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Li H, Liu Q, Liu C, Wang S, Zhang Y, Pan J, Liu K, Huang S, Chu T, Shang L, Song Q, Feng K, Wu Z. Identification of SNHG11 as a Therapeutic Target in Pulmonary Hypertension. Am J Respir Cell Mol Biol 2025; 72:244-257. [PMID: 39265177 DOI: 10.1165/rcmb.2023-0428oc] [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: 12/06/2023] [Accepted: 09/12/2024] [Indexed: 09/14/2024] Open
Abstract
Pulmonary hypertension (PH) is a life-threatening condition characterized by pulmonary vascular remodeling and endothelial dysfunction. Current therapies primarily target vasoactive imbalances but often fail to address adverse vascular remodeling. Long noncoding RNAs (lncRNAs), which are key regulators of various cellular processes, remain underexplored in the context of PH. To investigate the role of lncRNA in PH, we performed a comprehensive analysis using weighted gene coexpression network analysis on the GSE113439 dataset, comprising human lung tissue samples from different PH subtypes. Our analysis identified the lncRNA SNHG11 as consistently downregulated in PH. Functional assays in human pulmonary artery endothelial cells demonstrated that SNHG11 plays a critical role in modulating inflammation, cell proliferation, apoptosis, and the Janus kinase/signal transducers and activators of transcription and mitogen-activated protein kinase signaling pathways. Mechanistically, SNHG11 influences the stability of PRPF8, a crucial mRNA spliceosome component, thereby affecting multiple cellular functions beyond splicing. In vivo experiments using a hypoxic rat model showed that knockdown of SNHG11 alleviates PH development and improves right ventricular function. These findings highlight SNHG11 as a key regulator in PH pathogenesis and suggest it as a potential therapeutic target.
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Affiliation(s)
- Huayang Li
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Quan Liu
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Chiyu Liu
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shunjun Wang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Changsha Medical University, Changsha, China; and
| | - Yitao Zhang
- Department of Cardiology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinyu Pan
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Kaizheng Liu
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Suiqing Huang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Tongxin Chu
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Liqun Shang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Qingyang Song
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Kangni Feng
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhongkai Wu
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Beckers D, Jainarayanan AK, Dustin ML, Capera J. T Cell Resistance: On the Mechanisms of T Cell Non-activation. Immune Netw 2024; 24:e42. [PMID: 39801736 PMCID: PMC11711127 DOI: 10.4110/in.2024.24.e42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/28/2024] [Accepted: 11/12/2024] [Indexed: 01/16/2025] Open
Abstract
Immunological tolerance is a fundamental arm of any functioning immune system. Not only does tolerance mitigate collateral damage from host immune responses, but in doing so permits a robust response sufficient to clear infection as necessary. Yet, despite occupying such a cornerstone, research aiming to unravel the intricacies of tolerance induction is mired by interchangeable and often misused terminologies, with markers and mechanistic pathways that beg the question of redundancy. In this review we aim to define these boarders by providing new perspectives to long-standing theories of tolerance. Given the central role of T cells in enforcing immune cascades, in this review we choose to explore immunological tolerance through the perspective of T cell 'resistance to activation,' to delineate the contexts in which one tolerance mechanism has evolved over the other. By clarifying the important biological markers and cellular players underpinning T cell resistance to activation, we aim to encourage more purposeful and directed research into tolerance and, more-over, potential therapeutic strategies in autoimmune diseases and cancer. The tolerance field is in much need of reclassification and consideration, and in this review, we hope to open that conversation.
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Affiliation(s)
- Daniel Beckers
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom
| | - Ashwin K. Jainarayanan
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom
| | - Michael L. Dustin
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom
| | - Jesusa Capera
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom
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Ni Y, Chen H, Zhan Q, Zhuang Z. Nuclear export of PML promotes p53-mediated apoptosis and ferroptosis. Cell Signal 2024; 121:111278. [PMID: 38944257 DOI: 10.1016/j.cellsig.2024.111278] [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: 04/01/2024] [Revised: 06/14/2024] [Accepted: 06/26/2024] [Indexed: 07/01/2024]
Abstract
Promyelocytic leukemia protein (PML), a tumor suppressor protein, plays a key role in cell cycle regulation, apoptosis, senescence and cellular metabolism. Here, we report that PML promotes apoptosis and ferroptosis. Our data showed that PML over-expression inhibited cell proliferation and migration. PML over-expression increased apoptotic cells, nuclear condensation and the loss of mitochondrial membrane potential, accompanied by regulation of Bcl-2 family proteins and reactive oxygen species (ROS) level, suggesting that PML enhanced apoptosis. Meanwhile, PML over-expression not only increased lipid ROS accumulation and Malondialdehyde (MDA) content but also downregulated solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, indicating that PML enhanced ferroptosis. Additionally, knockdown of p53 attenuated the effect of PML on SLC7A11 and GPX4, and inhibited the increase of lipid ROS and ROS by PML over-expression. Moreover, translocation of PML from nucleus to cytoplasm not only promoted apoptosis and ferroptosis, but also inhibited cell proliferation. Taken together, PML promotes apoptosis and ferroptosis, in which the mediation of p53 and the nuclear export of PML play important roles.
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Affiliation(s)
- Yue Ni
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Centre for Optical and Electromagnetic Research, South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou 510631, China
| | - Hongce Chen
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
| | - Qiuqiang Zhan
- Centre for Optical and Electromagnetic Research, South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou 510631, China
| | - Zhengfei Zhuang
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
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Wagle SR, Kovacevic B, Foster T, Ionescu CM, Jones M, Mikov M, Wise A, Mooranian A, Al-Salami H. Probucol-bile acid nanoparticles: a novel approach and promising solution to prevent cellular oxidative stress in sensorineural hearing loss. J Drug Target 2024; 32:737-755. [PMID: 38758361 DOI: 10.1080/1061186x.2024.2349111] [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: 01/21/2024] [Revised: 04/22/2024] [Accepted: 04/24/2024] [Indexed: 05/18/2024]
Abstract
The use of antioxidants could thus prove an effective medication to prevent or facilitate recovery from oxidative stress-induced sensorineural hearing loss (SNHL). One promising strategy to prevent SNHL is developing probucol (PB)-based nanoparticles using encapsulation technology and administering them to the inner ear via the established intratympanic route. The preclinical, clinical and epidemiological studies support that PB is a proven antioxidant that could effectively prevent oxidative stress in different study models. Such findings suggest its applicability in preventing oxidative stress within the inner ear and its associated neural cells. However, several hurdles, such as overcoming the blood-labyrinth barrier, ensuring sustained release, minimising systemic side effects and optimising targeted delivery in the intricate inner ear structures, must be overcome to efficiently deliver PB to the inner ear. This review explores the background and pathogenesis of hearing loss, the potential of PB in treating oxidative stress and its cellular mechanisms, and the obstacles linked to inner ear drug delivery for effectively introducing PB to the inner ear.
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Affiliation(s)
- Susbin Raj Wagle
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia
| | - Bozica Kovacevic
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia
| | - Thomas Foster
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia
| | - Corina Mihaela Ionescu
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia
| | - Melissa Jones
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia
| | - Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | | | - Armin Mooranian
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia
- School of Pharmacy, University of Otago, Dunedin, Otago, New Zealand
| | - Hani Al-Salami
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia
- Medical School, University of Western Australia, Perth, Western Australia, Australia
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Wang S, Cheng L. The role of apoptosis in spinal cord injury: a bibliometric analysis from 1994 to 2023. Front Cell Neurosci 2024; 17:1334092. [PMID: 38293650 PMCID: PMC10825042 DOI: 10.3389/fncel.2023.1334092] [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: 11/06/2023] [Accepted: 12/29/2023] [Indexed: 02/01/2024] Open
Abstract
Background Apoptosis after spinal cord injury (SCI) plays a pivotal role in the secondary injury mechanisms, which cause the ultimate neurologic insults. A better understanding of the molecular and cellular basis of apoptosis in SCI allows for improved glial and neuronal survival via the administrations of anti-apoptotic biomarkers. The knowledge structure, development trends, and research hotspots of apoptosis and SCI have not yet been systematically investigated. Methods Articles and reviews on apoptosis and SCI, published from 1st January 1994 to 1st Oct 2023, were retrieved from the Web of Science™. Bibliometrix in R was used to evaluate annual publications, countries, affiliations, authors, sources, documents, key words, and hot topics. Results A total of 3,359 publications in accordance with the criterions were obtained, which exhibited an ascending trend in annual publications. The most productive countries were the USA and China. Journal of Neurotrauma was the most impactive journal; Wenzhou Medical University was the most prolific affiliation; Cuzzocrea S was the most productive and influential author. "Apoptosis," "spinal-cord-injury," "expression," "activation," and "functional recovery" were the most frequent key words. Additionally, "transplantation," "mesenchymal stemness-cells," "therapies," "activation," "regeneration," "repair," "autophagy," "exosomes," "nlrp3 inflammasome," "neuroinflammation," and "knockdown" were the latest emerging key words, which may inform the hottest themes. Conclusions Apoptosis after SCI may cause the ultimate neurological damages. Development of novel treatments for secondary SCI mainly depends on a better understanding of apoptosis-related mechanisms in molecular and cellular levels. Such therapeutic interventions involve the application of anti-apoptotic agents, free radical scavengers, as well as anti-inflammatory drugs, which can be targeted to inhibit core events in cellular and molecular injury cascades pathway.
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Affiliation(s)
- Siqiao Wang
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai, China
| | - Liming Cheng
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai, China
- Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai, China
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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Feng H, Zhao Z, Zhao X, Bai X, Fu W, Zheng L, Kang B, Wang X, Zhang Z, Dong C. A novel memory-like Tfh cell subset is precursor to effector Tfh cells in recall immune responses. J Exp Med 2024; 221:e20221927. [PMID: 38047912 PMCID: PMC10695277 DOI: 10.1084/jem.20221927] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 09/12/2023] [Accepted: 11/15/2023] [Indexed: 12/05/2023] Open
Abstract
T follicular helper (Tfh) cells, essential for germinal center reactions, are not identical, with different phenotypes reported. Whether, when, and how they generate memory cells is still poorly understood. Here, through single-cell RNA-sequencing analysis of CXCR5+Bcl6+ Tfh cells generated under different conditions, we discovered, in addition to PD-1hi effector Tfh cells, a CD62L+PD1low subpopulation. CD62L-expressing Tfh cells developed independently from PD-1+ cells and not in direct contact with B cells. More importantly, CD62L+ Tfh cells expressed memory- and stemness-associated genes, and with better superior long-term survival, they readily generated PD-1hi cells in the recall response. Finally, KLF2 and IL7R, also highly expressed by CD62L+ Tfh cells, were required to regulate their development. Our work thus demonstrates a novel Tfh memory-like cell subpopulation, which may benefit our understanding of immune responses and diseases.
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Affiliation(s)
- Han Feng
- Institute for Immunology, Tsinghua University, Beijing, China
| | - Zixuan Zhao
- Institute for Immunology, Tsinghua University, Beijing, China
| | - Xiaohong Zhao
- Institute for Immunology, Tsinghua University, Beijing, China
| | - Xue Bai
- Institute for Immunology, Tsinghua University, Beijing, China
| | - Weiwei Fu
- Institute for Immunology, Tsinghua University, Beijing, China
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Liangtao Zheng
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, and School of Life Sciences, Peking University, Beijing, China
| | - Boxi Kang
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, and School of Life Sciences, Peking University, Beijing, China
| | - Xiaohu Wang
- Institute for Immunology, Tsinghua University, Beijing, China
| | - Zemin Zhang
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, and School of Life Sciences, Peking University, Beijing, China
| | - Chen Dong
- Institute for Immunology, Tsinghua University, Beijing, China
- Shanghai Immune Therapy Institute and Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
- Westlake University School of Medicine, Hangzhou, China
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Zheng X, Tang J, Song A, Zhou Y, Miao J, Li Z, Pan L. Study on reproductive endocrine disturbance and DNA damage mechanism of female Ruditapes philippinarum under Benzo[a]pyrene stress. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 340:122844. [PMID: 37918772 DOI: 10.1016/j.envpol.2023.122844] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/22/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
The reproductive toxicity of polycyclic aromatic hydrocarbons (PAHs) in aquatic organisms has attracted increasing attention from scholars. Currently, research in this field primarily focuses on vertebrates such as zebrafish and other model species. However, there is still a significant knowledge gap in the toxicity of PAHs to invertebrates and its potential mechanisms. Benzo[a]pyrene (B[a]P) is one of the most representative PAHs. In this study, female Ruditapes philippinarum (R. philippinarum) was treated with B[a]P concentrations of 0, 0.8, 4, and 20 μg/L to investigate reproductive indicators in the proliferative, growth, mature, and spawn stages. Transcriptomics was used to investigate the expression of genes associated with the reproductive endocrine system, DNA repair, autophagy, apoptosis, and ovarian development at different reproductive stages. Our results suggested that B[a]P disrupted the endocrine system by interfering with the production of steroid hormones and the transmission of estrogen signals in female R. philippinarum. The structure of the ovarian DNA duplex is severely damaged under the stress of B[a]P, and a series of cellular responses caused by DNA damage are also interfered. Additionally, we observed a reduction in the gonadosomatic index (GSI) and mature oocytes numbers after B[a]P exposed. Tissue section indicated that severe damage to the ovarian structure at mature and spawn stages. In conclusion, this study combined transcriptomic and toxicological to explore the negative effects on ovarian development induced by B[a]P, focusing on reproductive endocrine disturbance and DNA damage.
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Affiliation(s)
- Xin Zheng
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, China
| | - Jian Tang
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, China
| | - Aimin Song
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, China
| | - Yueyao Zhou
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, China
| | - Jingjing Miao
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, China
| | - Zeyuan Li
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, China
| | - Luqing Pan
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, China.
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Mafi A, Rismanchi H, Gholinezhad Y, Mohammadi MM, Mousavi V, Hosseini SA, Milasi YE, Reiter RJ, Ghezelbash B, Rezaee M, Sheida A, Zarepour F, Asemi Z, Mansournia MA, Mirzaei H. Melatonin as a regulator of apoptosis in leukaemia: molecular mechanism and therapeutic perspectives. Front Pharmacol 2023; 14:1224151. [PMID: 37645444 PMCID: PMC10461318 DOI: 10.3389/fphar.2023.1224151] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/19/2023] [Indexed: 08/31/2023] Open
Abstract
Leukaemia is a dangerous malignancy that causes thousands of deaths every year throughout the world. The rate of morbidity and mortality is significant despite many advancements in therapy strategies for affected individuals. Most antitumour medications used now in clinical oncology use apoptotic signalling pathways to induce cancer cell death. Accumulated data have shown a direct correlation between inducing apoptosis in cancer cells with higher tumour regression and survival. Until now, the efficacy of melatonin as a powerful antitumour agent has been firmly established. A change in melatonin concentrations has been reported in multiple tumours such as endometrial, hematopoietic, and breast cancers. Findings show that melatonin's anticancer properties, such as its prooxidation function and ability to promote apoptosis, indicate the possibility of utilizing this natural substance as a promising agent in innovative cancer therapy approaches. Melatonin stimulates cell apoptosis via the regulation of many apoptosis facilitators, including mitochondria, cytochrome c, Bcl-2, production of reactive oxygen species, and apoptosis receptors. This paper aimed to further assess the anticancer effects of melatonin through the apoptotic pathway, considering the role that cellular apoptosis plays in the pathogenesis of cancer. The effect of melatonin may mean that it is appropriate for use as an adjuvant, along with other therapeutic approaches such as radiotherapy and chemotherapy.
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Affiliation(s)
- Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamidreza Rismanchi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Gholinezhad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Vahide Mousavi
- School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Seyed Ali Hosseini
- School of Medicine, Babol University of Medical Sciences, Babol, Mazandaran, Iran
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Russel J. Reiter
- Department of Cell Systems and Anatomy, UT Health Long School of Medicine, San Antonio, TX, United States
| | - Behrooz Ghezelbash
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Malihe Rezaee
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Fatemeh Zarepour
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Cuan X, Yang X, Zhu W, Zhao Y, Luo R, Huang Y, Wang X, Sheng J. Antitumor effects of erlotinib in combination with berberine in A431 cells. BMC Pharmacol Toxicol 2023; 24:29. [PMID: 37170144 PMCID: PMC10173514 DOI: 10.1186/s40360-023-00661-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 03/07/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, have been shown to target tumors with L858R (exon 21) and exon 19 deletions, resulting in significant clinical benefits. However, acquired resistance often occurs due to EGFR mutations. Therefore, novel therapeutic strategies for treatment of patients with EGFR-positive tumors are needed. Berberine (BBR) is an active alkaloid extracted from pharmaceutical plants such as Coptis chinensis. Berberine has been shown to significantly inhibit EGFR activity and mediate anticancer effects in multiple preclinical studies. We investigated whether combining BBR with erlotinib could augment erlotinib-induced cell growth inhibition of EGFR-positive cells in a mouse xenograft model. METHODS We examined the antitumor activities and potential mechanisms of erlotinib in combination with berberine in vitro and in vivo using the MTT assay, immunoblotting, flow cytometry, and tumor xenograft models. RESULTS In vitro studies with A431 cells showed that synergistic cell growth inhibition by the combination of BBR and erlotinib was associated with significantly greater inhibition of pEGFR and pAKT, and inhibition of cyclin D and Bcl-2 expression compared to that observed in response to BBR or erlotinib alone. The efficacy of the combination treatment was also investigated in nude mice. Consistent with the in vitro results, BBR plus erlotinib significantly reduced tumor growth. CONCLUSION Our data supported use of BBR in combination with erlotinib as a novel strategy for treatment of patients with EGFR positive tumors.
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Affiliation(s)
- Xiangdan Cuan
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China
| | - Xingying Yang
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China
| | - Weiwei Zhu
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China
| | - Yue Zhao
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China
| | - Rui Luo
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, China
| | - Yanping Huang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, No. 452, Fengyuan Road, Panlong District, Kunming, 650201, China.
- College of Science, Yunnan Agricultural University, Kunming, 650201, China.
| | - Xuanjun Wang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, No. 452, Fengyuan Road, Panlong District, Kunming, 650201, China.
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Kunming, 650201, China.
- Yunnan Research Institute of Plateau Characteristic Agricultural and Industry, Kunming, 650201, China.
| | - Jun Sheng
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, No. 452, Fengyuan Road, Panlong District, Kunming, 650201, China.
- College of Science, Yunnan Agricultural University, Kunming, 650201, China.
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Kunming, 650201, China.
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Barnard SJ, Haunschild J, Heiser L, Dieterlen MT, Klaeske K, Borger MA, Etz CD. Apoptotic Cell Death in Bicuspid-Aortic-Valve-Associated Aortopathy. Int J Mol Sci 2023; 24:ijms24087429. [PMID: 37108591 PMCID: PMC10138609 DOI: 10.3390/ijms24087429] [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: 03/01/2023] [Revised: 04/12/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
The bicuspid aortic valve (BAV) is the most common cardiovascular congenital abnormality and is frequently associated with proximal aortopathy. We analyzed the tissues of patients with bicuspid and tricuspid aortic valve (TAV) regarding the protein expression of the receptor for advanced glycation products (RAGE) and its ligands, the advanced glycation end products (AGE), as well as the S100 calcium-binding protein A6 (S100A6). Since S100A6 overexpression attenuates cardiomyocyte apoptosis, we investigated the diverse pathways of apoptosis and autophagic cell death in the human ascending aortic specimen of 57 and 49 patients with BAV and TAV morphology, respectively, to identify differences and explanations for the higher risk of patients with BAV for severe cardiovascular diseases. We found significantly increased levels of RAGE, AGE and S100A6 in the aortic tissue of bicuspid patients which may promote apoptosis via the upregulation of caspase-3 activity. Although increased caspase-3 activity was not detected in BAV patients, increased protein expression of the 48 kDa fragment of vimentin was detected. mTOR as a downstream protein of Akt was significantly higher in patients with BAV, whereas Bcl-2 was increased in patients with TAV, assuming a better protection against apoptosis. The autophagy-related proteins p62 and ERK1/2 were increased in patients with BAV, assuming that cells in bicuspid tissue are more likely to undergo apoptotic cell death leading to changes in the wall and finally to aortopathies. We provide first-hand evidence of increased apoptotic cell death in the aortic tissue of BAV patients which may thus provide an explanation for the increased risk of structural aortic wall deficiency possibly underlying aortic aneurysm formation or acute dissection.
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Affiliation(s)
- Sarah J Barnard
- Heisenberg Working Group, Saxonian Incubator for Clinical Translation, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
| | - Josephina Haunschild
- Heisenberg Working Group, Saxonian Incubator for Clinical Translation, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Linda Heiser
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Maja T Dieterlen
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Kristin Klaeske
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Michael A Borger
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Christian D Etz
- Heisenberg Working Group, Saxonian Incubator for Clinical Translation, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
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11
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Mai Z, Sun H, Yang F, Du M, Cheng X, Chen H, Sun B, Wen J, Wang X, Chen T. Bad is essential for Bcl-xL-enhanced Bax shuttling between mitochondria and cytosol. Int J Biochem Cell Biol 2023; 155:106359. [PMID: 36586532 DOI: 10.1016/j.biocel.2022.106359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/17/2022] [Accepted: 12/27/2022] [Indexed: 12/30/2022]
Abstract
Although Bcl-xL has been shown to retrotranslocate Bax from mitochondria to cytosol, other studies have found that Bcl-xL also stabilizes the mitochondrial localization of Bax. It is still unclear what causes the difference in Bcl-xL-regulated Bax localization. Bad, a BH3-only protein with a high affinity for Bcl-xL, may play an important role in Bcl-xL-regulated Bax shuttling. Here, we found that Bcl-xL enhanced both translocalization and retrotranslocation of mitochondrial Bax, as evidenced by quantitative co-localization, western blots and fluorescence loss in photobleaching (FLIP) analyses. Notably, Bad knockdown prevented Bcl-xL-mediated Bax retrotranslocation, indicating Bad was essential for this process. Quantitative fluorescence resonance energy transfer (FRET) imaging in living cells and co-immunoprecipitation analyses showed that the interaction of Bcl-xL with Bad was stronger than that with Bax. The Bad mimetic ABT-737 dissociated Bax from Bcl-xL on isolated mitochondria, suggesting that mitochondrial Bax was directly liberated to cytosol due to Bad binding to Bcl-xL. In addition, MK-2206, an Akt inhibitor, decreased Bad phosphorylation while increasing cytosolic Bax proportion. Our data firmly demonstrate a notion that Bad binds to mitochondrial Bcl-xL to release Bax, resulting in retrotranslocation of Bax to cytosol, and that the amount of Bad involved is regulated by Akt signaling.
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Affiliation(s)
- Zihao Mai
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Han Sun
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Fangfang Yang
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Mengyan Du
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Xuecheng Cheng
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Hongce Chen
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Beini Sun
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Junlin Wen
- Department of Pain Management, the First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Xiaoping Wang
- Department of Pain Management, the First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
| | - Tongsheng Chen
- MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
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12
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Torielli L, Serapian SA, Mussolin L, Moroni E, Colombo G. Integrating Protein Interaction Surface Prediction with a Fragment-Based Drug Design: Automatic Design of New Leads with Fragments on Energy Surfaces. J Chem Inf Model 2023; 63:343-353. [PMID: 36574607 PMCID: PMC9832486 DOI: 10.1021/acs.jcim.2c01408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Protein-protein interactions (PPIs) have emerged in the past years as significant pharmacological targets in the development of new therapeutics due to their key roles in determining pathological pathways. Herein, we present fragments on energy surfaces, a simple and general design strategy that integrates the analysis of the dynamic and energetic signatures of proteins to unveil the substructures involved in PPIs, with docking, selection, and combination of drug-like fragments to generate new PPI inhibitor candidates. Specifically, structural representatives of the target protein are used as inputs for the blind physics-based prediction of potential protein interaction surfaces using the matrix of low coupling energy decomposition method. The predicted interaction surfaces are subdivided into overlapping windows that are used as templates to direct the docking and combination of fragments representative of moieties typically found in active drugs. This protocol is then applied and validated using structurally diverse, important PPI targets as test systems. We demonstrate that our approach facilitates the exploration of the molecular diversity space of potential ligands, with no requirement of prior information on the location and properties of interaction surfaces or on the structures of potential lead compounds. Importantly, the hit molecules that emerge from our ab initio design share high chemical similarity with experimentally tested active PPI inhibitors. We propose that the protocol we describe here represents a valuable means of generating initial leads against difficult targets for further development and refinement.
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Affiliation(s)
- Luca Torielli
- Department
of Chemistry, University of Pavia, Via Taramelli 12, Pavia27100, Italy
| | - Stefano A. Serapian
- Department
of Chemistry, University of Pavia, Via Taramelli 12, Pavia27100, Italy
| | - Lara Mussolin
- Department
of Woman’s and Child’s Health, Pediatric Hematology,
Oncology and Stem Cell Transplant Center, University of Padua, Via Giustiniani, 3, Padua35128, Italy,Istituto
di Ricerca Pediatrica Città della Speranza, Corso Stati Uniti, 4 F, Padova35127, Italy
| | | | - Giorgio Colombo
- Department
of Chemistry, University of Pavia, Via Taramelli 12, Pavia27100, Italy,
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13
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Zheng Y, Yu Z, Li Y, Zhong S, Sun Y, Sun L, Zheng X, Qi X, Zhang S. Alcohol extracts of Chinese bayberry branch induce S-phase arrest and apoptosis in HepG2 cells. Food Sci Nutr 2023; 11:493-503. [PMID: 36655066 PMCID: PMC9834848 DOI: 10.1002/fsn3.3080] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 08/31/2022] [Accepted: 09/15/2022] [Indexed: 01/21/2023] Open
Abstract
The alcohol extracts of Chinese bayberry (Myrica rubra) branches (MRBE) are rich in flavonoids which have a variety of medicinal benefits, but their effects on human HepG2 were unknown. In this study, the effects of MRBE on HepG2 cell growth and its potential for inhibiting cancer were explored. The results displayed that MRBE inhibited HepG2 proliferation both by arresting cells in S phase and promoting apoptosis. Quantitative reverse-transcription PCR (qRT-PCR), western blotting, and immunofluorescence showed that MRBE induced S-phase arrest by upregulating p21, which in turn downregulated cyclin and cyclin-dependent kinase messenger RNA (mRNA) and protein. Apoptosis was induced by blocking the expression of BCL-2 and suppression of the Raf/ERK1 signaling pathways. These results indicated that MRBE may have the potential for treatment of human liver cancer, highlighting novel approaches for developing new pharmacological tools for the treatment of this deadly type cancer. Meanwhile, it provides a new direction for the medicinal added values of Chinese bayberry, which helped to broaden the diversified development of its industry chain.
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Affiliation(s)
- Yuanyuan Zheng
- Institute of HorticultureZhejiang Academy of Agricultural SciencesHangzhouChina
| | - Zheping Yu
- Institute of HorticultureZhejiang Academy of Agricultural SciencesHangzhouChina
| | - Yougui Li
- Institute of Sericultural and TeaZhejiang Academy of Agricultural SciencesHangzhouChina
| | - Shi Zhong
- Institute of Sericultural and TeaZhejiang Academy of Agricultural SciencesHangzhouChina
| | - Yuqing Sun
- Institute of Sericultural and TeaZhejiang Academy of Agricultural SciencesHangzhouChina
| | - Li Sun
- Institute of HorticultureZhejiang Academy of Agricultural SciencesHangzhouChina
| | - Xiliang Zheng
- Institute of HorticultureZhejiang Academy of Agricultural SciencesHangzhouChina
| | - Xingjiang Qi
- Institute of HorticultureZhejiang Academy of Agricultural SciencesHangzhouChina
- Xianghu LabHangzhouChina
| | - Shuwen Zhang
- Institute of HorticultureZhejiang Academy of Agricultural SciencesHangzhouChina
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14
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Guo KM, Li W, Wang ZH, He LC, Feng Y, Liu HS. Low-dose aspirin inhibits trophoblast cell apoptosis by activating the CREB/Bcl-2 pathway in pre-eclampsia. Cell Cycle 2022; 21:2223-2238. [PMID: 35792905 PMCID: PMC9586659 DOI: 10.1080/15384101.2022.2092814] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 05/06/2022] [Accepted: 05/31/2022] [Indexed: 11/03/2022] Open
Abstract
Excessive apoptosis of placental trophoblast cells is considered a major cause of pre-eclampsia (PE) pathogenesis. Phosphorylation of the widely expressed cAMP response element binding protein (CREB) regulates apoptosis and may be involved in PE incidence. Low-dose aspirin (LDA) is an effective approach for preventing PE with unclear mechanisms. Thus we examined whether LDA protects against PE by inhibiting trophoblast cell apoptosis through CREB. The effects of LDA on human PE placenta, PE model rat placenta, and hydrogen peroxide (H2O2)-induced HTR-8/SVneo cell apoptosis were analyzed. TUNEL assay, immunohistochemistry, Cell Counting Assay Kit-8 (CCK-8) assay, western blot, and flow cytometry assay were performed. In the placenta of human PE and rat PE models, the TUNEL index increased and was partially corrected with LDA pre-treatment. Meanwhile, decreased Bcl-2 and increased Bax expression were significantly reversed by LDA pre-treatment. In HTR-8/SVneo cells, H2O2 decreased cell viability, promoted apoptosis, reduced the Bcl-2/Bax ratio, aggravated loss of mitochondrial membrane potential (MMP), increased cytoplasmic cytochrome c release, and simultaneously activated caspase-9 and caspase-3. These effects were effectively restored by LDA pre-treatment in the cells. Moreover, LDA promoted CREB phosphorylation in trophoblast cells. CREB interference further promoted apoptosis, reduced the Bcl-2/Bax ratio, and increased MMP loss. CREB interference also reversed the inhibitory effect of LDA on H2O2-induced apoptosis in HTR-8/SVneo cells. Thus, LDA was shown to inhibit trophoblast cell mitochondrial apoptosis by activating the CREB/Bcl-2 pathway, providing novel evidence for the protective mechanism of LDA in PE.Abbreviations; PE: Pre-eclampsia; LDA: low-dose aspirin; CREB: cAMP response element binding protein; ROS: reactive oxygen species; H2O2: hydrogen peroxide; PBS: Phosphate-buffered saline; Bcl-2: B-cell lymphoma-2; MMP: Mitochondrial membrane potential; Cyt-c: CytochromeC.
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Affiliation(s)
- Kai-Min Guo
- Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wei Li
- Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, China
| | - Zhao-Hua Wang
- Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- Department of Histology and Embryology, Guangzhou Medical University, Guangzhou, China
| | - Lang-Chi He
- Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yan Feng
- Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Hui-Shu Liu
- Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
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15
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Zhou X, Li Y, Li X, Huang J, Kong R, Liu L, Cheng H. Carrier free nanomedicine to reverse anti-apoptosis and elevate endoplasmic reticulum stress for enhanced photodynamic therapy. Acta Biomater 2022; 152:507-518. [PMID: 36030050 DOI: 10.1016/j.actbio.2022.08.045] [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: 03/10/2022] [Revised: 08/04/2022] [Accepted: 08/19/2022] [Indexed: 11/01/2022]
Abstract
As a first studied and generally accepted programmed cell death regulator, Bcl-2 has been identified to overexpress in many types of cancer promoting tumor proliferation and progression. Herein, inspired by drug self-delivery systems, a self-assembled nanomedicine (designated as GosCe) was designed based on the hydrophobic interaction between chlorin e6 (Ce6) and gossypol (Gos). Without extra carriers, GosCe exhibited high drug loading rates, favorable size distribution, and a long-term stability at aqueous phase. More importantly, GosCe could be internalized by tumor cells more effectively than free Ce6, which brought about its multiple toxicity. Upon intravenous injection, GosCe preferred to accumulate in tumor site through enhanced permeability and retention (EPR) effect. After cellular internalization, Gos contributed to increasing the lethality of Ce6-guided photodynamic therapy (PDT) by down-regulating Bcl-2 protein expression and inducing endoplasmic reticulum (ER) stress. Both in vitro and in vivo investigations indicated that the Gos-assisted PDT greatly inhibit cell proliferation and tumor growth. This study might shed light on developing carrier free nanomedicine for PDT-based synergistic tumor therapy. STATEMENT OF SIGNIFICANCE: Metabolic abnormalities of tumor cells create defensive microenvironments which induce a therapeutic resistance against photodynamic therapy (PDT). Among which, the upregulated B-cell lymphoma (Bcl-2) in tumors could inhibit the PDT-induced cell apoptosis. In this work, a self-delivery nanomedicine (GosCe) was developed based on a Bcl-2 inhibitor and photosensitizer through intermolecular interactions, which had favorable size distribution, high drug contents and improved drug delivery efficiency. Importantly, GosCe increased the PDT efficacy by Bcl-2 inhibition and endoplasmic reticulum stress elevation. Thus, GosCe greatly inhibited the tumor growth while caused a reduced side effect in vivo. This carrier free nanomedicine with tumor microenvironment regulation would advance the development of photodynamic nanoplatform in tumor treatment.
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Affiliation(s)
- Xiang Zhou
- School of Biomedical Engineering and Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Yanmei Li
- School of Biomedical Engineering and Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Xinyu Li
- School of Biomedical Engineering and Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Jiaqi Huang
- School of Biomedical Engineering and Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Renjiang Kong
- School of Biomedical Engineering and Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Lingshan Liu
- School of Biomedical Engineering and Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Hong Cheng
- School of Biomedical Engineering and Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China.
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16
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Huda MN, Deaguero IG, Borrego EA, Kumar R, Islam T, Afrin H, Varela-Ramirez A, Aguilera RJ, Tanner EEL, Nurunnabi M. Ionic liquid-mediated delivery of a BCL-2 inhibitor for topical treatment of skin melanoma. J Control Release 2022; 349:783-795. [PMID: 35908622 PMCID: PMC9991868 DOI: 10.1016/j.jconrel.2022.07.035] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 07/04/2022] [Accepted: 07/23/2022] [Indexed: 01/28/2023]
Abstract
Skin melanoma is one of the most common cancer types in the United States and worldwide, and its incidence continues to grow. Primary skin melanoma can be removed surgically when feasible and if detected at an early stage. Anti-cancer drugs can be applied topically to treat skin cancer lesions and used as an adjunct to surgery to prevent the recurrence of tumor growth. We developed a topical formulation composed of Navitoclax (NAVI), a BCL-2 inhibitor that results in apoptosis, and an ionic liquid of choline octanoate (COA) to treat early-stage melanoma. NAVI is a small hydrophobic molecule that solubilizes at 20% (w/v) when dissolved in 50% COA. Although NAVI is a highly effective chemotherapeutic, it is equally thrombocytopenic. We found that COA-mediated topical delivery of NAVI enhanced its penetration into the skin and held the drug in the deeper skin layers for an extended period. Topical delivery of NAVI produced a higher cancer-cell killing efficacy than orally administrated NAVI. In vivo experiments in a mouse model of human melanoma-induced skin cancer confirmed the formulation's effectiveness via an apoptotic mechanism without any significant skin irritation or systemic absorption of NAVI. Overall, this topical approach may provide a safe and effective option for better managing skin cancer in the clinic.
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Affiliation(s)
- Md Nurul Huda
- Environmental Science & Engineering, University of Texas at El Paso, TX 79956, United States; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, TX 79902, United States
| | - Isaac G Deaguero
- Biomedical Engineering, University of Texas at El Paso, TX 79956, United States
| | - Edgar A Borrego
- Department of Biological Science, Border Biomedical Research Center, University of Texas at El Paso, TX 79956, United States
| | - Raj Kumar
- Environmental Science & Engineering, University of Texas at El Paso, TX 79956, United States
| | - Tamanna Islam
- Environmental Science & Engineering, University of Texas at El Paso, TX 79956, United States
| | - Humayra Afrin
- Environmental Science & Engineering, University of Texas at El Paso, TX 79956, United States
| | - Armando Varela-Ramirez
- Department of Biological Science, Border Biomedical Research Center, University of Texas at El Paso, TX 79956, United States
| | - Renato J Aguilera
- Department of Biological Science, Border Biomedical Research Center, University of Texas at El Paso, TX 79956, United States
| | - Eden E L Tanner
- Department of Chemistry & Biochemistry, The University of Mississippi, University, MS 38677, United States
| | - Md Nurunnabi
- Environmental Science & Engineering, University of Texas at El Paso, TX 79956, United States; Biomedical Engineering, University of Texas at El Paso, TX 79956, United States; Department of Biological Science, Border Biomedical Research Center, University of Texas at El Paso, TX 79956, United States; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, TX 79902, United States.
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17
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Zhang F, Zhang C, Fu S, Liu H, Han M, Fan X, Zhang H, Li W. Amphiphilic Cationic Peptide-Coated PHA Nanosphere as an Efficient Vector for Multiple-Drug Delivery. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:3024. [PMID: 36080060 PMCID: PMC9457696 DOI: 10.3390/nano12173024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/08/2022] [Accepted: 08/26/2022] [Indexed: 06/15/2023]
Abstract
Amphiphilic core-shell (ACS) nanoparticles are gaining increasing research interest for multi-drug delivery in cancer therapy. In this work, a new cationic peptide-coated PHA nanosphere was prepared by self-assembly of a hydrophobic core of biodegradable poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) and a hydrophilic shell of fusion proteins of PHA granule-associated protein (PhaP) and cationic peptide RALA through a strong hydrophobic effect. The hydrophobic drug curcumin (Cur) was encapsulated in PHBHHx nanoparticles. The chemotherapy drug 5-fluorouracil (5-FU) was administered in the form of its metabolite oligomeric 5-fluorodeoxyuridine (FUdR). Fifteen consecutive FUdR (FUdR15S) were adsorbed on the surface of PHBHHx nanoparticles by electrostatic interaction with RALA to form Cur@PHBX-PR/FUdR15S. Such amphiphilic cationic nanospheres had 88.3% EE of Cur and the drug loading of Cur and FUdR were 7.8% and 12.1%. The dual-drug-loaded nanospheres showed a time-differential release of Cur and FUdR. In addition, Cur@PHBX-PR/FUdR15S exhibited excellent anticancer activity and played a vital role in promoting the synergistic effect of FUdR and Cur in gastric cancer cells. The exploration of antitumor mechanisms demonstrated that Cur improved the activity of apoptosis-related proteins and cancer cells sensitized to FUdR. This amphiphilic core-shell system can serve as a general platform for sequential delivery of multiple drugs to treat several cancer cells.
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Affiliation(s)
- Fanghua Zhang
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
- Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China
| | - Chao Zhang
- Department of Life Science, Hengshui University, Hengshui 053000, China
| | - Shuangqing Fu
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Huandi Liu
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Mengnan Han
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Xueyu Fan
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Honglei Zhang
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Wei Li
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
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18
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Zhang C, Fu S, Zhang F, Han M, Wang X, Du J, Zhang H, Li W. Affibody Modified G-quadruplex DNA Micelles Incorporating Polymeric 5-Fluorodeoxyuridine for Targeted Delivery of Curcumin to Enhance Synergetic Therapy of HER2 Positive Gastric Cancer. NANOMATERIALS 2022; 12:nano12040696. [PMID: 35215023 PMCID: PMC8879187 DOI: 10.3390/nano12040696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 12/12/2022]
Abstract
Combination chemotherapy is emerging as an important strategy for cancer treatment with decreased side effects. However, chemotherapeutic drugs with different solubility are not easy to realize co-delivery in traditional nanocarriers. Herein, an affibody modified G-quadruplex DNA micellar prodrug (affi-F/GQs) of hydrophilic 5-fluorodeoxyuridine (FUdR) by integrating polymeric FUdRs into DNA strands is developed for the first time. To achieve synergistic efficacy with hydrophobic drugs, curcumin (Cur) is co-loaded into affi-F/GQs micelles to prepare the dual drug-loaded DNA micelles (Cur@affi-F/GQs), in which affibody is employed as a targeting moiety to facilitate HER2 receptor-mediated uptake. Cur@affi-F/GQs have a small size of approximately 130 nm and exhibit excellent stability. The system co-delivers FUdR and Cur in a ratiometric manner, and the drug loading rates are 21.1% and 5.6%, respectively. Compared with the physical combination of FUdR and Cur, Cur@affi-F/GQs show higher cytotoxicity and greater synergistic effect on HER2 positive gastric cancer N87 cells. Surprisingly, Cur@affi-F/GQs significantly enhance the expression and activity of apoptosis-associated proteins in Bcl-2/Bax-caspase 8, 9-caspase 3 apoptotic pathway, which is the main factor in the death of tumor cells induced by FUdR. Overall, this nanoencapsulation is a promising candidate for the targeted co-delivery of drugs with significant differences in solubility.
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Affiliation(s)
- Chao Zhang
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province-Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; (C.Z.); (S.F.); (F.Z.); (M.H.); (X.W.); (J.D.)
- Department of Life Science, Hengshui University, Hengshui 053000, China
| | - Shuangqing Fu
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province-Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; (C.Z.); (S.F.); (F.Z.); (M.H.); (X.W.); (J.D.)
| | - Fanghua Zhang
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province-Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; (C.Z.); (S.F.); (F.Z.); (M.H.); (X.W.); (J.D.)
| | - Mengnan Han
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province-Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; (C.Z.); (S.F.); (F.Z.); (M.H.); (X.W.); (J.D.)
| | - Xuming Wang
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province-Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; (C.Z.); (S.F.); (F.Z.); (M.H.); (X.W.); (J.D.)
| | - Jie Du
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province-Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; (C.Z.); (S.F.); (F.Z.); (M.H.); (X.W.); (J.D.)
| | - Honglei Zhang
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province-Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; (C.Z.); (S.F.); (F.Z.); (M.H.); (X.W.); (J.D.)
- Correspondence: (H.Z.); (W.L.)
| | - Wei Li
- College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province-Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; (C.Z.); (S.F.); (F.Z.); (M.H.); (X.W.); (J.D.)
- Correspondence: (H.Z.); (W.L.)
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Wang Y, Chen Y, Li C, Xiao Z, Yuan H, Zhang Y, Pang D, Tang X, Li M, Ouyang H. TERT Promoter Revertant Mutation Inhibits Melanoma Growth through Intrinsic Apoptosis. BIOLOGY 2022; 11:biology11010141. [PMID: 35053139 PMCID: PMC8773187 DOI: 10.3390/biology11010141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/08/2022] [Accepted: 01/12/2022] [Indexed: 12/15/2022]
Abstract
Simple Summary TERT -146 C>T frequently occurs in many cancer cells. Research targeting the telomerase reverse transcriptase (TERT) promoter contributes to a better understanding of cancer development and treatment. Many conventional cancer treatments aim to develop new drugs targeting TERT. Here, for TERT -146 we converted T to C. The proliferation, migration and invasion of melanoma cells in vitro, and the growth of the tumor in vivo were inhibited. Moreover, the downregulated protein expression of B-cell lymphoma 2 (Bcl-2) indicated that the TERT promoter revertant mutation abrogated the inhibitory effect of mutant TERT on apoptosis. These data elucidated the relationship between the TERT promoter revertant mutations and apoptosis for the first time, and also implied that TERT -146 may be a causal mutation of melanoma. This study provides a new insight into the TERT promoter revertant mutations and apoptosis. The TERT promoter provides preliminary validation of the potential tumor treatment. Abstract Human telomerase is a specialized DNA polymerase whose catalytic core includes both TERT and human telomerase RNA (hTR). Telomerase in humans, which is silent in most somatic cells, is activated to maintain the telomere length (TEL) in various types of cancer cells, including melanoma. In the vast majority of tumor cells, the TERT promoter is mutated to promote proliferation and inhibit apoptosis. Here, we exploited NG-ABEmax to revert TERT -146 T to -146 C in melanoma, and successfully obtained TERT promoter revertant mutant cells. These TERT revertant mutant cells exhibited significant growth inhibition both in vitro and in vivo. Moreover, A375−146C/C cells exhibited telomere shortening and the downregulation of TERT at both the transcription and protein levels, and migration and invasion were inhibited. In addition, TERT promoter revertant mutation abrogated the inhibitory effect of mutant TERT on apoptosis via B-cell lymphoma 2 (Bcl-2), ultimately leading to cell death. Collectively, the results of our work demonstrate that reverting mutations in the TERT promoter is a potential therapeutic option for melanoma.
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Affiliation(s)
- Yanbing Wang
- Key Laboratory for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China; (Y.W.); (Y.C.); (Z.X.); (H.Y.); (Y.Z.); (D.P.); (X.T.)
| | - Yiwu Chen
- Key Laboratory for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China; (Y.W.); (Y.C.); (Z.X.); (H.Y.); (Y.Z.); (D.P.); (X.T.)
| | - Chang Li
- College of Plant Sciences, Jilin University, Changchun 130062, China;
| | - Zhiwei Xiao
- Key Laboratory for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China; (Y.W.); (Y.C.); (Z.X.); (H.Y.); (Y.Z.); (D.P.); (X.T.)
| | - Hongming Yuan
- Key Laboratory for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China; (Y.W.); (Y.C.); (Z.X.); (H.Y.); (Y.Z.); (D.P.); (X.T.)
| | - Yuanzhu Zhang
- Key Laboratory for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China; (Y.W.); (Y.C.); (Z.X.); (H.Y.); (Y.Z.); (D.P.); (X.T.)
| | - Daxin Pang
- Key Laboratory for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China; (Y.W.); (Y.C.); (Z.X.); (H.Y.); (Y.Z.); (D.P.); (X.T.)
- Chongqing Research Institute, Jilin University, Chongqing 401123, China
- Chongqing Jitang Biotechnology Research Institute, Chongqing 401123, China
| | - Xiaochun Tang
- Key Laboratory for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China; (Y.W.); (Y.C.); (Z.X.); (H.Y.); (Y.Z.); (D.P.); (X.T.)
- Chongqing Research Institute, Jilin University, Chongqing 401123, China
- Chongqing Jitang Biotechnology Research Institute, Chongqing 401123, China
| | - Mengjing Li
- Key Laboratory for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China; (Y.W.); (Y.C.); (Z.X.); (H.Y.); (Y.Z.); (D.P.); (X.T.)
- Chongqing Research Institute, Jilin University, Chongqing 401123, China
- Chongqing Jitang Biotechnology Research Institute, Chongqing 401123, China
- Correspondence: (M.L.); (H.O.); Tel.: +86-0431-87836175 (H.O.)
| | - Hongsheng Ouyang
- Key Laboratory for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China; (Y.W.); (Y.C.); (Z.X.); (H.Y.); (Y.Z.); (D.P.); (X.T.)
- Chongqing Research Institute, Jilin University, Chongqing 401123, China
- Chongqing Jitang Biotechnology Research Institute, Chongqing 401123, China
- Correspondence: (M.L.); (H.O.); Tel.: +86-0431-87836175 (H.O.)
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Li H, Hao Z, Wang L, Yang J, Zhao Y, Cheng X, Yuan H, Wang J. Dietary Calcium Alleviates Fluorine-Induced Liver Injury in Rats by Mitochondrial Apoptosis Pathway. Biol Trace Elem Res 2022; 200:271-280. [PMID: 33629228 DOI: 10.1007/s12011-021-02641-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/14/2021] [Indexed: 12/18/2022]
Abstract
Excessive fluoride (F) exposure can lead to liver damage; moreover, recent studies found that the addition of appropriate calcium (Ca) can alleviate the symptom of skeletal fluorosis. However, whether Ca can relieve F-induced liver damage through the mitochondrial apoptosis pathway has not been reported yet. Therefore, we assessed the liver morphology, serum transaminase content, liver oxidative stress-related enzymes, and apoptosis-related gene and protein expression in Sprague Dawley (SD) rats treated with 150 mg/L sodium fluoride (NaF) and different concentrations of calcium carbonate (CaCO3) for 120 days. Our results showed that NaF brought out pathological changes in liver morphology, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels increased, total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) content decreased, and malondialdehyde (MDA) content increased, suggesting that NaF caused hepatotoxicity and oxidative stress. In addition, the results of quantitative real-time PCR (qRT-PCR) and immunohistochemistry showed that NaF exposure upregulated the expression of Bcl-2-associated x protein (Bax), rho-related coiled-coil kinase 1 (ROCK1), cytochrome C (Cyto-C) mRNA and protein (P < 0.01), and downregulated B cell lymphoma 2 (Bcl-2) protein and mRNA (P < 0.01), indicating that excessive F exposure activated mitochondrial-mediated apoptosis in the liver. However, the addition of 1% CaCO3 to the diet significantly increased the expression of anti-apoptotic gene Bcl-2 (P < 0.01), inhibited the activation of the mitochondrial apoptosis pathway, and reduced mitochondrial damage. In summary, supplementing 1% CaCO3 in the diet can alleviate the NaF-induced liver cell damage through the mitochondrial apoptosis pathway.
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Affiliation(s)
- Haojie Li
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
| | - Zijun Hao
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
| | - Li Wang
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
- Linjiang Sub-district Office, Tunliu District, Changzhi City, 046100, Shanxi Province, People's Republic of China
| | - Jiarong Yang
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
| | - Yangfei Zhao
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
| | - Xiaofang Cheng
- Department of Basic Science, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China
| | - Haiyan Yuan
- Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing, 210014, Jiangsu, People's Republic of China
| | - Jinming Wang
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China.
- Shanxi Key Laboratory of Environmental Veterinary Medicine, Shanxi Agricultural University, Jinzhong, Taigu, 030801, Shanxi, People's Republic of China.
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21
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Yang B, Zhang R, Sa Q, Du Y. Rhamnazin Ameliorates Traumatic Brain Injury in Mice via Reduction in Apoptosis, Oxidative Stress, and Inflammation. Neuroimmunomodulation 2022; 29:28-35. [PMID: 34265765 DOI: 10.1159/000516927] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/25/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) is posing serious health challenges for people across the globe due to high morbidity and mortality. However, none of the agents prevents or limits the damage caused by TBI because of its multifactorial etiology. Thus, the discovery of novel agents which can act via several pathways could serve the purpose and afford favorable consequence against TBI. Therefore, in the present article, we intended to investigate the protective effect of rhamnazin (RMZ), a dimethoxyflavone against experimentally induced TBI in mice. METHODS The effect of RMZ was investigated on cerebral edema and grip test score after induction of experimental brain injury in rats. The effect of RMZ was also investigated on neuronal degeneration in brain tissues of the experimental mice via Nissl staining and flow cytometry analysis. The expression of Bax and Bcl-2 was also quantified using Western blot analysis. The level of inflammatory cytokines (TNF-α and IL-1β) and oxidative stress markers (malondialdehyde, superoxide dismutase, and glutathione peroxidase) was also determined using enzyme-linked immunosorbent assay. RESULTS RMZ showed a significant reduction in edema and improved grip strength. It also prevented neuronal degeneration via inhibition of neuronal apoptosis as shown by flow cytometry analysis. RMZ showed an antiapoptotic effect via reduction of Bax and increased the expression of Bcl-2 in Western blot analysis. It also showed to inhibit oxidative stress and inflammation compared to the TBI group. CONCLUSION Collectively, our study is first to demonstrate the protective effect of RMZ against experimentally induced TBI in rats.
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Affiliation(s)
- Boxiao Yang
- Department of Neurosurgery, Hulunbeier People's Hospital, Hulunbeier, China
| | - Rui Zhang
- Department of Imaging, Hulunbeier People's Hospital, Hulunbeier, China
| | - Qire Sa
- Department of Ophthalmology, Hulunbeier People's Hospital, Hulunbeier, China
| | - Yanli Du
- Department of Neurosurgery, Hulunbeier People's Hospital, Hulunbeier, China
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22
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Zhao Y, Jiang Q, Zhang X, Zhu X, Dong X, Shen L, Zhang S, Niu L, Chen L, Zhang M, Jiang J, Chen D, Zhu L. l-Arginine Alleviates LPS-Induced Oxidative Stress and Apoptosis via Activating SIRT1-AKT-Nrf2 and SIRT1-FOXO3a Signaling Pathways in C2C12 Myotube Cells. Antioxidants (Basel) 2021; 10:antiox10121957. [PMID: 34943060 PMCID: PMC8750292 DOI: 10.3390/antiox10121957] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/04/2021] [Accepted: 12/06/2021] [Indexed: 12/27/2022] Open
Abstract
l-arginine (l-Arg) has been reported to possess a wide range of functions, including anti-inflammatory, anti-oxidative, and anti-apoptosis. However, the role of l-Arg in LPS-induced muscle injury and its potential protective mechanism has not been well elucidated. This study aimed to investigate the effects of l-Arg on the LPS-induced oxidative stress and apoptosis in differentiated C2C12 myotube cells. Our results demonstrated that myotube cells treated with 0.2 mg/mL LPS significantly decreased cell viability. l-Arg treatment significantly suppressed LPS induced ROS accumulation and cell apoptosis. Furthermore, l-Arg improved antioxidant-related enzymes’ activities; increased antioxidant ability via Akt-Nrf2 signaling pathway; maintained the mitochondrial membrane potential (MMP); and enhanced FOXO3a expression, leading to a decrease in the mitochondrial-associated apoptotic proteins. In addition, l-Arg exposure dramatically increased the mRNA and protein expressions of SIRT1. The cytoprotective effect of l-Arg was restricted by the SIRT1 inhibitor EX527, which led to an increase in ROS level, apoptosis rate, and decreased cell MMP. The results also demonstrated that EX527 treatment significantly eliminated the effect of l-Arg on LPS-induced oxidative damage and mitochondria-mediated cell apoptosis. Our findings revealed that l-Arg could be used as a potential nutraceutical in reducing muscle injury via regulating SIRT1-Akt-Nrf2 and SIRT1-FOXO3a-mitochondria apoptosis signaling pathways.
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Affiliation(s)
- Ye Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Qin Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Xuefei Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Xiaoxiao Zhu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Xia Dong
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Linyuan Shen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Shunhua Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Lili Niu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Lei Chen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Ming Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Jun Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
| | - Daiwen Chen
- Institute of Animal Nutrition, Sichuan Agricultural University, Ya’an 625014, China
- Correspondence: (D.C.); (L.Z.)
| | - Li Zhu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (Q.J.); (X.Z.); (X.Z.); (X.D.); (L.S.); (S.Z.); (L.N.); (L.C.); (M.Z.); (J.J.)
- Correspondence: (D.C.); (L.Z.)
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Wang C, Li Z, Zhong L, Chen Y. Inhibition of monoacylglycerol lipase restrains proliferation, migration, invasion, tumor growth and induces apoptosis in cervical cancer. J Obstet Gynaecol Res 2021; 48:456-466. [PMID: 34877750 DOI: 10.1111/jog.15110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/29/2021] [Accepted: 11/22/2021] [Indexed: 12/11/2022]
Abstract
AIM Cervical cancer is one of common diseases among women. There are limited therapies for patients with metastatic or recurrent cervical cancer. This study sought to explore the role of monoacylglycerol lipase (MAGL), an important metabolic enzyme, in cervical cancer progression. METHODS In in vitro experiments, MAGL expression was inhibited by si-MAGL or JZL184 in cervical cancer cells. Quantitative real-time polymerase chain reaction and western blotting were performed to measure the expression of target molecules. Proliferation of cervical cancer cells was assessed by CCK-8 and colony formation assays. Apoptosis and cell cycle progression were evaluated by flow cytometry. The migration and invasion were detected by transwell assay. The in vivo tumor growth was detected in nude mice. TUNEL was utilized to observe apoptotic cells in tumor tissues. RESULTS MAGL was upregulated in cervical cancer tissues and cells. Further, MAGL inhibition suppressed the growth of cervical cancer cells in vitro and in vivo. In addition, apoptosis and G1-phase cell cycle arrest were induced by MAGL knockdown. MAGL silencing-mediated upregulation of Bax and cleaved caspase-3, and downregulation of Bcl-2 was responsible for triggering apoptosis. More importantly, the migration and invasion of cervical cancer cells were restrained by MAGL depletion. CONCLUSIONS MAGL drives the progression of cervical cancer, which can be a promising candidate to identify effective therapy for cervical cancer.
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Affiliation(s)
- Chao Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Department of Gynecology and Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China
| | - Zhoulei Li
- Department of Head and Neck Surgery, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China
| | - Linlin Zhong
- Department of Gynecology and Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China
| | - Youguo Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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24
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Sun X, Meng Z, Yu Q, Wang X, Zhao Z. Engineering PDA-coated CM-CS nanoparticles for photothermo-chemotherapy of osteosarcoma and bone regeneration. Biochem Eng J 2021. [DOI: 10.1016/j.bej.2021.108138] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Li Y, Liu M, Yang K, Tian J. 6,6′-Bieckol induces apoptosis and suppresses TGF-β-induced epithelial-mesenchymal transition in non-small lung cancer cells. CHINESE HERBAL MEDICINES 2021; 14:254-262. [PMID: 36117661 PMCID: PMC9476679 DOI: 10.1016/j.chmed.2021.05.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 05/12/2021] [Accepted: 05/27/2021] [Indexed: 01/09/2023] Open
Abstract
Objective In this study, the aim was to investigate the inhibitory effect of 6,6′-bieckol on the migration and epithelial-mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC) cells, and explore its potential molecular mechanisms. Methods Cell migration was measured using a CCK8, wound healing, and transwell migration assay. Apoptosis was determined using an Annexin V/propidium iodide staining. Western blotting and immunofluorescence were used to examine the expression level of apoptosis-related proteins and EMT marker proteins. Results The results showed that 6,6′-bieckol inhibited migration and induced apoptosis of NSCLC cells. Furthermore, 6,6′-bieckol had significantly up-regulated the E-cadherin and down-regulated Snail1 and Twist1 transcriptional levels. 6,6′-Bieckol might inhibit TGF-β-induced EMT by down-regulating Snail1 and Twist1 and up-regulating E-cadherin in lung cancer cells. Conclusion It is suggested that 6,6′-bieckol has the potential to be developed as a therapeutic candidate for lung cancer.
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Lu D, Guo Y, Hu Y, Wang M, Li C, Gangrade A, Chen J, Zheng Z, Guo J. Fusion of apoptosis-related protein Cytochrome c with anti-HER-2 single-chain antibody targets the suppression of HER-2+ breast cancer. J Cell Mol Med 2021; 25:10638-10649. [PMID: 34697906 PMCID: PMC8581304 DOI: 10.1111/jcmm.17001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 01/19/2021] [Accepted: 09/30/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer treatment has gradually developed from toxic chemotherapy to targeted therapy with fewer side effects. Approximately 30% of breast cancer patients overexpress human epidermal growth factor receptor 2 (HER-2). Previous studies have successfully produced single-chain antibodies (scFv) targeting HER-2+ breast cancer; however, scFv have poor stability, easy aggregation and a shorter half-life, which have no significant effect on targeting therapy. Moreover, scFv has been considered as a drug delivery platform that can kill target cells by effector molecules. However, the functional killing domains of immunotoxins are mainly derived from plant or bacterial toxins, which have a large molecular weight, low tissue permeability and severe side effects. To address these concerns, we designed several apoptotic immune molecules to replace exogenous toxins using endogenous apoptosis-related protein DNA fragmentation factor 40 (DFF40) and tandem-repeat Cytochrome c base on caspase-3 responsive peptide (DEVD). Our results suggest that DFF40 or Cytc fusion scFv specifically targets HER-2 overexpressing breast cancer cells (SK-BR-3 and BT-474) rather than HER-2 negative cells (MDA-MB-231 and MCF-7). Following cellular internalization, apoptosis-related proteins inhibited tumour activity by initiating endogenous apoptosis pathways, which significantly reduced immunogenicity and toxic side effects. Therefore, we suggest that immunoapoptotic molecules may become potential drugs for targeted immunotherapy of breast cancer.
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Affiliation(s)
- DanDan Lu
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Key Laboratory of Drug Target and Drug for Degenerative Disease, Nanjing University of Chinese Medicine, Nanjing, China
| | - YiChen Guo
- Department of Surgery and Biomedical Engineering, University of Alabama at Birmingham (UAB), Birmingham, Alabama, USA
| | - YunFeng Hu
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Min Wang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chen Li
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Abhishek Gangrade
- Department of Surgery and Biomedical Engineering, University of Alabama at Birmingham (UAB), Birmingham, Alabama, USA
| | - JiaHui Chen
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - ZiHui Zheng
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jun Guo
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Key Laboratory of Drug Target and Drug for Degenerative Disease, Nanjing University of Chinese Medicine, Nanjing, China
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Murad F, Garcia-Saez AJ. Bcl-xL inhibits tBid and Bax via distinct mechanisms. Faraday Discuss 2021; 232:86-102. [PMID: 34528939 DOI: 10.1039/d0fd00045k] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The proteins of the Bcl-2 family are key regulators of apoptosis. They form a complex interaction network in the cytosol and in cellular membranes, whose outcome determines mitochondrial permeabilization and commitment to death. However, we still do not understand how the action of the different family members is orchestrated to regulate apoptosis. Here, we combined quantitative analysis of the interactions and the localization dynamics of the family representatives Bcl-xL, Bax and tBid, in living cells. We discovered that Bax and tBid are able to constitutively shuttle between cytosol and mitochondria in the absence of other Bcl-2 proteins. Bcl-xL clearly stabilized tBid at mitochondria, where they formed tight complexes. In contrast, Bcl-xL promoted Bax retrotranslocation to the cytosol without affecting its shuttling rate, but by forming weak inhibitory mitochondrial complexes. Furthermore, analysis of phospho-mimetics of Bcl-xL suggested that phosphorylation regulates the function of Bcl-xL via multiple mechanisms. Altogether, our findings support a model in which the Bcl-2 network not only modulates protein/protein interactions among the family members, but also their respective intracellular localization dynamics, to regulate apoptosis.
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Affiliation(s)
- Fabronia Murad
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
| | - Ana J Garcia-Saez
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany. .,Institute for Genetics, CECAD Research Center, University of Cologne, Cologne, Germany
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The Stress-Inducible BCL2A1 Is Required for Ovarian Cancer Metastatic Progression in the Peritoneal Microenvironment. Cancers (Basel) 2021; 13:cancers13184577. [PMID: 34572804 PMCID: PMC8469659 DOI: 10.3390/cancers13184577] [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] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/05/2021] [Accepted: 09/09/2021] [Indexed: 01/12/2023] Open
Abstract
Emerging evidence indicates that hypoxia plays a critical role in governing the transcoelomic metastasis of ovarian cancer. Hence, targeting hypoxia may be a promising approach to prevent the metastasis of ovarian cancer. Here, we report that BCL2A1, a BCL2 family member, acts as a hypoxia-inducible gene for promoting tumor progression in ovarian cancer peritoneal metastases. We demonstrated that BCL2A1 was induced not only by hypoxia but also other physiological stresses through NF-κB signaling and then was gradually reduced by the ubiquitin-proteasome pathway in ascites-derived ovarian cancer cells. The upregulated BCL2A1 was frequently found in advanced metastatic ovarian cancer cells, suggesting its clinical relevance in ovarian cancer metastatic progression. Functionally, BCL2A1 enhanced the foci formation ability of ovarian cancer cells in a stress-conditioned medium, colony formation in an ex vivo omental tumor model, and tumor dissemination in vivo. Under stress conditions, BCL2A1 accumulated and colocalized with mitochondria to suppress intrinsic cell apoptosis by interacting with the BH3-only subfamily BCL2 members HRK/BAD/BID in ovarian cancer cells. These findings indicate that BCL2A1 is an early response factor that maintains the survival of ovarian cancer cells in the harsh tumor microenvironment.
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Kulma M, Anderluh G. Beyond pore formation: reorganization of the plasma membrane induced by pore-forming proteins. Cell Mol Life Sci 2021; 78:6229-6249. [PMID: 34387717 PMCID: PMC11073440 DOI: 10.1007/s00018-021-03914-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 07/09/2021] [Accepted: 08/03/2021] [Indexed: 12/23/2022]
Abstract
Pore-forming proteins (PFPs) are a heterogeneous group of proteins that are expressed and secreted by a wide range of organisms. PFPs are produced as soluble monomers that bind to a receptor molecule in the host cell membrane. They then assemble into oligomers that are incorporated into the lipid membrane to form transmembrane pores. Such pore formation alters the permeability of the plasma membrane and is one of the most common mechanisms used by PFPs to destroy target cells. Interestingly, PFPs can also indirectly manipulate diverse cellular functions. In recent years, increasing evidence indicates that the interaction of PFPs with lipid membranes is not only limited to pore-induced membrane permeabilization but is also strongly associated with extensive plasma membrane reorganization. This includes lateral rearrangement and deformation of the lipid membrane, which can lead to the disruption of target cell function and finally death. Conversely, these modifications also constitute an essential component of the membrane repair system that protects cells from the lethal consequences of pore formation. Here, we provide an overview of the current knowledge on the changes in lipid membrane organization caused by PFPs from different organisms.
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Affiliation(s)
- Magdalena Kulma
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia.
| | - Gregor Anderluh
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia
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Estaras M, Gonzalez A. Modulation of cell physiology under hypoxia in pancreatic cancer. World J Gastroenterol 2021; 27:4582-4602. [PMID: 34366624 PMCID: PMC8326256 DOI: 10.3748/wjg.v27.i28.4582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/28/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
In solid tumors, the development of vasculature is, to some extent, slower than the proliferation of the different types of cells that form the tissue, both cancer and stroma cells. As a consequence, the oxygen availability is compromised and the tissue evolves toward a condition of hypoxia. The presence of hypoxia is variable depending on where the cells are localized, being less extreme at the periphery of the tumor and more severe in areas located deep within the tumor mass. Surprisingly, the cells do not die. Intracellular pathways that are critical for cell fate such as endoplasmic reticulum stress, apoptosis, autophagy, and others are all involved in cellular responses to the low oxygen availability and are orchestrated by hypoxia-inducible factor. Oxidative stress and inflammation are critical conditions that develop under hypoxia. Together with changes in cellular bioenergetics, all contribute to cell survival. Moreover, cell-to-cell interaction is established within the tumor such that cancer cells and the microenvironment maintain a bidirectional communication. Additionally, the release of extracellular vesicles, or exosomes, represents short and long loops that can convey important information regarding invasion and metastasis. As a result, the tumor grows and its malignancy increases. Currently, one of the most lethal tumors is pancreatic cancer. This paper reviews the most recent advances in the knowledge of how cells grow in a pancreatic tumor by adapting to hypoxia. Unmasking the physiological processes that help the tumor increase its size and their regulation will be of major relevance for the treatment of this deadly tumor.
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Affiliation(s)
- Matias Estaras
- Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres 10003, Spain
| | - Antonio Gonzalez
- Department of Physiology, Cell Biology and Communication Research Group, University of Extremadura, Caceres 10003, Spain
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Shi R, Fu Y, Zhao D, Boczek T, Wang W, Guo F. Cell death modulation by transient receptor potential melastatin channels TRPM2 and TRPM7 and their underlying molecular mechanisms. Biochem Pharmacol 2021; 190:114664. [PMID: 34175300 DOI: 10.1016/j.bcp.2021.114664] [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: 03/30/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 10/21/2022]
Abstract
Transient receptor potential melastatin (TRPM) channels are members of the transient receptor potential (TRP) channels, a family of evolutionarily conserved integral membrane proteins. TRPM channels are nonselective cation channels, mediating the influx of various ions including Ca2+, Na+ and Zn2+. The function of TRPM channels is vital for cell proliferation, cell development and cell death. Cell death is a key procedure during embryonic development, organism homeostasis, aging and disease. The category of cell death modalities, beyond the traditionally defined concepts of necrosis, autophagy, and apoptosis, were extended with the discovery of pyroptosis, necroptosis and ferroptosis. As upstream signaling regulators of cell death, TRPM channels have been involved inrelevant pathologies. In this review, we introduced several cell death modalities, then summarized the contribution of TRPM channels (especially TRPM2 and TRPM7) to different cell death modalities and discussed the underlying regulatory mechanisms. Our work highlighted the possibility of TRPM channels as potential therapeutic targets in cell death-related diseases.
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Affiliation(s)
- Ruixue Shi
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Yu Fu
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Dongyi Zhao
- The University of Tokyo, Department of Pharmaceutical Science, 1130033, Japan
| | - Tomasz Boczek
- Department of Molecular Neurochemistry, Medical University of Lodz, 92215, Poland.
| | - Wuyang Wang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China.
| | - Feng Guo
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China.
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Yu L, Chen Q, Chu X, Luo Y, Feng Z, Lu L, Zhang Y, Xu D. Expression and regulation of ccBAX by miR-124 in the caudal fin cell of C. auratus gibelio upon cyprinid herpesvirus 2 infection. JOURNAL OF FISH DISEASES 2021; 44:837-845. [PMID: 33400351 DOI: 10.1111/jfd.13313] [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] [Received: 10/10/2020] [Revised: 11/06/2020] [Accepted: 11/09/2020] [Indexed: 06/12/2023]
Abstract
Bcl2 family proteins play a critical role in cell death or survival. BAX, the death-promoting protein of bcl2 family, mediated mitochondrial pathway inducing cells' apoptosis in mammal. MiRNAs have been implicated as negative regulators down-regulating genes' expression after post-transcriptional level. At present, little is known about the regulatory mechanism of miRNA on the Bcl2 family proteins during CyHV-2 infection in silver crucian carp (Carassius auratus gibelio). In this study, the ccBAX (silver crucian carp BAX) gene was cloned and expressed, and polyclonal antibodies were raised in mouse against the purified ccBAX-GST fusion protein. The structure analysis indicated that ccBAX protein included four conserve domains (BH1, BH2, BH3 and transmembrane domains) and the expression of ccBAX protein occurred throughout the cells. Furthermore, two miRNAs (miR-124 and miRNA-29b) were identified to negatively regulate ccBAX gene expression in GiCF cell. miR-124 was found to suppress the expression of WT-ccBAX (wild type), but not the MT-ccBAX (mutant). Overall, the results demonstrated that the expression of the ccBAX gene was significantly down-regulated by miR-124 in silver crucian carp (Carassius auratus gibelio) during CyHV-2 infection.
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Affiliation(s)
- Lu Yu
- National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China
- Key Laboratory of Aquaculture Ministry for Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, China
| | - Qikang Chen
- National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China
- Key Laboratory of Aquaculture Ministry for Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, China
| | - Xin Chu
- National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China
- Key Laboratory of Aquaculture Ministry for Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, China
| | - Yang Luo
- National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China
- Key Laboratory of Aquaculture Ministry for Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, China
| | - Zizhao Feng
- National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China
- Key Laboratory of Aquaculture Ministry for Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, China
| | - Liqun Lu
- National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China
- Key Laboratory of Aquaculture Ministry for Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, China
- National Experimental Teaching Demonstration Center for Fishery Sciences, Shanghai Ocean University, Shanghai, China
| | - Ye Zhang
- National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China
- Key Laboratory of Aquaculture Ministry for Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, China
- National Experimental Teaching Demonstration Center for Fishery Sciences, Shanghai Ocean University, Shanghai, China
| | - Dan Xu
- National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China
- Key Laboratory of Aquaculture Ministry for Freshwater Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, China
- National Experimental Teaching Demonstration Center for Fishery Sciences, Shanghai Ocean University, Shanghai, China
- Guangxi Key Laboratory of Marine Natural Products and Combinatorial Biosynthesis Chemistry, Guangxi Academy of Sciences, Nanning, China
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Intrinsically Connected: Therapeutically Targeting the Cathepsin Proteases and the Bcl-2 Family of Protein Substrates as Co-regulators of Apoptosis. Int J Mol Sci 2021; 22:ijms22094669. [PMID: 33925117 PMCID: PMC8124540 DOI: 10.3390/ijms22094669] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 12/14/2022] Open
Abstract
Taken with the growing importance of cathepsin-mediated substrate proteolysis in tumor biology and progression, the focus and emphasis placed on therapeutic design and development is coming into fruition. Underpinning this approach is the invariable progression from the direction of fully characterizing cathepsin protease members and their substrate targets, towards targeting such an interaction with tangible therapeutics. The two groups of such substrates that have gained much attention over the years are the pro- and anti- apoptotic protein intermediates from the extrinsic and intrinsic signaling arms of the apoptosis pathway. As proteins that are central to determining cellular fate, some of them present themselves as very favorable candidates for therapeutic targeting. However, considering that both anti- and pro- apoptotic signaling intermediates have been reported to be downstream substrates for certain activated cathepsin proteases, therapeutic targeting approaches based on greater selectivity do need to be given greater consideration. Herein, we review the relationships shared by the cathepsin proteases and the Bcl-2 homology domain proteins, in the context of how the topical approach of adopting 'BH3-mimetics' can be explored further in modulating the relationship between the anti- and pro- apoptotic signaling intermediates from the intrinsic apoptosis pathway and their upstream cathepsin protease regulators. Based on this, we highlight important future considerations for improved therapeutic design.
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Wu G, Tu Z, Yang F, Mai Z, Chen H, Tang Q, Ye X, Wang K, Wang X, Chen T. Evaluating the inhibitory priority of Bcl-xL to Bad, tBid and Bax by using live-cell imaging assay. Cytometry A 2021; 99:1091-1101. [PMID: 33843148 DOI: 10.1002/cyto.a.24351] [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: 11/16/2020] [Revised: 03/17/2021] [Accepted: 04/07/2021] [Indexed: 01/02/2023]
Abstract
Molecular regulatory network among the B cell leukemia-2 (Bcl-2) family proteins is a research hotspot on apoptosis. The inhibitory priority of anti-apoptotic Bcl-2 family proteins (such as Bcl-xL) to pro-apoptotic Bcl-2 family proteins (such as Bad, tBid and Bax) determines the outcome of their interactions. Based on over-expression model system, we here evaluate the inhibitory priority of Bcl-xL to Bad, tBid and Bax by using live-cell imaging assay on cell viability. Fluorescence images of living cells co-expressing CFP-Bcl-xL and YFP-Bad or YFP-tBid or YFP-Bax showed that Bcl-xL markedly inhibited Bad/tBid/Bax-mediated apoptosis, revealing that Bcl-xL inhibits the proapoptotic function of Bad, tBid and Bax. In the case of equimolar co-expression of Bad and CFP-Bcl-xL, the inhibition of Bcl-xL on tBid/Bax mediate-apoptosis was completely relieved. Moreover, co-expression of tBid-P2A-CFP-Bcl-xL significantly relieved the inhibition of Bcl-xL on the pro-apoptotic ability Bax, suggesting that Bcl-xL preferentially inhibits the pro-apoptotic ability of Bad over tBid, subsequently to Bax.
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Affiliation(s)
- Ge Wu
- Key Laboratory of Laser Life Science, Ministry of Education, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China
| | - Zhuang Tu
- Key Laboratory of Laser Life Science, Ministry of Education, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China
| | - Fangfang Yang
- Key Laboratory of Laser Life Science, Ministry of Education, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China
| | - Zihao Mai
- Key Laboratory of Laser Life Science, Ministry of Education, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China
| | - Hongce Chen
- Key Laboratory of Laser Life Science, Ministry of Education, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China
| | - Qiling Tang
- Key Laboratory of Laser Life Science, Ministry of Education, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China
| | - Xianxin Ye
- Key Laboratory of Laser Life Science, Ministry of Education, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China
| | - Kunhao Wang
- Key Laboratory of Laser Life Science, Ministry of Education, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China
| | - Xiaoping Wang
- Department of Pain Management, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Tongsheng Chen
- Key Laboratory of Laser Life Science, Ministry of Education, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong, China.,SCNU Qingyuan Institute of Science and Technology Innovation Co. Ltd., South China Normal University, Qingyuan, China
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Mechanisms of mitochondrial cell death. Biochem Soc Trans 2021; 49:663-674. [PMID: 33704419 DOI: 10.1042/bst20200522] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 12/23/2022]
Abstract
Mitochondria are double-membrane bound organelles that not only provide energy for intracellular metabolism, but also play a key role in the regulation of cell death. Mitochondrial outer membrane permeabilization (MOMP), allowing the release of intermembrane space proteins like cytochrome c, is considered a point of no return in apoptosis. MOMP is controlled by the proteins of the B-cell lymphoma 2 (BCL-2) family, including pro-and anti-apoptotic members, whose balance determines the decision between cell death and survival. Other factors such as membrane lipid environment, membrane dynamics, and inter-organelle communications are also known to influence this process. MOMP and apoptosis have been acknowledged as immunologically silent. Remarkably, a growing body of evidence indicates that MOMP can engage in various pro-inflammatory signaling functions. In this mini-review, we discuss about our current knowledge on the mechanisms of mitochondrial apoptosis, as well as the involvement of mitochondria in other kinds of programmed cell death pathways.
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Held L, Siu C, Shadman M. Venetoclax as a therapeutic option for the treatment of chronic lymphocytic leukemia: the evidence so far. Expert Opin Pharmacother 2021; 22:655-665. [PMID: 33645381 DOI: 10.1080/14656566.2021.1882421] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Venetoclax, an oral, BCL-2 inhibitor, is approved by the FDA for treatment of CLL in all lines of therapy. Data from landmark studies, including the CLL14 and MURANO trials, demonstrated marked improvement in clinical outcomes compared to chemoimmunotherapy when venetoclax was used in combination with CD20 monoclonal antibodies for fixed treatment duration. AREAS COVERED This article reviews the mechanism of action of venetoclax and discusses how curtailing the BCL signaling pathway undermines CLL pathophysiology. The authors also give their clinical experience with the drug, with emphasis on assessing and managing the risk of venetoclax-associated tumor lysis syndrome (TLS). EXPERT OPINION Venetoclax has positioned itself as one of the primary treatment options for CLL, given the consistent efficacy and deep remissions it has elicited across multiple settings of the disease with a time-limited schedule. Accurate TLS risk evaluation and stringent adherence to the dose-escalation protocols will help optimize patient outcomes. Finally, we expect that current and future studies will (1) ascertain the ideal treatment duration using the minimal residual disease state as a guide and (2) help us understand the optimal role of venetoclax in combination or in sequence with other novel targeted therapies in the treatment of CLL.
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Affiliation(s)
- Lauren Held
- School of Pharmacy, University of Washington, Seattle, WA, USA.,Hematologic Malignancies, Seattle Cancer Care Alliance, Seattle, WA, USA
| | - Chloe Siu
- School of Pharmacy, University of Washington, Seattle, WA, USA.,Hematologic Malignancies, Seattle Cancer Care Alliance, Seattle, WA, USA
| | - Mazyar Shadman
- School of Pharmacy, University of Washington, Seattle, WA, USA.,Hematologic Malignancies, Seattle Cancer Care Alliance, Seattle, WA, USA.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Polygoni Multiflori Radix Preparat Delays Skin Aging by Inducing Mitophagy. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5847153. [PMID: 33511202 PMCID: PMC7822667 DOI: 10.1155/2021/5847153] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/26/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022]
Abstract
Background As the skin is the largest organ of the human body, it is aging inevitably and produces cosmetic and psychological problems, and even disease. Therefore, the molecular mechanisms related to the prevention of skin aging need to be further explored. Methods Aging models were constructed by D-galactose. Mice were administrated with polygoni multiflori radix preparat (PMRP), PMRP and 3-methyladenine, or PMRP and rapamycin intragastrically. The apparent and viscera index of aged rats was measured. Then, the physicochemical property, antioxidant ability, histological structure, mitochondrial membrane potential, ATP and ROS levels, and mitophagy of aged skins were determined. Finally, the expression of PINK1, Parkin, P62, and LC3II/I; apoptosis-related proteins; and the percentage of apoptotic cells were measured. Results PMRP relieved skin aging with reducing of thymus index, improvement of pathological damage and histological structure, increase of the expression area of fibrous tissue, the ratio of type I to type III collagen, and antioxidant ability of aged skins. Importantly, PMRP also improved mitochondrial dysfunction with an increase in the content of mitochondrial membrane potential and ATP and a decrease of ROS levels. Moreover, mitophagy was enhanced with the treatment of PMRP when observed using electron microscopy, and the expression of PINK1, Parkin, and LC3I/II was increased with PMRP treatment but P62 expression was decreased. Meanwhile, PMRP alleviated apoptosis with a decrease of apoptotic cell and the expression of Cleaved-cas3, Bax, Cyt-c, AIF, and Smac as well as an increase of Bcl-2 expression. Conclusion The results demonstrated that the polygoni multiflori radix preparata may delay skin aging by inducing mitophagy.
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Pore-forming proteins: From defense factors to endogenous executors of cell death. Chem Phys Lipids 2020; 234:105026. [PMID: 33309552 DOI: 10.1016/j.chemphyslip.2020.105026] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 12/07/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023]
Abstract
Pore-forming proteins (PFPs) and small antimicrobial peptides (AMPs) represent a large family of molecules with the common ability to punch holes in cell membranes to alter their permeability. They play a fundamental role as infectious bacteria's defensive tools against host's immune system and as executors of endogenous machineries of regulated cell death in eukaryotic cells. Despite being highly divergent in primary sequence and 3D structure, specific folds of pore-forming domains have been conserved. In fact, pore formation is considered an ancient mechanism that takes place through a general multistep process involving: membrane partitioning and insertion, oligomerization and pore formation. However, different PFPs and AMPs assemble and form pores following different mechanisms that could end up either in the formation of protein-lined or protein-lipid pores. In this review, we analyze the current findings in the mechanism of action of different PFPs and AMPs that support a wide role of membrane pore formation in nature. We also provide the newest insights into the development of state-of-art techniques that have facilitated the characterization of membrane pores. To understand the physiological role of these peptides/proteins or develop clinical applications, it is essential to uncover the molecular mechanism of how they perforate membranes.
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Shirokova OM, Pchelin PV, Mukhina IV. MERCs. The Novel Assistant to Neurotransmission? Front Neurosci 2020; 14:589319. [PMID: 33240039 PMCID: PMC7680918 DOI: 10.3389/fnins.2020.589319] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 10/19/2020] [Indexed: 12/11/2022] Open
Abstract
In neuroscience, much attention is paid to intercellular interactions, in particular, to synapses. However, many researchers do not pay due attention to the contribution of intracellular contacts to the work of intercellular interactions. Nevertheless, along with synapses, intracellular contacts also have complex organization and a tremendous number of regulatory elements. Mitochondria-endoplasmic reticulum contacts (MERCs) are a specific site of interaction between the two organelles; they provide a basis for a large number of cellular functions, such as calcium homeostasis, lipid metabolism, autophagy, and apoptosis. Despite the presence of these contacts in various parts of neurons and glial cells, it is yet not known whether they fulfill the same functions. There are still many unsolved questions about the work of these intracellular contacts, and one of the most important among them is if MERCs, with their broad implication into synaptic events, can be considered the assistant to neurotransmission?
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Affiliation(s)
- Olesya M Shirokova
- Central Scientific Research Laboratory, Institute of Fundamental Medicine, Privolzhsky Research Medical University, Nizhny Novgorod, Russia
| | - Pavel V Pchelin
- Central Scientific Research Laboratory, Institute of Fundamental Medicine, Privolzhsky Research Medical University, Nizhny Novgorod, Russia.,Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Irina V Mukhina
- Central Scientific Research Laboratory, Institute of Fundamental Medicine, Privolzhsky Research Medical University, Nizhny Novgorod, Russia.,Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
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Shan R, Liu N, Yan Y, Liu B. Apoptosis, autophagy and atherosclerosis: Relationships and the role of Hsp27. Pharmacol Res 2020; 166:105169. [PMID: 33053445 DOI: 10.1016/j.phrs.2020.105169] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/16/2020] [Accepted: 08/18/2020] [Indexed: 02/07/2023]
Abstract
Atherosclerosis is a multifactorial chronic inflammatory disease of the arterial wall, and an important pathological basis of coronary heart disease. Endothelial cells, vascular smooth muscle cells, and macrophages play important roles in the development of atherosclerosis. Of note, apoptosis and autophagy, two types of programmed cell death, influence the development and progression of atherosclerosis via the modulation of such cells. The small heat shock protein Hsp27 is a multifunctional protein induced by various stress factors and has a protective effect on cells. A large number of studies have demonstrated that Hsp27 plays an important role in regulating apoptosis. Recently, some studies have suggested that Hsp27 also participates in the autophagic process. Moreover, Hsp27 is closely related to the occurrence and development of atherosclerosis. Here, we summarize the molecular mechanisms of apoptosis and autophagy and discuss their effects on endothelial cells, vascular smooth muscle cells, and macrophages in the context of atherosclerotic procession. We further explore the involvement of Hsp27 in apoptosis, autophagy, and atherosclerosis. We speculate that Hsp27 may exert its anti-atherosclerotic role via the regulation of apoptosis and autophagy; this may provide the basis for the development of new approaches for the prevention and treatment of atherosclerosis.
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Affiliation(s)
- Ruiting Shan
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Ning Liu
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Youyou Yan
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Bin Liu
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, 130041, China.
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Abstract
Bax and Bak, two functionally similar, pro-apoptotic proteins of the Bcl-2 family, are known as the gateway to apoptosis because of their requisite roles as effectors of mitochondrial outer membrane permeabilization (MOMP), a major step during mitochondria-dependent apoptosis. The mechanism of how cells turn Bax/Bak from inert molecules into fully active and lethal effectors had long been the focal point of a major debate centered around two competing, but not mutually exclusive, models: direct activation and indirect activation. After intensive research efforts for over two decades, it is now widely accepted that to initiate apoptosis, some of the BH3-only proteins, a subclass of the Bcl-2 family, directly engage Bax/Bak to trigger their conformational transformation and activation. However, a series of recent discoveries, using previously unavailable CRISPR-engineered cell systems, challenge the basic premise that undergirds the consensus and provide evidence for a novel and surprisingly simple model of Bax/Bak activation: the membrane (lipids)-mediated spontaneous model. This review will discuss the evidence, rationale, significance, and implications of this new model.
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Affiliation(s)
- Xu Luo
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Alaska Medical Center, Omaha, ME, 68198-7696, USA.,Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA
| | - Katelyn L O'Neill
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Alaska Medical Center, Omaha, ME, 68198-7696, USA
| | - Kai Huang
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Alaska Medical Center, Omaha, ME, 68198-7696, USA.,Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA
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42
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Makarevich O, Sabirzhanov B, Aubrecht TG, Glaser EP, Polster BM, Henry RJ, Faden AI, Stoica BA. Mithramycin selectively attenuates DNA-damage-induced neuronal cell death. Cell Death Dis 2020; 11:587. [PMID: 32719328 PMCID: PMC7385624 DOI: 10.1038/s41419-020-02774-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 12/15/2022]
Abstract
DNA damage triggers cell death mechanisms contributing to neuronal loss and cognitive decline in neurological disorders, including traumatic brain injury (TBI), and as a side effect of chemotherapy. Mithramycin, which competitively targets chromatin-binding sites of specificity protein 1 (Sp1), was used to examine previously unexplored neuronal cell death regulatory mechanisms via rat primary neurons in vitro and after TBI in mice (males). In primary neurons exposed to DNA-damage-inducing chemotherapy drugs in vitro we showed that DNA breaks sequentially initiate DNA-damage responses, including phosphorylation of ATM, H2AX and tumor protein 53 (p53), transcriptional activation of pro-apoptotic BH3-only proteins, and mitochondrial outer membrane permeabilization (MOMP), activating caspase-dependent and caspase-independent intrinsic apoptosis. Mithramycin was highly neuroprotective in DNA-damage-dependent neuronal cell death, inhibiting chemotherapeutic-induced cell death cascades downstream of ATM and p53 phosphorylation/activation but upstream of p53-induced expression of pro-apoptotic molecules. Mithramycin reduced neuronal upregulation of BH3-only proteins and mitochondrial dysfunction, attenuated caspase-3/7 activation and caspase substrates' cleavage, and limited c-Jun activation. Chromatin immunoprecipitation indicated that mithramycin attenuates Sp1 binding to pro-apoptotic gene promoters without altering p53 binding suggesting it acts by removing cofactors required for p53 transactivation. In contrast, the DNA-damage-independent neuronal death models displayed caspase initiation in the absence of p53/BH3 activation and were not protected even when mithramycin reduced caspase activation. Interestingly, experimental TBI triggers a multiplicity of neuronal death mechanisms. Although markers of DNA-damage/p53-dependent intrinsic apoptosis are detected acutely in the injured cortex and are attenuated by mithramycin, these processes may play a reduced role in early neuronal death after TBI, as caspase-dependent mechanisms are repressed in mature neurons while other, mithramycin-resistant mechanisms are active. Our data suggest that Sp1 is required for p53-mediated transactivation of neuronal pro-apoptotic molecules and that mithramycin may attenuate neuronal cell death in conditions predominantly involving DNA-damage-induced p53-dependent intrinsic apoptosis.
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Affiliation(s)
- Oleg Makarevich
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Boris Sabirzhanov
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Taryn G Aubrecht
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Ethan P Glaser
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Brian M Polster
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Rebecca J Henry
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Alan I Faden
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Bogdan A Stoica
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
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43
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Han M, Chen XC, Sun MH, Gai MT, Yang YN, Gao XM, Ma X, Chen BD, Ma YT. Overexpression of IκBα in cardiomyocytes alleviates hydrogen peroxide-induced apoptosis and autophagy by inhibiting NF-κB activation. Lipids Health Dis 2020; 19:150. [PMID: 32580730 PMCID: PMC7315514 DOI: 10.1186/s12944-020-01327-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/16/2020] [Indexed: 12/27/2022] Open
Abstract
Background Inflammation and oxidative stress play predominant roles in the initiation and progression of ischaemia/reperfusion (I/R) injury, with nuclear factor kappa B (NF-κB) serving as a crucial mediator. Overexpression of the inhibitor of κB alpha (IκBα) gene is hypothesized to have protective effects against apoptosis and autophagy in cardiomyocytes subjected to hydrogen peroxide (H2O2) by inhibiting the NF-κB pathway. Methods The IκBαS32A, S36A gene was transfected via adeno-associated virus serotype 9 (AAV9) delivery into neonatal rat ventricular cardiomyocytes (NRVMs) prior to H2O2 treatment. NRVMs were divided into control, H2O2, GFP + H2O2, IκBα+H2O2, and pyrrolidine dithiocarbamate (PDTC) + H2O2 groups. Nuclear translocation of the NF-κB p65 subunit was evaluated by immunofluorescence and Western blotting. Cell viability was assessed by Cell Counting Kit-8 assay. Supernatant lactate dehydrogenase (LDH) and intracellular malondialdehyde (MDA) were measured to identify H2O2-stimulated cytotoxicity. Apoptosis was determined by Annexin V-PE/7-AAD staining, and the mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining. Western blotting was used to detect apoptosis- and autophagy-related proteins. Results IκBα transfection significantly increased cell viability and ΔΨm but decreased the supernatant LDH and cellular MDA levels in cardiomyocytes exposed to H2O2. Meanwhile, IκBα overexpression decreased H2O2-induced apoptosis by upregulating the Bcl-2/Bax ratio and reduced autophagy by downregulating the expression of Beclin-1 and the LC3-II/LC3-I ratio. These effects partly accounted for the ability of IκBα to inhibit the NF-κB signalling pathway, as evidenced by decreases in p65 phosphorylation and nuclear translocation. Indeed, the effects of inactivation of NF-κB signalling with the specific inhibitor PDTC resembled the cardioprotective effects of IκBα during H2O2 stimulation. Conclusion IκBα overexpression can ameliorate H2O2-induced apoptosis, autophagy, oxidative injury, and ΔΨm loss through inhibition of the NF-κB signalling pathway. These findings suggest that IκBα transfection can result in successful resistance to oxidative stress-induced damage by inhibiting NF-κB activation, which may provide a potential therapeutic target for the prevention of myocardial I/R injury.
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Affiliation(s)
- Min Han
- Xinjiang Key Laboratory of Cardiovascular Disease Research, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China.,Department of Cardiology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China
| | - Xiao-Cui Chen
- Xinjiang Key Laboratory of Cardiovascular Disease Research, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China
| | - Ming-Hui Sun
- Department of Nephrology, Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000, PR China
| | - Min-Tao Gai
- Xinjiang Key Laboratory of Cardiovascular Disease Research, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China
| | - Yi-Ning Yang
- Department of Cardiology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China
| | - Xiao-Ming Gao
- Xinjiang Key Laboratory of Cardiovascular Disease Research, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China
| | - Xiang Ma
- Department of Cardiology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China
| | - Bang-Dang Chen
- Xinjiang Key Laboratory of Cardiovascular Disease Research, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China.
| | - Yi-Tong Ma
- Xinjiang Key Laboratory of Cardiovascular Disease Research, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China. .,Department of Cardiology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, PR China.
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44
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Yang F, Qu W, Du M, Mai Z, Wang B, Ma Y, Wang X, Chen T. Stoichiometry and regulation network of Bcl-2 family complexes quantified by live-cell FRET assay. Cell Mol Life Sci 2020; 77:2387-2406. [PMID: 31492967 PMCID: PMC11104934 DOI: 10.1007/s00018-019-03286-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/26/2019] [Accepted: 08/23/2019] [Indexed: 01/07/2023]
Abstract
The stoichiometry and affinity of Bcl-2 family complexes are essential information for understanding how their interactome network is orchestrated to regulate mitochondrial permeabilization and apoptosis. Based on over-expression model system, FRET analysis was used to quantify the protein-protein interactions among Bax, Bcl-xL, Bad and tBid in healthy and apoptotic cells. Our data indicate that the stoichiometry and affinity of Bcl-2 complexes are dependent on their membrane environment. Bcl-xL, Bad and tBid can form hetero-trimers in mitochondria. Bcl-xL binds preferentially to Bad, then to tBid and Bax in mitochondria, whilst Bcl-xL displays higher affinity to Bad or tBid than to itself. Strikingly, Bax can bind to Bcl-xL in cytosol. In cytosol of apoptotic cells, Bcl-xL associates with Bax to form hetero-trimer with 1:2 stoichiometry, while Bcl-xL associates with Bad to form hetero-trimer with 2:1 stoichiometry and Bcl-xL associates with tBid to form hetero-dimer. In mitochondria, Bcl-xL associates with Bax/Bad to form hetero-dimer in healthy cells, while Bcl-xL associates with Bad to form hetero-tetramer with 3:1 stoichiometry in apoptotic cells.
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Affiliation(s)
- Fangfang Yang
- MOE Key Laboratory of Laser Life Science and College of Biophotonics, South China Normal University, Guangzhou, China
| | - Wenfeng Qu
- MOE Key Laboratory of Laser Life Science and College of Biophotonics, South China Normal University, Guangzhou, China
| | - Mengyan Du
- MOE Key Laboratory of Laser Life Science and College of Biophotonics, South China Normal University, Guangzhou, China
| | - Zihao Mai
- MOE Key Laboratory of Laser Life Science and College of Biophotonics, South China Normal University, Guangzhou, China
| | - Bin Wang
- MOE Key Laboratory of Laser Life Science and College of Biophotonics, South China Normal University, Guangzhou, China
| | - Yunyun Ma
- MOE Key Laboratory of Laser Life Science and College of Biophotonics, South China Normal University, Guangzhou, China
| | - Xiaoping Wang
- Department of Pain Management, The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Tongsheng Chen
- MOE Key Laboratory of Laser Life Science and College of Biophotonics, South China Normal University, Guangzhou, China.
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45
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D’Aguanno S, Del Bufalo D. Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer. Cells 2020; 9:cells9051287. [PMID: 32455818 PMCID: PMC7291206 DOI: 10.3390/cells9051287] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/18/2020] [Accepted: 05/19/2020] [Indexed: 12/30/2022] Open
Abstract
The dynamic interplay between pro-death and pro-survival Bcl-2 family proteins is responsible for a cell’s fate. Due to the recognized relevance of this family in cancer progression and response to therapy, different efforts have made in recent years in order to develop small molecules able to target anti-apoptotic proteins such as Bcl-2, Bcl-xL and Mcl-1. The limitations of the first Bcl-2 family targeted drugs, regarding on-target and off-target toxicities, have been overcome with the development of venetoclax (ABT-199), the first BH3 mimetic inhibitor approved by the FDA. The purpose of this review is to discuss the state-of-the-art in the development of drugs targeting Bcl-2 anti-apoptotic proteins and to highlight the potential of their application as single agents or in combination for improving anti-cancer therapy, focusing in particular on solid tumors.
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46
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Li Y, Ding H, Liu L, Song Y, Du X, Feng S, Wang X, Li X, Wang Z, Li X, Li J, Wu J, Liu G. Non-esterified Fatty Acid Induce Dairy Cow Hepatocytes Apoptosis via the Mitochondria-Mediated ROS-JNK/ERK Signaling Pathway. Front Cell Dev Biol 2020; 8:245. [PMID: 32411699 PMCID: PMC7198733 DOI: 10.3389/fcell.2020.00245] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 03/24/2020] [Indexed: 12/30/2022] Open
Abstract
Elevated plasma non-esterified fatty acid (NEFA) levels and hepatocytes damage are characteristics of ketosis in dairy cows. Oxidative stress is associated with the pathogenesis of NEFA-induced liver damage. However, the exact mechanism by which oxidative stress mediates NEFA-induced hepatocytes apoptosis and liver injury remains poorly understood. The results of the present study demonstrated that NEFA contribute to reactive oxygen species (ROS) generation, resulting in an imbalance between oxidative and antioxidant species, transcriptional activation of p53, transcriptional inhibition of nuclear factor E2-related factor 2 (Nrf2), loss of mitochondria membrane potential (MMP) and release of apoptosis-inducing factor (AIF) and cytochrome c (cyt c) into the cytosol, leading to hepatocytes apoptosis. Besides, NEFA triggered apoptosis in dairy cow hepatocytes via the regulation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), Bcl-2-associated X protein (Bax), B-cell lymphoma gene 2 (Bcl-2), caspase 9 and poly (ADP-ribose) polymerase (PARP). Pretreatment with the inhibitor SP600125 or PD98059 or the antioxidant N-acetylcysteine (NAC) revealed that NEFA-ROS-JNK/ERK-mediated mitochondrial signaling pathway plays a crucial role in NEFA-induced hepatocytes apoptosis. Moreover, the results suggested that the transcription factors p53 and Nrf2 function downstream of this NEFA-ROS-JNK/ERK pathway and are involved in NEFA-induced hepatocytes apoptosis. In conclusion, these findings indicate that the NEFA-ROS-JNK/ERK-mediated mitochondrial pathway plays an important role in NEFA-induced dairy cow hepatocytes apoptosis and strongly suggests that the inhibitors SP600125 and PD98059 and the antioxidant NAC may be developed as therapeutics to prevent hyperlipidemia-induced apoptotic damage in ketotic dairy cows.
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Affiliation(s)
- Yu Li
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China.,Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Hongyan Ding
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Leihong Liu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Yuxiang Song
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xiliang Du
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Shibin Feng
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Xichun Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Xiaobing Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zhe Wang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xinwei Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jinchun Li
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Jinjie Wu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Guowen Liu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
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47
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Ivanova H, Vervliet T, Monaco G, Terry LE, Rosa N, Baker MR, Parys JB, Serysheva II, Yule DI, Bultynck G. Bcl-2-Protein Family as Modulators of IP 3 Receptors and Other Organellar Ca 2+ Channels. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a035089. [PMID: 31501195 DOI: 10.1101/cshperspect.a035089] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The pro- and antiapoptotic proteins belonging to the B-cell lymphoma-2 (Bcl-2) family exert a critical control over cell-death processes by enabling or counteracting mitochondrial outer membrane permeabilization. Beyond this mitochondrial function, several Bcl-2 family members have emerged as critical modulators of intracellular Ca2+ homeostasis and dynamics, showing proapoptotic and antiapoptotic functions. Bcl-2 family proteins specifically target several intracellular Ca2+-transport systems, including organellar Ca2+ channels: inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs), Ca2+-release channels mediating Ca2+ flux from the endoplasmic reticulum, as well as voltage-dependent anion channels (VDACs), which mediate Ca2+ flux across the mitochondrial outer membrane into the mitochondria. Although the formation of protein complexes between Bcl-2 proteins and these channels has been extensively studied, a major advance during recent years has been elucidating the complex interaction of Bcl-2 proteins with IP3Rs. Distinct interaction sites for different Bcl-2 family members were identified in the primary structure of IP3Rs. The unique molecular profiles of these Bcl-2 proteins may account for their distinct functional outcomes when bound to IP3Rs. Furthermore, Bcl-2 inhibitors used in cancer therapy may affect IP3R function as part of their proapoptotic effect and/or as an adverse effect in healthy cells.
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Affiliation(s)
- Hristina Ivanova
- Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Tim Vervliet
- Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Giovanni Monaco
- Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Lara E Terry
- Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642
| | - Nicolas Rosa
- Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Mariah R Baker
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Structural Biology Imaging Center, Houston, Texas 77030
| | - Jan B Parys
- Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Irina I Serysheva
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Structural Biology Imaging Center, Houston, Texas 77030
| | - David I Yule
- Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642
| | - Geert Bultynck
- Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
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48
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Kaur P, Dhandayuthapani S, Venkatesan T, Gantor M, Rathinavelu A. Molecular mechanism of C-phycocyanin induced apoptosis in LNCaP cells. Bioorg Med Chem 2020; 28:115272. [PMID: 31883786 DOI: 10.1016/j.bmc.2019.115272] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 12/03/2019] [Accepted: 12/13/2019] [Indexed: 11/26/2022]
Abstract
The usefulness of Marine-derived products as the source of anticancer agents has been explored for many decades. The objective of our study was to investigate the molecular mechanism by which C-PC induces apoptosis in monotherapy as well as in combination treatment with a known chemotherapeutic drug named Topotecan (TPT) using prostate cancer cells (LNCaP). To determine the intracellular mechanism of action, we analyzed the gene expression profile of C-PC treated cells using human apoptosis RT2 profiler PCR array, which indicated that C-PC was able to regulate both anti- and pro-apoptotic genes significantly. Detailed analysis revealed increases in the levels of Bax, Apaf-1 (pro-apoptotic proteins) along with the activation of the key apoptotic proteases such as caspase-8, caspase-9, and caspase-3. Similarly, analysis of anti-apoptotic proteins demonstrated a decrease in the expression of Bcl-2, Mcl-1, and survivin. Results from the whole-cell incubation studies indicated that C-PC was only binding to the plasma membrane-associated receptor proteins. LNCaP cells treated with C-PC alone and in combination with TPT showed increased expression of the death receptor FAS (also known as FAS or CD95) along with cleaved PARP, confirming its importance. Our study is significant since it is providing greater insight into the apoptotic mechanisms triggered by C-PC as well as emphasizing the involvement of FAS in mediating its effects. Furthermore, our results with combination treatments suggest that-PC could improve the anticancer effects of drugs such as TPT that are currently used for cancer treatments. In addition, use of C-PC in combination can also diminish the side effects resulting from conventional chemotherapeutic agents such as TPT.
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Affiliation(s)
- Paramjot Kaur
- Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Sivanesan Dhandayuthapani
- Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Thiagarajan Venkatesan
- Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Miroslav Gantor
- Department of Biological Sciences, Florida International University, Miami, FL, USA
| | - Appu Rathinavelu
- Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, USA; College of Pharmacy, Health Professions Division, Nova Southeastern University, Fort Lauderdale, FL, USA.
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49
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Yu Z, Xiao Z, Shuai X, Tian J. Local delivery of sunitinib and Ce6 via redox-responsive zwitterionic hydrogels effectively prevents osteosarcoma recurrence. J Mater Chem B 2020; 8:6418-6428. [PMID: 32578660 DOI: 10.1039/d0tb00970a] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The local delivery of sunitinib and Ce6 via redox-responsive zwitterionic hydrogels effectively induces apoptosis and prevents osteosarcoma recurrence.
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Affiliation(s)
- Zhaolong Yu
- Department of Orthopaedics, Shanghai General Hospital
- Shanghai Jiao Tong University School of Medicine
- Shanghai 201620
- China
| | - Zecong Xiao
- PCFM Lab of Ministry of Education
- School of Materials Science and Engineering
- Sun Yat-sen University
- Guangzhou 510275
- China
| | - Xintao Shuai
- PCFM Lab of Ministry of Education
- School of Materials Science and Engineering
- Sun Yat-sen University
- Guangzhou 510275
- China
| | - Jiwei Tian
- Department of Orthopaedics, Shanghai General Hospital
- Shanghai Jiao Tong University School of Medicine
- Shanghai 201620
- China
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50
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Hong Z, Zheng C, Luo B, You X, Bian H, Liang H, Chen Z, Huang F. Two groups of copper II pyridine–triazole complexes with “open or close” pepper rings and their in vitro antitumor activities. RSC Adv 2020; 10:6297-6305. [PMID: 35496028 PMCID: PMC9049676 DOI: 10.1039/c9ra10677d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 01/24/2020] [Indexed: 12/15/2022] Open
Abstract
Based on 1,2-dimethoxyphenyl (veratrole, open) and 1,2-methylenedioxyphenyl (pepper ring, close)-derived pyridine–triazole analogues, two groups of copper(ii) complexes, namely, Group I(C1–C3) and Group II(C4–C6) were synthesized and fully characterized. All ligands and complexes were tested in vitro by MTT assays on seven tumour cell lines (T24, Hep-G2, Sk-Ov-3, MGC-803, HeLa, A549 and NCI-H460) and one normal liver cell line (HL-7702). Surprisingly, the pepper-ring-derived complexes (C4–C6) showed significantly enhanced cytotoxicity compared with the 1,2-bimethoxyphenyl ring-derived complexes (C1–C3) and the standard anticancer drug cisplatin. Cellular uptake assays indicated that the Cu accumulation was consistent with cytotoxicity. In addition, flow cytometry and western blot analysis showed that the apoptosis of the leading complex C4 may be induced by the Bcl-2 family-mediated proteins through the mitochondrial dysfunction pathway. Furthermore, UV-vis and fluorescence spectroscopy assays revealed that C4 has stronger insertion-binding interactions with CT-DNA than C1 and the fluorescence of C1 and C4 with BSA is mainly quenched by static quenching. The pepper ring-modified complexes (Group II, C4–C6) exhibited significant antitumor activity than veratrole-modified complexes (Group I, C1–C3) towards several cancer cells with IC50 ranging from 3.45 to 8.59 μM.![]()
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Affiliation(s)
- ZhaoGuo Hong
- State Key State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources
- School of Chemistry & Pharmacy
- Guangxi Normal University
- Guilin 541004
- PR China
| | - Chu Zheng
- State Key State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources
- School of Chemistry & Pharmacy
- Guangxi Normal University
- Guilin 541004
- PR China
| | - Bi Luo
- State Key State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources
- School of Chemistry & Pharmacy
- Guangxi Normal University
- Guilin 541004
- PR China
| | - Xin You
- State Key State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources
- School of Chemistry & Pharmacy
- Guangxi Normal University
- Guilin 541004
- PR China
| | - HeDong Bian
- School of Chemistry and Chemical Engineering
- Guangxi University for Nationalities
- Key Laboratory of Chemistry and Engineering of Forest Products
- Nanning 530008
- PR China
| | - Hong Liang
- State Key State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources
- School of Chemistry & Pharmacy
- Guangxi Normal University
- Guilin 541004
- PR China
| | - ZhenFeng Chen
- State Key State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources
- School of Chemistry & Pharmacy
- Guangxi Normal University
- Guilin 541004
- PR China
| | - FuPing Huang
- State Key State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources
- School of Chemistry & Pharmacy
- Guangxi Normal University
- Guilin 541004
- PR China
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