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1
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Morishita M, Matsuda S. SARM1 is essential for NMDA receptor-dependent endocytosis of AMPA receptors in hippocampal neurons. Neurosci Res 2025; 210:28-37. [PMID: 39349221 DOI: 10.1016/j.neures.2024.09.005] [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: 07/05/2024] [Revised: 09/03/2024] [Accepted: 09/26/2024] [Indexed: 10/02/2024]
Abstract
Long-term depression (LTD) is a form of synaptic plasticity thought to be the cellular basis of experience-dependent learning and memory. LTD is caused by an activity-dependent decrease in cell surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPA receptors) at the postsynaptic sites. However, the mechanism through which AMPA receptors are removed from the cell surface via neuronal activity is not fully understood. In this study, we showed that small interfering RNA (siRNA)-mediated knockdown of sterile alpha and toll/interleukin receptor motif containing 1 (SARM1) in cultured hippocampal neurons prevented the N-methyl-d-aspartate (NMDA)-induced reduction in cell surface AMPA receptors. However, the control RNA did not affect NMDA-mediated AMPA receptor trafficking. Overexpression of the siRNA-resistant form of SARM1 in SARM1-knocked-down neurons restored AMPA receptor trafficking. However, overexpression of SARM1, which lacks the mitochondrial transport signal, in the SARM1-knocked-down neurons did not restore NMDA-dependent AMPA receptor endocytosis. Moreover, the inhibition of the NADase activity of SARM1 blocked the NMDA-induced reduction of cell surface AMPA receptors. These results suggest that both the mitochondrial localization and NADase activity of SARM1 are essential for NMDA receptor-dependent AMPA receptor internalization in the hippocampal neurons.
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Affiliation(s)
- Misaki Morishita
- Department of Engineering Science, Graduate School of Informatics and Engineering, The University of Electro-Communications, Tokyo 182-8585, Japan
| | - Shinji Matsuda
- Department of Engineering Science, Graduate School of Informatics and Engineering, The University of Electro-Communications, Tokyo 182-8585, Japan; Center for Neuroscience and Biomedical Engineering (CNBE), The University of Electro-Communications, Tokyo 182-8585, Japan.
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2
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Manjunath M, Ravindran F, Sharma S, Siddiqua H, Raghavan SC, Choudhary B. Disarib, a Specific BCL2 Inhibitor, Induces Apoptosis in Triple-Negative Breast Cancer Cells and Impedes Tumour Progression in Xenografts by Altering Mitochondria-Associated Processes. Int J Mol Sci 2024; 25:6485. [PMID: 38928195 PMCID: PMC11203414 DOI: 10.3390/ijms25126485] [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: 04/03/2024] [Revised: 05/23/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Targeted cancer therapy aims to disrupt the functions of proteins that regulate cancer progression, mainly by using small molecule inhibitors (SMIs). SMIs exert their effect by modulating signalling pathways, organelle integrity, chromatin components, and several biosynthetic processes essential for cell division and survival. Antiapoptotic protein BCL2 is highly upregulated in many cancers compared with normal cells, making it an ideal target for cancer therapy. Around 75% of primary breast cancers overexpress BCL2, providing an opportunity to explore BCL2 inhibitors as a therapeutic option. Disarib is an SMI that has been developed as a selective BCL2 inhibitor. Disarib works by disrupting BCL2-BAK interaction and activating intrinsic apoptotic pathways in leukemic cells while sparing normal cells. We investigated the effects of Disarib, a BCL2 specific inhibitor, on breast cancer cells and xenografts. Cytotoxicity and fluorometric assays revealed that Disarib induced cell death by increasing reactive oxygen species and activating intrinsic apoptotic pathways in Triple-Negative Breast Cancer cells (MDA-MB-231 and MDA-MB-468). Disarib also affected the colony-forming properties of these cells. MDA-MB-231- and MDA-MB-468-derived xenografts showed a significant reduction in tumours upon Disarib treatment. Through the transcriptomics approach, we also explored the influence of BCL2 inhibitors on energy metabolism, mitochondrial dynamics, and epithelial-to-mesenchymal transition (EMT). Mitochondrial dynamics and glucose metabolism mainly regulate energy metabolism. The change in energetics regulates tumour growth through epithelial-mesenchymal transition, and angiogenesis. RNA sequencing (RNAseq) analysis revealed that BCL2 inhibitors ABT-199 and Disarib maintain Oxphos levels in MDA-MB-231. However, key glycolytic genes were significantly downregulated. Mitochondrial fission genes were seen to be downregulated both in RNAseq data and semi quantitative real time polymerase chain reaction (qRTPCR) in Disarib-treated TNBC cells and xenografts. Lastly, Disarib inhibited wound healing and epithelial-to-mesenchymal transition. This study showed that Disarib disrupts mitochondrial function, activates the intrinsic apoptotic pathway in breast cancer, and inhibits epithelial-to-mesenchymal transition both in vitro and in vivo. These findings highlight Disarib's potential as a multifaceted therapeutic strategy for patients with Triple-Negative Breast Cancer.
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Affiliation(s)
- Meghana Manjunath
- Department of Biotechnology and Applied Bioinformatics, Institute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bengaluru 560100, India
| | - Febina Ravindran
- Department of Biotechnology and Applied Bioinformatics, Institute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bengaluru 560100, India
| | - Shivangi Sharma
- Department of Biotechnology and Applied Bioinformatics, Institute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bengaluru 560100, India
- Indian Institute of Science, Bengaluru 560012, India; (H.S.); (S.C.R.)
| | - Humaira Siddiqua
- Indian Institute of Science, Bengaluru 560012, India; (H.S.); (S.C.R.)
| | | | - Bibha Choudhary
- Department of Biotechnology and Applied Bioinformatics, Institute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bengaluru 560100, India
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3
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Vu A, Glassman I, Campbell G, Yeganyan S, Nguyen J, Shin A, Venketaraman V. Host Cell Death and Modulation of Immune Response against Mycobacterium tuberculosis Infection. Int J Mol Sci 2024; 25:6255. [PMID: 38892443 PMCID: PMC11172987 DOI: 10.3390/ijms25116255] [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: 05/01/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb, therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb-induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.
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Affiliation(s)
| | | | | | | | | | | | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA (G.C.); (A.S.)
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4
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Mandal P, Paul D, Sharma H, Saha S, Chakrabarti P, Goswami RK. Structure-Activity Relationship Study of Biselyngbyolide B Reveals Mitochondrial Fission-Induced Cytotoxicity in Cancer. ACS Med Chem Lett 2024; 15:696-705. [PMID: 38746877 PMCID: PMC11089557 DOI: 10.1021/acsmedchemlett.4c00094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/11/2024] [Accepted: 04/12/2024] [Indexed: 05/11/2025] Open
Abstract
A systematic structure-activity relationship study of the potent anticancer marine macrolide biselyngbyolide B has been accomplished. A total of 11 structural variants of the parent natural product, of which 2 are natural analogues, have been studied against a human colorectal carcinoma cell line. The requisite functional units of the parent molecule responsible for the cytotoxic activities have been disclosed. Biselyngbyolide C, one of the natural analogues of biselyngbyolide B, has been studied in depth to explore its molecular mechanism. Interestingly, the in vitro data demonstrated an induction of dynamin-related protein 1-mediated mitochondrial fission and reactive oxygen species production which led to activation of ASK1/P38/JNK-mediated apoptosis in colon cancer cells as an important pathway for biselyngbyolide B-mediated cytotoxicity. Notably, this study revealed that a macrolide participated in mitochondrial fission to promote apoptosis of cancer cells, providing new insight.
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Affiliation(s)
- Pratiti Mandal
- Division
of Cell Biology & Physiology, CSIR-Indian
Institute of Chemical Biology, Jadavpur, Kolkata-700032, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Debobrata Paul
- School
of Chemical Sciences, Indian Association
for the Cultivation of Science, Kolkata-700032, India
| | - Himangshu Sharma
- School
of Chemical Sciences, Indian Association
for the Cultivation of Science, Kolkata-700032, India
| | - Sanu Saha
- School
of Chemical Sciences, Indian Association
for the Cultivation of Science, Kolkata-700032, India
| | - Partha Chakrabarti
- Division
of Cell Biology & Physiology, CSIR-Indian
Institute of Chemical Biology, Jadavpur, Kolkata-700032, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Rajib Kumar Goswami
- School
of Chemical Sciences, Indian Association
for the Cultivation of Science, Kolkata-700032, India
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Elradi M, Ahmed AI, Saleh AM, Abdel-Raouf KMA, Berika L, Daoud Y, Amleh A. Derivation of a novel antimicrobial peptide from the Red Sea Brine Pools modified to enhance its anticancer activity against U2OS cells. BMC Biotechnol 2024; 24:14. [PMID: 38491556 PMCID: PMC10943910 DOI: 10.1186/s12896-024-00835-8] [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: 11/10/2023] [Accepted: 02/06/2024] [Indexed: 03/18/2024] Open
Abstract
Cancer associated drug resistance is a major cause for cancer aggravation, particularly as conventional therapies have presented limited efficiency, low specificity, resulting in long term deleterious side effects. Peptide based drugs have emerged as potential alternative cancer treatment tools due to their selectivity, ease of design and synthesis, safety profile, and low cost of manufacturing. In this study, we utilized the Red Sea metagenomics database, generated during AUC/KAUST Red Sea microbiome project, to derive a viable anticancer peptide (ACP). We generated a set of peptide hits from our library that shared similar composition to ACPs. A peptide with a homeodomain was selected, modified to improve its anticancer properties, verified to maintain high anticancer properties, and processed for further in-silico prediction of structure and function. The peptide's anticancer properties were then assessed in vitro on osteosarcoma U2OS cells, through cytotoxicity assay (MTT assay), scratch-wound healing assay, apoptosis/necrosis detection assay (Annexin/PI assay), RNA expression analysis of Caspase 3, KI67 and Survivin, and protein expression of PARP1. L929 mouse fibroblasts were also assessed for cytotoxicity treatment. In addition, the antimicrobial activity of the peptide was also examined on E coli and S. aureus, as sample representative species of the human bacterial microbiome, by examining viability, disk diffusion, morphological assessment, and hemolytic analysis. We observed a dose dependent cytotoxic response from peptide treatment of U2OS, with a higher tolerance in L929s. Wound closure was debilitated in cells exposed to the peptide, while annexin fluorescent imaging suggested peptide treatment caused apoptosis as a major mode of cell death. Caspase 3 gene expression was not altered, while KI67 and Survivin were both downregulated in peptide treated cells. Additionally, PARP-1 protein analysis showed a decrease in expression with peptide exposure. The peptide exhibited minimal antimicrobial activity on critical human microbiome species E. coli and S. aureus, with a low inhibition rate, maintenance of structural morphology and minimal hemolytic impact. These findings suggest our novel peptide displayed preliminary ACP properties against U2OS cells, through limited specificity, while triggering apoptosis as a primary mode of cell death and while having minimal impact on the microbiological species E. coli and S. aureus.
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Affiliation(s)
- Mona Elradi
- Biotechnology Program, American University in Cairo, New Cairo, Egypt
| | - Ahmed I Ahmed
- Biology Department, American University in Cairo, New Cairo, Egypt
| | - Ahmed M Saleh
- Biology Department, American University in Cairo, New Cairo, Egypt
| | | | - Lina Berika
- Biology Department, American University in Cairo, New Cairo, Egypt
| | - Yara Daoud
- Biology Department, American University in Cairo, New Cairo, Egypt
| | - Asma Amleh
- Biotechnology Program, American University in Cairo, New Cairo, Egypt.
- Biology Department, American University in Cairo, New Cairo, Egypt.
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6
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Han Q, Yan P, Song R, Liu F, Tian Q. HOXC13-driven TIMM13 overexpression promotes osteosarcoma cell growth. Cell Death Dis 2023; 14:398. [PMID: 37407582 DOI: 10.1038/s41419-023-05910-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 06/11/2023] [Accepted: 06/19/2023] [Indexed: 07/07/2023]
Abstract
TIMM13 (translocase of inner mitochondrial membrane 13) located at the mitochondrial intermembrane space is vital for the integrity and function of mitochondria. We found that the mitochondrial protein TIMM13 is upregulated in human OS tissues and cells. In patient-derived primary OS cells and established cell lines, TIMM13 shRNA or knockout provoked mitochondrial dysfunction, causing mitochondrial depolarization, reactive oxygen species production, and oxidative injury, as well as lipid peroxidation, DNA damage, and ATP depletion. Moreover, TIMM13 depletion provoked OS cell apoptosis and inhibited cell proliferation and migration. Conversely, ectopic TIMM13 overexpression increased ATP contents, enhancing OS cell proliferation and migration. Moreover, we discovered that Akt-mTOR activation was inhibited with TIMM13 depletion in primary OS cells. Further studies revealed that HOXC13 (Homeobox C13)-dependent TIMM13 transcription was significantly increased in OS tissues and cells. Whereas TIMM13 transcription and expression were decreased following HOXC13 silencing in primary OS cells. In vivo, TIMM13 KO potently inhibited OS xenograft growth in the proximal tibia of nude mice. TIMM13 KO also induced Akt-mTOR inactivation, ATP depletion, oxidative injury, and apoptosis in the in situ OS tumors. Together, upregulation of the mitochondrial protein TIMM13 is important for OS cell growth, representing a novel and promising therapeutic target.
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Affiliation(s)
- Qicai Han
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Penghui Yan
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ruipeng Song
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Feifei Liu
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qing Tian
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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7
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Zhao M, Yang Y, Nian Q, Shen C, Xiao X, Liao W, Zheng Q, Zhang G, Chen N, Gong D, Tang J, Wen Y, Zeng J. Phytochemicals and mitochondria: Therapeutic allies against gastric cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 110:154608. [PMID: 36586205 DOI: 10.1016/j.phymed.2022.154608] [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: 02/23/2022] [Revised: 12/09/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Mitochondria are the energy factories of cells with the ability to modulate the cell cycle, cellular differentiation, signal transduction, growth, and apoptosis. Existing drugs targeting mitochondria in cancer treatment have disadvantages of drug resistance and side effects. Phytochemicals, which are widely found in plants, are bioactive compounds that could facilitate the development of new drugs for gastric cancer. Studies have shown that some phytochemicals can suppress the development of gastric cancer. METHODS We searched for data from PubMed, China National Knowledge Infrastructure, Web of Science, and Embase databases from initial establishment to December 2021 to review the mechanism by which phytochemicals suppress gastric cancer cell growth by modulating mitochondrial function. Phytochemicals were classified and summarized by their mechanisms of action. RESULTS Phytochemicals can interfere with mitochondria through several mechanisms to reach the goal of promoting apoptosis in gastric cancer cells. Some phytochemicals, e.g., daidzein and tetrandrine promoted cytochrome c spillover into the cytoplasm by modulating the members of the B-cell lymphoma-2 protein family and induced apoptotic body activity by activating the caspase protein family. Phytochemicals (e.g., celastrol and shikonin) could promote the accumulation of reactive oxygen species and reduce the mitochondrial membrane potential. Several phytochemicals (e.g., berberine and oleanolic acid) activated mitochondrial apoptotic submission via the phosphatidylinositol-3-kinase/Akt signaling pathway, thereby triggering apoptosis in gastric cancer cells. Several well-known phytochemicals that target mitochondria, including berberine, ginsenoside, and baicalein, showed the advantages of multiple targets, high efficacy, and fewer side effects. CONCLUSIONS Phytochemicals could target the mitochondria in the treatment of gastric cancer, providing potential directions and evidence for clinical translation. Drug discovery focused on phytochemicals has great potential to break barriers in cancer treatment.
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Affiliation(s)
- Maoyuan Zhao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China
| | - Yi Yang
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China
| | - Qing Nian
- Department of Blood Transfusion, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, PR China
| | - Caifei Shen
- Department of Endoscopy center, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China
| | - Xiaolin Xiao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China
| | - Wenhao Liao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China
| | - Qiao Zheng
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China
| | - Gang Zhang
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China
| | - Nianzhi Chen
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China
| | - Daoyin Gong
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Jianyuan Tang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China.
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China; Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China.
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8
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Jiang X, Yang C, Qiu J, Ma D, Xu C, Hu S, Han W, Yuan B, Lu Y. Nanomolar LL-37 induces permeability of a biomimetic mitochondrial membrane. NANOSCALE 2022; 14:17654-17660. [PMID: 36413063 DOI: 10.1039/d2nr05409d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
LL-37, the only human host cathelicidin peptide, is proposed to be able to induce host cell apoptosis through mitochondrial membrane permeabilization (MMP). Detailed pathways of the LL-37-triggered MMP are however still disputed. It is generally believed that cationic peptides permeate a membrane mostly in conditions of micromolar peptide concentrations and negatively charged membranes, which are not usually satisfied in the mitochondrial circumstance. Herein, using a variety of single-molecule techniques, we show that nanomolar LL-37 specifically induces permeability of a phosphoethanolamine (PE)-rich biomimetic mitochondrial membrane in a protein-independent manner. The insertion dynamics of single LL-37 molecules exhibit different metastable states in bilayers composed of different lipids. Moreover, the PE lipids significantly facilitate adsorption and accumulation of LL-37 on the PE-rich bilayer, and produce deeper insertion of peptide oligomers, especially tetramers, into the bilayer. This work offers an alternative pathway of the LL-37-triggered MMP and apoptosis.
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Affiliation(s)
- Xin Jiang
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China.
| | - Chenguang Yang
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jie Qiu
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China.
| | - Dongfei Ma
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China.
| | - Cheng Xu
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China.
- Center for Soft Condensed Matter Physics and Interdisciplinary Research & School of Physical Science and Technology, Soochow University, Suzhou, Jiangsu 215006, China
| | - Shuxin Hu
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Weijing Han
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China.
| | - Bing Yuan
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China.
| | - Ying Lu
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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9
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Olasehinde TA, Olaniran AO. Antiproliferative and apoptosis-inducing effects of aqueous extracts from Ecklonia maxima and Ulva rigida on HepG2 cells. J Food Biochem 2022; 46:e14498. [PMID: 36350831 DOI: 10.1111/jfbc.14498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/08/2022] [Accepted: 10/21/2022] [Indexed: 11/11/2022]
Abstract
This study examined the antiproliferative and apoptotic-inducing effects of Ecklonia maxima (KP) and Ulva rigida (URL) extracts in the human liver cancer (HepG2) cell line model. HepG2 cells were cultured and grown in an incubator (5% CO2 ) at 37°C. Cell viability was determined, while the effect of the extracts on apoptosis, ROS production, mitochondria membrane potential, and antioxidant enzymes were also assessed. KP and URL induced cytotoxic effects on HepG2 cells at the concentrations tested (0-1000 μg/ml). The morphological characteristics of the cells after treatment with KP and URL revealed cell shrinkage of the nucleus, cell injury, and damage compared to the control. The fluorescent micrographs from the apoptotic assay revealed induction of apoptosis and necrosis in HepG2 cells after treatment with KP and URL (200 and 400 μg/ml). The extracts also induced ROS production and reduced mitochondria membrane potential in HepG2 cells. The apoptotic-inducing effects, activation of ROS generation, and disruption of antioxidant enzymes are associated with the cytotoxic effects of the seaweed extracts. KP and URL showed good anticancer properties and could be explored as a good source of nutraceuticals, food additives, and dietary supplements to prevent uncontrolled proliferation of HepG2 cells. PRACTICAL APPLICATIONS: Seaweeds are reservoirs of nutrients and naturally occurring biologically active compounds, including sterols, phlorotannins, and polyunsaturated fatty acids. Due to the presence of these compounds, they are used as emulsifying agents, nutraceuticals, and additives in functional foods. Evidence suggests that seaweed bioactives may inhibit uncontrolled cell proliferation and induce apoptosis in cancer cells. Hence, exploring the antiproliferative and apoptotic-inducing effects of Ecklonia maxima and Ulva rigida will provide insights into their anticancer potentials as functional foods and nutraceuticals.
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Affiliation(s)
- Tosin A Olasehinde
- Nutrition and Toxicology Division, Food Technology Department, Federal Institute of Industrial Research Oshodi, Lagos, Nigeria
- Discipline of Microbiology, School of Life Sciences, University of Kwazulu-Natal, Durban, South Africa
| | - Ademola O Olaniran
- Discipline of Microbiology, School of Life Sciences, University of Kwazulu-Natal, Durban, South Africa
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10
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Youden B, Jiang R, Carrier AJ, Servos MR, Zhang X. A Nanomedicine Structure-Activity Framework for Research, Development, and Regulation of Future Cancer Therapies. ACS NANO 2022; 16:17497-17551. [PMID: 36322785 DOI: 10.1021/acsnano.2c06337] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Despite their clinical success in drug delivery applications, the potential of theranostic nanomedicines is hampered by mechanistic uncertainty and a lack of science-informed regulatory guidance. Both the therapeutic efficacy and the toxicity of nanoformulations are tightly controlled by the complex interplay of the nanoparticle's physicochemical properties and the individual patient/tumor biology; however, it can be difficult to correlate such information with observed outcomes. Additionally, as nanomedicine research attempts to gradually move away from large-scale animal testing, the need for computer-assisted solutions for evaluation will increase. Such models will depend on a clear understanding of structure-activity relationships. This review provides a comprehensive overview of the field of cancer nanomedicine and provides a knowledge framework and foundational interaction maps that can facilitate future research, assessments, and regulation. By forming three complementary maps profiling nanobio interactions and pathways at different levels of biological complexity, a clear picture of a nanoparticle's journey through the body and the therapeutic and adverse consequences of each potential interaction are presented.
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Affiliation(s)
- Brian Youden
- Department of Biology, University of Waterloo, 200 University Ave. W, Waterloo, Ontario N2L 3G1, Canada
| | - Runqing Jiang
- Department of Biology, University of Waterloo, 200 University Ave. W, Waterloo, Ontario N2L 3G1, Canada
- Department of Medical Physics, Grand River Regional Cancer Centre, Kitchener, Ontario N2G 1G3, Canada
| | - Andrew J Carrier
- Department of Chemistry, Cape Breton University, 1250 Grand Lake Road, Sydney, Nova Scotia B1P 6L2, Canada
| | - Mark R Servos
- Department of Biology, University of Waterloo, 200 University Ave. W, Waterloo, Ontario N2L 3G1, Canada
| | - Xu Zhang
- Department of Biology, University of Waterloo, 200 University Ave. W, Waterloo, Ontario N2L 3G1, Canada
- Department of Chemistry, Cape Breton University, 1250 Grand Lake Road, Sydney, Nova Scotia B1P 6L2, Canada
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11
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Antitumor Activity and Mechanism of Action of the Antimicrobial Peptide AMP-17 on Human Leukemia K562 Cells. Molecules 2022; 27:molecules27228109. [PMID: 36432210 PMCID: PMC9697079 DOI: 10.3390/molecules27228109] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/13/2022] [Accepted: 11/16/2022] [Indexed: 11/23/2022] Open
Abstract
Cancer is one of the most common malignant diseases in the world. Hence, there is an urgent need to search for novel drugs with antitumor activity against cancer cells. AMP-17, a natural antimicrobial peptide derived from Musca domestica, has antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and fungi. However, its antitumor activity and potential mechanism of action in cancer cells remain unclear. In this study, we focused on evaluating the in vitro antitumor activity and mechanism of AMP-17 on leukemic K562 cells. The results showed that AMP-17 exhibited anti-proliferative activity on K562 cells with an IC50 value of 58.91 ± 3.57 μg/mL. The membrane integrity of K562 was disrupted and membrane permeability was increased after AMP-17 action. Further observation using SEM and TEM images showed that the cell structure of AMP-17-treated cells was disrupted, with depressions and pore-like breaks on the cell surface, and vacuolated vesicles in the cytoplasm. Furthermore, further mechanistic studies indicated that AMP-17 induced excessive production of reactive oxygen species and calcium ions release in K562 cells, which led to disturbance of mitochondrial membrane potential and blocked ATP synthesis, followed by activation of Caspase-3 to induce apoptosis. In conclusion, these results suggest that the antitumor activity of AMP-17 may be achieved by disrupting cell structure and inducing apoptosis. Therefore, AMP-17 is expected to be a novel potential agent candidate for leukemia treatment.
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Pokharel M, Konarzewska P, Roberge JY, Han GS, Wang Y, Carman GM, Xue C. The Anticancer Drug Bleomycin Shows Potent Antifungal Activity by Altering Phospholipid Biosynthesis. Microbiol Spectr 2022; 10:e0086222. [PMID: 36036637 PMCID: PMC9602507 DOI: 10.1128/spectrum.00862-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 08/10/2022] [Indexed: 12/30/2022] Open
Abstract
Invasive fungal infections are difficult to treat with limited drug options, mainly because fungi are eukaryotes and share many cellular mechanisms with the human host. Most current antifungal drugs are either fungistatic or highly toxic. Therefore, there is a critical need to identify important fungal specific drug targets for novel antifungal development. Numerous studies have shown the fungal phosphatidylserine (PS) biosynthetic pathway to be a potential target. It is synthesized from CDP-diacylglycerol and serine, and the fungal PS synthesis route is different from that in mammalian cells, in which preexisting phospholipids are utilized to produce PS in a base-exchange reaction. In this study, we utilized a Saccharomyces cerevisiae heterologous expression system to screen for inhibitors of Cryptococcus PS synthase Cho1, a fungi-specific enzyme essential for cell viability. We identified an anticancer compound, bleomycin, as a positive candidate that showed a phospholipid-dependent antifungal effect. Its inhibition on fungal growth can be restored by ethanolamine supplementation. Further exploration of the mechanism of action showed that bleomycin treatment damaged the mitochondrial membrane in yeast cells, leading to increased generation of reactive oxygen species (ROS), whereas supplementation with ethanolamine helped to rescue bleomycin-induced damage. Our results indicate that bleomycin does not specifically inhibit the PS synthase enzyme; however, it may affect phospholipid biosynthesis through disruption of mitochondrial function, namely, the synthesis of phosphatidylethanolamine (PE) and phosphatidylcholine (PC), which helps cells maintain membrane composition and functionality. IMPORTANCE Invasive fungal pathogens cause significant morbidity and mortality, with over 1.5 million deaths annually. Because fungi are eukaryotes that share much of their cellular machinery with the host, our armamentarium of antifungal drugs is highly limited, with only three classes of antifungal drugs available. Drug toxicity and emerging resistance have limited their use. Hence, targeting fungi-specific enzymes that are important for fungal survival, growth, or virulence poses a strategy for novel antifungal development. In this study, we developed a heterologous expression system to screen for chemical compounds with activity against Cryptococcus phosphatidylserine synthase, Cho1, a fungi-specific enzyme that is essential for viability in C. neoformans. We confirmed the feasibility of this screen method and identified a previously unexplored role of the anticancer compound bleomycin in disrupting mitochondrial function and inhibiting phospholipid synthesis.
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Affiliation(s)
- Mona Pokharel
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
| | - Paulina Konarzewska
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
| | - Jacques Y. Roberge
- Molecular Design and Synthesis Core, Rutgers University Biomolecular Innovations Cores, Office for Research, Rutgers University, Piscataway, New Jersey, USA
| | - Gil-Soo Han
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, New Jersey, USA
| | - Yina Wang
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
| | - George M. Carman
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, New Jersey, USA
| | - Chaoyang Xue
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, New Jersey, USA
- Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Luo M, Luo D, Liu J, Wang H, Liu X, Yang M, Tian F, Qin S, Li Y. Ameliorative effect of the probiotic peptide against benzo(α)pyrene-induced inflammatory damages in enterocytes. Int Immunopharmacol 2022; 112:109255. [PMID: 36152539 DOI: 10.1016/j.intimp.2022.109255] [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: 05/11/2022] [Revised: 08/25/2022] [Accepted: 09/12/2022] [Indexed: 11/28/2022]
Abstract
Probiotics are living bacteria that provide health benefits to the host when consumed in sufficient quantities. However, the protective effect of the bioactive peptides isolated from the probiotics against benzo(α)pyrene (BaP) induced gastrointestinal injury has never been investigated. The current work used a bio-assay guided technique to identify-four new cyclic peptides in BaP-induced Caco-2 cell culture and mouse colitis model. Lactobacillus rhamnosus cycle (Thr-His-Ala-Trp) peptide-1 (LRCP-1) effectively inhibited BaP-induced epithelial cytokine over-release and intracellular ROS over-production. Simultaneously, LRCP-1 attenuated BaP-induced NAD (P)H: oxidases (NOXs), Matrix metalloproteinases (MMPs) over-expression, respectively. Furthermore, increased NAD (P)H: quinone oxidoreductase 1 (NQO1)/heme oxygenase-1 (HO-1)/nuclear factor E2-related factor 2 (Nrf2) expression and aryl hydrocarbon receptor (AhR) pathway activation induced by the BaP-exposure were also inhibited after the LRCP-1 treatment. Notably, LRCP-1 is a promising agent protecting gastrointestinal epithelial cells from BaP-induced inflammatory and oxidative damages.
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Affiliation(s)
- Min Luo
- Laboratory of inflammation and allergy, Department of respiratory and critical care medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Dan Luo
- Laboratory of inflammation and allergy, Department of respiratory and critical care medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Jie Liu
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen 518060, China
| | - Huailing Wang
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen 518060, China
| | - Xiaoyu Liu
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen 518060, China
| | - Min Yang
- Kexing Biopharm Co., Ltd, Shenzhen 518057, China
| | | | - Suofu Qin
- Kexing Biopharm Co., Ltd, Shenzhen 518057, China
| | - Yuying Li
- Laboratory of inflammation and allergy, Department of respiratory and critical care medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
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The mitochondrial RNA polymerase POLRMT promotes skin squamous cell carcinoma cell growth. Cell Death Dis 2022; 8:347. [PMID: 35922422 PMCID: PMC9349297 DOI: 10.1038/s41420-022-01148-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 11/08/2022]
Abstract
RNA polymerase mitochondrial (POLRMT) expression and the potential biological functions in skin squamous cell carcinoma (SCC) were explored. We showed that POLRMT is significantly elevated in skin SCC. Genetic depletion of POLRMT, using shRNA-induced knockdown or CRISPR/Cas9-mediated knockout (KO), resulted in profound anti-skin SCC cell activity. In patient-derived primary skin SCC cells or immortalized lines (A431 and SCC-9), POLRMT shRNA or KO potently suppressed mitochondrial DNA (mtDNA) transcription and suppressed cell viability, proliferation and migration. POLRMT shRNA or KO impaired mitochondrial functions in different skin SCC cells, leading to production of ROS (reactive oxygen species), depolarization of mitochondria and depletion of ATP. Moreover, mitochondrial apoptosis cascade was induced in POLRMT-depleted skin SCC cells. IMT1, a POLRMT inhibitor, largely inhibited proliferation and migration, while inducing depolarization of mitochondria and apoptosis in primary skin SCC cells. Contrarily, ectopic overexpression of POLRMT increased mtDNA transcription and augmented skin SCC cell growth. Importantly, POLRMT shRNA adeno-associated virus injection robustly hindered growth of the subcutaneous A431 xenografts in mice. In the POLRMT shRNA virus-treated A431 xenograft tissues, POLRMT depletion, mtDNA transcription inhibition, cell apoptosis, lipid peroxidation and ATP depletion were detected. Together, overexpressed POLRMT increases mtDNA transcription and promotes skin SCC growth.
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Mandal AK. Mitochondrial targeting of potent nanoparticulated drugs in combating diseases. J Biomater Appl 2022; 37:614-633. [PMID: 35790487 DOI: 10.1177/08853282221111656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Mitochondrial dysfunction, characterized by the electron transport chain (ETC) leakage and reduced adenosine tri-phosphate synthesis, occurs primarily due to free radicals -induced mutations in either the mitochondrial deoxyribonucleic acid (mtDNA) or nuclear (n) DNA caused by pathogenic infections, toxicant exposures, adverse drug-effects, or other environmental exposures, leading to secondary dysfunction affecting ischemic, diabetic, cancerous, and degenerative diseases. In these concerns, mitochondria-targeted remedies may include a significant role in the protection and treatment of mitochondrial function to enhance its activity. Coenzyme Q10 pyridinol and pyrimidinol antioxidant analogues and other potent drug-compounds for their multifunctional radical quencher and other anti-toxic activities may take a significant therapeutic effectivity for ameliorating mitochondrial dysfunction. Moreover, the encapsulation of these bioactive ligands-attached potent compounds in vesicular system may enable them a superb biological effective for the treatment of mitochondria-targeted dysfunction-related diseases with least side effects. This review depicts mainly on mitochondrial enzymatic dysfunction and their amelioration by potent drugs with the usages of nanoparticulated delivery system against mitochondria-affected diseases.
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Lang L, Loveless R, Dou J, Lam T, Chen A, Wang F, Sun L, Juarez J, Qin ZS, Saba NF, Shay C, Teng Y. ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development. J Exp Clin Cancer Res 2022; 41:43. [PMID: 35093151 PMCID: PMC8800319 DOI: 10.1186/s13046-022-02274-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 01/25/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Targeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme contributing to mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain ill-defined. METHODS We used head and neck squamous cell carcinoma (HNSCC) as a research platform and achieved gene depletion by lentiviral shRNA and CRISPR/Cas9. Molecular alterations were examined by RNA-sequencing, phospho-kinase profiling, Western blotting, RT-qPCR, immunohistochemistry, and immunoprecipitation. Cancer cell growth was assessed by MTT, colony formation, soft agar, and 3D cultures. The therapeutic efficacy in tumor development was evaluated in orthotopic tongue tumor NSG mice. RESULTS ATAD3A is highly expressed in HNSCC tissues and cell lines. Loss of ATAD3A expression suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. From a mechanistic perspective, the tumor suppression induced by the overexpression of the Walker A dead mutant of ATAD3A (K358) produces a potent dominant-negative effect due to defective ATP-binding. Moreover, ATAD3A binds to ERK1/2 in the mitochondria of HNSCC cells in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis drives HNSCC development in a RAS-independent fashion and, thus, tumor suppression is more effectively achieved when ATAD3A knockout is combined with RAS inhibitor treatment. CONCLUSIONS These findings highlight the novel function of ATAD3A in regulating mitochondrial ERK1/2 activation that favors HNSCC development. Combined targeting of ATAD3A and RAS signaling may potentiate anticancer activity for HNSCC therapeutics.
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Affiliation(s)
- Liwei Lang
- Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA
| | - Reid Loveless
- Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA
| | - Juan Dou
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 201 Dowman Dr, Atlanta, GA, 30322, USA
| | - Tiffany Lam
- Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA
| | - Alex Chen
- Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA
| | - Fang Wang
- Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA
| | - Li Sun
- Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA
| | - Jakeline Juarez
- Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA
| | - Zhaohui Steve Qin
- Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, 30322, USA
| | - Nabil F Saba
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 201 Dowman Dr, Atlanta, GA, 30322, USA
| | - Chloe Shay
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory, University, Atlanta, GA, 30322, USA
| | - Yong Teng
- Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA.
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 201 Dowman Dr, Atlanta, GA, 30322, USA.
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Alhakamy NA, Fahmy UA, Eldin SMB, Ahmed OAA, Aldawsari HM, Okbazghi SZ, Alfaleh MA, Abdulaal WH, Alamoudi AJ, Mady FM. Scorpion Venom-Functionalized Quercetin Phytosomes for Breast Cancer Management: In Vitro Response Surface Optimization and Anticancer Activity against MCF-7 Cells. Polymers (Basel) 2021; 14:93. [PMID: 35012116 PMCID: PMC8747200 DOI: 10.3390/polym14010093] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is a dangerous type of cancer in women. Quercetin (QRT), a naturally occurring flavonoid, has wide biological effects including antioxidant, anticarcinogenic, anti-inflammatory, antiallergic, and antiviral activities. The anticancer activity is considered the most valuable effect of QRT against several types of cancer, including prostate, liver, lung, colon, and breast cancer. Scorpion venom peptides (SV) has been found to induce apoptosis and aggravate cancer cells, making it a promising anticancer agent. QRT, SV, and Phospholipon® 90H (PL) were incorporated in a nano-based delivery platform to assess QRT's cellular uptake and antiproliferative efficacy against a lung cancer cell line derived from human breast cancer cells MCF-7. Several nanovesicles were prepared and optimized, using four-factor Box-Behnken, in an experimental design. The optimized phytosomes showed vesicle size and zeta potential values of 116.9 nm and 31.5 mV, respectively. The IC50 values revealed that MCF-7 cells were significantly more sensitive to the optimized QRT formula than the plain formula and raw QRT. Cell cycle analysis revealed that optimized QRT formula treatment resulted in significant cell cycle arrest at the S phase. The results also indicated that treatment with QRT formula significantly increased caspase-9, Bax, Bcl-2, and p53 mRNA expression, compared with the plain formula and QRT. In terms of the inflammatory markers, the QRT formula significantly reduced the activity of TNF-α and NF-κB, in comparison with the plain formula and QRT only. Overall, the findings from the study proved that a QRT formulation could be a promising therapeutic approach for the treatment of breast cancer.
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Affiliation(s)
- Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.E.); (O.A.A.A.); (H.M.A.); (M.A.A.)
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.E.); (O.A.A.A.); (H.M.A.); (M.A.A.)
| | - Shaimaa M. Badr Eldin
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.E.); (O.A.A.A.); (H.M.A.); (M.A.A.)
- Department of Pharmaceutics and Industrial Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.E.); (O.A.A.A.); (H.M.A.); (M.A.A.)
| | - Hibah M. Aldawsari
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.E.); (O.A.A.A.); (H.M.A.); (M.A.A.)
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Solomon Z. Okbazghi
- Global Analytical and Pharmaceutical Development, Alexion Pharmaceuticals, New Haven, CT 06510, USA;
| | - Mohamed A. Alfaleh
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.E.); (O.A.A.A.); (H.M.A.); (M.A.A.)
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Wesam H. Abdulaal
- Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Abdulmohsin J. Alamoudi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Fatma M. Mady
- Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
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Asfour HZ, Fahmy UA, Alharbi WS, Almehmady AM, Alamoudi AJ, Tima S, Mansouri RA, Omar UM, Ahmed OAA, Zakai SA, Aldarmahi AA, Bagalagel A, Diri R, Alhakamy NA. Phyto-Phospholipid Conjugated Scorpion Venom Nanovesicles as Promising Carrier That Improves Efficacy of Thymoquinone against Adenocarcinoma Human Alveolar Basal Epithelial Cells. Pharmaceutics 2021; 13:2144. [PMID: 34959424 PMCID: PMC8709205 DOI: 10.3390/pharmaceutics13122144] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/05/2021] [Accepted: 12/10/2021] [Indexed: 01/15/2023] Open
Abstract
Lung cancer is a dangerous type of cancer in men and the third leading cause of cancer-related death in women, behind breast and colorectal cancers. Thymoquinone (THQ), a main compound in black seed essential oils, has a variety of beneficial effects, including antiproliferative, anti-inflammatory, and antioxidant properties. On the other hand, scorpion venom peptides (SV) induce apoptosis in the cancer cells, making it a promising anticancer agent. THQ, SV, and Phospholipon® 90H (PL) were incorporated in a nano-based delivery platform to assess THQ's cellular uptake and antiproliferative efficacy against a lung cancer cell line derived from human alveolar epithelial cells (A549). Several nanovesicles were prepared and optimized using factorial experimental design. The optimized phytosome formulation contained 79.0 mg of PL and 170.0 mg of SV, with vesicle size and zeta potential of 209.9 nm and 21.1 mV, respectively. The IC50 values revealed that A549 cells were significantly more sensitive to the THQ formula than the plain formula and THQ. Cell cycle analysis revealed that THQ formula treatment resulted in significant cell cycle arrest at the S phase, increasing cell population in this phase by 22.1%. Furthermore, the THQ formula greatly increased cell apoptosis (25.17%) when compared to the untreated control (1.76%), plain formula (11.96%), or THQ alone (13.18%). The results also indicated that treatment with THQ formula significantly increased caspase-3, Bax, Bcl-2, and p53 mRNA expression compared to plain formula and THQ. In terms of the inflammatory markers, THQ formula significantly reduced the activity of TNF-α and NF-κB in comparison with the plain formula and THQ only. Overall, the findings from the study proved that a phytosome formulation of THQ could be a promising therapeutic approach for the treatment of lung adenocarcinoma.
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Affiliation(s)
- Hani Z. Asfour
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (H.Z.A.); (S.A.Z.)
| | - Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
| | - Waleed S. Alharbi
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Alshaimaa M. Almehmady
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
| | - Abdulmohsin J. Alamoudi
- Department of Pharmacology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Singkome Tima
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Rasha A. Mansouri
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (R.A.M.); (U.M.O.)
| | - Ulfat M. Omar
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (R.A.M.); (U.M.O.)
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Shadi A. Zakai
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (H.Z.A.); (S.A.Z.)
| | - Ahmed A. Aldarmahi
- College of Sciences and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia;
| | - Alaa Bagalagel
- Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.B.); (R.D.)
| | - Reem Diri
- Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.B.); (R.D.)
| | - Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Zeng Z, Fang C, Zhang Y, Chen CX, Zhang YF, Zhang K. Mitochondria-Targeted Nanocarriers Promote Highly Efficient Cancer Therapy: A Review. Front Bioeng Biotechnol 2021; 9:784602. [PMID: 34869294 PMCID: PMC8633539 DOI: 10.3389/fbioe.2021.784602] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 10/18/2021] [Indexed: 12/15/2022] Open
Abstract
Mitochondria are the primary organelles which can produce adenosine triphosphate (ATP). They play vital roles in maintaining normal functions. They also regulated apoptotic pathways of cancer cells. Given that, designing therapeutic agents that precisely target mitochondria is of great importance for cancer treatment. Nanocarriers can combine the mitochondria with other therapeutic modalities in cancer treatment, thus showing great potential to cancer therapy in the past few years. Herein, we summarized lipophilic cation- and peptide-based nanosystems for mitochondria targeting. This review described how mitochondria-targeted nanocarriers promoted highly efficient cancer treatment in photodynamic therapy (PDT), chemotherapy, combined immunotherapy, and sonodynamic therapy (SDT). We further discussed mitochondria-targeted nanocarriers’ major challenges and future prospects in clinical cancer treatment.
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Affiliation(s)
- Zeng Zeng
- Department of Medical Ultrasound, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Chao Fang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ying Zhang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Cong-Xian Chen
- Department of Medical Ultrasound, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Yi-Feng Zhang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kun Zhang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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Chen J, Wang M, Wang H, Long M. Zearalenone promotes apoptosis of mouse Leydig cells by targeting phosphatase and tensin homolog and thus inhibiting the PI3K/AKT signal pathway. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:67779-67787. [PMID: 34264493 DOI: 10.1007/s11356-021-15282-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/29/2021] [Indexed: 06/13/2023]
Abstract
Zearalenone (ZEA) is a mycotoxin with estrogenic activity whose main effect is to impair the reproductive systems of animals. It leads to reproductive disorders in livestock and thus causes serious losses to agriculture and animal husbandry. This study aims to examine whether ZEA induces toxicity in Leydig cells through the PI3K/AKT signaling pathway and also to investigate the role played by the upstream phosphatase and tensin homolog (PTEN) gene. An adenovirus vector model was constructed to interfere with the PTEN gene to investigate whether ZEA promotes the apoptosis of TM3 cells through the PI3K/AKT pathway. Apoptosis was detected cytometrically and the protein expression levels of PTEN, AKT, p-AKT, Bax, and Bcl-2 were evaluated via western blot analysis. The results show that ZEA induces apoptosis of TM3 cells. PTEN expression is significantly increased (P < 0.01), Bax expression is increased (P < 0.05), AKT and p-AKT expression of anti-apoptotic protein is significantly decreased (P < 0.01), and Bcl-2 protein expression is decreased (P < 0.05) in the ZEA group compared with the control group. In the shRNA+ZEA group, the expression levels of PTEN and Bax proteins are significantly decreased (P < 0.01), AKT protein is significantly increased (P < 0.01), and p-AKT protein is increased (P < 0.05) compared with the ZEA group. This study thus demonstrates that ZEA promotes apoptosis of TM3 cells by targeting PTEN and thus inhibiting the PI3K/AKT signal pathway.
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Affiliation(s)
- Jia Chen
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Mingyang Wang
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Hanli Wang
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Miao Long
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China.
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Pham TC, Nguyen VN, Choi Y, Lee S, Yoon J. Recent Strategies to Develop Innovative Photosensitizers for Enhanced Photodynamic Therapy. Chem Rev 2021; 121:13454-13619. [PMID: 34582186 DOI: 10.1021/acs.chemrev.1c00381] [Citation(s) in RCA: 798] [Impact Index Per Article: 199.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This review presents a robust strategy to design photosensitizers (PSs) for various species. Photodynamic therapy (PDT) is a photochemical-based treatment approach that involves the use of light combined with a light-activated chemical, referred to as a PS. Attractively, PDT is one of the alternatives to conventional cancer treatment due to its noninvasive nature, high cure rates, and low side effects. PSs play an important factor in photoinduced reactive oxygen species (ROS) generation. Although the concept of photosensitizer-based photodynamic therapy has been widely adopted for clinical trials and bioimaging, until now, to our surprise, there has been no relevant review article on rational designs of organic PSs for PDT. Furthermore, most of published review articles in PDT focused on nanomaterials and nanotechnology based on traditional PSs. Therefore, this review aimed at reporting recent strategies to develop innovative organic photosensitizers for enhanced photodynamic therapy, with each example described in detail instead of providing only a general overview, as is typically done in previous reviews of PDT, to provide intuitive, vivid, and specific insights to the readers.
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Affiliation(s)
- Thanh Chung Pham
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan 48513, Korea
| | - Van-Nghia Nguyen
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Korea
| | - Yeonghwan Choi
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan 48513, Korea
| | - Songyi Lee
- Department of Chemistry, Pukyong National University, Busan 48513, Korea.,Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan 48513, Korea
| | - Juyoung Yoon
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Korea
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Multifunctional lipidic nanocarriers for effective therapy of glioblastoma: recent advances in stimuli-responsive, receptor and subcellular targeted approaches. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2021. [DOI: 10.1007/s40005-021-00548-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Abstract
Background
Glioblastoma, or glioblastoma multiforme (GBM), remains a fatal cancer type despite the remarkable progress in understanding the genesis and propagation of the tumor. Current treatment modalities, comprising mainly of surgery followed by adjuvant chemoradiation, are insufficient for improving patients' survival owing to existing hurdles, including the blood–brain barrier (BBB). In contemporary practice, the prospect of long-term survival or cure continues to be a challenge for patients suffering from GBM. This review provides an insight into the drug delivery strategies and the significant efforts made in lipid-based nanoplatform research to circumvent the challenges in optimal drug delivery in GBM.
Area covered
Owing to the unique properties of lipid-based nanoplatforms and advancements in clinical translation, this article describes the application of various stimuli-responsive lipid nanocarriers and tumor subcellular organelle-targeted therapy to give an idea about the strategies that can be applied to enhance site-specific drug delivery for GBM. Furthermore, active targeting of drugs via surface-modified lipid-based nanostructures and recent findings in alternative therapeutic platforms such as gene therapy, immunotherapy, and multimodal therapy have also been overviewed.
Expert opinion
Lipid-based nanoparticles stand out among the other nanocarriers explored for GBM drug delivery, as they support both passive and active drug targeting by crossing/bypassing the BBB at the same time minimizing toxicity and projects better pharmacological parameters. Although these nanocarriers could be a plausible choice for treating GBM, in-depth research is essential to advance neuro-oncology research and enhance outcomes in patients with brain tumors.
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Md S, Alhakamy NA, Aldawsari HM, Ahmad J, Alharbi WS, Asfour HZ. Resveratrol loaded self-nanoemulsifying drug delivery system (SNEDDS) for pancreatic cancer: Formulation design, optimization and in vitro evaluation. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2021.102555] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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25
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Yoozbashi M, Rashidzadeh H, Kermanian M, Sadighian S, Hosseini MJ, Kaboli Z, Rostamizadeh K. Magnetic nanostructured lipid carrier for dual triggered curcumin delivery: Preparation, characterization and toxicity evaluation on isolated rat liver mitochondria. J Biomater Appl 2021; 36:1055-1063. [PMID: 34304637 DOI: 10.1177/08853282211034625] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In this research, magnetic nanostructured lipid carriers (Mag-NLCs) were synthesized for curcumin (CUR) delivery. NLCs are drug-delivery systems prepared by mixing solid and liquid (oil) lipids. For preparation of NLCs, cetylpalmitate was selected as solid lipid and fish oil as liquid lipid. CUR-Mag-NLCs were prepared using high-pressure homogenization technique and were characterized by methods including X-ray diffraction (XRD), transmission electron microscopy (TEM), vibrating sample magnetometer (VSM), and dynamic light scattering (DLS). The CUR-Mag-NLCs were developed as a particle with a size of 140 ± 3.6 nm, a polydispersity index of 0.196, and a zeta potential of -22.6 mV. VSM analysis showed that the CUR-Mag-NLCs have excellent magnetic properties. Release rate of the drug was higher at 42 °C than 37 °C, indicating that release of the synthesized nanoparticles is temperature-dependent. Evaluation of mitochondrial toxicity was done using the isolated rats liver mitochondria including glutathione (GSH), malondialdehyde (MDA), and the ferric- reducing ability of plasma (FRAP) assays to study biosafety of the CUR-Mag-NLCs. Results of In vitro study on the isolated mitochondria revealed that both CUR-Mag-NLCs and curcumin have no specific mitochondrial toxicity.
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Affiliation(s)
- Mohammad Yoozbashi
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Hamid Rashidzadeh
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mehraneh Kermanian
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Somayeh Sadighian
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mir-Jamal Hosseini
- Department of Toxicology and Pharmacology, Zanjan Applied Pharmacology Research Center, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Zahra Kaboli
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Kobra Rostamizadeh
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
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Xu C, Xiao L, Zhang X, Zhuang T, Mu L, Yang X. Synthesis and biological activities of novel mitochondria-targeted artemisinin ester derivatives. Bioorg Med Chem Lett 2021; 39:127912. [PMID: 33691167 DOI: 10.1016/j.bmcl.2021.127912] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/10/2021] [Accepted: 02/15/2021] [Indexed: 11/18/2022]
Abstract
A series of novel artemisinin ester derivatives were designed and synthesized for targeting mitochondria. Cytotoxicity against SMMC-7721, HepG2, OVCAR3, A549 and J82 cancer cell lines was evaluated. Compound 2c (IC50 = 3.0 μM) was the most potent anti-proliferative molecule against the OVCAR3 cells with low cytotoxicity in normal HUVEC cells. The mechanism of action of compound 2c was further investigated by analyzing cell apoptosis, mitochondrial membrane potential (Δψm) and intracellular ROS generation. The results indicated that compound 2c targeted mitochondria and induced cell apoptosis. ROS and heme attributed to the cytotoxicity and cell apoptosis of compound 2c. These promising findings indicated the compound 2c could serve as a great candidate against ovarian cancer for further investigation.
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Affiliation(s)
- Cangcang Xu
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Linfan Xiao
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Xia Zhang
- Department of Laboratory Medicine, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Tao Zhuang
- Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lingli Mu
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China.
| | - Xiaoping Yang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China.
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Gao T, Zhang Z, Yang Y, Zhang H, Li N, Liu B. Impact of RIM-BPs in neuronal vesicles release. Brain Res Bull 2021; 170:129-136. [PMID: 33581313 DOI: 10.1016/j.brainresbull.2021.02.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 02/04/2021] [Accepted: 02/05/2021] [Indexed: 12/13/2022]
Abstract
Accurate signal transmission between neurons is accomplished by vesicle release with high spatiotemporal resolution in the central nervous system. The vesicle release occurs mainly in the active zone (AZ), a unique area on the presynaptic membrane. Many structural proteins expressed in the AZ connect with other proteins nearby. They can also regulate the precise release of vesicles through protein-protein interactions. RIM-binding proteins (RIM-BPs) are one of the essential proteins in the AZ. This review summarizes the structures and functions of three subtypes of RIM-BPs, including the interaction between RIM-BPs and other proteins such as Bassoon and voltage-gated calcium channel, their significance in stabilizing the AZ structure in the presynaptic region and collecting ion channels, and ultimately regulating the fusion and release of neuronal vesicles.
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Affiliation(s)
- Tianyu Gao
- School of Biomedical Engineering, Liaoning Key Lab of Integrated Circuit and Biomedical Electronic System, Dalian University of Technology, Dalian, 116024, China
| | - Zhengyao Zhang
- School of Life and Pharmaceutical Sciences, Panjin Campus of Dalian University of Technology, Panjin, 124221, China
| | - Yunong Yang
- School of Biomedical Engineering, Liaoning Key Lab of Integrated Circuit and Biomedical Electronic System, Dalian University of Technology, Dalian, 116024, China
| | - Hangyu Zhang
- School of Biomedical Engineering, Liaoning Key Lab of Integrated Circuit and Biomedical Electronic System, Dalian University of Technology, Dalian, 116024, China
| | - Na Li
- School of Biomedical Engineering, Liaoning Key Lab of Integrated Circuit and Biomedical Electronic System, Dalian University of Technology, Dalian, 116024, China.
| | - Bo Liu
- School of Biomedical Engineering, Liaoning Key Lab of Integrated Circuit and Biomedical Electronic System, Dalian University of Technology, Dalian, 116024, China.
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28
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Hu JN, Yang JY, Jiang S, Zhang J, Liu Z, Hou JG, Gong XJ, Wang YP, Wang Z, Li W. Panax quinquefolium saponins protect against cisplatin evoked intestinal injury via ROS-mediated multiple mechanisms. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 82:153446. [PMID: 33387967 DOI: 10.1016/j.phymed.2020.153446] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 12/20/2020] [Accepted: 12/22/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Cisplatin is one of the most common chemotherapeutic drugs. Cisplatin-induced toxicity gives rise to gastrointestinal cell damage, subsequent diarrhea and vomiting, leading to the discontinuation of its clinical application in long-term cancer chemotherapy. Panax quinquefolium L., also known as American ginseng, has many pharmacological activities such as improving immunity, anti-tumor, anti-radiation and blood sugar lowering. PURPOSE Previously, our laboratory reported that American ginseng berry extract could alleviate chemotherapeutic agents-induced renal damage caused by cisplatin. Hence, this study further explored the protective effect of P. quinquefolium saponins (PQS) on cisplatin-induced intestinal injury in mice and the possible molecular mechanisms. METHODS Biochemical markers, levels of inflammatory factors, histopathological staining and western blotting were used to analyze intestinal injury based on various molecular mechanisms. RESULTS We demonstrated the destruction of the intestinal barrier caused by cisplatin exposure by detecting the activity of diamine oxidase (DAO) and the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin. Meanwhile, cisplatin exposure changed SOD and MDA levels in the small intestine, causing oxidative damage to the intestinal mucosa. The inflammation associated-intestinal damage was further explored by the measurement of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and analysis of nuclear factor-kappa B (NF-κB) inflammatory pathway protein expression. Moreover, apoptotic cells labeled with TUNEL staining-positive cells and activated caspase family proteins suggest that cisplatin induces intestinal apoptosis. Interestingly, PQS pretreatment significantly reversed these situations. CONCLUSION These evidences clearly suggest that PQS can alleviate cisplatin-induced intestinal damage by inhibiting oxidative stress, reducing the occurrence of inflammation and apoptosis, and improving intestinal barrier function.
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Affiliation(s)
- Jun-Nan Hu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118 China; National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, China
| | - Jia-Yu Yang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118 China; National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, China
| | - Shuang Jiang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118 China; National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, China
| | - Jing Zhang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118 China; National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, China
| | - Zhi Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118 China; National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, China
| | - Jin-Gang Hou
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118 China
| | - Xiao-Jie Gong
- College of Life Science, Dalian Minzu University, Dalian 116600 China
| | - Ying-Ping Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118 China; National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, China
| | - Zi Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118 China; National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, China
| | - Wei Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118 China; National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, China.
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Donatienne d'Hose, Danhier P, Northshield H, Isenborghs P, Jordan BF, Gallez B. A versatile EPR toolbox for the simultaneous measurement of oxygen consumption and superoxide production. Redox Biol 2020; 40:101852. [PMID: 33418140 PMCID: PMC7804984 DOI: 10.1016/j.redox.2020.101852] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 01/30/2023] Open
Abstract
In this paper, we describe an assay to analyze simultaneously the oxygen consumption rate (OCR) and superoxide production in a biological system. The analytical set-up uses electron paramagnetic resonance (EPR) spectroscopy with two different isotopically-labelled sensors: 15N-PDT (4-oxo-2,2,6,6-tetramethylpiperidine-d16-15N-1-oxyl) as oxygen-sensing probe and 14N-CMH (1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine, a cyclic hydroxylamine, as sensor of reactive oxygen species (ROS). The superoxide contribution to CMH oxidation is assessed using SOD or PEGSOD as controls. Because the EPR spectra are not superimposable, the variation of EPR linewidth of 15N-PDT (linked to OCR) and the formation of the nitroxide from 14N-CMH (linked to superoxide production) can be recorded simultaneously over time on a single preparation. The EPR toolbox was qualified in biological systems of increasing complexity. First, we used an enzymatic assay based on the hypoxanthine (HX)/xanthine oxidase (XO) which is a well described model of oxygen consumption and superoxide production. Second, we used a cellular model of superoxide production using macrophages exposed to phorbol 12-myristate 13-acetate (PMA) which stimulates the NADPH oxidase (NOX) to consume oxygen and produce superoxide. Finally, we exposed isolated mitochondria to established inhibitors of the electron transport chain (rotenone and metformin) in order to assess their impact on OCR and superoxide production. This EPR toolbox has the potential to screen the effect of intoxicants or drugs targeting the mitochondrial function.
OCR and superoxide production are crucial to assess mitochondrial (dys)function. The EPR toolbox analyzes simultaneously the OCR and superoxide production. The EPR toolbox was validated in enzymatic system, cells and isolated mitochondria. The EPR toolbox has the potential to screen compounds altering mitochondrial function.
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Affiliation(s)
- Donatienne d'Hose
- Biomedical Magnetic Resonance, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Pierre Danhier
- Nuclear and Electron Spin Technologies (NEST) Platform, Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Heidi Northshield
- Biomedical Magnetic Resonance, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Pauline Isenborghs
- Biomedical Magnetic Resonance, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Bénédicte F Jordan
- Biomedical Magnetic Resonance, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Bernard Gallez
- Biomedical Magnetic Resonance, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium.
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Natural Products Targeting the Mitochondria in Cancers. Molecules 2020; 26:molecules26010092. [PMID: 33379233 PMCID: PMC7795732 DOI: 10.3390/molecules26010092] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/23/2020] [Accepted: 12/25/2020] [Indexed: 12/13/2022] Open
Abstract
There are abundant sources of anticancer drugs in nature that have a broad prospect in anticancer drug discovery. Natural compounds, with biological activities extracted from plants and marine and microbial metabolites, have significant antitumor effects, but their mechanisms are various. In addition to providing energy to cells, mitochondria are involved in processes, such as cell differentiation, cell signaling, and cell apoptosis, and they have the ability to regulate cell growth and cell cycle. Summing up recent data on how natural products regulate mitochondria is valuable for the development of anticancer drugs. This review focuses on natural products that have shown antitumor effects via regulating mitochondria. The search was done in PubMed, Web of Science, and Google Scholar databases, over a 5-year period, between 2015 and 2020, with a keyword search that focused on natural products, natural compounds, phytomedicine, Chinese medicine, antitumor, and mitochondria. Many natural products have been studied to have antitumor effects on different cells and can be further processed into useful drugs to treat cancer. In the process of searching for valuable new drugs, natural products such as terpenoids, flavonoids, saponins, alkaloids, coumarins, and quinones cover the broad space.
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Sokkar HH, Abo Dena AS, Mahana NA, Badr A. Artichoke extracts in cancer therapy: do the extraction conditions affect the anticancer activity? FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2020. [DOI: 10.1186/s43094-020-00088-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Artichoke is an edible plant that is grown in the Mediterranean region and is known for its antimicrobial, antifungal, antibacterial, antioxidant and anticancer activities. Different artichoke extraction methods can impressively affect the nature as well as the yield of the extracted components.
Main body
The different methods of artichoke extraction and the influence of the extraction conditions on the extraction efficiency are summarized herein. In addition, cancer causalities and hallmarks together with the molecular mechanisms of artichoke active molecules in cancer treatment are also discussed. Moreover, a short background is given on the common types of cancer that can be treated with artichoke extracts as well as their pathogenesis. A brief discussion of the previous works devoted to the application of artichoke extracts in the treatment of these cancers is also given.
Conclusion
This review article covers the extraction methods, composition, utilization and applications of artichoke extracts in the treatment of different cancers.
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GDC-0349 inhibits non-small cell lung cancer cell growth. Cell Death Dis 2020; 11:951. [PMID: 33154352 PMCID: PMC7644631 DOI: 10.1038/s41419-020-03146-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 10/11/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023]
Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related human mortality with a clear need for new therapeutic intervention. GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor. In A549 cells and primary human NSCLC cells, GDC-0349 inhibited cell growth, proliferation, cell cycle progression, migration and invasion, while inducing significant apoptosis activation. Although GDC-0349 blocked Akt-mTORC1/2 activation in NSCLC cells, it also exerted cytotoxicity in Akt1-knockout A549 cells. Furthermore, restoring Akt-mTOR activation by a constitutively-active Akt1 only partially attenuated GDC-0349-induced A549 cell apoptosis, indicating the existence of Akt-mTOR-independent mechanisms. In NSCLC cells GDC-0349 induced sphingosine kinase 1 (SphK1) inhibition, ceramide accumulation, JNK activation and oxidative injury. Conversely, N-acetylcysteine, the JNK inhibitor and sphingosine 1-phosphate alleviated GDC-0349-induced NSCLC cell apoptosis. In vivo, daily oral administration of GDC-0349 potently inhibited NSCLC xenograft growth in mice. Akt-mTOR in-activation, SphK1 inhibition, JNK activation and oxidative stress were detected in NSCLC xenograft tissues with GDC-0349 administration. In summary, GDC-0349 inhibits NSCLC cell growth via Akt-mTOR-dependent and Akt-mTOR-independent mechanisms.
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Icsel C, Yilmaz VT, Aydinlik Ş, Aygun M. New manganese(II), iron(II), cobalt(II), nickel(II) and copper(II) saccharinate complexes of 2,6-bis(2-benzimidazolyl)pyridine as potential anticancer agents. Eur J Med Chem 2020; 202:112535. [DOI: 10.1016/j.ejmech.2020.112535] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/02/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023]
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Ester and amide derivatives of rhodamine B exert cytotoxic effects on different human tumor cell lines. Med Chem Res 2020. [DOI: 10.1007/s00044-020-02591-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
AbstractThree esters of rhodamine B (1–3) differing in their alkyl chain lengths as well as several rhodamine B amides (4–9) were synthesized in good yields and tested for their cytotoxicity in SRB assays employing several human tumor cell lines. The rhodamine B esters were unselective but showed cytotoxicity of as low as EC50 = 0.15 ± 0.02 µM. The rhodamine B amides were slightly less cytotoxic but showed good selectivity against MCF-7 and A2780 tumor cell lines. Especially a morpholinyl derivative 4 was ~20 time more cytotoxic for MCF-7 than for nonmalignant NIH 3T3 cells.
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Hyeraci M, Colalillo M, Labella L, Marchetti F, Samaritani S, Scalcon V, Rigobello MP, Dalla Via L. Platinum(II) Complexes Bearing Triphenylphosphine and Chelating Oximes: Antiproliferative Effect and Biological Profile in Resistant Cells. ChemMedChem 2020; 15:1464-1472. [DOI: 10.1002/cmdc.202000165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/27/2020] [Indexed: 11/11/2022]
Affiliation(s)
- Mariafrancesca Hyeraci
- Department of Pharmaceutical and Pharmacological SciencesUniversità di Padova Via F. Marzolo, 5 35131 Padova Italy
| | - Marialuigia Colalillo
- Dipartimento di Chimica e Chimica IndustrialeUniversità di Pisa Via G. Moruzzi 13 56124 Pisa Italy
| | - Luca Labella
- Dipartimento di Chimica e Chimica IndustrialeUniversità di Pisa Via G. Moruzzi 13 56124 Pisa Italy
| | - Fabio Marchetti
- Dipartimento di Chimica e Chimica IndustrialeUniversità di Pisa Via G. Moruzzi 13 56124 Pisa Italy
| | - Simona Samaritani
- Dipartimento di Chimica e Chimica IndustrialeUniversità di Pisa Via G. Moruzzi 13 56124 Pisa Italy
| | - Valeria Scalcon
- Department of Biomedical SciencesUniversità di Padova Via U. Bassi 58/b 35131 Padova Italy
| | - Maria Pia Rigobello
- Department of Biomedical SciencesUniversità di Padova Via U. Bassi 58/b 35131 Padova Italy
| | - Lisa Dalla Via
- Department of Pharmaceutical and Pharmacological SciencesUniversità di Padova Via F. Marzolo, 5 35131 Padova Italy
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Alhakamy NA, Fahmy UA, Badr-Eldin SM, Ahmed OAA, Asfour HZ, Aldawsari HM, Algandaby MM, Eid BG, Abdel-Naim AB, Awan ZA, Alruwaili NK, Mohamed AI. Optimized Icariin Phytosomes Exhibit Enhanced Cytotoxicity and Apoptosis-Inducing Activities in Ovarian Cancer Cells. Pharmaceutics 2020; 12:E346. [PMID: 32290412 PMCID: PMC7238269 DOI: 10.3390/pharmaceutics12040346] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/06/2020] [Accepted: 04/09/2020] [Indexed: 01/04/2023] Open
Abstract
Icariin (ICA) is a flavonol glycoside that has pleiotropic pharmacological actions. It has cytotoxic effects against ovarian cancer cells and increases their chemosensitivity to chemotherapeutic drugs. Phytosomes are identified for their potential in drug delivery of cytotoxic agents. Thus, the purpose of this study was to determine the potential enhancement of ICA cytotoxicity activity in OVCAR-3 ovarian cancer cells via its formulation in phytosomes. ICA-phytosomal formulation was optimized using a Box-Behnken design. Particle size, shape, and in vitro drug release were used to characterize the optimized formula. The optimized formulation exhibited enhanced in vitro drug release. ICA-phytosomes exhibited enhanced cytotoxicity against ovarian cancer cells. Cell cycle analysis indicated accumulation of cells challenged with ICA-phytosomes in G2/M and pre-G1 phases. Staining of cells with annexin V indicated significant elevation of percentage cells with early and late apoptosis as well as total cell death. In addition, the formulation significantly disturbed mitochondrial membrane potential and cellular content of caspase 3. In addition, intracellular release of reactive oxygen species (ROS) was enhanced by ICA-phytosomes. In conclusion, phytosome formulation of ICA significantly potentiates its cytotoxic activities against OVCAR-3 cells. This is mediated, at least partly, by enhanced ICA cellular permeation, apoptosis, and ROS.
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Affiliation(s)
- Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.-E.); (O.A.A.A.); (H.M.A.)
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.-E.); (O.A.A.A.); (H.M.A.)
| | - Shaimaa M. Badr-Eldin
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.-E.); (O.A.A.A.); (H.M.A.)
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.-E.); (O.A.A.A.); (H.M.A.)
| | - Hani Z. Asfour
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Hibah M. Aldawsari
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.-E.); (O.A.A.A.); (H.M.A.)
| | - Mardi M. Algandaby
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21579, Saudi Arabia;
| | - Basma G. Eid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (B.G.E.); (A.B.A.-N.)
| | - Ashraf B. Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (B.G.E.); (A.B.A.-N.)
| | - Zuhier A. Awan
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Nabil K. Alruwaili
- Department of Pharmaceutics, Faculty of Pharmacy, Jouf University, Skaka 2014, Saudi Arabia;
| | - Amir I. Mohamed
- Department of Pharmaceutics and Industrial Pharmacy, Military Medical Academy, Cairo 11757, Egypt;
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Yazici GN, Erdoğan D, Gürgen SG, Sunar M, Elmas Ç, Umur N, Ilgaz C. An immunohistochemical study of the effects of various antioxidants on rat lung during chemotherapy. Biotech Histochem 2020; 95:445-455. [PMID: 32043366 DOI: 10.1080/10520295.2020.1715480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
We investigated using immunohistochemistry the possible protective effects of ascorbic acid, α-tocopherol and selenium during chemotherapy treatment with cyclophosphamide. Thirty female Wistar rats were divided into five groups of six: group 1, untreated control; group 2, 75 µg/kg cyclophosphamide; group 3, 75 µg/kg cyclophosphamide + 150 µg/kg/day α-tocopherol; group 4, 75 µg/kg cyclophosphamide + 200 µg/kg/day ascorbic acid and group 5, 75 µg/kg cyclophosphamide + 40 ppm/kg/day selenium. Proliferating cell nuclear antigen (PCNA) staining was used to detect cell proliferation and AT1 was used to evaluate structural damage. Caspase-8, caspase-9 and caspase-3 signal molecules were used to investigate apoptosis. In group 2, epithelium, alveolar macrophages, infiltrated lymphocytes and connective tissue were immunostained moderately to strongly with PCNA. Bronchus, alveolar wall and infiltrated lymphocytes were immunostained moderately to strongly with AT1 and diffuse strong caspase immunoreactions were observed throughout the lung tissue. AT1 and caspase immunoreactions in groups 4 and 5 were similar to group 2. In group 3, PCNA immunoreactivity was strong in the bronchiolus epithelium, endothelial cell nuclei and in stacks of infiltrated lymphocyte cell nuclei. In group 3, AT1 and caspase immunoreactions were identical to group 1. It appears that α-tocopherol inhibits lung tissue damage in rats during chemotherapy.
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Affiliation(s)
- Gülce Naz Yazici
- Erzincan University , Faculty of Medicine, Department of Histology and Embryology, Erzincan, Turkey
| | - Deniz Erdoğan
- Gazi University , Faculty of Medicine, Department of Histology and Embryology, Ankara, Turkey
| | - Seren Gülşen Gürgen
- Manisa Celal Bayar University , School of Vocational Health Service, Department of Histology and Embryology, Manisa, Turkey
| | - Mukadder Sunar
- Erzincan University , Faculty of Medicine, Department of Anatomy, Erzincan, Turkey
| | - Çiğdem Elmas
- Gazi University , Faculty of Medicine, Department of Histology and Embryology, Ankara, Turkey
| | - Nurcan Umur
- Manisa Celal Bayar University , School of Vocational Health Service, Department of Molecular Biology, Manisa, Turkey
| | - Celal Ilgaz
- Gazi University , Faculty of Medicine, Department of Histology and Embryology, Ankara, Turkey
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Kuznetsova DA, Gaynanova GA, Vasileva LA, Sibgatullina GV, Samigullin DV, Sapunova AS, Voloshina AD, Galkina IV, Petrov KA, Zakharova LY. Mitochondria-targeted cationic liposomes modified with alkyltriphenylphosphonium bromides loaded with hydrophilic drugs: preparation, cytotoxicity and colocalization assay. J Mater Chem B 2019; 7:7351-7362. [PMID: 31696196 DOI: 10.1039/c9tb01853k] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The purpose of this work was to obtain cationic liposomes based on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine noncovalently modified using alkyltriphenylphosphonium bromides (TPPB-n) with different lengths of hydrocarbon tail for targeted delivery to mitochondria. The hydrodynamic diameter and electrokinetic potential of hybrid liposomes depending on the lipid/surfactant ratio were monitored in time with the aim to optimize the composition with sufficient stability and positive charge for mitochondria-targeted delivery. It was found that increasing the alkyl tail length of the surfactant (up to TPPB-14) leads to an increase in the positive charge of the liposomes. The most optimal results of stability were obtained for hybrid liposomes based on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and TPPB-12, TPPB-14. The obtained modified liposomes were loaded with hydrophilic substrates (a model probe Rhodamine B and medicines metronidazole and doxorubicin). This is one of the first examples of fabrication of liposomes noncovalently modified using an amphiphilic TPP cation, with the alkyl tail length of surfactant and TPP/lipid ratio optimized in terms of stability of the liposomes and the binding/release behavior of hydrophilic probes. Using the confocal microscopy method, it was shown that modification of liposomes with a triphenylphosphonium cation results in targeted delivery of encapsulated compounds to mitochondria.
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Affiliation(s)
- Darya A Kuznetsova
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov str., Kazan, 420088, Russian Federation.
| | - Gulnara A Gaynanova
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov str., Kazan, 420088, Russian Federation.
| | - Leysan A Vasileva
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov str., Kazan, 420088, Russian Federation. and Kazan National Research Technological University, 68 Karl Marx str., Kazan, 420015, Russian Federation
| | - Guzel V Sibgatullina
- Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevski str., Kazan, 420111, Russian Federation
| | - Dmitry V Samigullin
- Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevski str., Kazan, 420111, Russian Federation
| | - Anastasiia S Sapunova
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov str., Kazan, 420088, Russian Federation.
| | - Alexandra D Voloshina
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov str., Kazan, 420088, Russian Federation.
| | - Irina V Galkina
- Kazan Federal University, 18 Kremlyovskaya str., Kazan, 420008, Russian Federation
| | - Konstantin A Petrov
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov str., Kazan, 420088, Russian Federation. and Kazan Federal University, 18 Kremlyovskaya str., Kazan, 420008, Russian Federation
| | - Lucia Ya Zakharova
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov str., Kazan, 420088, Russian Federation.
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Martinis P, Grancara S, Kanamori Y, García-Argáez AN, Pacella E, Dalla Via L, Toninello A, Agostinelli E. Involvement of the biogenic active amine agmatine in mitochondrial membrane permeabilization and release of pro-apoptotic factors. Amino Acids 2019; 52:161-169. [DOI: 10.1007/s00726-019-02791-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 09/30/2019] [Indexed: 10/25/2022]
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Sepúlveda C, Núñez O, Torres A, Guzmán L, Wehinger S. Antitumor Activity of Propolis: Recent Advances in Cellular Perspectives, Animal Models and Possible Applications. FOOD REVIEWS INTERNATIONAL 2019. [DOI: 10.1080/87559129.2019.1649692] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- César Sepúlveda
- Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Olinda Núñez
- Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Alejandra Torres
- Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Luis Guzmán
- Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
| | - Sergio Wehinger
- Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
- Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca, Chile
- Laboratory of Cellular Communication, Center for Molecular Studies of the Cell (CEMC), Faculty of Medicine, Universidad de Chile, Santiago, Chile
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Mondal P, Shaw P, Bandyopadhyay A, Dey Bhowmik A, Chakraborty A, Sudarshan M, Chattopadhyay A. Mixture effect of arsenic and fluoride at environmentally relevant concentrations in zebrafish (Danio rerio) liver: Expression pattern of Nrf2 and related xenobiotic metabolizing enzymes. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2019; 213:105219. [PMID: 31195325 DOI: 10.1016/j.aquatox.2019.06.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/02/2019] [Accepted: 06/02/2019] [Indexed: 06/09/2023]
Abstract
Nrf2 is a crucial transcription factor that regulates the expression of cytoprotective enzymes and controls cellular redox homeostasis. Both arsenic and fluoride are potent toxicants that are known to induce Nrf2. They are reported to coexist in many areas of the world leading to complex mixture effects in exposed organisms. The present study investigated the expression of Nrf2 and related xenobiotic metabolizing enzymes along with other stress markers such as histopathological alterations, catalase activity, reduced glutathione content and lipid peroxidation in zebrafish liver as a function of combined exposure to environmentally relevant concentrations of arsenic (37.87 μgL-1 or 5.05 × 10-7 M) and fluoride (6.8 mg L-1 or 3.57 × 10-4 M) for 60 days. The decrease in the total reduced glutathione level was evident in all treatment conditions. Hyperactivity of catalase along with conspicuous elevation in reactive oxygen species, malondialdehyde content and histo-architectural anomalies signified the presence of oxidative stress in the treatment groups. Nrf2 was seen to be induced at both transcriptional and translational levels in case of both individual and co-exposure. The same pattern was observed in case of its nuclear translocation also. From the results of qRT-PCR it was evident that at each time point co-exposure to arsenic and fluoride seemed to alter the gene expression of Cu/Zn Sod, Mn Sod, Gpx and Nqo1 just like their individual exposure but at a very low magnitude. In conclusion, this study demonstrates for the first time the differential expression and activity of Nrf2 and other stress response genes in the zebrafish liver following individual and combined exposure to arsenic and fluoride.
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Affiliation(s)
- Paritosh Mondal
- Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India
| | - Pallab Shaw
- Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India
| | | | - Arpan Dey Bhowmik
- Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India
| | - Anindita Chakraborty
- UGC-DAE Consortium for Scientific Research, Kolkata Centre, 3/LB-8, Bidhan Nagar, Kolkata, 700098, West Bengal, India
| | - Muthammal Sudarshan
- UGC-DAE Consortium for Scientific Research, Kolkata Centre, 3/LB-8, Bidhan Nagar, Kolkata, 700098, West Bengal, India
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Khasiyatullina NR, Mironov VF, Gumerova SK, Voloshina AD, Sapunova AS. Versatile approach to naphthoquinone phosphonium salts and evaluation of their biological activity. MENDELEEV COMMUNICATIONS 2019. [DOI: 10.1016/j.mencom.2019.07.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Kim KD, Jung HY, Ryu HG, Kim B, Jeon J, Yoo HY, Park CH, Choi BH, Hyun CK, Kim KT, Fang S, Yang SH, Kim JB. Betulinic acid inhibits high-fat diet-induced obesity and improves energy balance by activating AMPK. Nutr Metab Cardiovasc Dis 2019; 29:409-420. [PMID: 30799179 DOI: 10.1016/j.numecd.2018.12.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 12/05/2018] [Accepted: 12/05/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM Metabolic syndromes are prevalent worldwide and result in various complications including obesity, cardiovascular disease and type II diabetes. Betulinic acid (BA) is a naturally occurring triterpenoid that has anti-inflammatory properties. We hypothesized that treatment with BA may result in decreased body weight gain, adiposity and hepatic steatosis in a diet-induced mouse model of obesity. METHODS AND RESULTS Mice fed a high-fat diet and treated with BA showed less weight gain and tissue adiposity without any change in calorie intake. Gene expression profiling of mouse tissues and cell lines revealed that BA treatment increased expression of lipid oxidative genes and decreased that of lipogenesis-related genes. This modulation was mediated by increased AMP-activated protein kinase (AMPK) phosphorylation, which facilitates energy expenditure, lipid oxidation and thermogenic capacity and exerts protective effects against obesity and nonalcoholic fatty liver disease. Overall, BA markedly inhibited the development of obesity and nonalcoholic fatty liver disease in mice fed a high-fat diet, and AMPK activation in various tissues and enhanced thermogenesis are two possible mechanisms underlying the antiobesity and antisteatogenic effects of BA. CONCLUSIONS The current findings suggest that treatment with BA is a potential dietary strategy for preventing obesity and nonalcoholic fatty liver disease.
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Affiliation(s)
- K-D Kim
- School of Life Science, Handong Global University, Pohang, Gyungbuk, South Korea
| | - H-Y Jung
- Division of Integrative Biosciences and Biotechnology, POSTECH, Pohang, Gyungbuk, South Korea; R&D Center, NovMetaPharma Co., Ltd., Pohang, Gyungbuk, South Korea
| | - H G Ryu
- Department of Life Sciences, POSTECH, Pohang, Gyungbuk, South Korea
| | - B Kim
- School of Life Science, Handong Global University, Pohang, Gyungbuk, South Korea; R&D Center, NovMetaPharma Co., Ltd., Pohang, Gyungbuk, South Korea
| | - J Jeon
- Division of Integrative Biosciences and Biotechnology, POSTECH, Pohang, Gyungbuk, South Korea; R&D Center, NovMetaPharma Co., Ltd., Pohang, Gyungbuk, South Korea
| | - H Y Yoo
- Division of Integrative Biosciences and Biotechnology, POSTECH, Pohang, Gyungbuk, South Korea
| | - C H Park
- Mistle Biotech Co., Ltd., Pohang, Gyungbuk, South Korea
| | - B-H Choi
- Advanced Bio Convergence Center, Pohang Technopark, Pohang, Gyungbuk, South Korea
| | - C-K Hyun
- School of Life Science, Handong Global University, Pohang, Gyungbuk, South Korea
| | - K-T Kim
- Division of Integrative Biosciences and Biotechnology, POSTECH, Pohang, Gyungbuk, South Korea; Department of Life Sciences, POSTECH, Pohang, Gyungbuk, South Korea
| | - S Fang
- Severance Biomedical Science Institute, BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - S H Yang
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Seoul National University Biomedical Research Institute, Seoul, South Korea
| | - J-B Kim
- School of Life Science, Handong Global University, Pohang, Gyungbuk, South Korea; Mistle Biotech Co., Ltd., Pohang, Gyungbuk, South Korea.
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ROS Induced by KillerRed Targeting Mitochondria (mtKR) Enhances Apoptosis Caused by Radiation via Cyt c/Caspase-3 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4528616. [PMID: 30984335 PMCID: PMC6431512 DOI: 10.1155/2019/4528616] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 01/02/2019] [Accepted: 01/22/2019] [Indexed: 12/12/2022]
Abstract
During radiotherapy, reactive oxygen species- (ROS-) induced apoptosis is one of the main mechanism of radiation. Based on KillerRed which can induce ROS burst in different cell substructures, here we hypothesized that KillerRed targeting mitochondria (mtKR) could induce ROS to enhance apoptosis by radiation. In this study, empty vector, mtKR, and mtmCherry plasmids were successfully constructed, and mitochondrial localization were detected in COS-7 and HeLa cells. After HeLa cells were transfected and irradiated by visible light and X-rays, ROS levels, mitochondrial membrane potential (Δψm), ATPase activities, adenosine triphosphate (ATP) content, apoptosis, and the expressions of mRNA and protein were measured, respectively. Data demonstrated that the ROS levels significantly increased after light exposure, and adding extra radiation, voltage-dependent anion channel 1 (VDAC1) protein increased in the mitochondria, while Na+-K+ and Ca2+-Mg2+ ATPase activities, ATP content, and Δψm significantly reduced. Additionally, the cell apoptotic rates dramatically increased, which referred to the increase of cytochrome c (Cyt c), caspase-9, and caspase-3 mRNA expressions, and Cyt c protein was released from the mitochondria into the cytoplasm; caspase-9 and -3 were activated. These results indicated that mtKR can increase the production of ROS, enhance mitochondrial dysfunction, and strengthen apoptosis by radiation via Cyt c/caspase-3 pathway.
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3, 3′-Diindolylmethane-encapsulated chitosan nanoparticles accelerate molecular events during chemical carcinogen-induced mammary cancer in Sprague Dawley rats. Breast Cancer 2019; 26:499-509. [DOI: 10.1007/s12282-019-00950-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 01/20/2019] [Indexed: 11/25/2022]
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Liu Z, Li J, Kong D, Tian M, Zhao Y, Xu Z, Gao W, Zhou Y. Dual Functional Half-Sandwich Ru(II) Complexes: Lysosome-Targeting Probes and Anticancer Agents. Eur J Inorg Chem 2019. [DOI: 10.1002/ejic.201801339] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Zhe Liu
- Institute of Anticancer Agents Development and Theranostic Application; The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine; Department of Chemistry and Chemical Engineering; Qufu Normal University; 273165 Qufu China
| | - JuanJuan Li
- Institute of Anticancer Agents Development and Theranostic Application; The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine; Department of Chemistry and Chemical Engineering; Qufu Normal University; 273165 Qufu China
| | - Deliang Kong
- Institute of Anticancer Agents Development and Theranostic Application; The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine; Department of Chemistry and Chemical Engineering; Qufu Normal University; 273165 Qufu China
| | - Meng Tian
- Institute of Anticancer Agents Development and Theranostic Application; The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine; Department of Chemistry and Chemical Engineering; Qufu Normal University; 273165 Qufu China
| | - Yao Zhao
- CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Institute of Chemistry; Chinese Academy of Sciences; 100190 Beijing PR China
| | - Zhishan Xu
- Institute of Anticancer Agents Development and Theranostic Application; The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine; Department of Chemistry and Chemical Engineering; Qufu Normal University; 273165 Qufu China
- Department of Chemistry and Chemical Engineering; Shandong Normal University; 250014 Jinan China
| | - Wenyuan Gao
- Institute of Anticancer Agents Development and Theranostic Application; The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine; Department of Chemistry and Chemical Engineering; Qufu Normal University; 273165 Qufu China
| | - Yumin Zhou
- Institute of Anticancer Agents Development and Theranostic Application; The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine; Department of Chemistry and Chemical Engineering; Qufu Normal University; 273165 Qufu China
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Dong J, Zhang X, Qu C, Rong X, Liu J, Qu Y. Structural characterization of Momordica charantia L. (Cucurbitaceae) oligopeptides and the detection of their capability in non-small cell lung cancer A549 cells: induction of apoptosis. RSC Adv 2019; 9:8300-8309. [PMID: 35518675 PMCID: PMC9061805 DOI: 10.1039/c9ra00090a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 02/23/2019] [Indexed: 01/03/2023] Open
Abstract
Oligopeptides are rarely reported from Chinese herbal medicine because they are often present in very low concentrations in a complex matrix. Twenty-eight oligopeptides were recently identified by high-performance liquid chromatography and quadrupole-time-of-flight-mass spectrometry (HPLC-Q-TOF-MS) from Momordica charantia L. (Cucurbitaceae), and a septapeptide, FHGKGHE (Phe-His-Gly-Lys-Gly-His-Glu), named MCLO-12, showed the best anticancer activity against the non-small cell lung cancer A549 cell line in vitro, with an IC50 value of 21.4 ± 2.21 mM. The anti-proliferative activity assay results showed that MCLO-12 induced apoptosis of A549 cells in a concentration-dependent manner. Treatment of the cells with MCLO-12 (10.7–42.8 mM mL−1) caused strong intracellular reactive oxygen species (ROS) up-regulating activities and activated caspase expression. MCLO-12 also suppressed the Trx system and subsequently activated a number of Trx-dependent pathways, including the ASK1, MAPK-p38 and JNK pathways. Thus, our research provides a good reference point for anti-NSCLC research into oligopeptides. MCLO-12 induced apoptosis by up-regulating the ROS, activating the caspases expressions, suppressing the Trx system and subsequently activating a number of Trx-dependent pathways.![]()
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Affiliation(s)
- Jiao Dong
- Department of Respiratory Medicine
- Qilu Hospital of Shandong University
- Jinan
- China
- Department of Respiratory Medicine
| | - Xianxin Zhang
- Department of Respiratory Medicine
- Shandong Provincial Chest Hospital
- Jinan
- China
| | - Chunxiao Qu
- Department of Pharmacy
- Shandong Provincial Chest Hospital
- Jinan
- China
| | - Xuedong Rong
- Department of Respiratory Medicine
- Shandong Provincial Chest Hospital
- Jinan
- China
| | - Jie Liu
- The Research Center of Allergy & Immunology
- Shenzhen University School of Medicine
- Shenzhen
- China
| | - Yiqing Qu
- Department of Respiratory Medicine
- Qilu Hospital of Shandong University
- Jinan
- China
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Chen X, Chen X, Zhang X, Wang L, Cao P, Rajamanickam V, Wu C, Zhou H, Cai Y, Liang G, Wang Y. Curcuminoid B63 induces ROS-mediated paraptosis-like cell death by targeting TrxR1 in gastric cells. Redox Biol 2018; 21:101061. [PMID: 30590310 PMCID: PMC6306695 DOI: 10.1016/j.redox.2018.11.019] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 11/25/2018] [Accepted: 11/26/2018] [Indexed: 01/07/2023] Open
Abstract
Gastric cancer is one of the leading causes of cancer-related deaths. Chemotherapy has improved long-term survival of patients with gastric cancer. Unfortunately, cancer readily develops resistance to apoptosis-inducing agents. New mechanisms, inducing caspase-independent paraptosis-like cell death in cancer cells is presently emerging as a potential direction. We previously developed a curcumin analog B63 as an anti-cancer agent in pre-clinical evaluation. In the present study, we evaluated the effect and mechanism of B63 on gastric cancer cells. Our studies show that B63 targets TrxR1 protein and increases cellular reactive oxygen species (ROS) level, which results in halting gastric cancer cells and inducing caspase-independent paraptotic modes of death. The paraptosis induced by B63 was mediated by ROS-mediated ER stress and MAPK activation. Either overexpression of TrxR1 or suppression of ROS normalized B63-induced paraptosis in gastric cancer cells. Furthermore, B63 caused paraptosis in 5-fluorouracil-resistant gastric cancer cells, and B63 treatment reduced the growth of gastric cancer xenografts, which was associated with increased ROS and paraptosis. Collectively, our findings provide a novel strategy for the treatment of gastric cancer by utilizing TrxR1-mediated oxidative stress generation and subsequent cell paraptosis.
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Affiliation(s)
- Xi Chen
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China
| | - Xiaoming Chen
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xi Zhang
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China
| | - Li Wang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Peihai Cao
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Vinothkumar Rajamanickam
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chao Wu
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Huiping Zhou
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yuepiao Cai
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China.
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China.
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ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to Thioridazine. Biomed Pharmacother 2018; 106:200-209. [DOI: 10.1016/j.biopha.2018.06.123] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 05/31/2018] [Accepted: 06/22/2018] [Indexed: 01/04/2023] Open
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