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Zhao W, Qian J, Li J, Su T, Deng X, Fu Y, Liang X, Cui H. From death to birth: how osteocyte death promotes osteoclast formation. Front Immunol 2025; 16:1551542. [PMID: 40165960 PMCID: PMC11955613 DOI: 10.3389/fimmu.2025.1551542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 02/28/2025] [Indexed: 04/02/2025] Open
Abstract
Bone remodeling is a dynamic and continuous process involving three components: bone formation mediated by osteoblasts, bone resorption mediated by osteoclasts, and bone formation-resorption balancing regulated by osteocytes. Excessive osteocyte death is found in various bone diseases, such as postmenopausal osteoporosis (PMOP), and osteoclasts are found increased and activated at osteocyte death sites. Currently, apart from apoptosis and necrosis as previously established, more forms of cell death are reported, including necroptosis, ferroptosis and pyroptosis. These forms of cell death play important role in the development of inflammatory diseases and bone diseases. Increasing studies have revealed that various forms of osteocyte death promote osteoclast formation via different mechanism, including actively secreting pro-inflammatory and pro-osteoclastogenic cytokines, such as tumor necrosis factor alpha (TNF-α) and receptor activator of nuclear factor-kappa B ligand (RANKL), or passively releasing pro-inflammatory damage associated molecule patterns (DAMPs), such as high mobility group box 1 (HMGB1). This review summarizes the established and potential mechanisms by which various forms of osteocyte death regulate osteoclast formation, aiming to provide better understanding of bone disease development and therapeutic target.
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Affiliation(s)
- Weijie Zhao
- Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Emergency Surgery, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Jiale Qian
- Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Emergency Surgery, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Ji Li
- Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Emergency Surgery, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Tian Su
- Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Haikou Trauma, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China
- Engineering Research Center for Hainan Bio-Smart Materials and Bio-Medical Devices, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Emergency and Trauma, College of pharmacy, Hainan Medical University, Haikou, China
| | - Xiaozhong Deng
- Department of Pain Treatment, Nanxi Shan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Yonghua Fu
- Department of Hand and Foot Microsurgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xuelong Liang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hongwang Cui
- Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Emergency Surgery, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou, China
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Cao Z, Tian K, Ran Y, Zhou H, Zhou L, Ding Y, Tang X. Beclin-1: a therapeutic target at the intersection of autophagy, immunotherapy, and cancer treatment. Front Immunol 2024; 15:1506426. [PMID: 39650649 PMCID: PMC11621085 DOI: 10.3389/fimmu.2024.1506426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/01/2024] [Indexed: 12/11/2024] Open
Abstract
The significant identification of Beclin-1's function in regulating autophagy flow signified a significant progression in our understanding of cellular operations. Beclin-1 acts as a scaffold for forming the PI3KC3 complex, controlling autophagy and cellular trafficking processes in a complicated way. This intricate protein has garnered considerable attention due to its substantial impact on the development of tumors. Strong evidence indicates Beclin-1 plays a critical role in controlling autophagy in various human cancer types and its intricate connection with apoptosis and ferroptosis. The potential of Beclin-1 as a viable target for cancer therapy is highlighted by its associations with key autophagy regulators such as AMPK, mTOR, and ATGs. Beclin-1 controls the growth and dissemination of tumors by autophagy. It also affects how tumors react to therapies such as chemotherapy and radiation therapy. The role of Beclin-1 in autophagy can influence apoptosis, depending on whether it supports cell survival or leads to cell death. Beclin-1 plays a crucial role in ferroptosis by increasing ATG5 levels, which in turn promotes autophagy-triggered ferroptosis. Finally, we analyzed the possible function of Beclin-1 in tumor immunology and drug sensitivity in cancers. In general, Beclin-1 has a significant impact on regulating autophagy, offering various potentials for medical intervention and altering our understanding of cancer biology.
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Affiliation(s)
- Zhumin Cao
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Ke Tian
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yincheng Ran
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Haonan Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Lei Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yana Ding
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
| | - Xiaowei Tang
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
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Akiyama M, Kanayama M, Umezawa Y, Nagao T, Izumi Y, Yamamoto M, Ohteki T. An early regulatory mechanism of hyperinflammation by restricting monocyte contribution. Front Immunol 2024; 15:1398153. [PMID: 39040105 PMCID: PMC11260625 DOI: 10.3389/fimmu.2024.1398153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 06/06/2024] [Indexed: 07/24/2024] Open
Abstract
Innate immune cells play a key role in inflammation as a source of pro-inflammatory cytokines. However, it remains unclear how innate immunity-mediated inflammation is fine-tuned to minimize tissue damage and assure the host's survival at the early phase of systemic inflammation. The results of this study with mouse models demonstrate that the supply of monocytes is restricted depending on the magnitude of inflammation. During the acute phase of severe inflammation, monocytes, but not neutrophils, were substantially reduced by apoptosis and the remaining monocytes were dysfunctional in the bone marrow. Monocyte-specific ablation of Casp3/7 prevented monocyte apoptosis but promoted monocyte necrosis in the bone marrow, leading to elevated levels of pro-inflammatory cytokines and the increased mortality of mice during systemic inflammation. Importantly, the limitation of monocyte supply was dependent on pro-inflammatory cytokines in vivo. Consistently, a reduction of monocytes was observed in the peripheral blood during cytokine-release syndrome (CRS) patients, a pathogen-unrelated systemic inflammation induced by chimeric antigen receptor-T cell (CAR-T cell) therapy. Thus, monocytes act as a safety valve to alleviate tissue damage caused by inflammation and ensure host survival, which may be responsible for a primitive immune-control mechanism that does not require intervention by acquired immunity.
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Affiliation(s)
- Megumi Akiyama
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Hematology, Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
| | - Masashi Kanayama
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yoshihiro Umezawa
- Department of Hematology, Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
| | - Toshikage Nagao
- Department of Hematology, Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
| | - Yuta Izumi
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Masahide Yamamoto
- Department of Hematology, Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
| | - Toshiaki Ohteki
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Farhan M. Cytotoxic Activity of the Red Grape Polyphenol Resveratrol against Human Prostate Cancer Cells: A Molecular Mechanism Mediated by Mobilization of Nuclear Copper and Generation of Reactive Oxygen Species. Life (Basel) 2024; 14:611. [PMID: 38792632 PMCID: PMC11122162 DOI: 10.3390/life14050611] [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: 04/14/2024] [Revised: 05/05/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Resveratrol, a polyphenolic compound found primarily in red grapes and pomegranates is known as an antioxidant but can act as a pro-oxidant when copper ions are present. Here, resveratrol is demonstrated to reduce cell growth (as evaluated by MTT assay) and promote apoptosis-like cell death (as measured by Histone/DNA ELISA) in prostate cancer cell lines PC3 and C42B. This effect is effectively inhibited by a copper chelator (neocuproine) and reactive oxygen species (ROS) scavengers (thiourea for hydroxyl radical, superoxide dismutase for superoxide anion, and catalase for hydrogen peroxide). These inhibitory effects provide evidence that intracellular copper reacts with resveratrol within cancer cells, resulting in DNA damage via the generation of reactive oxygen species. Additionally, it has been demonstrated that non-tumorigenic epithelial cell lines (MCF-10A) grown in media supplemented with copper are more susceptible to growth inhibition by resveratrol, as confirmed by the observed reduction in cell proliferation. Copper supplementation induces enhanced expression of the copper transporter CTR1 in MCF-10A cells, which is reduced by the addition of resveratrol to the media. The selective cell death of cancer cells generated by copper-mediated and ROS mechanisms may help to explain the anticancer properties of resveratrol.
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Affiliation(s)
- Mohd Farhan
- Department of Chemistry, College of Science, King Faisal University, Al Ahsa 31982, Saudi Arabia;
- Department of Basic Sciences, Preparatory Year, King Faisal University, Al Ahsa 31982, Saudi Arabia
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Eum DY, Jeong M, Park SY, Kim J, Jin Y, Jo J, Shim JW, Lee SR, Park SJ, Heo K, Yun H, Choi YJ. AM-18002, a derivative of natural anmindenol A, enhances radiosensitivity in mouse breast cancer cells. PLoS One 2024; 19:e0296989. [PMID: 38625901 PMCID: PMC11020960 DOI: 10.1371/journal.pone.0296989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 12/25/2023] [Indexed: 04/18/2024] Open
Abstract
Natural anmindenol A isolated from the marine-derived bacteria Streptomyces sp. caused potent inhibition of inducible nitric oxide synthase without any significant cytotoxicity. This compound consists of a structurally unique 3,10-dialkylbenzofulvene skeleton. We previously synthesized and screened the novel derivatives of anmindenol A and identified AM-18002, an anmindenol A derivative, as a promising anticancer agent. The combination of AM-18002 and ionizing radiation (IR) improved anticancer effects, which were exerted by promoting apoptosis and inhibiting the proliferation of FM3A mouse breast cancer cells. AM-18002 increased the production of reactive oxygen species (ROS) and was more effective in inducing DNA damage. AM-18002 treatment was found to inhibit the expansion of myeloid-derived suppressor cells (MDSC), cancer cell migration and invasion, and STAT3 phosphorylation. The AM-18002 and IR combination synergistically induced cancer cell death, and AM-18002 acted as a potent anticancer agent by increasing ROS generation and blocking MDSC-mediated STAT3 activation in breast cancer cells.
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Affiliation(s)
- Da-Young Eum
- Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Myeonggyo Jeong
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Soon-Yong Park
- Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea
| | - Jisu Kim
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Yunho Jin
- Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea
| | - Jeyun Jo
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Jae-Woong Shim
- Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea
| | - Seoung Rak Lee
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Seong-Joon Park
- Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea
| | - Kyu Heo
- Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea
| | - Hwayoung Yun
- College of Pharmacy, Pusan National University, Busan, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Yoo-Jin Choi
- Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea
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Manasseh R, Sathuvalli V, Pappu HR. Transcriptional and functional predictors of potato virus Y-induced tuber necrosis in potato ( Solanum tuberosum). FRONTIERS IN PLANT SCIENCE 2024; 15:1369846. [PMID: 38638354 PMCID: PMC11024271 DOI: 10.3389/fpls.2024.1369846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 02/26/2024] [Indexed: 04/20/2024]
Abstract
Introduction Potato (Solanum tuberosum L.), the fourth most important food crop in the world, is affected by several viral pathogens with potato virus Y (PVY) having the greatest economic impact. At least nine biologically distinct variants of PVY are known to infect potato. These include the relatively new recombinant types named PVY-NTN and PVYN-Wi, which induce tuber necrosis in susceptible cultivars. To date, the molecular plant-virus interactions underlying this pathogenicity have not been fully characterized. We hypothesized that this necrotic behavior is supported by transcriptional and functional signatures that are unique to PVY-NTN and PVYN-Wi. Methods To test this hypothesis, transcriptional responses of cv. Russet Burbank, a PVY susceptible cultivar, to three PVY strains PVY-O, PVY-NTN, and PVYN-Wi were studied using mRNA-Seq. A haploid-resolved genome assembly for tetraploid potato was used for bioinformatics analysis. Results The study revealed 36 GO terms and nine KEGG 24 pathways that overlapped across the three PVY strains, making them generic features of PVY susceptibility in potato. Ten GO terms and three KEGG pathways enriched for PVY-NTN and PVYN-Wi only, which made them candidate functional signatures associated with PVY-induced tuber necrosis in potato. In addition, five other pathways were enriched for PVYNTN or PVYN-Wi. One carbon pool by folate was enriched exclusively in response to PVY-NTN infection; PVYN-Wi infection specifically impacted cutin, suberine and wax biosynthesis, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and monoterpenoid biosynthesis. Discussion Results suggest that PVYN-Wi-induced necrosis may be mechanistically distinguishable from that of PVY-NTN. Our study provides a basis for understanding the mechanism underlying the development of PVY-induced tuber necrosis in potato.
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Affiliation(s)
- Richard Manasseh
- Department of Plant Pathology, Washington State University, Pullman, WA, United States
| | - Vidyasagar Sathuvalli
- Hermiston Agricultural Research and Extension Center, Oregon State University, Hermiston, OR, United States
| | - Hanu R. Pappu
- Department of Plant Pathology, Washington State University, Pullman, WA, United States
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Bock HJ, Lee HW, Lee NK, Paik HD. Probiotic Lactiplantibacillus plantarum KU210152 and its fermented soy milk attenuates oxidative stress in neuroblastoma cells. Food Res Int 2024; 177:113868. [PMID: 38225133 DOI: 10.1016/j.foodres.2023.113868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/05/2023] [Accepted: 12/14/2023] [Indexed: 01/17/2024]
Abstract
We evaluated the probiotic properties and neuroprotective effects of Lactiplantibacillus plantarum KU210152 and its application in soy milk. L. plantarum KU210152 exhibited high tolerance to artificial gastrointestinal conditions, high adhesion to intestinal cells (HT-29), and safe enzyme production. Conditioned medium acquired from HT-29 cells treated with heat-killed lactic acid bacteria (LAB-CM) was used to evaluate the neuroprotective effects. The CM exhibited neuroprotective effects via cell viability assay, morphological observations, and suppression of ROS production. Heat-killed L. plantarum KU210152 increased brain-derived neurotrophic factor (BDNF) and tyrosine hydroxylase (TH) expression in HT-29 cells. In SH-SY5Y cells, pretreatment with L. plantarum KU210152 CM decreased Bax/Bcl-2 ratio and upregulated BDNF and TH expression. The CM inhibited caspase-9 and caspase-3 activities. The neuroprotective effects of L. plantarum KU210152 were also confirmed in fermented soy milk. Therefore, both L. plantarum KU210152 and the fermented soy milk can be used as functional ingredients with neuroprotective effects against oxidative stress.
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Affiliation(s)
- Hyun-Ji Bock
- Department of Food Science and Biotechnology of Animal Resources, Konkuk University, Seoul 05029, Republic of Korea
| | - Hye-Won Lee
- Department of Food Science and Biotechnology of Animal Resources, Konkuk University, Seoul 05029, Republic of Korea
| | - Na-Kyoung Lee
- Department of Food Science and Biotechnology of Animal Resources, Konkuk University, Seoul 05029, Republic of Korea
| | - Hyun-Dong Paik
- Department of Food Science and Biotechnology of Animal Resources, Konkuk University, Seoul 05029, Republic of Korea.
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Xuan T. Tripartite Motif-containing Protein 11 Silencing Inhibits Proliferation and Glycolysis and Promotes Apoptosis of Esophageal Squamous Cell Carcinoma Cells by Inactivating Signal Transduction and Activation of Transcription Factor 3/c-Myc Signaling. CHINESE J PHYSIOL 2024; 67:37-46. [PMID: 38780271 DOI: 10.4103/ejpi.ejpi-d-23-00013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/10/2023] [Indexed: 05/25/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common type of human digestive tract cancer with poor survival. Tripartite motif-containing protein 11 (TRIM11) is an oncogene in certain cancers that can regulate glycolysis and signal transduction and activation of transcription factor 3 (STAT3) signaling. This study was designed to investigate the role and the mechanism of TRIM11 in ESCC. First, TRIM11 expression in ESCC tissues and the correlation between TRIM11 expression and prognosis were analyzed using bioinformatics tools. After TRIM11 expression was detected by Western blot in ESCC cells, TRIM11 was silenced to evaluate its effect on the malignant phenotypes of ESCC cells. Cell proliferation and apoptosis were assessed by cell counting kit-8 assay, ethynyl-2'- deoxyuridine staining, and flow cytometry, respectively. The glucose uptake and lactate secretion were detected to examine glycolysis. In addition, Western blot was employed to detect the expression of proteins related to apoptosis, glycolysis, and STAT3/c-Myc signaling. Then, ESCC cells were treated with STAT3 activator further to clarify the regulatory effect of TRIM11 on STAT3/c-Myc signaling. TRIM11 was upregulated in ESCC tissues and cells, and high expression of TRIM11 was associated with a poor prognosis. TRIM11 knockdown inhibited the proliferation and glycolysis while facilitating apoptosis of ESCC cells. Besides, the expression of p-STAT3 and c-Myc was significantly downregulated by TRIM11 silencing. Of note, the STAT3 activator partially reversed the effects of TRIM11 depletion on the proliferation, apoptosis, and glycolysis in ESCC cells. Collectively, TRIM11 loss-of-function affects the proliferation, apoptosis, and glycolysis in ESCC cells by inactivating STAT3/c-Myc signaling.
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Affiliation(s)
- Tingting Xuan
- Department of Radiotherapy, The First People's Hospital of Nantong, Nantong, Jiangsu, China
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Scheijde-Vermeulen MA, Kester LA, Westera L, Tops BBJ, Meyer-Wentrup FAG. Integration of RNA Sequencing, Whole Exome Sequencing, and Flow Cytometry Into Routine Diagnostic Workup of Pediatric Lymphomas. J Transl Med 2024; 104:100267. [PMID: 37898291 DOI: 10.1016/j.labinv.2023.100267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/13/2023] [Accepted: 10/19/2023] [Indexed: 10/30/2023] Open
Abstract
The study was conducted to assess the feasibility of integrating state-of-the-art sequencing techniques and flow cytometry into diagnostic workup of pediatric lymphoma. RNA sequencing (RNAseq), whole exome sequencing, and flow cytometry were implemented into routine diagnostic workup of pediatric biopsies with lymphoma in the differential diagnosis. Within 1 year, biopsies from 110 children (122 specimens) were analyzed because of suspected malignant lymphoma. The experience with a standardized workflow combining histology and immunohistochemistry, flow cytometry, and next-generation sequencing technologies is reported. Flow cytometry was performed with fresh tissue in 83% (102/122) of specimens and allowed rapid diagnosis of T-cell and B-cell non-Hodgkin lymphomas. RNAseq was performed in all non-Hodgkin lymphoma biopsies and 42% (19/45) of Hodgkin lymphoma samples. RNAseq detected all but one of the translocations found by fluorescence in situ hybridization and PCR. RNAseq and whole exome sequencing identified additional genetic abnormalities not detected by conventional approaches. Finally, 3 cases are highlighted to exemplify how synergy between different diagnostic techniques and specialists can be achieved. This study demonstrates the feasibility and discusses the added value of integrating modern sequencing techniques and flow cytometry into a workflow for routine diagnostic workup of lymphoma. The inclusion of RNA and DNA sequencing not only supports diagnostics but also will lay the ground for the development of novel research-based treatment strategies for pediatric lymphoma patients.
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Affiliation(s)
| | - Lennart A Kester
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Liset Westera
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Bastiaan B J Tops
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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Alexandrov YI, Sozinov AA, Svarnik OE, Gorkin AG, Kuzina EA, Gavrilov VV, Arutyunova KR. Determination of Neuronal Activity and Its Meaning for the Processes of Learning and Memory. ADVANCES IN NEUROBIOLOGY 2024; 41:3-38. [PMID: 39589708 DOI: 10.1007/978-3-031-69188-1_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
Despite the years of studies in the field of systems neuroscience, the functions of neural circuits and behavior-related systems are still not entirely understood. The systems description of brain activity has recently been associated with cognitive concepts, e.g., a cognitive map, reconstructed via place-cell activity analysis and the like, and a cognitive schema, modeled in consolidation research. The issue we find of importance is that cognitive concepts reconstructed in neuroscience research are mainly formulated in terms of the environment. In this chapter, we present the idea of an element of individual experience that serves as a model of behavioral interaction with the environment, rather than a model of the environment itself. This intangible difference entails the need for substantial revision of several well-known phenomena, including long-term potentiation. The principal questions we address are: how do elements of experience appear and change during learning and performance; and how do the links between these elements create the whole structure of individual experience? We argue that learning and memory research need a clear distinction between processes that provide the emergence of new elements of experience (functional systems) and processes underlying the retrieval and/or changes in the existing experience. We propose to view the activity of a neuron as an "action" directed to the future adaptive "microresult," essential for meeting its metabolic needs. This anticipatory neuronal activity is coordinated with the activity of many other cells of the body in the organism-wide functional system, ensuring the achievement of an adaptive "macroresult" at the behavioral level. From this perspective, the mechanisms of learning are considered as the formation of functional systems, and memory is considered as a dynamic structure constituted by systems formed at different stages of individual development.
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Affiliation(s)
- Yuri I Alexandrov
- Shvyrkov's Lab. Neural Bases of Mind, Institute of Psychology, Russian Academy of Sciences, Moscow, Russia
| | - A A Sozinov
- Shvyrkov's Lab. Neural Bases of Mind, Institute of Psychology, Russian Academy of Sciences, Moscow, Russia
- Faculty of Psychology, National Academic University of Humanities, Moscow, Russia
| | - O E Svarnik
- Shvyrkov's Lab. Neural Bases of Mind, Institute of Psychology, Russian Academy of Sciences, Moscow, Russia
| | - A G Gorkin
- Shvyrkov's Lab. Neural Bases of Mind, Institute of Psychology, Russian Academy of Sciences, Moscow, Russia
| | - E A Kuzina
- Shvyrkov's Lab. Neural Bases of Mind, Institute of Psychology, Russian Academy of Sciences, Moscow, Russia
| | - V V Gavrilov
- Shvyrkov's Lab. Neural Bases of Mind, Institute of Psychology, Russian Academy of Sciences, Moscow, Russia
| | - K R Arutyunova
- Shvyrkov's Lab. Neural Bases of Mind, Institute of Psychology, Russian Academy of Sciences, Moscow, Russia
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11
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Zhong Z, Zhong H. KIF22 promotes the proliferation and glycolysis of melanoma by activating EGFR/STAT3 signaling. Clinics (Sao Paulo) 2023; 78:100307. [PMID: 37944197 PMCID: PMC10661841 DOI: 10.1016/j.clinsp.2023.100307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/23/2023] [Accepted: 10/25/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVES Melanoma is one of the leading causes of cancer death. Kinesin Family member 22 (KIF22) is essential for the invasion of melanoma cells, but the role and mechanism of KIF22 in the proliferation and glycolysis in melanoma remains unknown. METHODS KIF22 expression in melanoma tissues and the relationship between KIF22 high expression and overall survival rate in patients with melanoma were analyzed using the Tnmplot database. KIF22 expression in melanoma cells was examined by western blot. Then, KIF22 was silenced and CCK-8 assay, EDU staining and flow cytometry analysis were adopted for assessing cell proliferation and apoptosis. In addition, the glycolysis metabolism of melanoma cells was reflected by detecting Extracellular Acidification Rates (ECAR) and Oxygen Consumption Rates (OCR). The expression of proteins related to apoptosis, glycolysis and EGFR/STAT3 signaling was tested by western blot. Subsequently, melanoma cells were treated with EGF or Colivelin to further elucidate the regulatory effect of KIF22 on EGFR/STAT3 signaling. RESULTS KIF22 expression was notably upregulated in melanoma tissues and cells, and KIF22 high expression was associated with a poor prognosis. Moreover, KIF22 insufficiency suppressed proliferation and accelerated apoptosis of melanoma cells. Additionally, glycolysis was reduced by KIF22 depletion, evidenced by the decreased ECAR and increased OCR, accompanied by the downregulated expression of HK2, PKM2 and LDHA. Importantly, the impacts of KIF22 depletion on the progression of melanoma were partially attenuated after EGF or Colivelin treatment. CONCLUSION Collectively, KIF22 knockdown suppressed the proliferation and glycolysis and facilitated the apoptosis of melanoma cells by inactivating EGFR/STAT3 signaling.
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Affiliation(s)
- Zhi Zhong
- Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
| | - Hua Zhong
- Department of Clean Operation, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
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An Y, Gu W, Miao M, Miao J, Zhou H, Zhao M, Jiang Y, Li Q, Miao Q. A Self-Assembled Organic Probe with Activatable Near-Infrared Fluoro-Photoacoustic Signals for In Vivo Evaluation of the Radiotherapy Effect. Anal Chem 2023; 95:13984-13991. [PMID: 37672619 DOI: 10.1021/acs.analchem.3c02578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Abstract
Early evaluation and prediction of the radiotherapy effect against tumors are crucial for effective radiotherapy management. The clinical approach generally relies on anatomical changes in tumor size, which is unable to promptly reflect clinical outcomes and guide a timely adjustment of therapy regimens. To resolve it, we herein develop a self-assembled organic probe (dCyFFs) with caspase-3 (Casp-3)-activatable near-infrared (NIR) fluoro-photoacoustic signals for early evaluation and prediction of radiotherapy efficacy. The probe contains an NIR dye that is caged with a Casp-3-cleavable substrate and linked to a self-assembly initiating moiety. In the presence of Casp-3, the self-assembled probe can undergo secondary assembly into larger nanoparticles and simultaneously activate NIR fluoro-photoacoustic signals. Such a design endows a superior real-time longitudinal imaging capability of Casp-3 generated by radiotherapy as it facilitates the passive accumulation of the probe into tumors, activated signal output with enhanced optical stability, and retention capacity relative to a nonassembling small molecular control probe (dCy). As a result, the probe enables precise prediction of the radiotherapy effect as early as 3 h posttherapy, which is further evidenced by the changes in tumor size after radiotherapy. Overall, the probe with Casp-3-mediated secondary assembly along with activatable NIR fluoro-photoacoustic signals holds great potential for evaluating and predicting the response of radiotherapy in a timely manner, which can also be explored for utilization in other therapeutic modalities.
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Affiliation(s)
- Yi An
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Wei Gu
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Minqian Miao
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Jia Miao
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Hui Zhou
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Min Zhao
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Yue Jiang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Qing Li
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Qingqing Miao
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
- School of Nuclear Science and Technology, University of Science and Technology of China, Hefei 230026, China
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Pilátová MB, Solárová Z, Mezencev R, Solár P. Ceramides and their roles in programmed cell death. Adv Med Sci 2023; 68:417-425. [PMID: 37866204 DOI: 10.1016/j.advms.2023.10.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/14/2023] [Accepted: 10/13/2023] [Indexed: 10/24/2023]
Abstract
Programmed cell death plays a crucial role in maintaining the homeostasis and integrity of multicellular organisms, and its dysregulation contributes to the pathogenesis of many diseases. Programmed cell death is regulated by a range of macromolecules and low-molecular messengers, including ceramides. Endogenous ceramides have different functions, that are influenced by their localization and the presence of their target molecules. This article provides an overview of the current understanding of ceramides and their impact on various types of programmed cell death, including apoptosis, anoikis, macroautophagy and mitophagy, and necroptosis. Moreover, it highlights the emergence of dihydroceramides as a new class of bioactive sphingolipids and their downstream targets as well as their future roles in cancer cell growth, drug resistance and tumor metastasis.
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Affiliation(s)
- Martina Bago Pilátová
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovak Republic
| | - Zuzana Solárová
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovak Republic
| | - Roman Mezencev
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Peter Solár
- Department of Medical Biology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovak Republic.
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14
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Saquib Q, Schwaiger S, Alilou M, Ahmed S, Siddiqui MA, Ahmad J, Faisal M, Abdel-Salam EM, Wahab R, Al-Rehaily AJ, Stuppner H, Al-Khedhairy AA. Marine Natural Compound (Neviotin A) Displays Anticancer Efficacy by Triggering Transcriptomic Alterations and Cell Death in MCF-7 Cells. Molecules 2023; 28:6289. [PMID: 37687120 PMCID: PMC10488820 DOI: 10.3390/molecules28176289] [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: 05/31/2023] [Revised: 08/20/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
We investigated the anticancer mechanism of a chloroform extract of marine sponge (Haliclona fascigera) (sample C) in human breast adenocarcinoma (MCF-7) cells. Viability analysis using MTT and neutral red uptake (NRU) assays showed that sample C exposure decreased the proliferation of cells. Flow cytometric data exhibited reactive oxygen species (ROS), nitric oxide (NO), dysfunction of mitochondrial potential, and apoptosis in sample C-treated MCF-7 cells. A qPCR array of sample C-treated MCF-7 cells showed crosstalk between different pathways of apoptosis, especially BIRC5, BCL2L2, and TNFRSF1A genes. Immunofluorescence analysis affirmed the localization of p53, bax, bcl2, MAPKPK2, PARP-1, and caspase-3 proteins in exposed cells. Bioassay-guided fractionation of sample C revealed Neviotin A as the most active compound triggering maximum cell death in MCF-7, indicating its pharmacological potency for the development of a drug for the treatment of human breast cancer.
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Affiliation(s)
- Quaiser Saquib
- Chair for DNA Research, Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.A.S.); (J.A.); (R.W.); (A.A.A.-K.)
| | - Stefan Schwaiger
- Institute of Pharmacy/Pharmacognosy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria; (S.S.); (M.A.); (H.S.)
| | - Mostafa Alilou
- Institute of Pharmacy/Pharmacognosy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria; (S.S.); (M.A.); (H.S.)
| | - Sarfaraz Ahmed
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (S.A.); (A.J.A.-R.)
| | - Maqsood A. Siddiqui
- Chair for DNA Research, Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.A.S.); (J.A.); (R.W.); (A.A.A.-K.)
| | - Javed Ahmad
- Chair for DNA Research, Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.A.S.); (J.A.); (R.W.); (A.A.A.-K.)
| | - Mohammad Faisal
- Department of Botany & Microbiology, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.F.); (E.M.A.-S.)
| | - Eslam M. Abdel-Salam
- Department of Botany & Microbiology, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.F.); (E.M.A.-S.)
| | - Rizwan Wahab
- Chair for DNA Research, Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.A.S.); (J.A.); (R.W.); (A.A.A.-K.)
| | - Adnan J. Al-Rehaily
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (S.A.); (A.J.A.-R.)
| | - Hermann Stuppner
- Institute of Pharmacy/Pharmacognosy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria; (S.S.); (M.A.); (H.S.)
| | - Abdulaziz A. Al-Khedhairy
- Chair for DNA Research, Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (M.A.S.); (J.A.); (R.W.); (A.A.A.-K.)
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15
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Jana B, Jin S, Go EM, Cho Y, Kim D, Kim S, Kwak SK, Ryu JH. Intra-Lysosomal Peptide Assembly for the High Selectivity Index against Cancer. J Am Chem Soc 2023; 145:18414-18431. [PMID: 37525328 DOI: 10.1021/jacs.3c04467] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
Lysosomes remain powerful organelles and important targets for cancer therapy because cancer cell proliferation is greatly dependent on effective lysosomal function. Recent studies have shown that lysosomal membrane permeabilization induces cell death and is an effective way to treat cancer by bypassing the classical caspase-dependent apoptotic pathway. However, most lysosome-targeted anticancer drugs have very low selectivity for cancer cells. Here, we show intra-lysosomal self-assembly of a peptide amphiphile as a powerful technique to overcome this problem. We designed a peptide amphiphile that localizes in the cancer lysosome and undergoes cathepsin B enzyme-instructed supramolecular assembly. This localized assembly induces lysosomal swelling, membrane permeabilization, and damage to the lysosome, which eventually causes caspase-independent apoptotic death of cancer cells without conventional chemotherapeutic drugs. It has specific anticancer effects and is effective against drug-resistant cancers. Moreover, this peptide amphiphile exhibits high tumor targeting when attached to a tumor-targeting ligand and causes significant inhibition of tumor growth both in cancer and drug-resistant cancer xenograft models.
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Affiliation(s)
- Batakrishna Jana
- Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
| | - Seongeon Jin
- Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
| | - Eun Min Go
- School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
| | - Yumi Cho
- School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
| | - Dohyun Kim
- Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
| | - Sangpil Kim
- Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
| | - Sang Kyu Kwak
- Department of Chemical and Biological Engineering, Korea University, Seoul 02841, Republic of Korea
| | - Ja-Hyoung Ryu
- Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
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16
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Magalhães HIR, Machado FA, Souza RF, Caetano MAF, Figliuolo VR, Coutinho-Silva R, Castelucci P. Study of the roles of caspase-3 and nuclear factor kappa B in myenteric neurons in a P2X7 receptor knockout mouse model of ulcerative colitis. World J Gastroenterol 2023; 29:3440-3468. [PMID: 37389242 PMCID: PMC10303518 DOI: 10.3748/wjg.v29.i22.3440] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/25/2023] [Accepted: 05/12/2023] [Indexed: 06/06/2023] Open
Abstract
BACKGROUND The literature indicates that the enteric nervous system is affected in inflammatory bowel diseases (IBDs) and that the P2X7 receptor triggers neuronal death. However, the mechanism by which enteric neurons are lost in IBDs is unknown.
AIM To study the role of the caspase-3 and nuclear factor kappa B (NF-κB) pathways in myenteric neurons in a P2X7 receptor knockout (KO) mouse model of IBDs.
METHODS Forty male wild-type (WT) C57BL/6 and P2X7 receptor KO mice were euthanized 24 h or 4 d after colitis induction by 2,4,6-trinitrobenzene sulfonic acid (colitis group). Mice in the sham groups were injected with vehicle. The mice were divided into eight groups (n = 5): The WT sham 24 h and 4 d groups, the WT colitis 24 h and 4 d groups, the KO sham 24 h and 4 d groups, and the KO colitis 24 h and 4 d groups. The disease activity index (DAI) was analyzed, the distal colon was collected for immunohistochemistry analyses, and immunofluorescence was performed to identify neurons immunoreactive (ir) for calretinin, P2X7 receptor, cleaved caspase-3, total caspase-3, phospho-NF-κB, and total NF-κB. We analyzed the number of calretinin-ir and P2X7 receptor-ir neurons per ganglion, the neuronal profile area (µm²), and corrected total cell fluorescence (CTCF).
RESULTS Cells double labeled for calretinin and P2X7 receptor, cleaved caspase-3, total caspase-3, phospho-NF-κB, or total NF-κB were observed in the WT colitis 24 h and 4 d groups. The number of calretinin-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups, respectively (2.10 ± 0.13 vs 3.33 ± 0.17, P < 0.001; 2.92 ± 0.12 vs 3.70 ± 0.11, P < 0.05), but was not significantly different between the KO groups. The calretinin-ir neuronal profile area was increased in the WT colitis 24 h group compared to the WT sham 24 h group (312.60 ± 7.85 vs 278.41 ± 6.65, P < 0.05), and the nuclear profile area was decreased in the WT colitis 4 d group compared to the WT sham 4 d group (104.63 ± 2.49 vs 117.41 ± 1.14, P < 0.01). The number of P2X7 receptor-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups, respectively (19.49 ± 0.35 vs 22.21 ± 0.18, P < 0.001; 20.35 ± 0.14 vs 22.75 ± 0.51, P < 0.001), and no P2X7 receptor-ir neurons were observed in the KO groups. Myenteric neurons showed ultrastructural changes in the WT colitis 24 h and 4 d groups and in the KO colitis 24 h group. The cleaved caspase-3 CTCF was increased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups, respectively (485949 ± 14140 vs 371371 ± 16426, P < 0.001; 480381 ± 11336 vs 378365 ± 4053, P < 0.001), but was not significantly different between the KO groups. The total caspase-3 CTCF, phospho-NF-κB CTCF, and total NF-κB CTCF were not significantly different among the groups. The DAI was recovered in the KO groups. Furthermore, we demonstrated that the absence of the P2X7 receptor attenuated inflammatory infiltration, tissue damage, collagen deposition, and the decrease in the number of goblet cells in the distal colon.
CONCLUSION Ulcerative colitis affects myenteric neurons in WT mice but has a weaker effect in P2X7 receptor KO mice, and neuronal death may be associated with P2X7 receptor-mediated caspase-3 activation. The P2X7 receptor can be a therapeutic target for IBDs.
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Affiliation(s)
| | | | | | | | - Vanessa Ribeiro Figliuolo
- Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Robson Coutinho-Silva
- Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
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Sahoo S, Pathak S, Kumar A, Nandi D, Chakravarty AR. Lysosome directed red light photodynamic therapy using glycosylated iron-(III) conjugates of boron-dipyrromethene. J Inorg Biochem 2023; 244:112226. [PMID: 37105008 DOI: 10.1016/j.jinorgbio.2023.112226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/10/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023]
Abstract
To overcome the drawbacks associated with chemotherapeutic and porphyrin-based photodynamic therapy (PDT) agents, the use of BODIPY (boron-dipyrromethene) scaffold has gained prominence in designing a new generation of photosensitizers-cum-cellular imaging agents. However, their poor cell permeability and limited solubility in aqueous medium inhibits the in-vitro application of their organic form. This necessitates the development of metal-BODIPY conjugates with improved physiological stability and enhanced therapeutic efficacy. We have designed two iron(III)-BODIPY conjugates, [Fe(L1/2)(L3)Cl] derived from benzyl-dipicolylamine and its glycosylated analogue along with a BODIPY-tagged catecholate. The complexes showed intense absorption bands (ε ∼ 55,000 M-1 cm-1) and demonstrated apoptotic PDT activity upon red-light irradiation (30 J/cm2, 600-720 nm). The complex with singlet oxygen quantum yield value of ∼0.34 gave sub-micromolar IC50 (half-maximal inhibitory concentration) value (∼0.08 μM) in both HeLa and H1299 cancer cells with a photocytotoxicity index value of >1200. Both the complexes were found to have significantly lower cytotoxic effects in non-cancerous HPL1D (human peripheral lung epithelial) cells. Singlet oxygen was determined to be the prime reactive oxygen species (ROS) responsible for cell damage from pUC19 DNA photo-cleavage studies, 1,3-diphenylisobenzofuran and SOSG (Singlet Oxygen Sensor Green) assays. Cellular imaging studies showed excellent fluorescence from complex 2 within 4 h, with localization in lysosomes. Significant drug accumulation into the core of 3D multicellular tumor spheroids was observed within 8 h from intense in-vitro emission. The complexes exemplify iron-based targeted PDT agents and show promising results as potential transition metal-based drugs for ROS mediated red light photocytotoxicity with low dosage requirement.
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Affiliation(s)
- Somarupa Sahoo
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Sir C.V. Raman Avenue, Bangalore 560012, India
| | - Sanmoy Pathak
- Department of Biochemistry, Indian Institute of Science, Sir C.V. Raman Avenue, Bangalore 560012, India
| | - Arun Kumar
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Sir C.V. Raman Avenue, Bangalore 560012, India
| | - Dipankar Nandi
- Department of Biochemistry, Indian Institute of Science, Sir C.V. Raman Avenue, Bangalore 560012, India.
| | - Akhil R Chakravarty
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Sir C.V. Raman Avenue, Bangalore 560012, India.
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Lü G, Wu R, Wang B, Li L, Li Y, Li X, He H, Wang X, Kuang L. SPTLC2 ameliorates chondrocyte dysfunction and extracellular matrix metabolism disturbance in vitro and in vivo in osteoarthritis. Exp Cell Res 2023; 425:113524. [PMID: 36828166 DOI: 10.1016/j.yexcr.2023.113524] [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: 08/30/2022] [Revised: 02/09/2023] [Accepted: 02/21/2023] [Indexed: 02/24/2023]
Abstract
Disturbances in chondrocyte extracellular matrix (ECM) metabolism in osteoarthritis (OA) are a major cause of OA and potentially lead to personal disability, placing a huge burden on society. Chondrocyte apoptosis and ECM catabolism have a major role in the OA process. Firstly, bioinformatics analysis was performed to screen differentially expressed genes (DEGs) in OA, and serine palmitoyltransferase subunit 2 (SPTLC2) was chosen, which had high-level expression in the OA cartilage tissues and OA chondrocytes. Overexpression and knockdown of SPTLC2 were achieved in OA chondrocytes and normal chondrocytes respectively to study the effect of SPTLC2 upon ECM metabolism of chondrocytes. Cell viability and apoptosis were measured using MTT and flow cytometry analyses; SPTLC2 overexpression enhanced the OA chondrocyte viability and decreased apoptotic rate. In addition, Western blot detection of ECM-related factors (Collagen I, Collage II, MMP-1, MMP-3, and MMP-13) revealed that SPTLC2 overexpression promoted the expression of collagens (Collagen I and Collage II) and suppressed matrix metalloproteinase (MMP-1, MMP-3, and MMP-13) level. In contrast, SPTLC2 knockdown in normal chondrocytes showed opposite effects on cell viability, apoptosis, and ECM degeneration. The articular cartilage of OA rats was transfected with lentivirus overexpressing SPTLC2; HE and Safranin-O fast green demonstrated that SPTLC2 overexpression could alleviate chondrocyte injuries and slow down the development of OA. In conclusion, SPTLC2 plays a role in OA and may be a potential target gene for the treatment of OA.
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Affiliation(s)
- Guohua Lü
- Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China; Department of Orthopaedics, The Second Xiangya Hospital of Central South University, China
| | - Ren Wu
- Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China; Department of Orthopaedics, The Second Xiangya Hospital of Central South University, China
| | - Bing Wang
- Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China; Department of Orthopaedics, The Second Xiangya Hospital of Central South University, China
| | - Lei Li
- Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China; Department of Orthopaedics, The Second Xiangya Hospital of Central South University, China
| | - Yunchao Li
- Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China; Department of Orthopaedics, The Second Xiangya Hospital of Central South University, China
| | - Xinyi Li
- Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China; Department of Orthopaedics, The Second Xiangya Hospital of Central South University, China
| | - Haoyu He
- Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China; Department of Orthopaedics, The Second Xiangya Hospital of Central South University, China
| | - Xiaoxiao Wang
- Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China; Department of Orthopaedics, The Second Xiangya Hospital of Central South University, China
| | - Lei Kuang
- Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China; Department of Orthopaedics, The Second Xiangya Hospital of Central South University, China.
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Shah H, Stankov M, Panayotova-Dimitrova D, Yazdi A, Budida R, Klusmann JH, Behrens GMN. Autolysosomal activation combined with lysosomal destabilization efficiently targets myeloid leukemia cells for cell death. Front Oncol 2023; 13:999738. [PMID: 36816923 PMCID: PMC9931186 DOI: 10.3389/fonc.2023.999738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 01/09/2023] [Indexed: 02/04/2023] Open
Abstract
Introduction Current cancer research has led to a renewed interest in exploring lysosomal membrane permeabilization and lysosomal cell death as a targeted therapeutic approach for cancer treatment. Evidence suggests that differences in lysosomal biogenesis between cancer and normal cells might open a therapeutic window. Lysosomal membrane stability may be affected by the so-called 'busy lysosomal behaviour' characterized by higher lysosomal abundance and activity and more intensive fusion or interaction with other vacuole compartments. Methods We used a panel of multiple myeloid leukemia (ML) cell lines as well as leukemic patient samples and updated methodology to study auto-lysosomal compartment, lysosomal membrane permeabilization and lysosomal cell death. Results Our analyses demonstrated several-fold higher constitutive autolysosomal activity in ML cells as compared to human CD34+ hematopoietic cells. Importantly, we identified mefloquine as a selective activator of ML cells' lysosomal biogenesis, which induced a sizeable increase in ML lysosomal mass, acidity as well as cathepsin B and L activity. Concomitant mTOR inhibition synergistically increased lysosomal activity and autolysosomal fusion and simultaneously decreased the levels of key lysosomal stabilizing proteins, such as LAMP-1 and 2. Discussion In conclusion, mefloquine treatment combined with mTOR inhibition synergistically induced targeted ML cell death without additional toxicity. Taken together, these data provide a molecular mechanism and thus a rationale for a therapeutic approach for specific targeting of ML lysosomes.
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Affiliation(s)
- Harshit Shah
- Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
| | - Metodi Stankov
- Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
| | - Diana Panayotova-Dimitrova
- Department of Dermatology and Allergology, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen, Germany
| | - Amir Yazdi
- Department of Dermatology and Allergology, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen, Germany
| | | | - Jan-Henning Klusmann
- Pediatric Hematology and Oncology, Department of Pediatrics, Goethe University Frankfurt, Frankfurt (Main), Germany
| | - Georg M. N. Behrens
- Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany,*Correspondence: Georg M. N. Behrens,
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20
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Nie Z, Zhu S, Wu L, Sun R, Shu J, He Y, Feng H. Progress on innate immune evasion and live attenuated vaccine of pseudorabies virus. Front Microbiol 2023; 14:1138016. [PMID: 36937252 PMCID: PMC10020201 DOI: 10.3389/fmicb.2023.1138016] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Pseudorabies virus (PRV) is a highly infectious disease that can infect most mammals, with pigs as the only natural host, has caused considerable economic losses to the pig husbandry of the world. Innate immunity is the first defense line of the host against the attack of pathogens and is essential for the proper establishment of adaptive immunity. The host uses the innate immune response to against the invasion of PRV; however PRV makes use of various strategies to inhibit the innate immunity to promote the virus replication. Currently, live attenuated vaccine is used to prevent pig from infection with the PRV worldwide, such as Bartha K61. However, a growing number of data indicates that these vaccines do not provide complete protection against new PRV variants that have emerged since late 2011. Here we summarized the interactions between PRV and host innate immunity and the current status of live attenuated PRV vaccines to promote the development of novel and more effective PRV vaccines.
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Affiliation(s)
- Zhenyu Nie
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
- Shaoxing Academy of Biomedicine, Zhejiang Sci-Tech University, Shaoxing, China
| | - Shunfan Zhu
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
- Shaoxing Academy of Biomedicine, Zhejiang Sci-Tech University, Shaoxing, China
| | - Li Wu
- Department of Biology, College of Life Sciences, China Jiliang University, Hangzhou, China
| | - Ruolin Sun
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Jianhong Shu
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yulong He
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Huapeng Feng
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
- *Correspondence: Huapeng Feng,
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21
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Hernandez A, Sonavane M, Smith KR, Seiger J, Migaud ME, Gassman NR. Dihydroxyacetone suppresses mTOR nutrient signaling and induces mitochondrial stress in liver cells. PLoS One 2022; 17:e0278516. [PMID: 36472985 PMCID: PMC9725129 DOI: 10.1371/journal.pone.0278516] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 11/17/2022] [Indexed: 12/12/2022] Open
Abstract
Dihydroxyacetone (DHA) is the active ingredient in sunless tanning products and a combustion product from e-juices in electronic cigarettes (e-cigarettes). DHA is rapidly absorbed in cells and tissues and incorporated into several metabolic pathways through its conversion to dihydroxyacetone phosphate (DHAP). Previous studies have shown DHA induces cell cycle arrest, reactive oxygen species, and mitochondrial dysfunction, though the extent of these effects is highly cell-type specific. Here, we investigate DHA exposure effects in the metabolically active, HepG3 (C3A) cell line. Metabolic and mitochondrial changes were evaluated by characterizing the effects of DHA in metabolic pathways and nutrient-sensing mechanisms through mTOR-specific signaling. We also examined cytotoxicity and investigated the cell death mechanism induced by DHA exposure in HepG3 cells. Millimolar doses of DHA were cytotoxic and suppressed glycolysis and oxidative phosphorylation pathways. Nutrient sensing through mTOR was altered at both short and long time points. Increased mitochondrial reactive oxygen species (ROS) and mitochondrial-specific injury induced cell cycle arrest and cell death through a non-classical apoptotic mechanism. Despite its carbohydrate nature, millimolar doses of DHA are toxic to liver cells and may pose a significant health risk when higher concentrations are absorbed through e-cigarettes or spray tanning.
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Affiliation(s)
- Arlet Hernandez
- Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham AL, United States of America
| | - Manoj Sonavane
- Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham AL, United States of America
| | - Kelly R. Smith
- University of South Alabama Mitchell Cancer Institute, Mobile, Alabama, United States of America
| | - Jensyn Seiger
- University of South Alabama Mitchell Cancer Institute, Mobile, Alabama, United States of America
| | - Marie E. Migaud
- University of South Alabama Mitchell Cancer Institute, Mobile, Alabama, United States of America
- Department of Pharmacology, University of South Alabama Whiddon College of Medicine, Mobile, AL, United States of America
| | - Natalie R. Gassman
- Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham AL, United States of America
- * E-mail:
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22
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Endoplasmic Reticulum Stress Signaling and Neuronal Cell Death. Int J Mol Sci 2022; 23:ijms232315186. [PMID: 36499512 PMCID: PMC9740965 DOI: 10.3390/ijms232315186] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/27/2022] [Accepted: 11/30/2022] [Indexed: 12/07/2022] Open
Abstract
Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments, and the regulation of Ca2+ homeostasis. Before leaving the organelle, proteins must be folded and post-translationally modified. Protein folding and revision require molecular chaperones and a favorable ER environment. When in stressful situations, ER luminal conditions or chaperone capacity are altered, and the cell activates signaling cascades to restore a favorable folding environment triggering the so-called unfolded protein response (UPR) that can lead to autophagy to preserve cell integrity. However, when the UPR is disrupted or insufficient, cell death occurs. This review examines the links between UPR signaling, cell-protective responses, and death following ER stress with a particular focus on those mechanisms that operate in neurons.
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23
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Davuluri KS, Chauhan DS. microRNAs associated with the pathogenesis and their role in regulating various signaling pathways during Mycobacterium tuberculosis infection. Front Cell Infect Microbiol 2022; 12:1009901. [PMID: 36389170 PMCID: PMC9647626 DOI: 10.3389/fcimb.2022.1009901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/03/2022] [Indexed: 11/22/2022] Open
Abstract
Despite more than a decade of active study, tuberculosis (TB) remains a serious health concern across the world, and it is still the biggest cause of mortality in the human population. Pathogenic bacteria recognize host-induced responses and adapt to those hostile circumstances. This high level of adaptability necessitates a strong regulation of bacterial metabolic characteristics. Furthermore, the immune reponse of the host virulence factors such as host invasion, colonization, and survival must be properly coordinated by the pathogen. This can only be accomplished by close synchronization of gene expression. Understanding the molecular characteristics of mycobacterial pathogenesis in order to discover therapies that prevent or resolve illness relies on the bacterial capacity to adjust its metabolism and replication in response to various environmental cues as necessary. An extensive literature details the transcriptional alterations of host in response to in vitro environmental stressors, macrophage infection, and human illness. Various studies have recently revealed the finding of several microRNAs (miRNAs) that are believed to play an important role in the regulatory networks responsible for adaptability and virulence in Mycobacterium tuberculosis. We highlighted the growing data on the existence and quantity of several forms of miRNAs in the pathogenesis of M. tuberculosis, considered their possible relevance to disease etiology, and discussed how the miRNA-based signaling pathways regulate bacterial virulence factors.
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24
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Laghezza Masci V, Bernini R, Villanova N, Clemente M, Cicaloni V, Tinti L, Salvini L, Taddei AR, Tiezzi A, Ovidi E. In Vitro Anti-Proliferative and Apoptotic Effects of Hydroxytyrosyl Oleate on SH-SY5Y Human Neuroblastoma Cells. Int J Mol Sci 2022; 23:12348. [PMID: 36293207 PMCID: PMC9604296 DOI: 10.3390/ijms232012348] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/24/2022] Open
Abstract
The antitumor activity of polyphenols derived from extra virgin olive oil and, in particular the biological activity of HTyr, has been studied extensively. However, the use of HTyr as a therapeutic agent for clinical applications is limited by its low bioavailability and rapid excretion in humans. To overcome these limitations, several synthetic strategies have been optimized to prepare lipophenols and new compounds derived from HTyr to increase lipophilicity and bioavailability. One very promising ester is hydroxytyrosyl oleate (HTyr-OL) because the chemical structure of HTyr, which is responsible for several biological activities, is linked to the monounsaturated chain of oleic acid (OA), giving the compound high lipophilicity and thus bioavailability in the cellular environment. In this study, the in vitro cytotoxic, anti-proliferative, and apoptotic induction activities of HTyr-OL were evaluated against SH-SY5Y human neuroblastoma cells, and the effects were compared with those of HTyr and OA. The results showed that the biological activity of HTyr was maintained in HTyr-OL treatments at lower dosages. In addition, the shotgun proteomic approach was used to study HTyr-OL-treated and untreated neuroblastoma cells, revealing that the antioxidant, anti-proliferative and anti-inflammatory activities of HTyr-OL were observed in the unique proteins of the two groups of samples.
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Affiliation(s)
- Valentina Laghezza Masci
- Department for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), University of Tuscia, Largo dell’Università, 01100 Viterbo, Italy
| | - Roberta Bernini
- Department of Agriculture and Forest Sciences (DAFNE), University of Tuscia, Via San Camillo de Lellis snc, 01100 Viterbo, Italy
| | - Noemi Villanova
- Department of Agriculture and Forest Sciences (DAFNE), University of Tuscia, Via San Camillo de Lellis snc, 01100 Viterbo, Italy
| | - Mariangela Clemente
- Department of Agriculture and Forest Sciences (DAFNE), University of Tuscia, Via San Camillo de Lellis snc, 01100 Viterbo, Italy
| | - Vittoria Cicaloni
- Toscana Life Science Foundation, Via Fiorentina 1, 53100 Siena, Italy
| | - Laura Tinti
- Toscana Life Science Foundation, Via Fiorentina 1, 53100 Siena, Italy
| | - Laura Salvini
- Toscana Life Science Foundation, Via Fiorentina 1, 53100 Siena, Italy
| | - Anna Rita Taddei
- High Equipment Centre, Tuscia University, Largo dell’Università snc, 01100 Viterbo, Italy
| | - Antonio Tiezzi
- Department for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), University of Tuscia, Largo dell’Università, 01100 Viterbo, Italy
| | - Elisa Ovidi
- Department for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), University of Tuscia, Largo dell’Università, 01100 Viterbo, Italy
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25
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Metronomic doses and drug schematic combination response tested within chambered coverslips for the treatment of breast cancer cells (JIMT-1). PLoS One 2022; 17:e0274911. [PMID: 36174026 PMCID: PMC9522273 DOI: 10.1371/journal.pone.0274911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/06/2022] [Indexed: 11/24/2022] Open
Abstract
Low-dose metronomic (LDM) chemotherapy is an alternative to conventional chemotherapy and is the most frequently used approach in low dose chemotherapy regimens. The selection of patients, drug dosages, and dosing intervals in LDM is empirical. In this study, we systematically examined the schedule-dependent interaction of drugs on a breast cancer cell line (BCC) cultured in chambered coverslips. The LDM studies were combined with cell staining in order to better characterize different cell states and cell death modes, including caspase-dependent apoptosis, caspase-independent cell death and autophagy-dependent cell death. Microscope images were examined using the Fiji Trainable Weka Segmentation plugin to analyse cell area in 7500 images showing different modes of cell death. Paclitaxel combined with LDM chemotherapy demonstrated a reduction in the area covered by live cells. In contrast, there was an induction of high levels of cell death due to caspase-dependent apoptosis.
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26
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Farhan M, Rizvi A, Ali F, Ahmad A, Aatif M, Malik A, Alam MW, Muteeb G, Ahmad S, Noor A, Siddiqui FA. Pomegranate juice anthocyanidins induce cell death in human cancer cells by mobilizing intracellular copper ions and producing reactive oxygen species. Front Oncol 2022; 12:998346. [PMID: 36147917 PMCID: PMC9487716 DOI: 10.3389/fonc.2022.998346] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/17/2022] [Indexed: 02/05/2023] Open
Abstract
Anthocyanidins are the most abundant polyphenols in pomegranate juice. This class of molecules includes Delphinidin (Del), Cyanidin (Cya), and Pelargonidin (Pel). Using prostate, breast and pancreatic cancer cell lines PC3, MDA-MB-231, BxPC-3 and MiaPaCa-2, we show that anthocyanidins inhibit cell proliferation (measured by MTT assay) and induce apoptosis like cell death (measured by DNA/Histone ELISA). Copper chelator neocuproine and reactive oxygen species scavengers (thiourea for hydroxyl radical and superoxide dismutase for superoxide anion) significantly inhibit this reaction thus demonstrating that intracellular copper reacts with anthocyanidins in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitizes normal breast epithelial cells (MCF-10A) to Del-mediated growth inhibition as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters Ctr1 and ATP7A in MCF-10A cells, which is attenuated by the addition of Del in the medium. We propose that the copper mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of anthocyanidins.
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Affiliation(s)
- Mohd Farhan
- Department of Basic Sciences, Preparatory Year Deanship, King Faisal University, Al-Ahsa, Saudi Arabia,*Correspondence: Mohd Farhan,
| | - Asim Rizvi
- Department of Kulliyat, Faculty of Unani Medicine, Aligarh Muslim University, Aligarh, India
| | - Ferasat Ali
- Department of Kulliyat, Faculty of Unani Medicine, Aligarh Muslim University, Aligarh, India
| | - Aamir Ahmad
- Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Mohammad Aatif
- Department of Public Health, College of Applied Medical Sciences, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Arshi Malik
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mir Waqas Alam
- Department of Physics, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Ghazala Muteeb
- Department of Nursing, College of Applied Medical Sciences, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Saheem Ahmad
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, Saudi Arabia
| | - Awal Noor
- Department of Basic Sciences, Preparatory Year Deanship, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Farhan Asif Siddiqui
- Department of Laboratory and Blood Bank, King Fahad Hospital, Al Ahsa, Saudi Arabia
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27
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Bischof G, Witte F, Terjung N, Heinz V, Juadjur A, Gibis M. Metabolic, proteomic and microbial changes postmortem and during beef aging. Crit Rev Food Sci Nutr 2022; 64:1076-1109. [PMID: 36004604 DOI: 10.1080/10408398.2022.2113362] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The purpose of this review is to provide an overview of the current knowledge about proteomic and metabolic changes in beef, the microbiological alteration postmortem and during aging, and observe the influence on beef quality parameters, such as tenderness, taste and flavor. This review will also focus on the different aging types (wet- and dry-aging), the aging or postmortem time of beef and their effect on the proteome and metabolome of beef. The Ca2+ homeostasis and adenosine 5'-triphosphate breakdown are the main reactions in the pre-rigor phase. After rigor mortis, the enzymatic degradation of connective tissues and breakdown of energy metabolism dominate molecular changes in beef. Important metabolic processes leading to the formation of saccharides, nucleotides, organic acids (e.g. lactic acid), creatine and fatty acids are considered in this context as possible flavor precursors or formers of beef flavor and taste. Flavor precursors are substrates for lipid oxidation, Strecker degradation and Maillard reaction during cooking or roasting. The findings presented should serve as a basis for a better understanding of beef aging and its molecular effects and are intended to contribute to meeting the challenges of improving beef quality.
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Affiliation(s)
- Greta Bischof
- Chemical Analytics, German Institute of Food Technologies (DIL e.V.), Quakenbrück, Germany
- Department of Food Material Science, Institute of Food Science and Biotechnology, University of Hohenheim, Stuttgart, Germany
| | - Franziska Witte
- Product Innovation, German Institute of Food Technologies (DIL e.V.), Quakenbrück, Germany
| | - Nino Terjung
- Product Innovation, DIL Technology GmbH, Quakenbrück, Germany
| | - Volker Heinz
- Research Directorate, German Institute of Food Technologies (DIL e.V.), Quakenbrück, Germany
| | - Andreas Juadjur
- Chemical Analytics, German Institute of Food Technologies (DIL e.V.), Quakenbrück, Germany
| | - Monika Gibis
- Department of Food Material Science, Institute of Food Science and Biotechnology, University of Hohenheim, Stuttgart, Germany
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28
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de Castro Nobre AC, Pimentel CF, do Rêgo GMS, Paludo GR, Pereira Neto GB, de Castro MB, Nitz N, Hecht M, Dallago B, Hagström L. Insights from the use of erythropoietin in experimental Chagas disease. Int J Parasitol Drugs Drug Resist 2022; 19:65-80. [PMID: 35772309 PMCID: PMC9253553 DOI: 10.1016/j.ijpddr.2022.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 05/26/2022] [Accepted: 05/31/2022] [Indexed: 11/23/2022]
Abstract
In addition to the long-established role in erythropoiesis, erythropoietin (Epo) has protective functions in a variety of tissues, including the heart. This is the most affected organ in chronic Chagas disease, caused by the protozoan Trypanosoma cruzi. Despite seven million people being infected with T. cruzi worldwide, there is no effective treatment preventing the disease progression to the chronic phase when the pathological involvement of the heart is often observed. Chronic chagasic cardiomyopathy has a wide variety of manifestations, like left ventricular systolic dysfunction, dilated cardiomyopathy, and heart failure. Since Epo may help maintain cardiac function by reducing myocardial necrosis, inflammation, and fibrosis, this study aimed to evaluate whether the Epo has positive effects on experimental Chagas disease. For that, we assessed the earlier (acute phase) and also the later (chronic phase) use of Epo in infected C57BL/6 mice. Blood cell count, biochemical parameters, parasitic load, and echocardiography data were evaluated. In addition, histopathological analysis was carried out. Our data showed that Epo had no trypanocide effect nor did it modify the production of anti-T. cruzi antibodies. Epo-treated groups exhibited parasitic burden much lower in the heart compared to blood. No pattern of hematological changes was observed combining infection with treatment with Epo. Chronic Epo administration reduced CK-MB serum activity from d0 to d180, irrespectively of T. cruzi infection. Likewise, echocardiography and histological results indicate that Epo treatment is more effective in the chronic phase of experimental Chagas disease. Since treatment is one of the greatest challenges of Chagas disease, alternative therapies should be investigated, including Epo combined with benznidazole.
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Affiliation(s)
| | - Carlos Fernando Pimentel
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasília, Brazil
| | - George Magno Sousa do Rêgo
- Laboratory of Veterinary Clinical Pathology, Faculty of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Giane Regina Paludo
- Laboratory of Veterinary Clinical Pathology, Faculty of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Glaucia Bueno Pereira Neto
- Veterinary Hospital, Faculty of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Márcio Botelho de Castro
- Laboratory of Veterinary Pathology, Faculty of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Nadjar Nitz
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasília, Brazil
| | - Mariana Hecht
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasília, Brazil
| | - Bruno Dallago
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasília, Brazil; Veterinary Hospital, Faculty of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Luciana Hagström
- Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasília, Brazil; Faculty of Physical Education, University of Brasília, Brasília, Brazil.
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29
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Naumenko VA, Vishnevskiy DA, Stepanenko AA, Sosnovtseva AO, Chernysheva AA, Abakumova TO, Valikhov MP, Lipatova AV, Abakumov MA, Chekhonin VP. In Vivo Tracking for Oncolytic Adenovirus Interactions with Liver Cells. Biomedicines 2022; 10:biomedicines10071697. [PMID: 35885002 PMCID: PMC9313019 DOI: 10.3390/biomedicines10071697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/01/2022] [Accepted: 07/10/2022] [Indexed: 11/28/2022] Open
Abstract
Hepatotoxicity remains an as yet unsolved problem for adenovirus (Ad) cancer therapy. The toxic effects originate both from rapid Kupffer cell (KCs) death (early phase) and hepatocyte transduction (late phase). Several host factors and capsid components are known to contribute to hepatotoxicity, however, the complex interplay between Ad and liver cells is not fully understood. Here, by using intravital microscopy, we aimed to follow the infection and immune response in mouse liver from the first minutes up to 72 h post intravenous injection of three Ads carrying delta-24 modification (Ad5-RGD, Ad5/3, and Ad5/35). At 15–30 min following the infusion of Ad5-RGD and Ad5/3 (but not Ad5/35), the virus-bound macrophages demonstrated signs of zeiosis: the formation of long-extended protrusions and dynamic membrane blebbing with the virus release into the blood in the membrane-associated vesicles. Although real-time imaging revealed interactions between the neutrophils and virus-bound KCs within minutes after treatment, and long-term contacts of CD8+ T cells with transduced hepatocytes at 24–72 h, depletion of neutrophils and CD8+ T cells affected neither rate nor dynamics of liver infection. Ad5-RGD failed to complete replicative cycle in hepatocytes, and transduced cells remained impermeable for propidium iodide, with a small fraction undergoing spontaneous apoptosis. In Ad5-RGD-immune mice, the virus neither killed KCs nor transduced hepatocytes, while in the setting of hepatic regeneration, Ad5-RGD enhanced liver transduction. The clinical and biochemical signs of hepatotoxicity correlated well with KC death, but not hepatocyte transduction. Real-time in vivo tracking for dynamic interactions between virus and host cells provides a better understanding of mechanisms underlying Ad-related hepatotoxicity.
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Affiliation(s)
- Victor A. Naumenko
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
- Correspondence:
| | - Daniil A. Vishnevskiy
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
| | - Aleksei A. Stepanenko
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
- Department of Medical Nanobiotechnology, N.I Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
| | - Anastasiia O. Sosnovtseva
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
| | - Anastasiia A. Chernysheva
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
| | - Tatiana O. Abakumova
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, 121205 Moscow, Russia;
| | - Marat P. Valikhov
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
| | - Anastasiia V. Lipatova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;
| | - Maxim A. Abakumov
- Department of Medical Nanobiotechnology, N.I Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
- Laboratory of Biomedical Nanomaterials, National University of Science and Technology (MISIS), 119049 Moscow, Russia
| | - Vladimir P. Chekhonin
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
- Department of Medical Nanobiotechnology, N.I Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
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30
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Wlodkowic D, Bownik A, Leitner C, Stengel D, Braunbeck T. Beyond the behavioural phenotype: Uncovering mechanistic foundations in aquatic eco-neurotoxicology. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 829:154584. [PMID: 35306067 DOI: 10.1016/j.scitotenv.2022.154584] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/09/2022] [Accepted: 03/11/2022] [Indexed: 06/14/2023]
Abstract
During the last decade, there has been an increase in awareness of how anthropogenic pollution can alter behavioural traits of diverse aquatic organisms. Apart from understanding profound ecological implications, alterations in neuro-behavioural indices have emerged as sensitive and physiologically integrative endpoints in chemical risk assessment. Accordingly, behavioural ecotoxicology and broader eco-neurotoxicology are becoming increasingly popular fields of research that span a plethora of fundamental laboratory experimentations as well as applied field-based studies. Despite mounting interest in aquatic behavioural ecotoxicology studies, there is, however, a considerable paucity in deciphering the mechanistic foundations underlying behavioural alterations upon exposure to pollutants. The behavioural phenotype is indeed the highest-level integrative neurobiological phenomenon, but at its core lie myriads of intertwined biochemical, cellular, and physiological processes. Therefore, the mechanisms that underlie changes in behavioural phenotypes can stem among others from dysregulation of neurotransmitter pathways, electrical signalling, and cell death of discrete cell populations in the central and peripheral nervous systems. They can, however, also be a result of toxicity to sensory organs and even metabolic dysfunctions. In this critical review, we outline why behavioural phenotyping should be the starting point that leads to actual discovery of fundamental mechanisms underlying actions of neurotoxic and neuromodulating contaminants. We highlight potential applications of the currently existing and emerging neurobiology and neurophysiology analytical strategies that should be embraced and more broadly adopted in behavioural ecotoxicology. Such strategies can provide new mechanistic discoveries instead of only observing the end sum phenotypic effects.
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Affiliation(s)
- Donald Wlodkowic
- The Neurotox Laboratory, School of Science, RMIT University, Melbourne, Australia.
| | - Adam Bownik
- Department of Hydrobiology and Protection of Ecosystems, Faculty of Environmental Biology, University of Life Sciences, Lublin, Poland
| | - Carola Leitner
- Aquatic Ecology and Toxicology, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany
| | - Daniel Stengel
- Aquatic Ecology and Toxicology, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany
| | - Thomas Braunbeck
- Aquatic Ecology and Toxicology, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany
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31
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Kang KR, Kim CY, Kim J, Ryu B, Lee SG, Baek J, Kim YJ, Lee JM, Lee Y, Choi SO, Woo DH, Park IH, Chung HM. Establishment of Neurotoxicity Assessment Using Microelectrode Array (MEA) with hiPSC-Derived Neurons and Evaluation of New Psychoactive Substances (NPS). Int J Stem Cells 2022; 15:258-269. [PMID: 35769054 PMCID: PMC9396014 DOI: 10.15283/ijsc21217] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/01/2022] [Accepted: 04/01/2022] [Indexed: 11/09/2022] Open
Abstract
Background and Objectives Currently, safety pharmacological tests for the central nervous system depend on animal behavioral analysis. However, due to the subjectivity of behavioral analysis and differences between species, there is a limit to appropriate nervous system toxicity assessment, therefore a new neurotoxicity assessment that can simulate the human central nervous system is required. Methods and Results In our study, we developed an in vitro neurotoxicity assessment focusing on neuronal function. To minimize the differences between species and fast screening, hiPSC-derived neurons and a microelectrode array (MEA) that could simultaneously measure the action potentials of the neuronal networks were used. After analyzing the molecular and electrophysiological characters of our neuronal network, we conducted a neurotoxicity assessment on neurotransmitters, neurotoxicants, illicit drugs, and new psychoactive substances (NPS). We found that most substances used in our experiments responded more sensitively to our MEA-based neurotoxicity assessment than to the conventional neurotoxicity assessment. Also, this is the first paper that evaluates various illicit drugs and NPS using MEA-based neurotoxicity assessment using hiPSC-derived neurons. Conclusions Our study expanded the scope of application of neurotoxicity assessment using hiPSC-derived neurons to NPS, and accumulated evaluation data of various toxic substances for hiPSC-derived neurons.
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Affiliation(s)
- Kyu-Ree Kang
- Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Korea
| | - C-Yoon Kim
- Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Korea.,Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, Korea
| | - Jin Kim
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea
| | - Bokyeong Ryu
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea
| | - Seul-Gi Lee
- Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Korea
| | - Jieun Baek
- Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Korea
| | - Ye-Ji Kim
- Drug Abuse Research Group, Research Center of Convergence Toxicology, Korea Institute of Toxicology, Daejeon, Korea
| | - Jin-Moo Lee
- Pharmacological Research Division, Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju, Korea
| | - Yootmo Lee
- Pharmacological Research Division, Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju, Korea
| | - Sun-Ok Choi
- Pharmacological Research Division, Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju, Korea
| | - Dong Ho Woo
- Drug Abuse Research Group, Research Center of Convergence Toxicology, Korea Institute of Toxicology, Daejeon, Korea
| | - Il Hwan Park
- Departments of Thoracis and Cardiovascular Surgery, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hyung Min Chung
- Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Korea
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Hsieh MY, Hsieh MJ, Lo YS, Lin CC, Chuang YC, Chen MK, Chou MC. Xanthohumol targets the JNK1/2 signaling pathway in apoptosis of human nasopharyngeal carcinoma cells. ENVIRONMENTAL TOXICOLOGY 2022; 37:1509-1520. [PMID: 35229981 DOI: 10.1002/tox.23502] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/23/2022] [Accepted: 02/13/2022] [Indexed: 06/14/2023]
Abstract
Nasopharyngeal carcinoma (NPC) is one of the most aggressive malignant tumors of the head and neck. Xanthohumol (Xn) is a compound extracted in a high concentration from the hard resin of hops (Humulus lupulus L.), the basic raw material of beer. This study investigated the apoptotic effect and anticancer properties of Xn in human NPC cell lines. Our study demonstrated that at the concentration 40 μM, Xn significantly reduced cell viability and promoted cell cycle arrest in the G2/M phase in two cell lines. The results indicated that Xn induced apoptosis in NPC cell lines through annexin V/propidium iodide staining, chromatin condensation, and apoptosis-related pathways. Xn upregulated the expression of apoptosis-related proteins, namely DR5, cleaved RIP, caspase-3, caspase-8, caspase-9, PARP, Bim, and Bak, and it downregulated the expression of Bcl-2. Xn upregulated the c-Jun N-terminal kinase (JNK) in the mitogen-activated protein kinase (MAPK), and the inhibition of JNK clearly resulted in decreasing expression of Xn-activated cleaved caspase-3 and PARP. Our research provides sufficient evidence to confirm that Xn induces the MAPK JNK pathway to promote apoptosis of NPC and is expected to become a safe and acceptable treatment option for human NPC.
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Affiliation(s)
- Ming-Yu Hsieh
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ming-Ju Hsieh
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Yu-Sheng Lo
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Chia-Chieh Lin
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Ching Chuang
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Mu-Kuan Chen
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Chih Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Division of Thoracic Surgery, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
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Fan Z, Zheng Y, Li X, Deng X, Ba Y, Feng K, Su J, Wang H, Suo Z, Li L. Promoting role of pentraxin-3 in esophageal squamous cell carcinoma. Mol Ther Oncolytics 2022; 24:772-787. [PMID: 35317523 PMCID: PMC8908267 DOI: 10.1016/j.omto.2022.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 02/03/2022] [Indexed: 12/24/2022] Open
Abstract
Pentraxin 3 (PTX3) is an inflammatory molecule that is closely related to the proliferation, invasion, and metastasis of cancer. In order to explore the role of PTX3 in the occurrence and development of esophageal carcinoma (ESCA), we modified the PTX3 gene in ESCA cell lines to obtain the model of gene knockout and overexpression and studied cell proliferation, cycle, apoptosis, migration ability, energy metabolism, and sensitivity to chemotherapy and radiotherapy. We observed the increase in cell proliferation, cycle, apoptosis, migration ability, and sensitivity to chemotherapy and radiotherapy in the PTX3 knockout model, while in the PTX3 overexpression model, these phenomena were significantly reduced. Knockout of the PTX3 also resulted in decreased cell glycolysis and increased oxidative phosphorylation, which is consistent with other findings that PTX3 affects the tumorigenic ability of cells and their sensitivity to docetaxel. In ESCA, SOX9 directly regulates the expression of PTX3, while human leukocyte antigen (HLA)-system-related genes are significantly up-regulated when lacking PTX3. These results indicate that SOX9 may play a crucial role in regulating PTX3 and affecting the HLA system in ESCA.
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Affiliation(s)
- Zhirui Fan
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yuanyuan Zheng
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.,Internet Medical and System Applications of National Engineering Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Xiaoli Li
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Xiaoming Deng
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yan Ba
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Kun Feng
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Jin Su
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Hui Wang
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Zhenhe Suo
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.,Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, 999026 Montebello, Oslo, Norway
| | - Lifeng Li
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.,Internet Medical and System Applications of National Engineering Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
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In Vitro and In Vivo Evaluation of a Cyclic LyP-1-Modified Nanosystem for Targeted Endostatin Delivery in a KYSE-30 Cell Xenograft Athymic Nude Mice Model. Pharmaceuticals (Basel) 2022; 15:ph15030353. [PMID: 35337150 PMCID: PMC8955112 DOI: 10.3390/ph15030353] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/01/2023] Open
Abstract
This work investigated the use of LyP-1 as a homing peptide for p32 receptor targeting on the surface of an endostatin (ENT)-loaded chitosan-grafted nanosystem intended for intracellular delivery of ENT and mitochondrial targeting in a squamous cell carcinoma (SCC) cell line (KYSE-30) model. The angiogenic factors for VEGF-C and MMP2 were assessed with in vivo evaluation of the nanosystem upon ENT release and tumor necrosis in nude mice with a KYSE-30 cell xenograft. The LyP-1-modified nanosystem revealed a three-fold decrease in proliferation at 1000 µg/mL compared with the control and facilitated receptor-mediated cellular uptake and internalization. In addition, targeting of the Lyp-1-functionalized nanosystem to mitochondrial and nuclear proteins in vitro and in vivo was achieved. Up to 60% inhibition of KYSE-30 cell migration was observed and the expressions of VEGF-C and MMP-2 as angiogenic markers were reduced 3- and 2-fold, respectively. A marked reduction in tumor mass was recorded (43.25%) with the control, a 41.36% decrease with the nanoparticles and a 61.01% reduction with the LyP-1-modified nanosystem following treatment in mice. The LyP-1-functionalized nanosystem targeted tumor lymphatics, instigated nuclear rupture and mitochondrial distortion, and decreased cell proliferation and migration with inhibition of VEGF-C and MMP2 expression.
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35
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Urla C, Corteletti I, Raible AS, Handgretinger R, Fuchs J, Warmann SW, Schmid E. D,L-Methadone enhances the cytotoxic activity of standard chemotherapeutic agents on pediatric rhabdomyosarcoma. J Cancer Res Clin Oncol 2022; 148:1337-1350. [PMID: 35182225 PMCID: PMC9114081 DOI: 10.1007/s00432-022-03945-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 02/02/2022] [Indexed: 12/01/2022]
Abstract
Purpose In advanced tumor stages, pediatric rhabdomyosarcoma (RMS) shows an intrinsic resistance to standard chemotherapy, which is associated with a dismal prognosis. Alternative therapeutic approaches and optimization of already existent treatment protocols are urgently needed in these conditions. The µ-opioid receptor (OPRM1) agonist, D,L-methadone is frequently used for analgesia in oncological patients. Recent evidence has shown that D,L-methadone in combination with chemotherapeutic agents may enhance their cytotoxic effect against cancer cells. There are no related data in pediatric rhabdomyosarcoma (RMS). Methods Antitumor effects of combined D,L-methadone and doxorubicin, carboplatin, and vincristine on RMS cell lines RD and RH30 were analyzed using following outcome data: expression of the OPRM1 receptor (Western blot), cell growth inhibition (MTT assay), cell migration (wound-healing assay), apoptosis induction (caspase-3/7 assay), and reactive oxygen species (ROS) production (flow cytometry). Results In both cell lines, OPRM1 expression was significantly increased after combined treatment of D,L-methadone with all three cytotoxic drugs tested, which resulted in suppression of tumor cell growth and increase of apoptosis rates. These effects were mediated by increased ROS production and up-regulation of caspase-3/7 activity. Doxorubicin combined with D,L-methadone significantly reduced cell migration in both cell lines. Carboplatin or vincristine in combination with D,L-methadone had only an impact on cell migration in RH30 cells. Conclusions This new therapeutic approach in RMS provides strong antitumor effects in vitro. The combination of standard chemotherapy and D,L-methadone requires further investigation. Especially advanced tumors with a limited effectiveness of conventional treatment regimens seem a potential target of this approach. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-022-03945-y.
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Affiliation(s)
- Cristian Urla
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany
| | - Irene Corteletti
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.,Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35121, Padova, Italy
| | - Ann-Sophie Raible
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.,Department of Pediatric Hematology and Oncology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tuebingen, Germany
| | - Rupert Handgretinger
- Department of Pediatric Hematology and Oncology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tuebingen, Germany
| | - Jörg Fuchs
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany
| | - Steven W Warmann
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany
| | - Evi Schmid
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.
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The concept of intrinsic versus extrinsic apoptosis. Biochem J 2022; 479:357-384. [PMID: 35147165 DOI: 10.1042/bcj20210854] [Citation(s) in RCA: 117] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 12/12/2022]
Abstract
Regulated cell death is a vital and dynamic process in multicellular organisms that maintains tissue homeostasis and eliminates potentially dangerous cells. Apoptosis, one of the better-known forms of regulated cell death, is activated when cell-surface death receptors like Fas are engaged by their ligands (the extrinsic pathway) or when BCL-2-family pro-apoptotic proteins cause the permeabilization of the mitochondrial outer membrane (the intrinsic pathway). Both the intrinsic and extrinsic pathways of apoptosis lead to the activation of a family of proteases, the caspases, which are responsible for the final cell demise in the so-called execution phase of apoptosis. In this review, I will first discuss the most common types of regulated cell death on a morphological basis. I will then consider in detail the molecular pathways of intrinsic and extrinsic apoptosis, discussing how they are activated in response to specific stimuli and are sometimes overlapping. In-depth knowledge of the cellular mechanisms of apoptosis is becoming more and more important not only in the field of cellular and molecular biology but also for its translational potential in several pathologies, including neurodegeneration and cancer.
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37
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Durante M, Frosini M, Chiaino E, Fusi F, Gamberucci A, Gorelli B, Chegaev K, Riganti C, Saponara S. Sdox, a H 2S releasing anthracycline, with a safer profile than doxorubicin toward vasculature. Vascul Pharmacol 2022; 143:106969. [PMID: 35149209 DOI: 10.1016/j.vph.2022.106969] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/24/2022] [Accepted: 02/04/2022] [Indexed: 01/18/2023]
Abstract
Sdox is a synthetic H2S-releasing doxorubicin (Dox) less cardiotoxic and more effective than Dox in pre-clinical, Dox-resistant tumour models. The well-known anthracycline vascular toxicity, however, might limit Sdox clinical use. This study aimed at evaluating Sdox vascular toxicity in vitro, using Dox as reference compound. Both vascular smooth muscle A7r5 and endothelial EA.hy926 cells were more sensitive to Dox than Sdox, although both drugs equally increased intracellular free radical levels. Sdox released H2S in both cell lines. The H2S scavenger hydroxocobalamin partially reverted Sdox-induced cytotoxicity in A7r5, but not in EA.hy926 cells, suggesting a role for H2S in smooth muscle cell death. Markers of Sdox-induced apoptosis were significantly lower than, in A7r5 cells, and comparable to those of Dox in EA.hy926 cells. In A7r5 cells, Dox increased the activity of caspase 3, 8, and 9, Sdox affecting only that of caspase 3. Moreover, both drugs induced comparable DNA damage in A7r5 cells, while Sdox was less toxic than Dox in Ea.hy926 cells. In fresh aorta rings, only Dox weakly increased phenylephrine-induced contraction when endothelium was present. In rings cultured with both drugs for 7 days, Sdox blunted phenylephrine- and high K+-induced contractions though at a concentration 10-fold higher than that of Dox. In conclusion, Sdox may represent the prototype of an innovative anthracycline, effective against Dox-resistant tumours, displaying a more favourable vascular toxicity profile compared to the parent compound.
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Affiliation(s)
- Miriam Durante
- Dipartimento di Scienze della Vita, Università di Siena, Siena, Italy
| | - Maria Frosini
- Dipartimento di Scienze della Vita, Università di Siena, Siena, Italy
| | - Elda Chiaino
- Dipartimento di Scienze della Vita, Università di Siena, Siena, Italy
| | - Fabio Fusi
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Siena, Italy
| | - Alessandra Gamberucci
- Dipartimento di Medicina Molecolare e dello Sviluppo, Università di Siena, Siena, Italy
| | - Beatrice Gorelli
- Dipartimento di Scienze della Vita, Università di Siena, Siena, Italy
| | - Konstantin Chegaev
- Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Torino, Italy
| | - Chiara Riganti
- Dipartimento di Oncologia, Università di Torino, Torino, Italy
| | - Simona Saponara
- Dipartimento di Scienze della Vita, Università di Siena, Siena, Italy.
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Yurtdaş-Kırımlıoğlu G, Görgülü Ş, Güleç K, Kıyan HT. Nanoarchitectonics of PLGA based polymeric nanoparticles with oseltamivir phosphate for lung cancer therapy: In vitro-in vivo evaluation. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2021.102996] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Das S, Amin SA, Datta S, Adhikari N, Jha T. Synthesis, biological activity, structure activity relationship study and liposomal formulation development of some arylsulfonyl pyroglutamic acid derivatives. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2021.131512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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40
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Wei C, Li Y, Feng X, Hu Z, Paquet-Durand F, Jiao K. RNA Biological Characteristics at the Peak of Cell Death in Different Hereditary Retinal Degeneration Mutants. Front Genet 2021; 12:728791. [PMID: 34777465 PMCID: PMC8586524 DOI: 10.3389/fgene.2021.728791] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 09/21/2021] [Indexed: 11/13/2022] Open
Abstract
Purpose: The present work investigated changes in the gene expression, molecular mechanisms, and pathogenesis of inherited retinal degeneration (RD) in three different disease models, to identify predictive biomarkers for their varied phenotypes and to provide a better scientific basis for their diagnosis, treatment, and prevention. Methods: Differentially expressed genes (DEGs) between retinal tissue from RD mouse models obtained during the photoreceptor cell death peak period (Pde6b rd1 at post-natal (PN) day 13, Pde6b rd10 at PN23, Prph rd2 at PN29) and retinal tissue from C3H wild-type mice were identified using Illumina high-throughput RNA-sequencing. Co-expression gene modules were identified using a combination of GO and KEGG enrichment analyses and gene co-expression network analysis. CircRNA-miRNA-mRNA network interactions were studied by genome-wide circRNA screening. Results: Pde6b rd1 , Pde6b rd10 , and Prph rd2 mice had 1,926, 3,096, and 375 DEGs, respectively. Genes related to ion channels, stress, inflammatory processes, tumor necrosis factor (TNF) production, and microglial cell activation were up-regulated, while genes related to endoplasmic reticulum regulation, metabolism, and homeostasis were down-regulated. Differential expression of transcription factors and non-coding RNAs generally implicated in other human diseases was detected (e.g., glaucoma, diabetic retinopathy, and inherited retinal degeneration). CircRNA-miRNA-mRNA network analysis indicated that these factors may be involved in photoreceptor cell death. Moreover, excessive cGMP accumulation causes photoreceptor cell death, and cGMP-related genes were generally affected by different pathogenic gene mutations. Conclusion: We screened genes and pathways related to photoreceptor cell death. Additionally, up-stream regulatory factors, such as transcription factors and non-coding RNA and their interaction networks were analyzed. Furthermore, RNAs involved in RD were functionally annotated. Overall, this study lays a foundation for future studies on photoreceptor cell death mechanisms.
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Affiliation(s)
- Chunling Wei
- Kunming Medical University, Kunming, China.,Department of Ophthalmology, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China
| | - Yan Li
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China.,Key Laboratory of Yunnan Province, Yunnan Eye Institute, Kunming, China
| | - Xiaoxiao Feng
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China.,Key Laboratory of Yunnan Province, Yunnan Eye Institute, Kunming, China
| | - Zhulin Hu
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China.,Key Laboratory of Yunnan Province, Yunnan Eye Institute, Kunming, China
| | - François Paquet-Durand
- Institute for Ophthalmic Research, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
| | - Kangwei Jiao
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China.,Key Laboratory of Yunnan Province, Yunnan Eye Institute, Kunming, China
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Evangelinellis MM, Souza RF, Mendes CE, Castelucci P. Effects of a P2X7 receptor antagonist on myenteric neurons in the distal colon of an experimental rat model of ulcerative colitis. Histochem Cell Biol 2021; 157:65-81. [PMID: 34626216 DOI: 10.1007/s00418-021-02039-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2021] [Indexed: 12/20/2022]
Abstract
Inflammatory bowel diseases (IBDs) are chronic diseases of the gastrointestinal tract that include ulcerative colitis and Crohn's disease and affect enteric neurons. Research has shown that Brilliant Blue G (BBG), a P2X7 receptor antagonist, restores enteric neurons following ischemia and reperfusion. This study aimed to evaluate the effect of BBG on myenteric neurons of the distal colon in an experimental rat model of ulcerative colitis. Colitis was induced by injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the large intestine. BBG was administered 1 h after colitis induction and for five consecutive days thereafter. Distal colons were collected 24 h or 7 days after TNBS injection. The animals were divided into 24-h and 7-day sham (vehicle injection rather than colitis induction), 24-h colitis, 24-h BBG, 7-day colitis and 7-day BBG groups. The disease activity index (DAI), neuronal density and profile of neuronal nitric oxide synthase (nNOS)-, choline acetyltransferase (ChAT)- and P2X7 receptor-immunoreactive enteric neurons were analyzed, and histological analysis was performed. The results showed recovery of the DAI and histological tissue integrity in the BBG groups compared to those in the colitis groups. In addition, the numbers of neurons positive for nNOS, ChAT and the P2X7 receptor per area were decreased in the colitis groups, and these measures were recovered in the BBG groups. Neuronal size was increased in the colitis groups and restored in the BBG groups. In conclusion, BBG is effective in improving experimental ulcerative colitis, and the P2X7 receptor may be a therapeutic target.
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Affiliation(s)
- Mariá Munhoz Evangelinellis
- Department of Surgery, Faculty of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr Orlando Marques de Paiva, 87, São Paulo, CEP 05508-270, Brazil
| | - Roberta Figueiroa Souza
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Dr. Lineu Prestes, 2415, São Paulo, CEP 05508-900, Brazil
| | - Cristina Eusébio Mendes
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Dr. Lineu Prestes, 2415, São Paulo, CEP 05508-900, Brazil
| | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Dr. Lineu Prestes, 2415, São Paulo, CEP 05508-900, Brazil.
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Design, synthesis, and antitumor activity evaluation of steroidal oximes. Bioorg Med Chem 2021; 46:116360. [PMID: 34425478 DOI: 10.1016/j.bmc.2021.116360] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/30/2021] [Accepted: 08/01/2021] [Indexed: 01/30/2023]
Abstract
Steroidal compounds were proven to be efficient drugs against several types of cancer. Oximes are also chemical structures frequently associated with anticancer activity. The main goal of this work was to combine the two referred structures by synthesizing steroidal oximes and evaluating them in several cancer cell lines. Compounds (17E)-5α-androst-3-en-17-one oxime (3,4 - OLOX), (17E)-3α,4α-epoxy-5α-androstan-17-one oxime (3,4 - EPOX), (17E)-androst-4-en-17-one oxime (4,5 - OLOX) and (17E)-4α,5α-epoxyandrostan-17-one oxime (4,5 - EPOX) were synthesized and their cytotoxicity evaluated in four human cancer cell lines, namely colorectal adenocarcinoma (WiDr), non-small cell lung cancer (H1299), prostate cancer (PC3) and hepatocellular carcinoma (HepG2). A human non-tumour cell line, CCD841 CoN (normal colon cell line) was also used. MTT assay, flow cytometry, fluorescence and hemocompatibility techniques were performed to further analyse the cytotoxicity of the compounds. 3,4 - OLOX was the most effective compound in decreasing tumour cell proliferation in all cell lines, especially in WiDr (IC50 = 9.1 μM) and PC3 (IC50 = 13.8 μM). 4,5 - OLOX also showed promising results in the same cell lines (IC50 = 16.1 μM in WiDr and IC50 = 14.5 μM in PC3). Further studies also revealed that 3,4 - OLOX and 4,5 - OLOX induced a decrease in cell viability accompanied by an increase in cell death, mainly by apoptosis/necroptosis for 3,4 - OLOX in both cell lines and for 4,5 - OLOX in WiDr cells, and by necrosis for 4,5 - OLOX in PC3 cells. These compounds might also exert their cytotoxicity by ROS production and are not toxic for non-tumour CCD841 CoN cells. Additionally, both compounds did not induce haemoglobin release, proving to be safe for intravenous administration. 3,4 - OLOX and 4,5 - OLOX might be the starting point for an optimization program towards the discover of new steroidal oximes for anticancer treatment.
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Ehigie AF, Wei P, Wei T, Yan X, Olorunsogo OO, Ojeniyi FD, Ehigie LO. Momordica charantia L. induces non-apoptotic cell death in human MDA-MB-436 breast and A549 lung cancer cells by disrupting energy metabolism and exacerbating reactive oxygen species' generation. JOURNAL OF ETHNOPHARMACOLOGY 2021; 277:114036. [PMID: 33753145 DOI: 10.1016/j.jep.2021.114036] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/03/2021] [Accepted: 03/15/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bitter melon, Momordica charantia L. (MC), is an ethnomedicinal plant cultivated in different climes. It's cytotoxic effect on several cancer cell lines has been evaluated. However, there have been contrasting reports on the actual mechanism (s) involved in the observed cell death induced by MC. AIMS OF THE STUDY To probe the mechanism of cell death induction in MDA-MB-436 (Breast) and A549 (lung) cancer cell lines treated with fractions (ethyl acetate, dichloromethane and hexane) derived from the aqueous extract of MC. MATERIALS AND METHODS Aqeous extract of the leaves of MC were fractionated using solvents of different polarities (ethyl acetate (D3), n-hexane (D4), dichloromethane (D5)). The cells were incubated with 100 and 125 μg/mL of the fractions 24 hours. Combination of fluorescence microscopy, enzyme assays, Western blot analyses and flow cytometry were employed in the study. RESULTS Treatment of the cells with MC fractions reduced Mitochondrial Membrane Potential (MMP) and intracellular ATP levels, while increasing reactive oxygen species levels without classical biochemical and morphological apoptotic features were seen. However, the fractions failed in upregulating either caspase-3 activation or cytochrome c release in the cancer cells. CONCLUSION Overall, these results suggest that the cytotoxic effect of MC on the selected cancer cells is mediated by loss of mitochondrial function via loss of respiration leading to cell death rather than by the classical release of cytochrome c or caspase-3 activated apoptosis.
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Affiliation(s)
- Adeola Folasade Ehigie
- Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
| | - Peng Wei
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Taotao Wei
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiyun Yan
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Olufunso O Olorunsogo
- Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria.
| | | | - Leonard Ona Ehigie
- Laboratories for Biomembrane Research and Biotechnology, Biochemistry Department, College of Medicine, University of Ibadan, Ibadan, Nigeria
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Oseltamivir phosphate loaded pegylated-Eudragit nanoparticles for lung cancer therapy: Characterization, prolonged release, cytotoxicity profile, apoptosis pathways and in vivo anti-angiogenic effect by using CAM assay. Microvasc Res 2021; 139:104251. [PMID: 34520775 DOI: 10.1016/j.mvr.2021.104251] [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: 05/03/2021] [Revised: 08/12/2021] [Accepted: 09/06/2021] [Indexed: 12/13/2022]
Abstract
The target of the current investigation was the delivery of oseltamivir phosphate (OSE) into the lung adenocarcinoma tissues by means of designing nanosized, non-toxic and biocompatible pegylated Eudragit based NPs and investigating their anticancer and antiangiogenic activity. The rationale for this strategy is to provide a novel perspective to cancer treatment with OSE loaded pegylated ERS NPs under favor of smaller particle size, biocompatible feature, cationic characteristic, examining their selective effectiveness on lung cell lines (A549 lung cancer cell line and CCD-19Lu normal cell line) and examining antiangiogenic activity by in vivo CAM analysis. For this purpose, OSE encapsulated pegylated ERS based NPs were developed and investigated for zeta potential, particle size, encapsulation efficiency, morphology, DSC, FT-IR, 1H NMR analyses. In vitro release, cytotoxicity, determination apoptotic pathways and in vivo CAM assay were carried out. Considering characterizations, NPs showed smaller particle size, cationic zeta potential, relatively higher EE%, nearly spherical shape, amorphous matrix formation and prolonged release pattern (Peppas-Sahlin and Weibull model with Fickian and non-Fickian release mechanisms). Flow cytometry was used to assess the apoptotic pathways using the Annexin V-FITC/PI staining assay, FITC Active Caspase-3 staining assay, and mitochondrial membrane potential detection tests. Activations on caspase-3 pathways made us think that OSE loaded pegylated ERS NPs triggered to apoptosis using intrinsic pathway. As regards to the in vivo studies, OSE loaded pegylated ERS based NPs demonstrated strong and moderate antiangiogenic activity for ERS-OSE 2 and ERS-OSE 3, respectively. With its cationic character, smaller particle size, relative superior EE%, homogenous amorphous polymeric matrix constitution indicated using solid state tests, prolonged release manner, highly selective to the human lung adenocarcinoma cell lines, could trigger apoptosis intrinsically and effectively, possess good in vivo antiangiogenic activity, ERS-OSE 2 formulation is chosen as a promising candidate and a potent drug delivery system to treat lung cancer.
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Lubkowska A, Pluta W, Strońska A, Lalko A. Role of Heat Shock Proteins (HSP70 and HSP90) in Viral Infection. Int J Mol Sci 2021; 22:ijms22179366. [PMID: 34502274 PMCID: PMC8430838 DOI: 10.3390/ijms22179366] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Heat shock proteins (HSPs) are a large group of chaperones found in most eukaryotes and bacteria. They are responsible for the correct protein folding, protection of the cell against stressors, presenting immune and inflammatory cytokines; furthermore, they are important factors in regulating cell differentiation, survival and death. Although the biological function of HSPs is to maintain cell homeostasis, some of them can be used by viruses both to fold their proteins and increase the chances of survival in unfavorable host conditions. Folding viral proteins as well as replicating many different viruses are carried out by, among others, proteins from the HSP70 and HSP90 families. In some cases, the HSP70 family proteins directly interact with viral polymerase to enhance viral replication or they can facilitate the formation of a viral replication complex and/or maintain the stability of complex proteins. It is known that HSP90 is important for the expression of viral genes at both the transcriptional and the translational levels. Both of these HSPs can form a complex with HSP90 and, consequently, facilitate the entry of the virus into the cell. Current studies have shown the biological significance of HSPs in the course of infection SARS-CoV-2. A comprehensive understanding of chaperone use during viral infection will provide new insight into viral replication mechanisms and therapeutic potential. The aim of this study is to describe the molecular basis of HSP70 and HSP90 participation in some viral infections and the potential use of these proteins in antiviral therapy.
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Affiliation(s)
- Anna Lubkowska
- Department of Functional Diagnostics and Physical Medicine, Pomeranian Medical University in Szczecin, Żołnierska 54, 71-210 Szczecin, Poland;
- Correspondence:
| | - Waldemar Pluta
- Department of Functional Diagnostics and Physical Medicine, Pomeranian Medical University in Szczecin, Żołnierska 54, 71-210 Szczecin, Poland;
| | - Aleksandra Strońska
- Department of Pharmacognosy and Natural Medicines, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Alicja Lalko
- Student Research at the Chair and Department of Functional Diagnostics and Physical Medicine, Pomeranian Medical University, Żołnierska 54, 71-210 Szczecin, Poland;
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Valente A, Podolski-Renić A, Poetsch I, Filipović N, López Ó, Turel I, Heffeter P. Metal- and metalloid-based compounds to target and reverse cancer multidrug resistance. Drug Resist Updat 2021; 58:100778. [PMID: 34403910 DOI: 10.1016/j.drup.2021.100778] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 12/19/2022]
Abstract
Drug resistance remains the major cause of cancer treatment failure especially at the late stage of the disease. However, based on their versatile chemistry, metal and metalloid compounds offer the possibility to design fine-tuned drugs to circumvent and even specifically target drug-resistant cancer cells. Based on the paramount importance of platinum drugs in the clinics, two main areas of drug resistance reversal strategies exist: overcoming resistance to platinum drugs as well as multidrug resistance based on ABC efflux pumps. The current review provides an overview of both aspects of drug design and discusses the open questions in the field. The areas of drug resistance covered in this article involve: 1) Altered expression of proteins involved in metal uptake, efflux or intracellular distribution, 2) Enhanced drug efflux via ABC transporters, 3) Altered metabolism in drug-resistant cancer cells, 4) Altered thiol or redox homeostasis, 5) Altered DNA damage recognition and enhanced DNA damage repair, 6) Impaired induction of apoptosis and 7) Altered interaction with the immune system. This review represents the first collection of metal (including platinum, ruthenium, iridium, gold, and copper) and metalloid drugs (e.g. arsenic and selenium) which demonstrated drug resistance reversal activity. A special focus is on compounds characterized by collateral sensitivity of ABC transporter-overexpressing cancer cells. Through this approach, we wish to draw the attention to open research questions in the field. Future investigations are warranted to obtain more insights into the mechanisms of action of the most potent compounds which target specific modalities of drug resistance.
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Affiliation(s)
- Andreia Valente
- Centro de Química Estrutural and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa, Portugal
| | - Ana Podolski-Renić
- Department of Neurobiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Serbia
| | - Isabella Poetsch
- Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Nenad Filipović
- Department of Chemistry and Biochemistry, Faculty of Agriculture, University of Belgrade, Belgrade, Serbia
| | - Óscar López
- Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla, Spain
| | - Iztok Turel
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| | - Petra Heffeter
- Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
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Han L, Wang Y, Wang G, Chen Y, Lin H, Zhang Y, Shen Y. Acupuncture ameliorates neurological function in rats with cerebral ischemia-reperfusion by regulating the opening of large-conductance Ca 2+ -activated potassium channels. Brain Behav 2021; 11:e2286. [PMID: 34333869 PMCID: PMC8413763 DOI: 10.1002/brb3.2286] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 07/01/2021] [Accepted: 07/01/2021] [Indexed: 11/12/2022] Open
Abstract
Acupuncture has a good effect on improving neurological function after cerebral ischemia-reperfusion, but there are few studies on the neuroprotective effect of acupuncture from the perspective of ion channel cellular electrophysiology. Studies have shown that the over activation of large-conductance Ca2+ -activated potassium channel （BKCa） after cerebral ischemia-reperfusion can reduce the excitability of neurons and induce apoptosis. This study intends to establish middle cerebral artery occlusion/reperfusion (MCAO/R) model, with acupuncture at GV26 as the intervention measure, using patch-clamp technique to record the electrophysiological changes of BKCa channel. The results showed that the neurological function score of MCAO/R rats was significantly decreased, and the conductance, open dwell time and open probability of BKCa channel in hippocampal CA1 neurons of MCAO/R rats were significantly increased. Acupuncture at GV26 could significantly improve the neurological function scores of MCAO/R rats, and reduce the conductance, open dwell time, and open probability of BKCa channel. The effect of acupuncture at GV26 was significantly better than acupuncture at non-acupuncture point. The neuroprotective effect of acupuncture at GV26 after cerebral ischemia-reperfusion may be related to regulating the electrophysiological characteristics of BKCa channel opening.
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Affiliation(s)
- Lin Han
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yong Wang
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China
| | - Guanran Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yingying Chen
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Haiping Lin
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yanan Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.,Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin, China
| | - Yan Shen
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.,Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin, China
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Selected Kefir Water from Malaysia Attenuates Hydrogen Peroxide-Induced Oxidative Stress by Upregulating Endogenous Antioxidant Levels in SH-SY5Y Neuroblastoma Cells. Antioxidants (Basel) 2021; 10:antiox10060940. [PMID: 34200854 PMCID: PMC8230435 DOI: 10.3390/antiox10060940] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/03/2021] [Accepted: 06/08/2021] [Indexed: 01/27/2023] Open
Abstract
Kefir, a fermented probiotic drink was tested for its potential anti-oxidative, anti-apoptotic, and neuroprotective effects to attenuate cellular oxidative stress on human SH-SY5Y neuroblastoma cells. Here, the antioxidant potentials of the six different kefir water samples were analysed by total phenolic content (TPC), total flavonoid content (TFC), ferric reducing antioxidant power (FRAP), and 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH) assays, whereas the anti-apoptotic activity on hydrogen peroxide (H2O2) induced SH-SY5Y cells was examined using MTT, AO/PI double staining, and PI/Annexin V-FITC assays. The surface and internal morphological features of SH-SY5Y cells were studied using scanning and transmission electron microscopy. The results indicate that Kefir B showed the higher TPC (1.96 ± 0.54 µg GAE/µL), TFC (1.09 ± 0.02 µg CAT eq/µL), FRAP (19.68 ± 0.11 mM FRAP eq/50 µL), and DPPH (0.45 ± 0.06 mg/mL) activities compared to the other kefir samples. The MTT and PI/Annexin V-FITC assays showed that Kefir B pre-treatment at 10 mg/mL for 48 h resulted in greater cytoprotection (97.04%), and a significantly lower percentage of necrotic cells (7.79%), respectively. The Kefir B pre-treatment also resulted in greater protection to cytoplasmic and cytoskeleton inclusion, along with the conservation of the surface morphological features and the overall integrity of SH-SY5Y cells. Our findings indicate that the anti-oxidative, anti-apoptosis, and neuroprotective effects of kefir were mediated via the upregulation of SOD and catalase, as well as the modulation of apoptotic genes (Tp73, Bax, and Bcl-2).
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Castellanos NL, Ferreira-Filho NA, Rodrigues HS, Martínez LC, Serrão JE, Oliveira EE. Imidacloprid-mediated alterations on the salivary glands of the Neotropical brown stink bug, Euschistus heros. ECOTOXICOLOGY (LONDON, ENGLAND) 2021; 30:678-688. [PMID: 33788078 DOI: 10.1007/s10646-021-02388-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/04/2021] [Indexed: 06/12/2023]
Abstract
The management of the Neotropical brown stinkbug Euschistus heros (Hemiptera: Pentatomidae) in soybean fields has been heavily dependent on the application of neonicotinoid insecticides. Neonicotinoids act primarily by impairing the function of the nicotinic acetylcholine receptors of the nervous system. These compounds also target specific organs (e.g., salivary glands), which may potentiate their insecticidal efficacy. Here, we evaluated whether the exposure to the neonicotinoid imidacloprid would cause cytomorphological changes in the salivary glands of E. heros. First, we determined the lethal concentrations (LCs) of imidacloprid through contact and ingestion. Subsequently, the cytomorphology of the salivary glands were evaluated in insect groups that survived exposure to the LC5 (3.75 mg a.i./L), LC50 (112.5 mg a.i./L), or LC75 (375.0 mg a.i./L, equivalent to the recommended field rate) doses. Imidacloprid induced apoptosis and necrosis in the salivary gland cells according to the insecticide concentration and salivary gland region. All concentrations increased apoptosis and injured cells (e.g., vacuolization, chromatin condensation, swelling of organelles, and plasma membrane rupture) in the principal and accessory salivary glands. Individuals that survived exposure to the highest concentrations (i.e., LC5 and LC50) were more affected, and exhibited several necrotic cells on their main principal salivary glands. Collectively, our results indicate that imidacloprid exerts toxic effects on the non-target organs, such as the salivary glands, which increases the efficacy of this compound in the management of stink bug infestations.
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Affiliation(s)
- Nathaly L Castellanos
- Departamento de Entomologia, Universidade Federal de Viçosa, Viçosa, MG, 36570-900, Brasil.
| | | | - Higor S Rodrigues
- Departamento de Entomologia, Universidade Federal de Viçosa, Viçosa, MG, 36570-900, Brasil
| | - Luis Carlos Martínez
- Departamento de Biologia Geral, Universidade Federal de Viçosa, Viçosa, MG, 36570-900, Brasil
| | - José E Serrão
- Departamento de Biologia Geral, Universidade Federal de Viçosa, Viçosa, MG, 36570-900, Brasil
| | - Eugenio E Oliveira
- Departamento de Entomologia, Universidade Federal de Viçosa, Viçosa, MG, 36570-900, Brasil.
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Liu Z, Wang W, Luo J, Zhang Y, Zhang Y, Gan Z, Shen X, Zhang Y, Meng X. Anti-Apoptotic Role of Sanhuang Xiexin Decoction and Anisodamine in Endotoxemia. Front Pharmacol 2021; 12:531325. [PMID: 33967742 PMCID: PMC8099151 DOI: 10.3389/fphar.2021.531325] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 03/24/2021] [Indexed: 02/06/2023] Open
Abstract
Endotoxemia is characterized by initial uncontrollable inflammation, terminal immune paralysis, significant cell apoptosis and tissue injury, which can aggravate or induce multiple diseases and become one of the complications of many diseases. Therefore, anti-inflammatory and anti-apoptotic therapy is a valuable strategy for the treatment of endotoxemia-induced tissue injury. Traditional Chinese medicine exhibits great advantages in the treatment of endotoxemia. In this review, we have analyzed and summarized the active ingredients and their metabolites of Sanhuang Xiexin Decoction, a famous formula in endotoxemia therapy. We then have summarized the mechanisms of Sanhuang Xiexin Decoction against endotoxemia and its mediated tissue injury. Furthermore, silico strategy was used to evaluate the anti-apoptotic mechanism of anisodamine, a well-known natural product that widely used to improve survival in patients with septic shock. Finally, we also have summarized other anti-apoptotic natural products as well as their therapeutic effects on endotoxemia and its mediated tissue injury.
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Affiliation(s)
- Zixuan Liu
- Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenxiang Wang
- Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jie Luo
- Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yingrui Zhang
- Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunsen Zhang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhiqiang Gan
- Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofei Shen
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yi Zhang
- Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xianli Meng
- Innovative Institutes of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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