Farhat S. Khan
- Biology Department, College of Arts and Sciences, Dehran Al-Junub, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia;
| | - Md. Habibur Rahman
- Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea;
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Imran SJ, Vagaska B, Kriska J, Anderova M, Bortolozzi M, Gerosa G, Ferretti P, Vrzal R. Aryl Hydrocarbon Receptor (AhR)-Mediated Signaling in iPSC-Derived Human Motor Neurons. Pharmaceuticals (Basel) 2022; 15:ph15070828. [PMID: 35890127 PMCID: PMC9321538 DOI: 10.3390/ph15070828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/26/2022] [Accepted: 07/01/2022] [Indexed: 12/04/2022] Open
Abstract
Exposure to environmental pollutants and endogenous metabolites that induce aryl hydrocarbon receptor (AhR) expression has been suggested to affect cognitive development and, particularly in boys, also motor function. As current knowledge is based on epidemiological and animal studies, in vitro models are needed to better understand the effects of these compounds in the human nervous system at the molecular level. Here, we investigated expression of AhR pathway components and how they are regulated by AhR ligands in human motor neurons. Motor neurons generated from human induced pluripotent stem cells (hiPSCs) were characterized at the molecular level and by electrophysiology. mRNA levels of AhR target genes, CYP1A1 and CYP1B1 (cytochromes P450 1A1/1B1), and AhR signaling components were monitored in hiPSCs and in differentiated neurons following treatment with AhR ligands, 2,3,7,8,-tetrachlodibenzo-p-dioxin (TCDD), L-kynurenine (L-Kyn), and kynurenic acid (KA), by RT-qPCR. Changes in AhR cellular localization and CYP1A1 activity in neurons treated with AhR ligands were also assessed. The neurons we generated express motor neuron-specific markers and are functional. Transcript levels of CYP1B1, AhR nuclear translocators (ARNT1 and ARNT2) and the AhR repressor (AhRR) change with neuronal differentiation, being significantly higher in neurons than hiPSCs. In contrast, CYP1A1 and AhR transcript levels are slightly lower in neurons than in hiPSCs. The response to TCDD treatment differs in hiPSCs and neurons, with only the latter showing significant CYP1A1 up-regulation. In contrast, TCDD slightly up-regulates CYP1B1 mRNA in hiPSCs, but downregulates it in neurons. Comparison of the effects of different AhR ligands on AhR and some of its target genes in neurons shows that L-Kyn and KA, but not TCDD, regulate AhR expression and differently affect CYP1A1 and CYP1B1 expression. Finally, although TCDD does not significantly affect AhR transcript levels, it induces AhR protein translocation to the nucleus and increases CYP1A1 activity. This is in contrast to L-Kyn and KA, which either do not affect or reduce, respectively, CYP1A1 activity. Expression of components of the AhR signaling pathway are regulated with neuronal differentiation and are differently affected by TCDD, suggesting that pluripotent stem cells might be less sensitive to this toxin than neurons. Crucially, AhR signaling is affected differently by TCDD and other AhR ligands in human motor neurons, suggesting that they can provide a valuable tool for assessing the impact of environmental pollutants.
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Affiliation(s)
- Saima Jalil Imran
- Department of Cell Biology and Genetics, Faculty of Science, 77147 Olomouc, Czech Republic
- Stem Cells and Regenerative Medicine Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; (B.V.); (P.F.)
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, 35128 Padua, Italy;
- Correspondence: (S.J.I.); (R.V.); Tel.: +39-498212410 (S.J.I.); +420-58-5634904 (R.V.)
| | - Barbora Vagaska
- Stem Cells and Regenerative Medicine Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; (B.V.); (P.F.)
| | - Jan Kriska
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.K.); (M.A.)
| | - Miroslava Anderova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine, Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.K.); (M.A.)
- Second Faculty of Medicine, Charles University, 15006 Prague, Czech Republic
| | - Mario Bortolozzi
- Department of Physics and Astronomy “G. Galilei”, University of Padua, 35131 Padua, Italy;
- Veneto Institute of Molecular Medicine (VIMM), 35129 Padua, Italy
| | - Gino Gerosa
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, 35128 Padua, Italy;
| | - Patrizia Ferretti
- Stem Cells and Regenerative Medicine Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; (B.V.); (P.F.)
| | - Radim Vrzal
- Department of Cell Biology and Genetics, Faculty of Science, 77147 Olomouc, Czech Republic
- Correspondence: (S.J.I.); (R.V.); Tel.: +39-498212410 (S.J.I.); +420-58-5634904 (R.V.)
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21
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Histomorphological and ultrastructural cadmium-induced kidney injuries and precancerous lesions in rats and screening for biomarkers. Biosci Rep 2022; 42:231305. [PMID: 35678542 PMCID: PMC9202506 DOI: 10.1042/bsr20212516] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 04/20/2022] [Accepted: 05/13/2022] [Indexed: 11/20/2022] Open
Abstract
Long-term exposure to cadmium (Cd) can severely damage the kidney, where orally absorbed Cd accumulates. However, the molecular mechanisms of Cd-induced kidney damage, especially the early biomarkers of Cd-induced renal carcinogenesis, are unclear. In the present study, we established a rat kidney injury model by intragastric administration of Cd to evaluate the morphological and biochemical aspects of kidney injury. We randomly divided Sprague-Dawley rats into control, low Cd (3 mg/kg), and high Cd (6 mg/kg) groups and measured biochemical indices associated with renal toxicity after 2, 4, and 8 weeks of treatment. The Cd-exposed mice had significantly higher Cd concentrations in blood and renal tissues as well as blood urea nitrogen (BUN), β2-microglobulin (β2-MG), urinary protein excretion, and tumor necrosis factor-α (TNF-α) levels. Furthermore, histopathological and transmission electron microscopy (TEM) observations revealed structural disruption of renal tubules and glomeruli after 8 weeks of exposure to the high Cd regimen. Besides, microarray technology experiments showed that Cd increased the expression of genes related to the chemical carcinogenesis pathway in kidney tissue. Finally, combining the protein–protein interaction (PPI) network of the Cd carcinogenesis pathway genes with the microarray and Comparative Toxicogenomics Database (CTD) results revealed two overlapping genes, CYP1B1 and UGT2B. Therefore, the combined molecular and bioinformatics experiments’ results suggest that CYP1B1 and UGT2B are biomarkers of Cd-induced kidney injury with precancerous lesions.
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22
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Chen Q, Zhang H, Yang Y, Zhang S, Wang J, Zhang D, Yu H. Metformin Attenuates UVA-Induced Skin Photoaging by Suppressing Mitophagy and the PI3K/AKT/mTOR Pathway. Int J Mol Sci 2022; 23:ijms23136960. [PMID: 35805987 PMCID: PMC9266365 DOI: 10.3390/ijms23136960] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/19/2022] [Accepted: 06/21/2022] [Indexed: 02/01/2023] Open
Abstract
Ultraviolet (UV) radiation is a major cause of photoaging that can induce DNA damage, oxidative stress, and cellular aging. Metformin (MF) can repair DNA damage, scavenge reactive oxygen species (ROS), and protect cells. However, the mechanism by which MF inhibits cell senescence in chronic skin damage induced by UVA is unclear. In this study, human foreskin fibroblasts (HFFs) treated with UVA were used as an in vitro model and UVA-induced skin photoaging in Kunming mice was used as an in vivo model to investigate the potential skin protective mechanism of MF. The results revealed that MF treatment attenuated UVA-induced cell viability, skin aging, and activation of the PI3K/AKT/mTOR signaling pathway. Furthermore, MF treatment alleviated the mitochondrial oxidative stress and decreased mitophagy. Knockdown of Parkin by siRNA increased the clearance of MF in senescent cells. The treatment of Kunming mice with MF at a dose of 10 mg/kg/day significantly reduced UVA-induced skin roughness, epidermal thinning, collagen degradation, and skin aging. In conclusion, our experimental results suggest that MF exerts anti-photoaging effects by inhibiting mitophagy and the PI3K/AKT/mTOR signaling pathway. Therefore, our study improves the current understanding of the protective mechanism of MF against photoaging.
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Affiliation(s)
- Qiuyan Chen
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (Q.C.); (H.Z.); (Y.Y.); (S.Z.); (D.Z.)
| | - Haiying Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (Q.C.); (H.Z.); (Y.Y.); (S.Z.); (D.Z.)
| | - Yimeng Yang
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (Q.C.); (H.Z.); (Y.Y.); (S.Z.); (D.Z.)
| | - Shuming Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (Q.C.); (H.Z.); (Y.Y.); (S.Z.); (D.Z.)
| | - Jing Wang
- Department of Pharmacology, School of Pharmacy, Jilin University, Changchun 130021, China;
| | - Dawei Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (Q.C.); (H.Z.); (Y.Y.); (S.Z.); (D.Z.)
| | - Huimei Yu
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (Q.C.); (H.Z.); (Y.Y.); (S.Z.); (D.Z.)
- Correspondence: ; Tel.: +86-0-431-8561-9485
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23
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Zhao X, Huang X, Peng W, Han M, Zhang X, Zhu K, Shao B. Chlorine disinfection byproduct of diazepam affects nervous system function and possesses gender-related difference in zebrafish. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 238:113568. [PMID: 35490575 DOI: 10.1016/j.ecoenv.2022.113568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/19/2022] [Accepted: 04/25/2022] [Indexed: 06/14/2023]
Abstract
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.
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Affiliation(s)
- Xiaole Zhao
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China; Institute of Food Science and Engineering, Wuhan Polytechnic University, Wuhan 430023, People's Republic of China
| | - Xiaoyong Huang
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, People's Republic of China
| | - Wenjing Peng
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China
| | - Muke Han
- Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, People's Republic of China
| | - Xin Zhang
- Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, People's Republic of China
| | - Kui Zhu
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China.
| | - Bing Shao
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, People's Republic of China.
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24
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Torres-Zárate C, Vences-Mejía A, Espinosa-Aguirre JJ, Díaz-Díaz E, Palacios-Acosta JM, Cárdenas-Cardós R, Hernández-Arrazola D, Shalkow-Klincovstein J, Jurado RR, Santes-Palacios R, Molina-Ortiz D. Expression of Cytochrome P450 Enzymes in Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas: Possible Role in Carcinogenesis and Treatment Response. Int J Toxicol 2022; 41:234-242. [PMID: 35437033 DOI: 10.1177/10915818221085909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The 5-year relative survival rate estimate of treated patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) is ∼50% since they generally present with tumor progression, relapse, metastasis, and/or chemoresistance. The expression of cytochrome P450 (CYP) enzymes in malignancies can affect the pharmacology of drugs commonly used in chemotherapy or confer susceptibility to development of chemical carcinogenesis; in addition, their specific tumor expression can be used as a therapeutic target. Using qPCR and Western blot assays, the expression of CYP1B1, CYP2E1, CYP3A4, and CYP3A5 were analyzed in a cohort of tumor tissue paired with non-malignant adjacent tissue of patients with NRSTS. The mRNA and protein expression of CYP1B1, CYP2E1, and CYP3A4 were significantly increased in tumor tissue. We propose that the expression of these isoforms is related to carcinogenesis and chemoresistance frequently observed in these neoplasms.
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Affiliation(s)
- Carmen Torres-Zárate
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - Araceli Vences-Mejía
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
| | | | - Eduardo Díaz-Díaz
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
| | | | | | | | | | - Rodolfo R Jurado
- Departamento de Anatomía Patológica, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - Rebeca Santes-Palacios
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - Dora Molina-Ortiz
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
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Lin Q, Cao J, Du X, Yang K, Yang X, Liang Z, Shi J, Zhang J. CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation. Cell Commun Signal 2022; 20:31. [PMID: 35292057 PMCID: PMC8922936 DOI: 10.1186/s12964-021-00807-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 11/22/2021] [Indexed: 11/10/2022] Open
Abstract
Background Resistance to androgen deprivation therapy remains a major challenge for the clinical treatment of patients with castration-resistant prostate cancer (CRPC). CYP1B1, a critical enzyme that catalyzes the conversion of estradiol to 4-Hydroxy-17β-estradiol (4-OHE2), has been reported to promote the development and progression of hormone-related cancer, but its role in CRPC is unclear. Methods To explore the underlying mechanism which CYP1B1 promotes the prostate cancer stem cells (PCSCs) characteristics, bioinformatics analyses of human clinical prostate cancer (PCa) datasets were performed. CYP1B1, IL6, and estrogen receptor-α (ERα) expression levels were evaluated in PCa and CRPC tissues via immunohistochemistry. The high-performance liquid chromatography-mass spectrometry assay was carried out to examine intracellular 4-OHE2 levels. Serum-free suspension culture and flow cytometry assays were performed to evaluate PCSCs. Chromatin immunoprecipitation was used to validate that 4-OHE2 recruited ERα to the IL6 promoter. Results CYP1B1 expression was significantly increased in CRPC tissues and androgen-independent PCa cell lines. CYP1B1+ PCa cells were significantly enriched in bicalutamide-treated LNCaP cells, and CYP1B1 knockdown reduced the cell viability under bicalutamide treatment. In addition, CYP1B1 knockdown decreased the intracellular 4-OHE2 concentration, accompanied by reduced PCSC characteristics. In PCa cells, 4-OHE2 stimulated ERα transcriptional activity and upregulated the expression of IL6 and downstream genes of the IL6-STAT3 signaling. 4-OHE2 increased cell viability under bicalutamide treatment and promoted PCSC characteristics, while IL6 neutralizing antibody reversed these effects. Mechanistically, siERα and the ER antagonist ICI182780 significantly attenuated 4-OHE2-induced IL6 expression, and 4-OHE2 promoted the binding of ERα to the estrogen response element of the IL6 promoter. Conclusions Our findings indicate that CYP1B1-catalyzed 4-OHE2 enhanced PCSC characteristics and attenuated bicalutamide sensitivity by ERα-mediated the IL6-STAT3 pathway activation. Our study further emphasizes the role of CYP1B1 in castration resistance and illustrates a novel mechanism of CRPC development. Graphical Abstract ![]()
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