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Wei T, Fu G, Zhao J, Cao F, Guo D. Acyl-CoA dehydrogenase long chain acts as a tumor-suppressive factor in lung adenocarcinoma progression. Cell Adh Migr 2025; 19:2495676. [PMID: 40262559 PMCID: PMC12026206 DOI: 10.1080/19336918.2025.2495676] [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: 06/26/2024] [Revised: 09/12/2024] [Accepted: 04/05/2025] [Indexed: 04/24/2025] Open
Abstract
This study investigated the role of long-chain acyl-CoA dehydrogenase (ACADL) in lung adenocarcinoma (LUAD). ACADL was significantly downregulated in human LUAD tissues compared to normal lung tissues. In vitro, ectopic expression of ACADL in murine LLC cells decreased cell viability, migration, and invasion, while ACADL knockdown exhibited the opposite effect. In vivo, ACADL overexpression impeded tumor growth and metastasis. Mechanistically, ACADL hindered tumor progression by inducing cell cycle arrest, promoting apoptosis, and suppressing the epithelial-mesenchymal transition (EMT) process. These findings suggest ACADL acts as a tumor suppressor in LUAD progression.
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Affiliation(s)
- Tingju Wei
- Department of Cardiac Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guowei Fu
- Department of Cardiac Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junjie Zhao
- Department of Cardiac Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fengan Cao
- Department of Respiratory Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Guo
- Henan Key Laboratory for Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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2
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Abuzahrah S, Bakhsh T, Mekky RH, Elbehairi SEI, Juaid N. Exploring the Metabolic Profiling and Anticancer Activities of Red Sea Sponges Echinodictyum asperum and Callyspongia siphonella against Human Breast Cancer Cells: A Comparative Study. ACS OMEGA 2025; 10:9402-9425. [PMID: 40092807 PMCID: PMC11904698 DOI: 10.1021/acsomega.4c10202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 02/05/2025] [Accepted: 02/11/2025] [Indexed: 03/19/2025]
Abstract
Marine sponges are noteworthy sources of bioactive secondary metabolites that demonstrate fundamental functions in defense mechanisms and ecological interactions. This study focused on the extraction and characterization of metabolites from two sponge species, Echinodictyum asperum and Callyspongia siphonella, obtained from the Red Sea coast of Saudi Arabia. Methanol extraction generated EAE and CSE extracts, which were subjected to metabolic profiling, illuminating 44 identified metabolites involving fatty acids, sterols, terpenoids, long-chain amides, and alkaloids. The cytotoxic effects of both were assessed versus MDA-MB-231 and MCF-7 breast cancer cell lines, utilizing the sulforhodamine B (SRB) assay, with IC50 values of about 2.7 μg/mL for CSE and 0.5 μg/mL for EAE on MCF-7 cells and 8.7 μg/mL for EAE and 45.3 μg/mL for CSE on MDA-MB-231 cells. Flow cytometry analysis indicated that both extracts induced apoptosis and necrosis across cell lines. Particularly, EAE induced the G2 phase arrest in MCF-7 cells, while CSE elevated the S phase population in both cell lines. As well, CSE boosted autophagy especially in MDA-MB-231 cells. Comparative analyses with the existing literature underscore the therapeutic potential of these sponge-derived metabolites in cancer medication. Molecular docking studies demonstrated robust binding affinities between selected metabolites and key targets involving MCL-1, BCL-2, and ERα. In conclusion, this research emphasizes the significant cytotoxic features of EAE and CSE extracts, proposing their potential purposes in cancer treatment via distinct mechanisms of action.
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Affiliation(s)
- Samah
S. Abuzahrah
- Department
of Biological Sciences, College of Science, University of Jeddah, P.O. Box 21959, Jeddah 21959, Saudi Arabia
| | - Tahani Bakhsh
- Department
of Biological Sciences, College of Science, University of Jeddah, P.O. Box 21959, Jeddah 21959, Saudi Arabia
| | - Reham Hassan Mekky
- Department
of Pharmacognosy, Faculty of Pharmacy, Egyptian
Russian University, Cairo-Suez Road, Badr City, Cairo 11829, Egypt
| | - Serag Eldin I. Elbehairi
- Faculty
of Science, Biology Department, King Khalid
University, Abha 9004, Saudi Arabia
- Tissue
Culture and Cancer Biology Research Laboratory, King Khalid University, Abha 9004, Saudi Arabia
| | - Nouf Juaid
- Basic
Medical Science Department, Inaya Medical
College, Riyadh 12211, Saudi Arabia
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3
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Pan Y, Fan Z, Yu S, Xia L, Li J. ROS-responsive supramolecular antimicrobial peptides-based nanoprodrugs for cervical cancer therapy. Colloids Surf B Biointerfaces 2025; 247:114411. [PMID: 39613501 DOI: 10.1016/j.colsurfb.2024.114411] [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: 10/17/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 12/01/2024]
Abstract
Although antimicrobial peptides (AMPs) as a promising natural drugs can efficiently inhibit cervical cancer, poor bioavailability, low tumor selectivity, and non-selective toxicity still hinder its further application in vivo. In order to effectively address these challenges, we have developed a reactive oxygen species (ROS)-responsive targeting nanoprodrug designed for selective therapy of cervical cancer. Such nanoprodrugs (CEC-OxbCD) are fabricated by the supramolecular self-assembly of the modified β-cyclodextrin (β-CD) and AMPs. Antimicrobial peptide, CecropinXJ (CEC), is a cationic antibacterial peptide isolated from 3rd instar larvae of Bombyx mori from Xinjiang, China. OxbCD is an oxidation-responsive β-cyclodextrin material. CEC-OxbCD were synthesized using the nanoprecipitation/self-assembly method. Subsequently, the particle size distribution, morphology, drug loading efficiency, and release behaviour of CEC-OxbCD were characterised. In vitro and in vivo anti-cancer activities were also evaluated. Nanoprodrugs can be effectively disassembled under stimuli of the tumor- endogenous ROS, resulting in a rapid and on-demand release of antimicrobial peptides (AMPs) with a release rate of 90 %. Furthermore, both in vitro and in vivo experimental results demonstrate that our nanoprodrugs exhibit remarkable therapeutic efficacy against cervical cancer. This work not only provides an effective and promising therapeutic strategy for cervical cancer, but also explores a novel application for AMPs.
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Affiliation(s)
- Yanzhu Pan
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China
| | - Zhongxiong Fan
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China
| | - Shaoqi Yu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China
| | - Lijie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China.
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China.
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Gurbilek M, Deniz CD, Eroglu Gunes C, Kurar E, Reisli I, Kursunel MA, Topcu C, Koc M. Anticancer activity of thymoquinone in non-small cell lung cancer and possible involvement of PPAR- γ pathway. Int J Radiat Biol 2025; 101:370-381. [PMID: 39946226 DOI: 10.1080/09553002.2025.2449953] [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: 07/29/2023] [Revised: 09/12/2024] [Accepted: 12/30/2024] [Indexed: 03/29/2025]
Abstract
PURPOSE Thymoquinone (TQ) is an ingredient of Nigella sativa and Cisplatin (CDDP) is the most active chemotherapeutic agent in lung cancer. The objective of this study was to assess the anticancer effects of TQ in non-small cell lung cancer (NSCLC) cells, and its effect on the peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway. METHODS Annexin-V FITC assay was used in the NCI-H460 cell line for apoptosis. The mRNA expression of PPAR-γ, P53, BCL-2, Retinoblastoma (Rb), Cyclin-D1, RELA, Tumor necrosis Factor alpha and in a dose-dependent manner TQ activated caspases 9, 8, 7, and 3 were examined using quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS PPAR-γ protein levels elevated in all treatment groups, especially in the CDDP + TQ group as observed in mRNA results. In the CDDP + TQ + IR group, the reduction of NF-κB pathway, which provides survival and growth signaling, confirms the potential of this treatment in lung cancer treatment approach similar to p53, Rb, and PPAR-γ results. When the effect of treatment on the viability of NSCLC cells was assessed with flow cytometry analyzes, TQ alone supported death compared to control, cell viability also decreased in the CDDP or IR groups to which TQ was added. CONCLUSION As a result, combined therapy of TQ, CDDP, and IR have been shown to increase apoptosis by sensitizing NSCLC cells to IR. These in vitro results are the basis because they demonstrate that it may be useful to include TQ in combined NSCLC cell treatments to reduce tumor progression.
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Affiliation(s)
- Mehmet Gurbilek
- Department of Medical Biochemistry, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkiye
| | - Cigdem D Deniz
- Department of Medical Biochemistry, Health Sciences University, Konya City Hospital, Konya, Turkey
| | - Canan Eroglu Gunes
- Department of Medical Biology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Ercan Kurar
- Department of Medical Biology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Ismail Reisli
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Muammer A Kursunel
- Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Cemile Topcu
- Department of Medical Biochemistry, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkiye
| | - Mehmet Koc
- Department of Radiation Oncology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
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Wang Y, Zhang R, Huang X, He X, Geng S, Pan S, Guo W, Liu X, Dang Y, Qu J, Ma H, Zhao X. CD39 inhibitor (POM-1) enhances radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells by promoting apoptosis through the Bax/Bcl-2/Caspase 9/Caspase 3 pathway. Int Immunopharmacol 2024; 142:113242. [PMID: 39321701 DOI: 10.1016/j.intimp.2024.113242] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/27/2024]
Abstract
CD39 inhibitor (sodium polyoxotungstate, POM-1) has been reported to have antitumor effects. However, the synergistic effect of POM-1 with radiotherapy requires further elucidation. This study aimed to investigate the role and the molecular mechanism of POM-1 in esophageal squamous cell carcinoma (ESCC) radiosensitization. Firstly, the expression of CD39 in ESCC cells and normal esophageal epithelial cells were detected. Then radioresistant ESCC cells (Eca109R and KYSE150R) were constructed and CD39 expression was analyzed. Furthermore, the effect of POM-1 on radiosensitivity for parent cells and radioresistant cells were observed. Then, we analyzed the effect of POM-1 and CD39 siRNA on radiotherapy-induced apoptosis and determined whether POM-1 modulated the radioresistance of ESCC cells depending on the apoptotic signaling pathway. Finally, we validated the synergistic effect of POM-1 combined with radiotherapy in vivo. Our results showed that CD39 was highly expressed in ESCC cells and radioresistant ESCC cells (p < 0.05). POM-1 reduced radioresistance and proliferation of parent cells and radioresistant cells (p < 0.05). Further mechanistic exploration showed that inhibition of CD39 promoted radiation-induced apoptosis (p < 0.05). Bax knockdown reversed the effect of POM-1 on ESCC cells (p < 0.01). Animal experiments also validated that radiotherapy combined with POM-1 enhanced tumor inhibition in vivo (p < 0.05). These results suggested that POM-1 had synergistic effect with radiotherapy by enhancing cell apoptosis through Bax/Bcl-2 signal pathway in ESCC. The combination of POM-1 and radiotherapy is expected to enhance the anti-tumor effect in ESCC.
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Affiliation(s)
- Yuchen Wang
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ruijuan Zhang
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xinran Huang
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xinyu He
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shangyi Geng
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shupei Pan
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wei Guo
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaoxiao Liu
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yongze Dang
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jingkun Qu
- The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Hongbing Ma
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Xixi Zhao
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Cai Y, Chen Z, Chen E, Zhang D, Wei T, Sun M, Lian Y. Succinic Acid Ameliorates Concanavalin A-Induced Hepatitis by Altering the Inflammatory Microenvironment and Expression of BCL-2 Family Proteins. Inflammation 2024; 47:2000-2012. [PMID: 38613638 DOI: 10.1007/s10753-024-02021-6] [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: 02/03/2024] [Revised: 03/25/2024] [Accepted: 04/03/2024] [Indexed: 04/15/2024]
Abstract
Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease that currently lacks feasible drug treatment methods. Our study aimed to evaluate the protective effect of succinic acid against AIH and provide a reliable method for the clinical treatment of AIH. We performed an in vivo study of the effects of succinic acid on concanavalin A (ConA)-induced liver injury in mice. We examined liver transaminase levels, performed hematoxylin and eosin (HE) staining, and observed apoptotic phenotypes in mice. We performed flow cytometry to detect changes in the number of neutrophils and monocytes, and used liposomes to eliminate the liver Kupffer cells and evaluate their role. We performed bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting to detect mitochondrial apoptosis-induced changes in proteins from the B-cell lymphoma 2(Bcl-2) family. Succinic acid ameliorated ConA-induced AIH in a concentration-dependent manner, as reflected in the survival curve. HE and TUNEL staining and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed decreased alanine transaminase and aspartate aminotransferase levels, and reduced liver inflammation and apoptosis. RT-qPCR and enzyme-linked immunosorbent assay revealed that succinic acid significantly reduced liver pro-inflammatory cytokine levels. Flow cytometry revealed significantly decreased levels of liver neutrophils. Moreover, the protective effect of succinic acid disappeared after the Kupffer cells were eliminated, confirming their important role in the effect. Bioinformatics analysis, RT-qPCR, and western blotting showed that succinic acid-induced changes in proteins from the Bcl-2 family involved mitochondrial apoptosis, indicating the molecular mechanism underlying the protective effect of succinic acid. Succinic acid ameliorated ConA-induced liver injury by regulating immune balance, inhibiting pro-inflammatory factors, and promoting anti-apoptotic proteins in the liver. This study provides novel insights into the biological functions and therapeutic potential of succinic acid in the treatment of autoimmune liver injury.
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Affiliation(s)
- Ying Cai
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Zhiyuan Chen
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Ermei Chen
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Dongdong Zhang
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Tao Wei
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Mingyang Sun
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Yifan Lian
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China.
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China.
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Qiao H, Li H. PLP2 Could Be a Prognostic Biomarker and Potential Treatment Target in Glioblastoma Multiforme. Pharmgenomics Pers Med 2023; 16:991-1009. [PMID: 37964785 PMCID: PMC10642424 DOI: 10.2147/pgpm.s425251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 10/16/2023] [Indexed: 11/16/2023] Open
Abstract
Objective This study aimed to discern the association between PLP2 expression, its biological significance, and the extent of immune infiltration in human GBM. Methods Utilizing the GEPIA2 and TCGA databases, we contrasted the expression levels of PLP2 in GBM against normal tissue. We utilized GEPIA2 and LinkedOmics for survival analysis, recognized genes co-expressed with PLP2 via cBioPortal and GEPIA2, and implemented GO and KEGG analyses. The STRING database facilitated the construction of protein-protein interaction networks. We evaluated the relationship of PLP2 with tumor immune infiltrates using ssGSEA and the TIMER 2.0 database. An IHC assay assessed PLP2 and PDL-1 expression in GBM tissue, and the Drugbank database aided in identifying potential PLP2-targeting compounds. Molecular docking was accomplished using Autodock Vina 1.2.2. Results PLP2 expression was markedly higher in GBM tissues in comparison to normal tissues. High PLP2 expression correlated with a decrease in overall survival across two databases. Functional analyses highlighted a focus of PLP2 functions within leukocyte. Discrepancies in PLP2 expression were evident in immune infiltration, impacting CD4+ T cells, neutrophils, myeloid dendritic cells, and macrophages. There was a concomitant increase in PLP2 and PD-L1 expression in GBM tissues, revealing a link between the two. Molecular docking with ethosuximide and praziquantel yielded scores of -7.441 and -4.295 kcal/mol, correspondingly. Conclusion PLP2's upregulation in GBM may adversely influence the lifespan of GBM patients. The involvement of PLP2 in pathways linked to leukocyte function is suggested. The positive correlation between PLP2 and PD-L1 could provide insights into PLP2's role in glioma modulation. Our research hints at PLP2's potential as a therapeutic target for GBM, with ethosuximide and praziquantel emerging as potential treatment candidates, especially emphasizing the potential of these compounds in GBM treatment targeting PLP2.
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Affiliation(s)
- Hao Qiao
- The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
| | - Huanting Li
- The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
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Lei L, Qiao X, Siqi Y, Ke Y. Effects of Propofol Combined with Sufentanil Target-Controlled Intravenous Anesthesia on Expression of Bax, Bcl-2, and Caspase-3 Genes in Spontaneous Hypertensive Rats with Cerebral Hemorrhage: a Prospective Case-Controlled Study. Appl Biochem Biotechnol 2023; 195:6068-6080. [PMID: 36807871 DOI: 10.1007/s12010-023-04378-0] [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] [Accepted: 01/26/2023] [Indexed: 02/23/2023]
Abstract
It is a well-known fact that general anesthesia leads to cerebral hemorrhage in patients with spontaneous hypertension apart of the fact that the hypertension is under control. The literature is already flooded with this debate, and still, there appears a lag regarding the effects of high blood pressure on pathological changes in the brain after cerebral hemorrhage. They are still not well recognized. Furthermore, it is the stage of anesthesia resuscitation which is known to have adverse effects on the body during cerebral hemorrhage. Owing to the lag of knowledge in the above said facts, the objectives of this study were to evaluate the effects of propofol combined with sufentanil on the expression of Bax, BCL-2, and caspase-3 genes in spontaneously hypertensive rats suffering with cerebral hemorrhage. The initial sample consisted of 54 male Wrister rats. All were of the age of 7 to 8 months with a weight of 500 ± 100 gm. All the rats were evaluated by the investigators before enrolment. A total of 0.5 mg/kg ketamine followed by a 10 mg/kg intravenous injection of propofol was introduced to each included rat. It was followed by a total of 1 μG/kg/h of sufentanil which was administered to rats who had cerebral hemorrhage (n = 27). The rest 27 normal rats were not administered with sufentanil. Hemodynamic parameters, biochemistry, western blot assay, and immunohistochemical staining were performed. The results were statistically analyzed. Heart rate (p < 0.0001) was higher for rats who had a cerebral hemorrhage. The cytokine levels of rats who had cerebral hemorrhage were higher than those of normal rats (p < 0.01 for all). Bacl-2 (p < 0.01), bax (p < 0.01), and caspase-3 (p < 0.01) expressions were reported to be disturbed in rats who had cerebral hemorrhage. Urine volume was reduced in rats who had cerebral hemorrhage (p < 0.01). It was concluded that in spontaneously hypertensive rats with cerebral hemorrhage, propofol combined with sufentanil target-controlled intravenous anesthesia increased hemodynamic parameters and cytokine levels. Furthermore, cerebral hemorrhage disturbs the expression of bacl-2, Bax, and caspase-3 expressions.
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Affiliation(s)
- Li Lei
- Department of Anesthesiology of The Affiliated people's hospital of Ningbo university, No.251 Baizhang East Road, Yinzhou District, Ningbo City, Zhejiang Province, People's Republic of China.
| | - Xu Qiao
- Department of Anesthesiology of The Affiliated people's hospital of Ningbo university, No.251 Baizhang East Road, Yinzhou District, Ningbo City, Zhejiang Province, People's Republic of China
| | - Ye Siqi
- Department of Anesthesiology of The Affiliated people's hospital of Ningbo university, No.251 Baizhang East Road, Yinzhou District, Ningbo City, Zhejiang Province, People's Republic of China
| | - Yan Ke
- Department of Anesthesiology of The Affiliated people's hospital of Ningbo university, No.251 Baizhang East Road, Yinzhou District, Ningbo City, Zhejiang Province, People's Republic of China
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9
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Ren G, Yang EJ, Tao S, Mou PK, Pu Y, Chen LJ, Shim JS. MDM2 inhibition is synthetic lethal with PTEN loss in colorectal cancer cells via the p53-dependent mechanism. Int J Biol Sci 2023; 19:3544-3557. [PMID: 37496993 PMCID: PMC10367566 DOI: 10.7150/ijbs.82566] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/27/2023] [Indexed: 07/28/2023] Open
Abstract
Colorectal cancer (CRC) driven by PTEN deficiency exhibits high risk of metastasis, advancement of tumor stages and chemotherapy resistance, where no effective therapy has been developed. In this study, we performed a synthetic lethal drug screening in CRC and found that PTEN-deficient CRC cells are highly vulnerable to MDM2 inhibition. MDM2 inhibitor treatment or its silencing selectively inhibited the growth of PTEN-deficient CRC in vitro and in mice models. Mechanistically, PTEN loss increased the level of active AKT and subsequently increased MDM2 phosphorylation, thereby limiting the p53 functions in PTEN-/- CRC cells. MDM2 inhibition in turn activated p53 in CRC, particularly in PTEN-/- CRC cells. The synthetic lethal effect of MDM2 inhibitor was largely dependent on p53, because p53 silenced cells or cells lacking p53 failed to exhibit synthetic lethality in PTEN-deficient cells. We further showed that MDM2 inhibition led to the p53-dependent reversal of Bcl2-Bax ratio, which contributed to mitochondria-mediated apoptotic cell death in PTEN-deficient CRC. This study suggests that pharmacological targeting of MDM2 could be a potential therapeutic strategy for PTEN-deficient CRC.
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Affiliation(s)
- Guowen Ren
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Eun Ju Yang
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Shishi Tao
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Pui Kei Mou
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Yue Pu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Li-Jie Chen
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Joong Sup Shim
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
- MOE Frontiers Science Centre for Precision Oncology, University of Macau, Taipa, Macau SAR, China
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10
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Castro DTH, Leite DF, da Silva Baldivia D, Dos Santos HF, Balogun SO, da Silva DB, Carollo CA, de Picoli Souza K, Dos Santos EL. Structural Characterization and Anticancer Activity of a New Anthraquinone from Senna velutina (Fabaceae). Pharmaceuticals (Basel) 2023; 16:951. [PMID: 37513863 PMCID: PMC10385181 DOI: 10.3390/ph16070951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/20/2023] [Accepted: 06/25/2023] [Indexed: 07/30/2023] Open
Abstract
In this study, a novel compound was isolated, identified, and its chemical structure was determined from the extract of the roots of Senna velutina. In addition, we sought to evaluate the anticancer potential of this molecule against melanoma and leukemic cell lines and identify the pathways of cell death involved. To this end, a novel anthraquinone was isolated from the barks of the roots of S. velutina, analyzed by HPLC-DAD, and its molecular structure was determined by nuclear magnetic resonance (NMR). Subsequently, their cytotoxic activity was evaluated by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) method against non-cancerous, melanoma, and leukemic cells. The migration of melanoma cells was evaluated by the scratch assay. The apoptosis process, caspase-3 activation, analysis of mitochondrial membrane potential, and measurement of ROS were evaluated by flow cytometry technique. In addition, the pharmacological cell death inhibitors NEC-1, RIP-1, BAPTA, Z-VAD, and Z-DEVD were used to confirm the related cell death mechanisms. With the results, it was possible to elucidate the novel compound characterized as 2'-OH-Torosaol I. In normal cells, the compound showed no cytotoxicity in PBMC but reduced the cell viability of all melanoma and leukemic cell lines evaluated. 2'-OH-Torosaol I inhibited chemotaxis of B16F10-Nex2, SK-Mel-19, SK-Mel-28 and SK-Mel-103. The cytotoxicity of the compound was induced by apoptosis via the intrinsic pathway with reduced mitochondrial membrane potential, increased levels of reactive oxygen species, and activation of caspase-3. In addition, the inhibitors demonstrated the involvement of necroptosis and Ca2+ in the death process and confirmed caspase-dependent apoptosis death as one of the main programmed cell death pathways induced by 2'-OH-Torosaol I. Taken together, the data characterize the novel anthraquinone 2'-OH-Torosaol I, demonstrating its anticancer activity and potential application in cancer therapy.
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Affiliation(s)
- David Tsuyoshi Hiramatsu Castro
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism (GEBBAM), Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
| | - Daniel Ferreira Leite
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism (GEBBAM), Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
| | - Debora da Silva Baldivia
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism (GEBBAM), Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
| | - Helder Freitas Dos Santos
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism (GEBBAM), Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
| | - Sikiru Olaitan Balogun
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism (GEBBAM), Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
| | - Denise Brentan da Silva
- Laboratory of Natural Products and Mass Spectrometry, Universidade Federal do Mato Grosso do Sul, Cidade Universitária, Campo Grande 79070-900, Brazil
| | - Carlos Alexandre Carollo
- Laboratory of Natural Products and Mass Spectrometry, Universidade Federal do Mato Grosso do Sul, Cidade Universitária, Campo Grande 79070-900, Brazil
| | - Kely de Picoli Souza
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism (GEBBAM), Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
| | - Edson Lucas Dos Santos
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism (GEBBAM), Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal da Grande Dourados, Dourados 79804-970, Brazil
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Niu X, Yang Y, Yu J, Song H, Yu J, Huang Q, Liu Y, Zhang D, Han T, Li W. Panlongqi tablet suppresses adjuvant-induced rheumatoid arthritis by inhibiting the inflammatory reponse in vivo and in vitro. JOURNAL OF ETHNOPHARMACOLOGY 2023; 308:116250. [PMID: 36791928 DOI: 10.1016/j.jep.2023.116250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Panlongqi Tablet is prepared with the ancestral secret recipe provided by Mr. Wang Jiacheng, a famous specialist in orthopedics and traumatology of China. The efficacy and safety of PLQT have been supported by years of clinical practice in the treatment of joint-related conditions. Has remarkable effect for treating rheumatoid arthritis (RA) clinically. However, its mechanism is not entirely clear. AIM OF THE STUDY We aim to evaluate the anti-inflammatory activity of PLQT and explore its mechanism in adjuvant-induced arthritis (AA) mice and LPS-induced Human fibroblast-like synovial (HFLS) cells. MATERIALS AND METHODS To this end, we analyzed the active ingredients in PLQT by HPLC-MS/MS. Furthermore, the anti-RA effect of PLQT was studied through proliferation, apoptosis, foot swelling, cytokine levels, immune organ index, histopathology and related signal pathways in LPS-induced HFLS cells and AA-treated mice. RESULTS HPLC-MS/MS results showed that PLQT contained a variety of active compounds, such as epicatechin, imperatorin, hydroxysafflor yellow A and so on. PLQT significantly inhibited the abnormal proliferation of HFLS cells induced by LPS, promoted cell apoptosis. In AA-treated mice, PLQT alleviated RA symptoms by alleviating paw swelling, synovial hyperplasia, pannus formation, inflammatory cell infiltration, and inhibiting abnormal immune responses. The results showed that PLQT significantly decreased the expression of inflammatory mediators (IL-1β, IL-6, IL-17) in vivo and in vitro, which may be related to the regulation of PI3K/Akt, MAPK and JAK/STAT signaling pathways. CONCLUSION Based on serum pharmacology and in vivo pharmacology studies, PLQT may regulate RA symptoms by regulating inflammatory and immune response-related pathways, which is an effective method for the treatment of RA.
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Affiliation(s)
- Xiaofeng Niu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Yajie Yang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Jinjin Yu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Huixin Song
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Jiabao Yu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Qiuxia Huang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Yang Liu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Dezhu Zhang
- Shaanxi Panlong Pharmaceutical Group Limited By Share LTD, Xi'an, PR China
| | - Tengfei Han
- Shaanxi Panlong Pharmaceutical Group Limited By Share LTD, Xi'an, PR China.
| | - Weifeng Li
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China.
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Thapa Magar TB, Lee J, Lee JH, Jeon J, Gurung P, Lim J, Kim YW. Novel Chlorin e6-Curcumin Derivatives as a Potential Photosensitizer: Synthesis, Characterization, and Anticancer Activity. Pharmaceutics 2023; 15:1577. [PMID: 37376026 DOI: 10.3390/pharmaceutics15061577] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Novel series of chlorin e6-curcumin derivatives were designed and synthesized. All the synthesized compounds 16, 17, 18, and 19 were tested for their photodynamic treatment (PDT) efficacy against human pancreatic cancer cell lines: AsPC-1, MIA-PaCa-2, and PANC-1. The cellular uptake study was performed in the aforementioned cell lines using fluorescence-activated cell sorting (FACS). 17, among the synthesized compounds with IC50 values of 0.27, 0.42, and 0.21 µM against AsPC-1, MIA PaCa-2, and PANC-1 cell lines, respectively, demonstrated excellent cellular internalization capability and exhibited higher phototoxicity relative to the parent Ce6. The quantitative analyses using Annexin V-PI staining revealed that the 17-PDT-induced apoptosis was dose-dependent. In pancreatic cell lines, 17 reduced the expression of the anti-apoptotic protein, Bcl-2, and increased the pro-apoptotic protein, cytochrome C, which indicates the activation of intrinsic apoptosis, the primary cause of cancer cell death. Structure-activity relationship studies have shown that the incorporation of additional methyl ester moiety and conjugation to the enone moiety of curcumin enhances cellular uptake and PDT efficacy. Moreover, in vivo PDT testing in melanoma mouse models revealed that 17-PDT greatly reduced tumor growth. Therefore, 17 might be an effective photosensitizer for PDT anticancer therapy.
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Affiliation(s)
| | - Jusuk Lee
- A&J Science Co., Ltd., Daegu 41061, Republic of Korea
| | - Ji Hoon Lee
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
| | - Juhee Jeon
- Dongsung Cancer Center, Dongsung Biopharmaceutical, Daegu 41061, Republic of Korea
| | - Pallavi Gurung
- Dongsung Cancer Center, Dongsung Biopharmaceutical, Daegu 41061, Republic of Korea
| | - Junmo Lim
- Dongsung Cancer Center, Dongsung Biopharmaceutical, Daegu 41061, Republic of Korea
| | - Yong-Wan Kim
- Dongsung Cancer Center, Dongsung Biopharmaceutical, Daegu 41061, Republic of Korea
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Waseem M, Wang BD. Promising Strategy of mPTP Modulation in Cancer Therapy: An Emerging Progress and Future Insight. Int J Mol Sci 2023; 24:5564. [PMID: 36982637 PMCID: PMC10051994 DOI: 10.3390/ijms24065564] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/04/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023] Open
Abstract
Cancer has been progressively a major global health concern. With this developing global concern, cancer determent is one of the most significant public health challenges of this era. To date, the scientific community undoubtedly highlights mitochondrial dysfunction as a hallmark of cancer cells. Permeabilization of the mitochondrial membranes has been implicated as the most considerable footprint in apoptosis-mediated cancer cell death. Under the condition of mitochondrial calcium overload, exclusively mediated by oxidative stress, an opening of a nonspecific channel with a well-defined diameter in mitochondrial membrane allows free exchange between the mitochondrial matrix and the extra mitochondrial cytosol of solutes and proteins up to 1.5 kDa. Such a channel/nonspecific pore is recognized as the mitochondrial permeability transition pore (mPTP). mPTP has been established for regulating apoptosis-mediated cancer cell death. It has been evident that mPTP is critically linked with the glycolytic enzyme hexokinase II to defend cellular death and reduce cytochrome c release. However, elevated mitochondrial Ca2+ loading, oxidative stress, and mitochondrial depolarization are critical factors leading to mPTP opening/activation. Although the exact mechanism underlying mPTP-mediated cell death remains elusive, mPTP-mediated apoptosis machinery has been considered as an important clamp and plays a critical role in the pathogenesis of several types of cancers. In this review, we focus on structure and regulation of the mPTP complex-mediated apoptosis mechanisms and follow with a comprehensive discussion addressing the development of novel mPTP-targeting drugs/molecules in cancer treatment.
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Affiliation(s)
- Mohammad Waseem
- Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA;
| | - Bi-Dar Wang
- Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA;
- Hormone Related Cancers Program, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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Wu Y, Li Q, Lv LL, Chen JX, Ying HF, Ruan M, Zhu WH, Xu JY, Zhang CY, Zhang KY, Guo YB, Zhu WR, Zheng L. Nobiletin inhibits breast cancer cell migration and invasion by suppressing the IL-6-induced ERK-STAT and JNK-c-JUN pathways. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 110:154610. [PMID: 36584607 DOI: 10.1016/j.phymed.2022.154610] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 11/16/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Breast cancer is one of the most common cancers in women, affecting more than 2 million women worldwide annually. However, effective treatments for breast cancer are limited. Nobiletin is a flavonoid present in the dried mature pericarp of mandarin orange (Citrus reticulata Blanco), which is used to prepare Citri Renetulatae Pericarpium and can inhibit tumour growth and progression according to modern pharmacological studies. However, whether nobiletin exhibits an antimetastatic role in breast cancer and its potential mechanism need to be further investigated. PURPOSE This study aims to evaluate the inhibitory effect of nobiletin on breast cancer and to elucidate potential mechanisms against invasion and migration. METHODS Cell viability was determined by cell counting kit-8 and colony formation assays. Wound healing and Boyden chamber assays detected cancer cell migration and invasion capabilities. Immunoblotting and qPCR were applied to determine the protein and mRNA expression levels of extracellular signal-regulated kinases (ERK) and the c-Jun N-terminal kinase (JNK) signalling pathways. Molecular docking was used to assess the degree of nobiletin binding to phosphatidylinositol 3-kinase (PI3K). Xenografts and liver metastases were constructed in BALB/c nude mice to evaluate the anticancer effect of nobiletin in vivo. H&E staining and immunohistochemistry were used to detect proliferation and the expression of related proteins. RESULTS Nobiletin induced cell death in a concentration- and time-dependent manner and possessed anti-invasion and anti-migration effects on MCF-7 and T47D cells by suppressing the interleukin-6-induced ERK and JNK signalling pathways. In addition, nobiletin docked with the binding site of PI3K, and the binding score was -8.0 kcal/mol. Furthermore, the inhibition of breast cancer growth and metastasis by nobiletin was demonstrated by constructing xenografts and liver metastases in vivo. CONCLUSION Nobiletin inhibited liver metastasis of breast cancer by downregulating the ERK-STAT and JNK-c-JUN pathways, and its safety and efficacy were verified, indicating the potential of nobiletin as an anticancer agent.
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Affiliation(s)
- Yuan Wu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Qiong Li
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Ling-Ling Lv
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Jing-Xian Chen
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Hai-Feng Ying
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Ming Ruan
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Wen-Hua Zhu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Jia-Yue Xu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Chen-Yiyu Zhang
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Kai-Yuan Zhang
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Yuan-Biao Guo
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Wei-Rong Zhu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Lan Zheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China.
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15
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Mahmoud GA, Ali HE, Radwan RR. Design of pH-responsive polymeric nanocarrier for targeted delivery of pyrogallol with enhanced antitumor potential in colon cancer. Arch Biochem Biophys 2022; 731:109431. [DOI: 10.1016/j.abb.2022.109431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 10/04/2022] [Accepted: 10/08/2022] [Indexed: 11/25/2022]
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16
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Mir SA, Hamid L, Bader GN, Shoaib A, Rahamathulla M, Alshahrani MY, Alam P, Shakeel F. Role of Nanotechnology in Overcoming the Multidrug Resistance in Cancer Therapy: A Review. Molecules 2022; 27:6608. [PMID: 36235145 PMCID: PMC9571152 DOI: 10.3390/molecules27196608] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 09/29/2022] [Accepted: 10/02/2022] [Indexed: 11/06/2022] Open
Abstract
Cancer is one of the leading causes of morbidity and mortality around the globe and is likely to become the major cause of global death in the coming years. As per World Health Organization (WHO) report, every year there are over 10 and 9 million new cases and deaths from this disease. Chemotherapy, radiotherapy, and surgery are the three basic approaches to treating cancer. These approaches are aiming at eradicating all cancer cells with minimum off-target effects on other cell types. Most drugs have serious adverse effects due to the lack of target selectivity. On the other hand, resistance to already available drugs has emerged as a major obstacle in cancer chemotherapy, allowing cancer to proliferate irrespective of the chemotherapeutic agent. Consequently, it leads to multidrug resistance (MDR), a growing concern in the scientific community. To overcome this problem, in recent years, nanotechnology-based drug therapies have been explored and have shown great promise in overcoming resistance, with most nano-based drugs being explored at the clinical level. Through this review, we try to explain various mechanisms involved in multidrug resistance in cancer and the role nanotechnology has played in overcoming or reversing this resistance.
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Affiliation(s)
- Suhail Ahmad Mir
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, India
| | - Laraibah Hamid
- Department of Zoology, University of Kashmir, Hazratbal, Srinagar 190006, India
| | - Ghulam Nabi Bader
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, India
| | - Ambreen Shoaib
- Department of Pharmacy Practice, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Mohamed Rahamathulla
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia
| | - Mohammad Y. Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia
| | - Prawez Alam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Faiyaz Shakeel
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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17
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Roth HE, De Lima Leite A, Palermo NY, Powers R. Leveraging the Structure of DNAJA1 to Discover Novel Potential Pancreatic Cancer Therapies. Biomolecules 2022; 12:1391. [PMID: 36291603 PMCID: PMC9599757 DOI: 10.3390/biom12101391] [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: 08/18/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic cancer remains one of the deadliest forms of cancer with a 5-year survival rate of only 11%. Difficult diagnosis and limited treatment options are the major causes of the poor outcome for pancreatic cancer. The human protein DNAJA1 has been proposed as a potential therapeutic target for pancreatic cancer, but its cellular and biological functions remain unclear. Previous studies have suggested that DNAJA1's cellular activity may be dependent upon its protein binding partners. To further investigate this assertion, the first 107 amino acid structures of DNAJA1 were solved by NMR, which includes the classical J-domain and its associated linker region that is proposed to be vital to DNAJA1 functionality. The DNAJA1 NMR structure was then used to identify both protein and ligand binding sites and potential binding partners that may suggest the intracellular roles of DNAJA1. Virtual drug screenings followed by NMR and isothermal titration calorimetry identified 5 drug-like compounds that bind to two different sites on DNAJA1. A pull-down assay identified 8 potentially novel protein binding partners of DNAJA1. These proteins in conjunction with our previously published metabolomics study support a vital role for DNAJA1 in cellular oncogenesis and pancreatic cancer.
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Affiliation(s)
- Heidi E. Roth
- Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Aline De Lima Leite
- Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
- Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Nicolas Y. Palermo
- Computational Chemistry Core Facility, VCR Cores, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Robert Powers
- Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
- Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
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18
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Tai YJ, Ou CM, Chiang YC, Chang CF, Chen CA, Cheng WF. Overexpression of transmembrane protein 102 implicates poor prognosis and chemoresistance in epithelial ovarian carcinoma patients. Am J Cancer Res 2022; 12:4211-4226. [PMID: 36225641 PMCID: PMC9548018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/11/2022] [Indexed: 06/16/2023] Open
Abstract
Most ovarian cancer patients experience disease recurrence and chemotherapeutic resistance, and the underlying mechanisms are unclear. Identifying relevant pathways could reveal new therapeutic targets. Here we examined expression of transmembrane protein 102 (TMEM102), a biomarker of prognosis and chemoresistance, in epithelial ovarian cancer (EOC), and assessed its role in inhibiting tumor cell apoptosis. We performed qRT-PCR to investigate the association of TMEM102 expression with clinical outcomes in 226 EOC patients. We also conducted in vitro studies to explore possible mechanisms through which TMEM102 may influence chemoresistance, including the effects of downregulating TMEM102 expression with small interfering RNA. Serous and high-grade carcinomas expressed significantly higher TMEM102 than normal ovarian tissues. TMEM102 was also overexpressed in patients with advanced-stage disease and chemoresistance. Reduction of TMEM102 expression by small interfering RNA induced ovarian cancer cell apoptosis after cytotoxic treatment. TMEM102 overexpression enhanced chemoresistance via upregulation of heat shock proteins 27, 60, and 70; and survivin, resulting in decreased cytochrome c in the mitochondria and decreased caspase 9 expression. Our results indicate that TMEM102 overexpression may promote chemoresistance via inhibition of a mitochondria-associated apoptotic pathway.
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Affiliation(s)
- Yi-Jou Tai
- Department of Obstetrics and Gynecology, College of Medicine, National Taiwan UniversityTaipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan UniversityTaipei, Taiwan
| | - Cheng-Miao Ou
- Institute of Molecular Medicine, College of Medicine, National Taiwan UniversityTaipei, Taiwan
| | - Ying-Cheng Chiang
- Department of Obstetrics and Gynecology, College of Medicine, National Taiwan UniversityTaipei, Taiwan
| | - Chi-Fang Chang
- Department of Obstetrics and Gynecology, College of Medicine, National Taiwan UniversityTaipei, Taiwan
| | - Chi-An Chen
- Department of Obstetrics and Gynecology, College of Medicine, National Taiwan UniversityTaipei, Taiwan
| | - Wen-Fang Cheng
- Department of Obstetrics and Gynecology, College of Medicine, National Taiwan UniversityTaipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan UniversityTaipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan UniversityTaipei, Taiwan
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Mitochondria-targeted cancer therapy based on functional peptides. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.107817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Xin Y, Zheng T, Zhang M, Zhang R, Zhu S, Li D, Zhao D, Ma Y, Ho CT, Huang Q. Demethylnobiletin and its major metabolites: Efficient preparation and mechanism of their anti-proliferation activity in HepG2 cells. FOOD SCIENCE AND HUMAN WELLNESS 2022. [DOI: 10.1016/j.fshw.2022.04.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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The Effects and Mechanisms of Sennoside A on Inducing Cytotoxicity, Apoptosis, and Inhibiting Metastasis in Human Chondrosarcoma Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:8063497. [PMID: 36091590 PMCID: PMC9451980 DOI: 10.1155/2022/8063497] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/07/2022] [Accepted: 08/04/2022] [Indexed: 12/01/2022]
Abstract
Currently, developing therapeutic strategies for chondrosarcoma (CS) remains important. Sennoside A (SA), a dianthrone glycoside from Senna and Rhubarb, is widely used as an irritant laxative, weight-loss agent, or dietary supplement, which possesses various bioactive properties such as laxative, antiobesity, and hypoglycemic activities. For the first time, our results suggested that cell proliferation and metastasis were inhibited by SA in CS SW1353 cells. SA induced cell growth arrest by inhibiting cell proliferation. The changes of N-cadherin and E-cadherin levels, the markers associated with epithelial mesenchymal transition (EMT), suggested the EMT-related mechanism of SA in inhibiting cell metastasis. Besides, SA significantly stimulated apoptosis in CS SW1353 cells, leading to cell death. The increase of Bax/Bcl2 ratio confirmed that the internal mitochondrial pathway of apoptosis was regulated by SA. In addition, the prediction of network pharmacology analysis suggested that the possible pathways of SA treatment for CS included the Wnt signaling pathway. Notably, the protein levels of the components in the Wnt pathway, such as Wnt3a, β-catenin, and c-Myc, were downregulated by SA in CS SW1353 cells. To sum up, these results demonstrated that the suppression of the growth, metastasis and the stimulation of cytotoxicity, and apoptosis mediated by SA in CS SW1353 cells were possibly caused by the inhibition of the Wnt/β-catenin pathway, indicating an underlying therapeutic prospect of SA for chondrosarcoma.
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Hu QG, Yang Z, Chen JW, Kazobinka G, Tian L, Li WC. MiR-183-5p-PNPT1 Axis Enhances Cisplatin-induced Apoptosis in Bladder Cancer Cells. Curr Med Sci 2022; 42:785-796. [PMID: 35788944 DOI: 10.1007/s11596-022-2580-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 12/29/2021] [Indexed: 12/30/2022]
Abstract
OBJECTIVE It has been reported that intrinsic apoptosis is associated with the progression of bladder cancer (BC). Recent evidence suggests that polyribonucleotide nucleotidyltransferase 1 (PNPT1) is a pivotal mediator involved in RNA decay and cell apoptosis. However, the regulation and roles of PNPT1 in bladder cancer remain largely unclear. METHODS The upstream miRNA regulators were predicted by in silico analysis. The expression levels of PNPT1 were evaluated by real-time PCR, Western blotting, and immunohistochemistry (IHC), while miR-183-5p levels were evaluated by qPCR in BC cell lines and tissues. In vitro and in vivo assays were performed to investigate the function of miR-183-5p and PNPT1 in apoptotic RNA decay and the tumorigenic capability of bladder cancer cells. RESULTS PNPT1 expression was decreased in BC tissues and cell lines. Overexpression of PNPT1 significantly promoted cisplatin-induced intrinsic apoptosis of BC cells, whereas depletion of PNPT1 potently alleviated these effects. Moreover, oncogenic miR-183-5p directly targeted the 3' UTR of PNPT1 and reversed the tumor suppressive role of PNPT1. Intriguingly, miR-183-5p modulated not only PNPT1 but also Bcl2 modifying factor (BMF) to inhibit the mitochondrial outer membrane permeabilization (MOMP) in BC cells. CONCLUSION Our results provide new insight into the mechanisms underlying intrinsic apoptosis in BC, suggesting that the miR-183-5p-PNPT1 regulatory axis regulates the apoptosis of BC cells and might represent a potential therapeutic avenue for the treatment of BC.
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Affiliation(s)
- Qing-Gang Hu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhi Yang
- Department of Urology, Luoshan County People's Hospital, Xinyang, 464000, China
| | - Jia-Wei Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Gallina Kazobinka
- Urology Unit, La Nouvelle Polyclinique Centrale de Bujumbura, Bujumbura, 378, Burundi
| | - Liang Tian
- Department of Urology, Wuhan Red Cross Hospital, Wuhan, 430015, China.
| | - Wen-Cheng Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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23
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Bansal A, Saleh-E-In MM, Kar P, Roy A, Sharma NR. Synthesis of Carvacrol Derivatives as Potential New Anticancer Agent against Lung Cancer. Molecules 2022; 27:molecules27144597. [PMID: 35889476 PMCID: PMC9323284 DOI: 10.3390/molecules27144597] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/14/2022] [Accepted: 07/16/2022] [Indexed: 02/01/2023] Open
Abstract
Lung cancer remains a major public health concern among all cancer diseases due to the toxicity and side-effects of the available commercially synthesized drugs. Natural product-derived synthesized anticancer drugs are now of promising interest to fight against cancer death. Carvacrol is a major component of most essential oil-bearing plants with potential pharmacological activity, especially against various cancer cell lines. Among the other organometallic compounds, copper complexes have been reported to be effective anticancer agents against various cancer cell lines, especially lung and leukemia cancers, due to the nontoxic nature of copper in normal cells since it is an endogenic metal. In this study, we synthesized three carvacrol derivatives, i.e., carvacrol aldehyde, Schiff base, and copper–Schiff base complex, through an established synthesis protocol and characterized the synthesized product using various spectroscopic techniques. The synthesized derivatives were evaluated for in vitro cytotoxic activity against different cancer cell lines, including human lung cancer (A549) and human fibroblast (BALB-3T3). Our findings showed that the copper–Schiff base complex derived from carvacrol inhibited the proliferation and migration of the A549 cell lines in a dose-dependent manner. This activity might be due to the inhibition of cell proliferation and migration at the G2/M cell-cycle phase, as well as apoptosis, possibly through the activation of the mitochondrial apoptotic pathway. To our knowledge, this is the first report on the activity of the copper–Schiff base complex of carvacrol against A549 cell lines. Our result highlights that a new synthesized copper complex from carvacrol could be a novel potential drug in the treatment of lung cancer.
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Affiliation(s)
- Anu Bansal
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, India;
| | - Md. Moshfekus Saleh-E-In
- Division of Forest Resources, College of Forest and Environmental Sciences, Kangwon National University, Chunchon 200701, Korea;
| | - Pallab Kar
- B.S. Diagnostic and Pathology Laboratory, Siliguri 734001, India;
| | - Ayan Roy
- Mailman School of Public Health, Columbia University, New York, NY 10032, USA;
| | - Neeta Raj Sharma
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, India;
- Correspondence: ; Tel.: +91-828-3921-144
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24
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Lopez A, Reyna DE, Gitego N, Kopp F, Zhou H, Miranda-Roman MA, Nordstrøm LU, Narayanagari SR, Chi P, Vilar E, Tsirigos A, Gavathiotis E. Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer. Nat Commun 2022; 13:1199. [PMID: 35256598 PMCID: PMC8901805 DOI: 10.1038/s41467-022-28741-7] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 02/09/2022] [Indexed: 01/20/2023] Open
Abstract
Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment. Deregulation of the BCL-2 family interactions ensures cancer resistance to apoptosis and is a major challenge to current treatments. Here the authors describe a novel therapeutic strategy to overcome two anti-apoptotic mechanisms for cancer therapy.
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25
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Wang J, Zhang Y, Zhang M, Sun S, Zhong Y, Han L, Xu Y, Wan D, Zhang J, Zhu H. Feasibility of Catalpol Intranasal Administration and Its Protective Effect on Acute Cerebral Ischemia in Rats via Anti-Oxidative and Anti-Apoptotic Mechanisms. Drug Des Devel Ther 2022; 16:279-296. [PMID: 35115763 PMCID: PMC8801896 DOI: 10.2147/dddt.s343928] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/21/2021] [Indexed: 12/31/2022] Open
Abstract
Purpose Patients and Methods Results Conclusion
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Affiliation(s)
- Jinghui Wang
- College of Pharmaceutical Sciences & College of Chinese Medicine, Southwest University, Chongqing, 400715, People’s Republic of China
| | - Yuhua Zhang
- Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei, 445000, People’s Republic of China
| | - Meifeng Zhang
- College of Pharmaceutical Sciences & College of Chinese Medicine, Southwest University, Chongqing, 400715, People’s Republic of China
| | - Si Sun
- College of Pharmaceutical Sciences & College of Chinese Medicine, Southwest University, Chongqing, 400715, People’s Republic of China
| | - Yang Zhong
- College of Pharmaceutical Sciences & College of Chinese Medicine, Southwest University, Chongqing, 400715, People’s Republic of China
| | - Lei Han
- College of Pharmaceutical Sciences & College of Chinese Medicine, Southwest University, Chongqing, 400715, People’s Republic of China
| | - Yitong Xu
- College of Pharmaceutical Sciences & College of Chinese Medicine, Southwest University, Chongqing, 400715, People’s Republic of China
| | - Dong Wan
- Department of Emergency and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Junhui Zhang
- Health Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Junhui Zhang Health Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China Email
| | - Huifeng Zhu
- College of Pharmaceutical Sciences & College of Chinese Medicine, Southwest University, Chongqing, 400715, People’s Republic of China
- Correspondence: Huifeng Zhu College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing, 400715, People’s Republic of China Email
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He Y, Li F, Zhang C, Geng X, Syeda MZ, Du X, Shao Z, Hua W, Li W, Chen Z, Ying S, Shen H. Therapeutic Effects of the Bcl-2 Inhibitor on Bleomycin-induced Pulmonary Fibrosis in Mice. Front Mol Biosci 2021; 8:645846. [PMID: 34692765 PMCID: PMC8529052 DOI: 10.3389/fmolb.2021.645846] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 09/21/2021] [Indexed: 12/30/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a distressing lung disorder with poor prognosis and high mortality rates. Limited therapeutic options for IPF is a major clinical challenge. Well-known for its anti-apoptotic properties, B-cell lymphoma 2 (Bcl-2) plays a critical role in the pathology of malignancies and inflammatory diseases, including IPF. In this study, we aimed to investigate the therapeutic effect of a Bcl-2 homology domain 3 mimetic inhibitor, ABT-199, on bleomycin (BLM)-induced pulmonary fibrosis in mice, and explore possible underlying mechanism. The lung inflammation and fibrosis model was established by intratracheal instillation of a single dose of BLM. We observed elevated Bcl-2 in the alveolar macrophages and fibroblasts derived from BLM-instilled mice from day 7. Further, we obtained in vivo evidence that early therapeutic treatment with Bcl-2 inhibitor ABT-199 from day 3, and late treatment from day 10, both alleviated airway inflammation and lung fibrosis induced by BLM. Our data suggest that ABT-199 might be an effective antifibrotic agent that interferes with profibrogenic cells, which may be a promising therapy in the treatment of clinical IPF patients.
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Affiliation(s)
- Yicheng He
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Fei Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Zhang
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xinwei Geng
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
| | - Madiha Zahra Syeda
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
| | - Xufei Du
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zhehua Shao
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Wen Hua
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Wen Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zhihua Chen
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Songmin Ying
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
| | - Huahao Shen
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,State Key Lab of Respiratory Disease, Guangzhou, China
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27
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Discovery of potent and selective Bcl-2 inhibitors with acyl sulfonamide skeleton. Bioorg Med Chem 2021; 47:116350. [PMID: 34536651 DOI: 10.1016/j.bmc.2021.116350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/26/2021] [Accepted: 07/30/2021] [Indexed: 12/23/2022]
Abstract
The antiapoptotic protein B-cell lymphoma 2 (Bcl-2), overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, a series of novel derivatives with acyl sulfonamide skeleton was designed, synthesized, and evaluated as Bcl-2 inhibitors by means of bioisosteric replacement. Among them, compound 24g demonstrated equal efficient inhibition activity against RS4;11 cell line compared to positive control ABT-199. Moreover, it showed improved selectivity for Bcl-2/Bcl-xL inhibitory effects, the result of which was consistent with platelet toxicity studies. In vitro and in vivo pharmacokinetic properties of compound 24g had a significantly improved profiles. Taken together, those results suggested it as a promising candidate for development of novel therapeutics targeting Bcl-2 in cancer.
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28
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Garrido-Cano I, Pattanayak B, Adam-Artigues A, Lameirinhas A, Torres-Ruiz S, Tormo E, Cervera R, Eroles P. MicroRNAs as a clue to overcome breast cancer treatment resistance. Cancer Metastasis Rev 2021; 41:77-105. [PMID: 34524579 PMCID: PMC8924146 DOI: 10.1007/s10555-021-09992-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 09/02/2021] [Indexed: 12/31/2022]
Abstract
Breast cancer is the most frequent cancer in women worldwide. Despite the improvement in diagnosis and treatments, the rates of cancer relapse and resistance to therapies remain higher than desirable. Alterations in microRNAs have been linked to changes in critical processes related to cancer development and progression. Their involvement in resistance or sensitivity to breast cancer treatments has been documented by different in vivo and in vitro experiments. The most significant microRNAs implicated in modulating resistance to breast cancer therapies are summarized in this review. Resistance to therapy has been linked to cellular processes such as cell cycle, apoptosis, epithelial-to-mesenchymal transition, stemness phenotype, or receptor signaling pathways, and the role of microRNAs in their regulation has already been described. The modulation of specific microRNAs may modify treatment response and improve survival rates and cancer patients' quality of life. As a result, a greater understanding of microRNAs, their targets, and the signaling pathways through which they act is needed. This information could be useful to design new therapeutic strategies, to reduce resistance to the available treatments, and to open the door to possible new clinical approaches.
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Affiliation(s)
| | | | | | - Ana Lameirinhas
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain
| | | | - Eduardo Tormo
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain.,Center for Biomedical Network Research On Cancer, CIBERONC-ISCIII, 28029, Madrid, Spain
| | | | - Pilar Eroles
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain. .,Center for Biomedical Network Research On Cancer, CIBERONC-ISCIII, 28029, Madrid, Spain. .,Department of Physiology, University of Valencia, 46010, Valencia, Spain.
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29
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Ali HE, Radwan RR. Synthesis, characterization and evaluation of resveratrol-loaded functionalized carbon nanotubes as a novel delivery system in radiation enteropathy. Eur J Pharm Sci 2021; 167:106002. [PMID: 34517108 DOI: 10.1016/j.ejps.2021.106002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 08/05/2021] [Accepted: 09/08/2021] [Indexed: 01/13/2023]
Abstract
Radiation-induced enteropathy is a major clinical challenge during radiotherapy. Resveratrol displays beneficial pharmacological activities; however, low oral bioavailability limits its effectiveness. This study aims at preparing methacrylic acid (MAAc) functionalized multi-walled carbon nanotubes (MWCNTs-MAAc) as carriers for pH triggered controlled release of resveratrol in an effort to improve the drug therapeutic potential. MWCNTs-MAAc were prepared using radiation technique and then characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), scanning electron microscope (SEM), X-ray diffraction (XRD) and Fourier transform-infrared (FT-IR) spectroscopy. In vitro drug release profile at different pH values was analyzed. Furthermore, the designed RES-MWCNTs-MAAc nanocomplex was evaluated against radiation-induced enteropathy in rats. Oral administration of RES-MWCNTs-MAAc restored colonic redox state and elevated antioxidant enzymes activities glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) and reduced colonic inflammatory mediators tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interferone-γ (IFN-γ) contents in addition to declining the intrinsic apoptotic pathway as evidenced by down-regulation of Bax and caspase-3 proteins expression accompanied by up-regulation of Bcl-2 protein expression. RES-MWCNTs-MAAc was more efficient than free resveratrol due to the delivery system that allowed prolonged resveratrol release at target site. Thus, this formulation could serve as a beneficial anti-inflammatory approach for patients during radiotherapy.
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Affiliation(s)
- Hussein E Ali
- Radiation Chemistry Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Rasha R Radwan
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, P.O. Box 29, Nasr City, Cairo, Egypt.
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30
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Jang JH, Lee TJ, Sung EG, Song IH, Kim JY. Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP (L) expression and reducing Bcl-2 protein stability. Oncol Lett 2021; 22:743. [PMID: 34466155 PMCID: PMC8387863 DOI: 10.3892/ol.2021.13004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/28/2021] [Indexed: 12/02/2022] Open
Abstract
Pioglitazone is an anti-diabetic agent used in the treatment of type 2 diabetes, which belongs to the thiazolidinediones (TZDs) group. TZDs target peroxisome proliferator-activated receptor γ (PPARγ), which functions as a transcription factor of the nuclear hormone receptor. Pioglitazone has antitumor effects in several cancer types and could be a tool for drug therapy in various cancer treatments. Nevertheless, the molecular basis for pioglitazone-induced anticancer effects in renal cancer (RC) has not yet been elucidated. Thus, the aim of the present study was to investigate the detailed signaling pathway underlying pioglitazone-induced apoptosis in Caki cells derived from human clear cell renal cell carcinoma. As a result, it was demonstrated by flow cytometry analysis and Annexin V-propidium iodide staining that pioglitazone treatment induced apoptotic cell death in a dose-dependent manner in Caki cells. The protein expression levels of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP)(L) and Bcl-2, which were determined by western blotting, decreased after pioglitazone treatment in Caki cells. Flow cytometry and western blot analyses demonstrated that pioglitazone-mediated apoptosis was blocked following pretreatment with the pan-caspase inhibitor, z-VAD-fmk, indicating that pioglitazone-induced apoptosis was mediated via a caspase-dependent signaling pathway. However, the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), did not affect pioglitazone-mediated apoptosis and degradation of c-FLIP(L) and Bcl-2 protein. Of note, it was found by western blot analysis that Bcl-2 protein expression was downregulated by the decreased protein stability of Bcl-2 in pioglitazone-treated Caki cells. In conclusion, these findings indicated that pioglitazone-induced apoptosis is regulated through caspase-mediated degradation of FLIP(L) and reduction of Bcl-2 protein stability, suggesting that pioglitazone is a feasible apoptotic agent that could be used in the treatment of human RC.
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Affiliation(s)
- Ji Hoon Jang
- Department of Anatomy, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Tae-Jin Lee
- Department of Anatomy, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Eon-Gi Sung
- Department of Anatomy, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - In-Hwan Song
- Department of Anatomy, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Joo-Young Kim
- Department of Anatomy, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
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31
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Xia P, Liang J, Jin D, Jin Z. Reversine inhibits proliferation, invasion and migration and induces cell apoptosis in gastric cancer cells by downregulating TTK. Exp Ther Med 2021; 22:929. [PMID: 34306198 PMCID: PMC8281506 DOI: 10.3892/etm.2021.10361] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 03/02/2021] [Indexed: 12/29/2022] Open
Abstract
Reversine (Rev) has been used for the treatment of a number of cancers. However, there have been no previous reports for the use of Rev for gastric cancer (GC). The aim of the present study was to investigate the effect of Rev on cell proliferation, migration, invasion and cell apoptosis in human GC cells and TTK expression. Cell Counting Kit-8 and colony formation were used to assess cell proliferation. Wound healing and Transwell assays were performed to examine cell migration and invasion, respectively. Cell apoptosis was measured using TUNEL staining and western blotting. Reverse transcription-quantitative PCR and western blotting were performed to determine TTK expression in AGS and NCI-N87 GC cells. Rev treatment inhibited the viability of the two GC cells lines in a dose-dependent manner and suppressed their capacities of clone formation, migration and invasion. Rev-treated cells exhibited reduced matrix metalloproteinase (MMP)2/9 expression and increased apoptosis compared with those in control cells. In addition, expression of the anti-apoptotic protein Bcl-2 was significantly decreased, whilst the expression levels of the pro-apoptotic factors Bax and cleaved-caspase-3/9 were increased by Rev treatment compared with that in the control group that were not treated with Rev. In addition, TTK protein expression was decreased in cells treated with Rev compared with that in untreated cells. However, overexpression of TTK significantly reversed the aforementioned effects of Rev in GC cells. These results suggest that Rev may inhibit the proliferation, invasion and migration of GC cells whilst inducing cell apoptosis by suppressing TTK expression. Therefore, Rev may confer potential properties as a therapeutic anti-cancer agent. Additionally, TTK may serve as a molecular target for the treatment of gastric cancer.
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Affiliation(s)
- Pengfei Xia
- Department of Liver-Gallbladder and Gastric Diseases, Wuhan Hospital of Traditional Chinese Medicine, Wuhan, Hubei 430061, P.R. China
| | - Jin Liang
- Department of Liver-Gallbladder and Gastric Diseases, Wuhan Hospital of Traditional Chinese Medicine, Wuhan, Hubei 430061, P.R. China
| | - Di Jin
- Department of Liver-Gallbladder and Gastric Diseases, Wuhan Hospital of Traditional Chinese Medicine, Wuhan, Hubei 430061, P.R. China
| | - Zhanyong Jin
- Department of Liver-Gallbladder and Gastric Diseases, Wuhan Hospital of Traditional Chinese Medicine, Wuhan, Hubei 430061, P.R. China
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Nor Hisam NS, Ugusman A, Rajab NF, Ahmad MF, Fenech M, Liew SL, Mohamad Anuar NN. Combination Therapy of Navitoclax with Chemotherapeutic Agents in Solid Tumors and Blood Cancer: A Review of Current Evidence. Pharmaceutics 2021; 13:pharmaceutics13091353. [PMID: 34575429 PMCID: PMC8468743 DOI: 10.3390/pharmaceutics13091353] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/25/2021] [Accepted: 08/25/2021] [Indexed: 01/19/2023] Open
Abstract
Combination therapy emerges as a fundamental scheme in cancer. Many targeted therapeutic agents are developed to be used with chemotherapy or radiation therapy to enhance drug efficacy and reduce toxicity effects. ABT-263, known as navitoclax, mimics the BH3-only proteins of the BCL-2 family and has a high affinity towards pro-survival BCL-2 family proteins (i.e., BCL-XL, BCL-2, BCL-W) to induce cell apoptosis effectively. A single navitoclax action potently ameliorates several tumor progressions, including blood and bone marrow cancer, as well as small cell lung carcinoma. Not only that, but navitoclax alone also therapeutically affects fibrotic disease. Nevertheless, outcomes from the clinical trial of a single navitoclax agent in patients with advanced and relapsed small cell lung cancer demonstrated a limited anti-cancer activity. This brings accumulating evidence of navitoclax to be used concomitantly with other chemotherapeutic agents in several solid and non-solid tumors that are therapeutically benefiting from navitoclax treatment in preclinical studies. Initially, we justify the anti-cancer role of navitoclax in combination therapy. Then, we evaluate the current evidence of navitoclax in combination with the chemotherapeutic agents comprehensively to indicate the primary regulator of this combination strategy in order to produce a therapeutic effect.
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Affiliation(s)
- Nur Syahidah Nor Hisam
- Programme of Biomedical Science, Centre for Toxicology & Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia; (N.S.N.H.); (S.L.L.)
| | - Azizah Ugusman
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia;
| | - Nor Fadilah Rajab
- Center for Healthy Ageing & Wellness, Programme of Biomedical Science, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia; (N.F.R.); (M.F.)
| | - Mohd Faizal Ahmad
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia;
| | - Michael Fenech
- Center for Healthy Ageing & Wellness, Programme of Biomedical Science, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia; (N.F.R.); (M.F.)
- Genome Health Foundation, North Brighton, SA 5048, Australia
| | - Sze Ling Liew
- Programme of Biomedical Science, Centre for Toxicology & Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia; (N.S.N.H.); (S.L.L.)
| | - Nur Najmi Mohamad Anuar
- Programme of Biomedical Science, Centre for Toxicology & Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia; (N.S.N.H.); (S.L.L.)
- Correspondence: ; Tel.: +60-13-3845844
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The Application of Citrus folium in Breast Cancer and the Mechanism of Its Main Component Nobiletin: A Systematic Review. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:2847466. [PMID: 34257674 PMCID: PMC8260297 DOI: 10.1155/2021/2847466] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/28/2021] [Accepted: 06/19/2021] [Indexed: 02/07/2023]
Abstract
Citrus folium and its main ingredient nobiletin (NOB) have received widespread attention in recent years due to their antitumor effects. The antitumor effect of Citrus folium is related to the traditional use, mainly in its Chinese medicinal properties of soothing the liver and promoting qi, resolving phlegm, and dispelling stagnation. Some studies have proved that Citrus folium and NOB are more effective for triple-negative breast cancer (TNBC), which is related to the syndrome of stagnation of liver qi. From the perspective of modern biomedical research, NOB has anticancer effects. Its potential molecular mechanisms include inhibition of the cell cycle, induction of apoptosis, and inhibition of angiogenesis, invasion, and migration. Citrus folium and NOB can also reduce the side effects of chemotherapy drugs and reverse multidrug resistance (MDR). However, more research studies are needed to clarify the underlying mechanisms. The modern evidence of Citrus folium and NOB in breast cancer treatment has a strong connection with the traditional concepts and laws of applying Citrus folium in Chinese medicine (CM). As a low-toxic anticancer drug candidate, NOB and its structural changes, Citrus folium, and compound prescriptions will attract scientists to use advanced technologies such as genomics, proteomics, and metabolomics to study its potential anticancer effects and mechanisms. On the contrary, there are relatively few studies on the anticancer effects of Citrus folium and NOB in vivo. The clinical application of Citrus folium and NOB as new cancer treatment drugs requires in vivo verification and further anticancer mechanism research. This review aims to provide reference for the treatment of breast cancer by Chinese medicine.
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Li M. The role of P53 up-regulated modulator of apoptosis (PUMA) in ovarian development, cardiovascular and neurodegenerative diseases. Apoptosis 2021; 26:235-247. [PMID: 33783663 PMCID: PMC8197724 DOI: 10.1007/s10495-021-01667-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2021] [Indexed: 12/14/2022]
Abstract
P53 up-regulated modulator of apoptosis (PUMA), a pro-apoptotic BCL-2 homology 3 (BH3)-only member of the BCL-2 family, is a direct transcriptional target of P53 that elicits mitochondrial apoptosis under treatment with radiation and chemotherapy. It also induces excessive apoptosis in cardiovascular and/or neurodegenerative diseases. PUMA has been found to play a critical role in ovarian apoptosis. In the present paper, we review the progress of the study in PUMA over the past two decades in terms of its inducement and/or amplification of programmed cell death and describe recent updates to the understanding of both P53-dependent and P53-independent PUMA-mediated apoptotic pathways that are implicated in physiology and pathology, including the development of the ovary and cardiovascular and neurodegenerative diseases. We propose that PUMA may be a key regulator during ovary development, provide a model for PUMA-mediated apoptotic pathways, including intrinsic and extrinsic apoptotic pathways.
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Affiliation(s)
- Mei Li
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, China.
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Yuan W, Wu J, Zhang Q, Liang Y, Zhang M, Qin H, Li CS. Shen-fu injection alleviates acute renal injury by reducing cytokine levels and modulating apoptosis in a porcine hemorrhagic shock model. Acta Cir Bras 2021; 36:e360405. [PMID: 34076082 PMCID: PMC8184256 DOI: 10.1590/acb360405] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/16/2021] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Shen-fu injection (SFI) was used to intervene in the resuscitation of porcine hemorrhagic shock (HS) model to study its protective effects on acute kidney injury. METHODS After 60 min of HS, 28 animals were randomly assigned into four groups. The groups were as follows: hemorrhagic shock group (HS); HS resuscitation with shed-blood group (HSR); HS resuscitation with shed-blood and SFI (1 mL·kg-1) group (HSR-SFI); and the sham operation group (Sham). The bloods were analyzed for serum creatinine (sCr), cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL). BAX, Bcl-2, and caspase-3 protein expressions by Western blot analysis and immunohistochemical staining. The renal tissues were removed and pathologic changes were observed. RESULTS Mean aortic pressure (MAP) in HSR-SFI groups were higher than that in HSR groups after shock. At the 6th hour after shock, the urine volume per hour in the HSR-SFI groups was more than that in the HSR groups. The sCr, NGAL, CysC and cytokine levels of HSR-SFI groups were lower. The Bcl-2 expression was increased in the HSR-SFI groups. The BAX and caspase-3 expressions were reduced. The histopathologic score in the HSR-SFI was lower. CONCLUSIONS SFI may reduce the risk of acute kidney injury (AKI) following hemorrhagic shock by attenuating systemic inflammatory responses, and regulating the expression of apoptosis-related proteins.
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Affiliation(s)
- Wei Yuan
- Capital Medical University, China
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Berthenet K, Castillo Ferrer C, Fanfone D, Popgeorgiev N, Neves D, Bertolino P, Gibert B, Hernandez-Vargas H, Ichim G. Failed Apoptosis Enhances Melanoma Cancer Cell Aggressiveness. Cell Rep 2021; 31:107731. [PMID: 32521256 DOI: 10.1016/j.celrep.2020.107731] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 04/13/2020] [Accepted: 05/14/2020] [Indexed: 12/22/2022] Open
Abstract
Triggering apoptosis remains an efficient strategy to treat cancer. However, apoptosis is no longer a final destination since cancer cells can undergo partial apoptosis without dying. Recent evidence shows that partial mitochondrial permeabilization and non-lethal caspase activation occur under certain circumstances, although it remains unclear how failed apoptosis affects cancer cells. Using a cancer cell model to trigger non-lethal caspase activation, we find that melanoma cancer cells undergoing failed apoptosis have a particular transcriptomic signature associated with focal adhesions, transendothelial migration, and modifications of the actin cytoskeleton. In line with this, cancer cells surviving apoptosis gain migration and invasion properties in vitro and in vivo. We further demonstrate that failed apoptosis-associated gain in invasiveness is regulated by the c-Jun N-terminal kinase (JNK) pathway, whereas its RNA sequencing signature is found in metastatic melanoma. These findings advance our understanding of how cell death can both cure and promote cancer.
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Affiliation(s)
- Kevin Berthenet
- Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS 5286, Lyon, France; Cancer Cell Death Laboratory, Part of LabEx DEVweCAN, Université de Lyon, Lyon, France
| | - Camila Castillo Ferrer
- Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Grenoble Alpes University, Grenoble, France; EPHE, PSL Research University, Paris, France
| | - Deborah Fanfone
- Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS 5286, Lyon, France; Cancer Cell Death Laboratory, Part of LabEx DEVweCAN, Université de Lyon, Lyon, France
| | | | | | - Philippe Bertolino
- Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS 5286, Lyon, France
| | - Benjamin Gibert
- Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS 5286, Lyon, France; Apoptosis, Cancer and Development Laboratory, Labeled by "La Ligue Contre le Cancer," Part of LabEx DEVweCAN and Convergence PLAsCAN Institute, Lyon, France
| | - Hector Hernandez-Vargas
- Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS 5286, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France
| | - Gabriel Ichim
- Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS 5286, Lyon, France; Cancer Cell Death Laboratory, Part of LabEx DEVweCAN, Université de Lyon, Lyon, France.
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Quintana M, Saavedra E, del Rosario H, González I, Hernández I, Estévez F, Quintana J. Ethanol Enhances Hyperthermia-Induced Cell Death in Human Leukemia Cells. Int J Mol Sci 2021; 22:ijms22094948. [PMID: 34066632 PMCID: PMC8125413 DOI: 10.3390/ijms22094948] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/04/2021] [Accepted: 05/04/2021] [Indexed: 12/23/2022] Open
Abstract
Ethanol has been shown to exhibit therapeutic properties as an ablative agent alone and in combination with thermal ablation. Ethanol may also increase sensitivity of cancer cells to certain physical and chemical antitumoral agents. The aim of our study was to assess the potential influence of nontoxic concentrations of ethanol on hyperthermia therapy, an antitumoral modality that is continuously growing and that can be combined with classical chemotherapy and radiotherapy to improve their efficiency. Human leukemia cells were included as a model in the study. The results indicated that ethanol augments the cytotoxicity of hyperthermia against U937 and HL60 cells. The therapeutic benefit of the hyperthermia/ethanol combination was associated with an increase in the percentage of apoptotic cells and activation of caspases-3, -8 and -9. Apoptosis triggered either by hyperthermia or hyperthermia/ethanol was almost completely abolished by a caspase-8 specific inhibitor, indicating that this caspase plays a main role in both conditions. The role of caspase-9 in hyperthermia treated cells acquired significance whether ethanol was present during hyperthermia since the alcohol enhanced Bid cleavage, translocation of Bax from cytosol to mitochondria, release of mitochondrial apoptogenic factors, and decreased of the levels of the anti-apoptotic factor myeloid cell leukemia-1 (Mcl-1). The enhancement effect of ethanol on hyperthermia-activated cell death was associated with a reduction in the expression of HSP70, a protein known to interfere in the activation of apoptosis at different stages. Collectively, our findings suggest that ethanol could be useful as an adjuvant in hyperthermia therapy for cancer.
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Ma Y, Yan G, Guo J, Li F, Zheng H, Wang C, Chen Y, Ye Y, Dai H, Qi Z, Zhuang G. Berberine Prolongs Mouse Heart Allograft Survival by Activating T Cell Apoptosis via the Mitochondrial Pathway. Front Immunol 2021; 12:616074. [PMID: 33732240 PMCID: PMC7959711 DOI: 10.3389/fimmu.2021.616074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 01/18/2021] [Indexed: 11/25/2022] Open
Abstract
Berberine, which is a traditional Chinese medicine can inhibit tumorigenesis by inducing tumor cell apoptosis. However, the immunoregulatory of effects berberine on T cells remains poorly understood. Here, we first examined whether berberine can prolong allograft survival by regulating the recruitment and function of T cells. Using a major histocompatibility complex complete mismatch mouse heterotopic cardiac transplantation model, we found that the administration of moderate doses (5 mg/kg) of berberine significantly prolonged heart allograft survival to 19 days and elicited no obvious berberine-related toxicity. Compared to that with normal saline treatment, berberine treatment decreased alloreactive T cells in recipient splenocytes and lymph node cells. It also inhibited the activation, proliferation, and function of alloreactive T cells. Most importantly, berberine treatment protected myocardial cells by decreasing CD4+ and CD8+ T cell infiltration and by inhibiting T cell function in allografts. In vivo and in vitro assays revealed that berberine treatment eliminated alloreactive T lymphocytes via the mitochondrial apoptosis pathway, which was validated by transcriptome sequencing. Taken together, we demonstrated that berberine prolongs allograft survival by inducing apoptosis of alloreactive T cells. Thus, our study provides more evidence supporting the potential use of berberine in translational medicine.
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Affiliation(s)
- Yunhan Ma
- Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Organ Transplantation Institute, Xiamen University, Xiamen, China
| | - Guoliang Yan
- School of Medicine, Xiamen University, Xiamen, China
| | - Junjun Guo
- School of Medicine, Xiamen University, Xiamen, China
| | - Fujun Li
- Department of Anesthesiology, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Haiping Zheng
- School of Medicine, Xiamen University, Xiamen, China
| | - Chenxi Wang
- School of Medicine, Xiamen University, Xiamen, China
| | - Yingyu Chen
- Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Organ Transplantation Institute, Xiamen University, Xiamen, China
| | - Yuhan Ye
- Department of Pathology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, China
| | - Helong Dai
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.,Clinical Research Center for Organ Transplantation in Hunan Province, Changsha, China.,Clinical Immunology Center, Central South University, Changsha, China
| | - Zhongquan Qi
- Medical College, Guangxi University, Nanning, China
| | - Guohong Zhuang
- Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Organ Transplantation Institute, Xiamen University, Xiamen, China
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Choi YS, Han JM, Kang YJ, Jung HJ. Chloroform extract of Citrus unshiu Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells. Mol Med Rep 2020; 23:86. [PMID: 33236129 PMCID: PMC7716394 DOI: 10.3892/mmr.2020.11727] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
Cervical cancer is the second most common cancer among women worldwide. However, chemotherapies for this cancer often cause many side effects and chemoresistance. Citrus unshiu Markovich peel (CECU) has been used as a traditional medicine for the treatment of various diseases in East Asia. Recently, the anticancer activities and mechanisms of action of CECU extract have been reported in a number of different cancer cell types, but no study has evaluated the therapeutic effect of this natural product on cervical cancer cells. In the current study, the anticancer activity and the underlying molecular mechanism of the chloroform extract of CECU was investigated on HeLa human cervical cancer cells. The results showed that CECU effectively inhibited the proliferation and migration of HeLa cells. Treatment of cells with CECU led to cell cycle arrest at the G2/M phase and activation of extrinsic and intrinsic apoptotic pathways. Furthermore, the proliferation inhibitory effect of CECU was due to the inactivation of AKT and ERK signaling, upregulation of p53 and p21, and downregulation of cyclin B1 and cyclin D1, but not reactive oxygen species (ROS) generation. Furthermore, CECU inhibited the stem‑like features of HeLa cells by downregulating key cancer stemness biomarkers. Therefore, CECU may be an effective complementary and alternative medicine for the prevention and treatment of cervical cancer.
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Affiliation(s)
- Ye Seul Choi
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea
| | - Jang Mi Han
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea
| | - Yue Jai Kang
- Department of Aquatic Life and Medical Sciences, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea
| | - Hye Jin Jung
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea
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Anticancer Activity of Tetrandrine by Inducing Apoptosis in Human Breast Cancer Cell Line MDA-MB-231 In Vivo. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:6823520. [PMID: 32714412 PMCID: PMC7345956 DOI: 10.1155/2020/6823520] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/15/2020] [Indexed: 01/02/2023]
Abstract
Tetrandrine (TET) is an alkaloid extracted from a traditional Chinese medicinal plant. It exerts remarkable anticancer activity and induces apoptotic cell death in various human cancer cells. The present study aimed to investigate the effects of TET on the inhibition of tumor growth and the induction of apoptosis in MDA-MB-231 breast cancer in xenograft mice. Tumor weight and volume were measured. The histopathological changes in the tumor tissue were observed. Immunohistochemistry analysis of Bcl-2-associated X protein (Bax) and B-cell lymphoma/leukemia-2 (Bcl-2) was carried out. The expression of apoptosis-associated genes and proteins, such as cysteine aspartic acid-specific protease-3 (Caspase-3), Survivin, Bax, Bcl-2, BH3-interacting domain death agonist (Bid), and poly ADP-ribose polymerase (PARP), was measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. TET inhibited tumor growth and induced apoptosis in TNBC cell line MDA-MB-231. The mechanism underlying this effect might be mediated by TET-upregulated Caspase-3, Bax, and Bid and downregulated by Bcl-2, Survivin, and PARP. Taken together, this study supported the fact that TET is a promising therapeutic agent for the treatment of TNBC, thereby providing experimental evidence for its use in the treatment of breast cancer.
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Lu HT, Xu YQ, Wang H, Zhang XL. miR-424-5p regulates apoptosis and cell proliferation via targeting Bcl2 in nucleus pulposus cells. Anim Cells Syst (Seoul) 2020; 24:136-142. [PMID: 33209193 PMCID: PMC7651851 DOI: 10.1080/19768354.2020.1775699] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
miRNAs play an important role in the pathogenesis of intervertebral disc degeneration (IDD). The role and the underlying mechanism of miR-424-5p in human nucleus pulposus (NP) are still unknown. We aimed to explore the role of miR-424-5p in IDD. Real-time PCR was used to detect the expression of miR-424-5p and Bcl2 in IDD tissues and idiopathic scoliosis tissues. Human NP cells were used in our study. MTT and Hoechst apoptosis assays were used to detect the proliferation and apoptosis of NP cells, respectively. Western blotting assays were used to detect the expression levels of Bcl-2, cleaved caspase-3, cleaved caspase-9, caspase-3 and caspase-9 in degenerative NP cells. A luciferase reporter assay was applied to confirm the relationship between miR-424-5p and Bcl2. Our results showed that the expression of miR-424-5p was increased and Bcl2 was decreased in degenerative NP cells. miR-425-5p expression was negatively correlated with Bcl2 expression in IDD tissues. Suppression of miR-424-5p using an inhibitor increased Bcl2 expression at both the mRNA and protein levels, and it promoted cell viability and inhibited apoptosis. Furthermore, the levels of cleaved caspase-3 and cleaved caspase-9 were downregulated in miR-424-5p-silenced NP cells. Interestingly, we found that silencing miR-424-5p increased p62 expression at both the mRNA and protein levels. Finally, a luciferase reporter assay verified the binding of the miR-424-5p and the 3’UTR of Bcl2. These results suggested that silencing miR-424-5p suppressed NP cell apoptosis by upregulating Bcl2. Therefore, miR-424-5p might be a novel target for IDD therapies.
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Affiliation(s)
- Hua-Tuo Lu
- Graduate school of kunming medical university, Kunming, PR People's Republic of China.,Department of orthopedics, 920th Hospital of Joint Logistics Support Force, Kunming, PR People's Republic of China
| | - Yong-Qing Xu
- Department of orthopedics, 920th Hospital of Joint Logistics Support Force, Kunming, PR People's Republic of China
| | - Hai Wang
- Department of orthopedics, 920th Hospital of Joint Logistics Support Force, Kunming, PR People's Republic of China.,Kunming university of science and technology, Kunming, PR People's Republic of China.,Department of orthopedics, xingsha branch of hunan provincianal people's hospital, Changsha, PR People's Republic of China
| | - Xu-Lin Zhang
- Graduate school of kunming medical university, Kunming, PR People's Republic of China.,Department of orthopedics, 920th Hospital of Joint Logistics Support Force, Kunming, PR People's Republic of China
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Wang J, Wu T, Ma L, Guo Y, Huang Y, Zheng L. Action of Akt Pathway on La-Induced Hippocampal Neuron Apoptosis of Rats in the Growth Stage. Neurotox Res 2020; 38:434-446. [PMID: 32385838 DOI: 10.1007/s12640-020-00206-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/04/2020] [Accepted: 04/08/2020] [Indexed: 11/28/2022]
Abstract
This study investigated the influences of lanthanum (La) exposure on learning and memory and the expression of apoptosis-related proteins in offspring rats. Wistar female rats were randomly divided into a control group (NC) and 0.25%, 0.5% and 1.0% LaCl3 treatment groups, with eight per group. La dye was transmitted to offspring rats through parental blood circulation and breast milk before delactation and through water drinking after delectation. Offspring rats were killed at 14, 28 and 42 days after birth. Hippocampal neurons were observed by microscope, and apoptosis and necrosis were tested. The expression levels of apoptosis-related proteins were detected by Western blot, and Morris water maze experiments were used to measure learning and memory abilities. LaCl3 groups showed longer escape latency periods and swimming distances than the NC group (p < 0.05). The 1.0% LaCl3 group passed across the target quadrants and platforms more times and stayed in the target quadrants for less time, than the NC group (p < 0.05). At 42 days, the apoptosis rate and necrosis in the hippocampus of the 1.0% LaCl3 group were significantly higher than those of other groups. There was a significant difference among LaCl3 groups in terms of protein expressions measured in the hippocampus. In LaCl3 groups, caspase-3 and caspase-9 were significantly higher than in the NC group (p < 0.05). Therefore, La exposure can promote neuronal apoptosis by regulating the protein expressions of Akt, Bcl-2, Bcl-xl, Bax, Bad, caspase-3 and caspase-9, thus damaging learning and memory and the hippocampal neurons of offspring rats.
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Affiliation(s)
- Jinting Wang
- Institute of Molecular Medicine, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China.,Department of Nursing, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China
| | - Tianwei Wu
- Institute of Molecular Medicine, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China.,Department of Nursing, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China
| | - Lan Ma
- Institute of Molecular Medicine, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China.,Department of Nursing, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China
| | - Ying Guo
- Institute of Molecular Medicine, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China.,Department of Nursing, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China
| | - Yali Huang
- Institute of Molecular Medicine, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China.,Department of Nursing, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China
| | - Linlin Zheng
- Institute of Molecular Medicine, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China. .,Department of Nursing, School of medicine, Eastern Liaoning University, Dandong, 118003, Liaoning, People's Republic of China.
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Down-regulation of Bcl2 and Survivin, and up-regulation of Bax involved in copper (II) phenylthiosemicarbazone complex-induced apoptosis in leukemia stem-like KG1a cells. Process Biochem 2020. [DOI: 10.1016/j.procbio.2020.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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44
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Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target. Cell Death Dis 2020; 11:268. [PMID: 32327636 PMCID: PMC7181796 DOI: 10.1038/s41419-020-2463-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/05/2020] [Accepted: 04/06/2020] [Indexed: 02/08/2023]
Abstract
BAK and BAX, which drive commitment to apoptosis, are activated principally by certain BH3-only proteins that bind them and trigger major rearrangements. One crucial conformation change is exposure of their BH3 domain which allows BAK or BAX to form homodimers, and potentially to autoactivate other BAK and BAX molecules to ensure robust pore formation and cell death. Here, we test whether full-length BAK or mitochondrial BAX that are specifically activated by antibodies can then activate other BAK or BAX molecules. We found that antibody-activated BAK efficiently activated BAK as well as mitochondrial or cytosolic BAX, but antibody-activated BAX unexpectedly proved a poor activator. Notably, autoactivation by BAK involved transient interactions, as BAK and BAX molecules it activated could dissociate and homodimerize. The results suggest that BAK-driven autoactivation may play a substantial role in apoptosis, including recruitment of BAX to the mitochondria. Hence, directly targeting BAK rather than BAX may prove particularly effective in inhibiting unwanted apoptosis, or alternatively, inducing apoptosis in cancer cells.
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Chen RJ, Rui QL, Wang Q, Tian F, Wu J, Kong XQ. Shenfu injection attenuates lipopolysaccharide-induced myocardial inflammation and apoptosis in rats. Chin J Nat Med 2020; 18:226-233. [PMID: 32245593 DOI: 10.1016/s1875-5364(20)30025-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Indexed: 11/18/2022]
Abstract
Shenfu injection (SFI), a Chinese medicinal product, shows potent efficacy in treating sepsis. The aim of the present study was to clarify the protective effects of SFI against lipopolysaccharide (LPS)-induced myocardial inflammation and apoptosis. Experiments were carried out in Sprague-Dawley (SD) rats treated with LPS or LPS + SFI, and in H9C2 cardiomyocytes. The sepsis-associated myocardial inflammation and apoptosis was induced by the intraperitoneal injection of LPS (20 mg·kg-1). SFI attenuated the increased expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β induced by LPS both in serum and heart. In LPS group, cell viability was reduced, and reversed after SFI administration. LPS treatment increased the expression levels of cleaved-caspase 3 and Bax, and those of Bcl2 and Bcl2/Bax. These two trends were reversed by SFI administration. The expression levels of phosphorylated mitogen-activated protein kinase kinase (p-MEK) and phosphorylated extracellular regulated protein kinases (p-ERK) were increased by LPS, and reversed by SFI. MEK inhibitor U0126 attenuated the apoptosis induced by LPS. These results indicate that SFI could treat LPS-induced cardiac dysfunction. In conclusion, SFI attenuates the inflammation and apoptosis induced by LPS via downregulating the MEK and ERK signaling pathways.
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Affiliation(s)
- Rui-Juan Chen
- Cardiology Department, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; Emergency Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Qing-Lin Rui
- Emergency Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Qiong Wang
- Clinical Pharmacology Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Fang Tian
- Central Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Jian Wu
- Central Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Xiang-Qing Kong
- Cardiology Department, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
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Sun DZ, Song CQ, Xu YM, Dong XS. Role of the MAPK pathway in human lung epithelial-like A549 cells apoptosis induced by paraquat. Genet Mol Biol 2020; 43:e20190137. [PMID: 32251495 PMCID: PMC7198013 DOI: 10.1590/1678-4685-gmb-2019-0137] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 01/07/2020] [Indexed: 12/18/2022] Open
Abstract
This study aims to investigate the value of mitogen-activated protein kinases
(MAPKs) for paraquat (PQ)-induced apoptosis in human lung epithelial-like A549
cells and the specific mechanism. A549 cell apoptosis were induced by PQ. These
cells were divided into six groups: control group (cells were cultured in
RPMI-1640 medium); SP600125 group (cells were preconditioned with SP600125);
SB203580 group (cells were preconditioned with SB203580); PQ group (cells were
treated with PQ); SP600125+PQ group (cells were preconditioned with SP600125
following PQ); SB203580+PQ group (cells were preconditioned with SB203580
following PQ). The cell survival rate, apoptosis rate, and activities of
caspase-3 and -9 were detected. When compared with the control group, both
SP600125 and SB203580 groups had no significant difference in the detected
indicators. When compared with PQ group, the cells in both SP600125+PQ group and
SB203580+PQ group had significantly increased viability and level of
anti-apoptotic protein Bcl-2; and had decreased apoptotic rates, decreased
levels of caspase-3 and -9, and decreased level of pro-apoptotic protein Bax.
The ratio of p-JNK/JNK protein expression in the SP600125+PQ group significantly
decreased, while the ratio of the p-P38/P38 protein expression in the
SB203580+PQ group decreased. PQ induced A549 cell apoptosis through the MAPKs
pathway.
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Affiliation(s)
- Da-Zhuang Sun
- Department of Emergency, The First Affiliated Hospital, China Medical University, Shenyang 110001, China
| | - Chun-Qing Song
- Department of Emergency, The First Affiliated Hospital, China Medical University, Shenyang 110001, China
| | - Yong-Min Xu
- Department of Emergency, The First Affiliated Hospital, China Medical University, Shenyang 110001, China
| | - Xue-Song Dong
- Department of Emergency, The First Affiliated Hospital, China Medical University, Shenyang 110001, China
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Feng X, Zhang H, Shi M, Chen Y, Yang T, Fan H. Toxic effects of hydrogen sulfide donor NaHS induced liver apoptosis is regulated by complex IV subunits and reactive oxygen species generation in rats. ENVIRONMENTAL TOXICOLOGY 2020; 35:322-332. [PMID: 31680430 DOI: 10.1002/tox.22868] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/15/2019] [Accepted: 10/16/2019] [Indexed: 06/10/2023]
Abstract
In recent years, the protective effect of hydrogensulfide donor sodium hydrosulfide(NaHS) on multiple organs has been widely reported. The study aimed to explorethe effect of commonly used concentration of NaHS on theliver and its potential damage mechanism. Rats divided into 4 groups: control, NaHS I (1 mg/kg), II (3 mg/kg) and III(5 mg/kg) groups, and each group is divided into four-timepoints (2, 6, 12, and 24 hours). Results showed that H2S concentration increased, mitochondrial complex IV activity inhibited, the COX I and IV subunits and mitochondrial apoptosis pathway-related proteins expression increased in atime- and dose-dependent manner. We confirmed that 1 mg/kg NaHS had no injuryeffect on the liver, 3 and 5 mg/kg NaHS inhibitsthe activity of mitochondrial complex IV by promoting COX I and IV subunits expression, leading to the increase in ROS and ultimately inducing apoptosis and liver injury.
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Affiliation(s)
- Xiujing Feng
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Haiyang Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Mingxian Shi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Yongping Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Tianyuan Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Honggang Fan
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
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Bak DH, Lee E, Choi MJ, Lee BC, Kwon TR, Kim JH, Jeon ES, Oh W, Mun SK, Park BC, Na J, Kim BJ. Protective effects of human umbilical cord blood‑derived mesenchymal stem cells against dexamethasone‑induced apoptotic cell death in hair follicles. Int J Mol Med 2019; 45:556-568. [PMID: 31894311 PMCID: PMC6984800 DOI: 10.3892/ijmm.2019.4447] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 11/29/2019] [Indexed: 12/12/2022] Open
Abstract
Alopecia is a common and distressing condition, and developing new therapeutic agents to prevent hair loss is important. Human umbilical cord blood‑derived mesenchymal stem cells (hUCB‑MSCs) have been studied intensively in regenerative medicine. However, the therapeutic potential of these cells against hair loss and hair organ damage remains unclear, and the effects of hUCB‑MSC transplantation on hair loss require evaluation. The current study aimed to investigate the effects of hUCB‑MSCs on hair regression in vivo and restoration of anagen conduction on hair growth in vitro. The effects of hUCB‑MSCs were explored in mouse catagen induction models using a topical treatment of 0.1% dexamethasone to induce hair regression. Dexamethasone was also used to simulate a stress environment in vitro. The results demonstrated that hUCB‑MSCs significantly prevented hair regression induced by dexamethasone topical stimulation in vivo. Additionally, hUCB‑MSCs significantly increased the proliferation of human dermal papilla cells (hDPCs) and HaCaT cells, which are key constituent cells of the hair follicle. Stimulation of vascular endothelial growth factor secretion and decreased expression of DKK‑1 by hUCB‑MSCs were also observed in hDPCs. Restoration of cell viability by hUCB‑MSCs suggested that these cells exerted a protective effect on glucocorticoid stress‑associated hair loss. In addition, anti‑apoptotic effects and regulation of the autophagic flux recovery were observed in HaCaT cells. The results of the present study indicated that hUCB‑MSCs may have the capacity to protect hair follicular dermal papilla cells and keratinocytes, thus preventing hair loss. Additionally, the protective effects of hUCB‑MSCs may be resistant to dysregulation of autophagy under harmful stress.
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Affiliation(s)
- Dong Ho Bak
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, North Jeolla 56212, Republic of Korea
| | - Esther Lee
- Department of Dermatology, College of Medicine, Seoul 06973, Republic of Korea
| | - Mi Ji Choi
- Department of Dermatology, College of Medicine, Seoul 06973, Republic of Korea
| | - Byung Chul Lee
- Department of Dermatology, College of Medicine, Seoul 06973, Republic of Korea
| | - Tae-Rin Kwon
- Department of Dermatology, College of Medicine, Seoul 06973, Republic of Korea
| | - Jong-Hwan Kim
- Department of Dermatology, College of Medicine, Seoul 06973, Republic of Korea
| | - Eun Su Jeon
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Seongnam, Gyeonggi 13494, Republic of Korea
| | - Wonil Oh
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Seongnam, Gyeonggi 13494, Republic of Korea
| | - Seog Kyun Mun
- Department of Otorhinolaryngology, College of Medicine, Chung‑Ang University, Seoul 06973, Republic of Korea
| | - Byung Cheol Park
- Department of
Dermatology, Dankook Medical College, Cheonan, South Chungcheong 31116, Republic of Korea
| | - Jungtae Na
- Department of Dermatology, College of Medicine, Seoul 06973, Republic of Korea
| | - Beom Joon Kim
- Department of Dermatology, College of Medicine, Seoul 06973, Republic of Korea
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Xu Y, Li Z, Zhang S, Zhang H, Teng X. miR-187-5p/apaf-1 axis was involved in oxidative stress-mediated apoptosis caused by ammonia via mitochondrial pathway in chicken livers. Toxicol Appl Pharmacol 2019; 388:114869. [PMID: 31863799 DOI: 10.1016/j.taap.2019.114869] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 12/16/2019] [Accepted: 12/17/2019] [Indexed: 12/21/2022]
Abstract
Ammonia (NH3), a toxic gas, is an important cause of atmospheric haze and one of the main pollutants in air environment of poultry houses, threatening the health of human beings and poultry. However, little is known about the effect of NH3 on liver apoptotic damage. This study aimed to investigate the mechanism of oxidative stress-mediated apoptosis caused by NH3 in chicken livers and whether miR-187-5p/apaf-1 axis was involved in this mechanism. Here we duplicated NH3 poisoning model of chickens for fattening to study the ultrastructure of chicken livers, apoptosis rate, oxidative stress indexes, miR-187-5p, and apoptosis-related genes. Obvious apoptotic characteristics of liver tissues exposed to excess NH3 were observed, and the apoptosis rate increased. Excess NH3 decreased the activities of catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px), and increased the content of malondialdehyde (MDA), suggesting that oxidative stress occurred. miR-187-5p decreased, and apoptotic protease activating factor-1 (apaf-1) increased, indicating that excess NH3 dysregulated miR-187-5p/apaf-1 axis. The expression of tumor protein p53 (p53), Bcl-2 associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak), Cytochrome-c (Cyt-c), Caspase-9, Caspase-8, and Caspase-3 was promoted, and the expression of B-cell lymphoma-2 (Bcl-2) was inhibited, resulting in apoptosis. Moreover, oxidative stress indexes, miR-187-5p, and apoptosis-related genes changed in dose- and time-dependent manner. Altogether, miR-187-5p/apaf-1 axis participated in oxidative stress-mediated apoptosis caused by NH3 via mitochondrial pathway in the livers of chickens for fattening. This study may provide new ideas to study the mechanism of liver apoptotic damage induced by NH3 exposure.
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Affiliation(s)
- Yanmin Xu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, People's Republic of China
| | - Zhuo Li
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, People's Republic of China
| | - Shuai Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, People's Republic of China
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, People's Republic of China.
| | - Xiaohua Teng
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, People's Republic of China.
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50
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Alzate JM, Montoya-Florez LM, Pérez JE, Rocha NS, Pedraza-Ordonez FJ. The role of the multi-drug resistance 1, p53, b cell lymphoma 2, and bcl 2-associated X genes in the biologic behavior and chemotherapeutic resistance of canine transmissible venereal tumors. Vet Clin Pathol 2019; 48:730-739. [PMID: 31777108 DOI: 10.1111/vcp.12805] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 02/02/2019] [Accepted: 02/16/2019] [Indexed: 11/27/2022]
Abstract
BACKGROUND Canine transmissible venereal tumors (CTVTs) generally have different cytomorphologic subtypes and phases of progression. Some tumors have variable biologic behavior including a progressive increase in tumor aggressiveness and variable responses to chemotherapy. This behavior is partially due to high p-glycoprotein expression by tumor cells, which leads to the expulsion of chemotherapeutic drugs. Other possible causes include changes in pro- and anti-apoptotic genes from the BCL-2 family and DNA repair systems, which are associated with the p53 gene family. OBJECTIVES We aimed to determine the relative expression of the multi-drug resistance 1 (MDR1), p53, b-cell lymphoma 2 (BCL2), and bcl 2-associated X (BAX) genes in CTVT before and after therapy and establish a relationship with treatment responses, cytomorphologic patterns, and tumor progression identified with histopathology. METHODS RT-qPCR was performed on 21 CTVT tumor samples before and after initiating chemotherapy to determine specific gene expression. Normal canine testicular tissue was used as a negative control for all experiments. RESULTS MDR1 expression was decreased before and after initiating vincristine therapy in CTVT tumor tissues compared with normal canine testicular tissue; p53 and BAX were overexpressed at both time points compared with normal tissue, and no statistical differences were seen between the different morphologic types. However, BAX expression was decreased in the group with quick therapeutic responses but was still overexpressed compared with normal testicular tissue. In the group with the slowest chemotherapeutic responses, BCL2 was overexpressed. CONCLUSION The findings of this study showed a relative increase in MDR1 gene expression in response to chemotherapy and higher expression in plasmacytoid CTVTs compared with the other cytomorphologic patterns. BCL2 overexpression was related to a favorable prognosis, and p53, BAX, and BCL2 were expressed independent of the cytomorphologic CTVT type. All of the genes were expressed independent of tumor progression, as noted on histopathology.
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Affiliation(s)
- Juliana M Alzate
- Faculty of Agricultural Sciences, Veterinary Medicine Department, Universidad de Pamplona, Pamplona, Colombia
| | - Luis M Montoya-Florez
- Faculty of Veterinary Medicine, Universidad Nacional de Colombia, Bogotá, Colombia.,Research Group in Veterinary Medicine and Husbandry - GIDIMEVETZ, Pedagogical and Technological University of Colombia, Tunja, Colombia
| | - Jorge E Pérez
- Basic Sciences Department, Universidad de Caldas, Manizales, Colombia
| | - Noeme S Rocha
- Laboratory of Investigative and Comparative Pathology, FMVZ-UNESP, Botucatu, Brazil
| | - Francisco J Pedraza-Ordonez
- Research Group in Veterinary Pathology, Animal Health Department, Universidad de Caldas, Manizales, Colombia
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