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Gu A, Zhang Y, He J, Zhao M, Ding L, Liu W, Xiao J, Huang J, Liu M, Liu X. Chronic Oxidative Stress and Stress Granule Formation in UBQLN2 ALS Neurons: Insights into Neuronal Degeneration and Potential Therapeutic Targets. Int J Mol Sci 2024; 25:13448. [PMID: 39769213 PMCID: PMC11678478 DOI: 10.3390/ijms252413448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/26/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
The pathogenesis of neurodegenerative diseases results from the interplay between genetic and environmental factors. Aging and chronic oxidative stress are critical contributors to neurodegeneration. UBQLN2, a ubiquitin-related protein, aids in protein degradation and protects against oxidative stress. In ALS neurons harboring UBQLN2 mutations, oxidative stress accelerates pathological changes, yet the precise mechanisms remain unclear. Using induced motor neurons (iMNs) derived from UBQLN2 P497H iPSCs, we observed ALS-like phenotypes, including TDP-43 mislocalization, increased cell death, and reduced viability. Sodium arsenite (SA)-induced oxidative stress triggered stress granule formation, while autophagy dysfunction exacerbated neuronal degeneration. CHX and bosutinib treatments reduced ubiquitinated protein accumulation and alleviated degeneration, highlighting potential therapeutic pathways. These findings emphasize the role of chronic oxidative stress and stress granule formation in UBQLN2 ALS, offering insights into novel therapeutic targets.
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Affiliation(s)
- Ao Gu
- MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China; (A.G.); (Y.Z.); (J.H.); (M.Z.)
| | - Yiti Zhang
- MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China; (A.G.); (Y.Z.); (J.H.); (M.Z.)
| | - Jianfeng He
- MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China; (A.G.); (Y.Z.); (J.H.); (M.Z.)
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410017, China
| | - Mingri Zhao
- MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China; (A.G.); (Y.Z.); (J.H.); (M.Z.)
| | - Lingjie Ding
- MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China; (A.G.); (Y.Z.); (J.H.); (M.Z.)
| | - Wanxi Liu
- MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China; (A.G.); (Y.Z.); (J.H.); (M.Z.)
| | - Jianing Xiao
- MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China; (A.G.); (Y.Z.); (J.H.); (M.Z.)
| | - Jiali Huang
- MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China; (A.G.); (Y.Z.); (J.H.); (M.Z.)
| | - Mujun Liu
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410017, China
- Hunan Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410017, China
| | - Xionghao Liu
- MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China; (A.G.); (Y.Z.); (J.H.); (M.Z.)
- Hunan Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410017, China
- Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha 410017, China
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Grootaert MOJ. Cell senescence in cardiometabolic diseases. NPJ AGING 2024; 10:46. [PMID: 39433786 PMCID: PMC11493982 DOI: 10.1038/s41514-024-00170-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 09/05/2024] [Indexed: 10/23/2024]
Abstract
Cellular senescence has been implicated in many age-related pathologies including atherosclerosis, heart failure, age-related cardiac remodeling, diabetic cardiomyopathy and the metabolic syndrome. Here, we will review the characteristics of senescent cells and their endogenous regulators, and summarize the metabolic stressors that induce cell senescence. We will discuss the evidence of cell senescence in the onset and progression of several cardiometabolic diseases and the therapeutic potential of anti-senescence therapies.
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Affiliation(s)
- Mandy O J Grootaert
- Endocrinology, Diabetes and Nutrition, UCLouvain, Brussels, Belgium.
- Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
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Cai Y, Han Z, Cheng H, Li H, Wang K, Chen J, Liu ZX, Xie Y, Lin Y, Zhou S, Wang S, Zhou X, Jin S. The impact of ageing mechanisms on musculoskeletal system diseases in the elderly. Front Immunol 2024; 15:1405621. [PMID: 38774874 PMCID: PMC11106385 DOI: 10.3389/fimmu.2024.1405621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 04/22/2024] [Indexed: 05/24/2024] Open
Abstract
Ageing is an inevitable process that affects various tissues and organs of the human body, leading to a series of physiological and pathological changes. Mechanisms such as telomere depletion, stem cell depletion, macrophage dysfunction, and cellular senescence gradually manifest in the body, significantly increasing the incidence of diseases in elderly individuals. These mechanisms interact with each other, profoundly impacting the quality of life of older adults. As the ageing population continues to grow, the burden on the public health system is expected to intensify. Globally, the prevalence of musculoskeletal system diseases in elderly individuals is increasing, resulting in reduced limb mobility and prolonged suffering. This review aims to elucidate the mechanisms of ageing and their interplay while exploring their impact on diseases such as osteoarthritis, osteoporosis, and sarcopenia. By delving into the mechanisms of ageing, further research can be conducted to prevent and mitigate its effects, with the ultimate goal of alleviating the suffering of elderly patients in the future.
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Affiliation(s)
- Yijin Cai
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhongyu Han
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hong Cheng
- School of Automation Engineering, University of Electronic Science and Technology, Chengdu, China
| | - Hongpeng Li
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ke Wang
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia Chen
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhi-Xiang Liu
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yulong Xie
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yumeng Lin
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shuwei Zhou
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Siyu Wang
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Xiao Zhou
- Second Clinical Medical College, Heilongjiang University of Chinese Medicine, Heilongjiang, China
| | - Song Jin
- Department of Rehabilitation, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Parvaresh H, Paczek K, Al-Bari MAA, Eid N. Mechanistic insights into fasting-induced autophagy in the aging heart. World J Cardiol 2024; 16:109-117. [PMID: 38576517 PMCID: PMC10989221 DOI: 10.4330/wjc.v16.i3.109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/01/2024] [Accepted: 03/04/2024] [Indexed: 03/21/2024] Open
Abstract
Autophagy is a prosurvival mechanism for the clearance of accumulated abnormal proteins, damaged organelles, and excessive lipids within mammalian cells. A growing body of data indicates that autophagy is reduced in aging cells. This reduction leads to various diseases, such as myocardial hypertrophy, infarction, and atherosclerosis. Recent studies in animal models of an aging heart showed that fasting-induced autophagy improved cardiac function and longevity. This improvement is related to autophagic clearance of damaged cellular components via either bulk or selective autophagy (such as mitophagy). In this editorial, we summarize the mechanisms of autophagy in normal and aging hearts. In addition, the protective effect of fasting-induced autophagy in cardiac aging has been highlighted.
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Affiliation(s)
- Hannaneh Parvaresh
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
| | - Katarzyna Paczek
- Department of Chiropractic, International Medical University, Kuala Lumpur 57000, Malaysia
| | | | - Nabil Eid
- Department of Anatomy, Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia.
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Chen A, Li J, Shen N, Huang H, Hang Q. Vitamin K: New insights related to senescence and cancer metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189057. [PMID: 38158025 DOI: 10.1016/j.bbcan.2023.189057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/04/2023] [Accepted: 12/13/2023] [Indexed: 01/03/2024]
Abstract
Several clinical trials and experimental studies have recently shown that vitamin K (VK) supplementation benefits the human body. Specifically, VK participates in coagulation and is associated with cellular senescence and cancer. VK has a potential anticancer effect in various cancers, such as pancreatic and prostate cancers. Through anti-inflammatory and antioxidant effects, VK can prevent senescence and inhibit cancer metastasis. Therefore, cancer prognosis can be improved by preventing cellular senescence. In addition, VK can inhibit the proliferation, growth, and differentiation of cancer cells through various mechanisms, including induction of c-myc and c-fos genes, regulation of B-cell lymphoma-2 (Bcl-2) and p21 genes, and angiogenesis inhibition. This review aims to discuss the relationship among VK, cellular senescence, and cancer metastasis and thus may improve comprehension of the specific functions of VK in human health. The potential application of VK as an adjuvant therapy for cancer (or in combination with traditional chemotherapy drugs or other vitamins) has also been highlighted.
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Affiliation(s)
- Anqi Chen
- Medical College, Yangzhou University, Yangzhou 225001, China
| | - Jialu Li
- Medical College, Yangzhou University, Yangzhou 225001, China
| | - Nianxuan Shen
- Medical College, Yangzhou University, Yangzhou 225001, China
| | - Haifeng Huang
- Department of Laboratory Medicine, The First People's Hospital of Yancheng, Yancheng 224006, China; Department of Laboratory Medicine, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng 224006, China.
| | - Qinglei Hang
- Department of Laboratory Medicine, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225001, China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou 225001, China.
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Rasouli M, Fattahi R, Nuoroozi G, Zarei-Behjani Z, Yaghoobi M, Hajmohammadi Z, Hosseinzadeh S. The role of oxygen tension in cell fate and regenerative medicine: implications of hypoxia/hyperoxia and free radicals. Cell Tissue Bank 2024; 25:195-215. [PMID: 37365484 DOI: 10.1007/s10561-023-10099-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 06/18/2023] [Indexed: 06/28/2023]
Abstract
Oxygen pressure plays an integral role in regulating various aspects of cellular biology. Cell metabolism, proliferation, morphology, senescence, metastasis, and angiogenesis are some instances that are affected by different tensions of oxygen. Hyperoxia or high oxygen concentration, enforces the production of reactive oxygen species (ROS) that disturbs physiological homeostasis, and consequently, in the absence of antioxidants, cells and tissues are directed to an undesired fate. On the other side, hypoxia or low oxygen concentration, impacts cell metabolism and fate strongly through inducing changes in the expression level of specific genes. Thus, understanding the precise mechanism and the extent of the implication of oxygen tension and ROS in biological events is crucial to maintaining the desired cell and tissue function for application in regenerative medicine strategies. Herein, a comprehensive literature review has been performed to find out the impacts of oxygen tensions on the various behaviors of cells or tissues.
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Affiliation(s)
- Mehdi Rasouli
- Student Research Committee, Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roya Fattahi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Ghader Nuoroozi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Zeinab Zarei-Behjani
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maliheh Yaghoobi
- Engineering Department, Faculty of Chemical Engineering, Zanjan University, Zanjan, Iran
| | - Zeinab Hajmohammadi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran.
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Zhang J, Yu H, Man M, Hu L. Aging in the dermis: Fibroblast senescence and its significance. Aging Cell 2024; 23:e14054. [PMID: 38040661 PMCID: PMC10861215 DOI: 10.1111/acel.14054] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 10/29/2023] [Accepted: 11/15/2023] [Indexed: 12/03/2023] Open
Abstract
Skin aging is characterized by changes in its structural, cellular, and molecular components in both the epidermis and dermis. Dermal aging is distinguished by reduced dermal thickness, increased wrinkles, and a sagging appearance. Due to intrinsic or extrinsic factors, accumulation of excessive reactive oxygen species (ROS) triggers a series of aging events, including imbalanced extracellular matrix (ECM) homeostasis, accumulation of senescent fibroblasts, loss of cell identity, and chronic inflammation mediated by senescence-associated secretory phenotype (SASP). These events are regulated by signaling pathways, such as nuclear factor erythroid 2-related factor 2 (Nrf2), mechanistic target of rapamycin (mTOR), transforming growth factor beta (TGF-β), and insulin-like growth factor 1 (IGF-1). Senescent fibroblasts can induce and accelerate age-related dysfunction of other skin cells and may even cause systemic inflammation. In this review, we summarize the role of dermal fibroblasts in cutaneous aging and inflammation. Moreover, the underlying mechanisms by which dermal fibroblasts influence cutaneous aging and inflammation are also discussed.
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Affiliation(s)
- Jing Zhang
- Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)Tianjin Medical UniversityTianjinChina
| | - Haoyue Yu
- Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)Tianjin Medical UniversityTianjinChina
| | - Mao‐Qiang Man
- Dermatology HospitalSouthern Medical UniversityGuangdongChina
- Department of DermatologyUniversity of California San Francisco and Veterans Affairs Medical CenterSan FranciscoCaliforniaUSA
| | - Lizhi Hu
- Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)Tianjin Medical UniversityTianjinChina
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8
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Apparoo Y, Wei Phan C, Rani Kuppusamy U, Chan EWC. Potential role of ergothioneine rich mushroom as anti-aging candidate through elimination of neuronal senescent cells. Brain Res 2024; 1824:148693. [PMID: 38036238 DOI: 10.1016/j.brainres.2023.148693] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 12/02/2023]
Abstract
Oxidative stress can upset the antioxidant balance and cause accelerated aging including neurodegenerative diseases and decline in physiological function. Therefore, an antioxidant-rich diet plays a crucial role in healthy aging. This study aimed to identify and quantify mushrooms with the highest ergothioneine content through HPLC analysis and evaluate their anti-aging potential as a natural antioxidant and antisenescence in HT22 cells. Among the 14 evaluated mushroom species, Lentinula edodes (LE), shiitake mushroom contains the highest ergothioneine content and hence was used for the in-vitro studies. The cells were preincubated with ethanolic extract of ergothioneine-rich mushroom and the equimolar concentration of EGT on t-BHP-induced senescence HT22 cells. The extract was analyzed for its free radical scavenging properties using DPPH and ABTS methods. Then, the neuroprotective effect was conducted by measuring the cell viability using MTT. Senescence-associated markers and ROS staining were also analyzed. Our results revealed that a low dose of t-BHP reduces cell viability and induces senescence in HT22 cells as determined through β-galactosidase staining and expressions of P16INK4a, P21CIPL which are the markers of cellular senescence. However, the pretreatment with ethanolic extract of LE for 8 h significantly improved the cell viability, reversed the t-BHP-induced cellular senescence in the neuronal cells, and reduced the reactive oxygen species visualized through DCFH-DA staining. These results suggest that ergothioneine-rich mushroom is a potential candidate for anti-aging exploration through the elimination of senescent cells.
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Affiliation(s)
- Yasaaswini Apparoo
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya 50603, Kuala Lumpur, Malaysia
| | - Chia Wei Phan
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya 50603, Kuala Lumpur, Malaysia; Mushroom Research Centre, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Umah Rani Kuppusamy
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Eric Wei Chiang Chan
- Department of Food Science and Nutrition, Faculty of Applied Sciences, UCSI University, 56000 Kuala Lumpur, Malaysia
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Conceição-Santos AL, Ferreira ACA, Sá NAR, Palomino GJQ, Silva AFB, Oliveira AC, Velarde JMDS, Celestino JJH, Rodrigues APR, Figueiredo JR. Anethole supplementation during in vitro maturation increases in vitro goat embryo production in a concentration-dependent manner. Theriogenology 2024; 215:78-85. [PMID: 38016304 DOI: 10.1016/j.theriogenology.2023.11.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 11/17/2023] [Accepted: 11/17/2023] [Indexed: 11/30/2023]
Abstract
During in vitro maturation (IVM) cumulus-oocyte complexes (COCs) are exposed to conditions that can trigger oxidative stress, thus, reducing oocyte maturation and viability. Aiming to mitigate these detrimental conditions, the effects of IVM medium supplementation with anethole have been tested. Anethole, also known as trans-anethole (1-methoxy-4 [1-propenyl]-benzene), is a naturally occurring phenylpropanoid with various pharmacological properties, including antioxidant effects. However, no study has examined anethole effect on goat COCs during IVM. Thus, the aim of this study was to evaluate the effects of different anethole concentrations on oocyte maturation, oxidative stress, and in vitro development of caprine embryos after parthenogenetic activation. Goat COCs were selected and randomly distributed into the following treatments: TCM-199+ medium (control), or TCM-199+ medium supplemented with 30 μg/mL (AN30); 300 μg/mL (AN300) or 2000 μg/mL (AN2000) of anethole. After IVM, part of the COCs was chosen for oocyte viability and chromatin configuration, intracellular reactive oxygen species levels, and mitochondrial membrane potential assessment. Another part of COCs was parthenogenetically activated, and presumptive zygotes were cultured for 7 days. Results demonstrated that anethole at 30 μg/mL increased oocyte maturation and cleavage rates when compared to the other treatments (P < 0.05), as well as oocyte viability and in vitro embryo production when compared to the control treatment (P < 0.05). Additionally, treatment with anethole at 2000 μg/mL decreased oocyte nuclear maturation and cleavage rates when compared to other treatments (P < 0.05) and embryo production if compared to control and AN30 treatments (P < 0.05). Moreover, anethole at 2000 μg/mL increased mitochondrial membrane potential when compared to the other treatments (P < 0.05). In conclusion, anethole exerts a concentration-dependent effect during goat COCs IVM. For a more desirable outcome of oocyte viability and maturation, and in vitro embryo production, the use of anethole at 30 μg/mL is recommended.
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Affiliation(s)
- A L Conceição-Santos
- Laboratory of Manipulation of Oocytes and Preantral Follicles, Faculty of Veterinary, State University of Ceará, Fortaleza, CE, Brazil
| | - A C A Ferreira
- Laboratory of Manipulation of Oocytes and Preantral Follicles, Faculty of Veterinary, State University of Ceará, Fortaleza, CE, Brazil
| | - N A R Sá
- Laboratory of Manipulation of Oocytes and Preantral Follicles, Faculty of Veterinary, State University of Ceará, Fortaleza, CE, Brazil
| | - G J Q Palomino
- Laboratory of Manipulation of Oocytes and Preantral Follicles, Faculty of Veterinary, State University of Ceará, Fortaleza, CE, Brazil
| | - A F B Silva
- Laboratory of Manipulation of Oocytes and Preantral Follicles, Faculty of Veterinary, State University of Ceará, Fortaleza, CE, Brazil
| | - A C Oliveira
- Superior Institute of Biomedical Science, State University of Ceará, Fortaleza, CE, Brazil
| | - J M D S Velarde
- Department of Animal Science, Center of Agrarian Sciences, Federal University of Sergipe, São Cristóvão, SE, Brazil
| | - J J H Celestino
- Institute of Health Sciences, University of International Integration of Afro-Brazilian Lusophony, Redenção, CE, Brazil
| | - A P R Rodrigues
- Laboratory of Manipulation of Oocytes and Preantral Follicles, Faculty of Veterinary, State University of Ceará, Fortaleza, CE, Brazil
| | - J R Figueiredo
- Laboratory of Manipulation of Oocytes and Preantral Follicles, Faculty of Veterinary, State University of Ceará, Fortaleza, CE, Brazil.
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10
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Lee SK, Han MS, Tung CH. In vivo senescence imaging nanoprobe targets the associated reactive oxygen species. NANOSCALE 2024; 16:1371-1383. [PMID: 38131616 DOI: 10.1039/d3nr04083f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
Cellular senescence, a cell-cycle arrest state upon stress or damage, can adversely impact aging and cancers. We have designed a novel near infrared fluorogenic nanoprobe, named D3, which can only be turned on by highly elevated levels of reactive oxygen species (ROS), critical players for the induction and maintenance of senescence, for real-time senescence sensing and imaging. In contrast to glowing senescent cells, non-senescent cells whose ROS levels are too low to activate the D3 signal remain optically silent. Upon systemic injection into senescent tumor-bearing mice, the D3 nanoprobe quickly accumulates in tumors, and its fluorescence signal is turned on specifically by senescence-associated ROS in the senescent tumors. The fluorescence signal at senescent tumors was 3-fold higher than that of non-senescent tumors. This groundbreaking design introduces a novel activation mechanism and a powerful imaging nanoprobe to identify and assess cellular senescence in living organisms.
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Affiliation(s)
- Seung Koo Lee
- Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, 413 East 69th Street, Box 290, New York, NY 10021, USA.
| | - Myung Shin Han
- Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, 413 East 69th Street, Box 290, New York, NY 10021, USA.
| | - Ching-Hsuan Tung
- Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, 413 East 69th Street, Box 290, New York, NY 10021, USA.
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Heo JW, Lee HE, Lee J, Choi LS, Shin J, Mun JY, Park HS, Park SC, Nam CH. Vutiglabridin Alleviates Cellular Senescence with Metabolic Regulation and Circadian Clock in Human Dermal Fibroblasts. Antioxidants (Basel) 2024; 13:109. [PMID: 38247533 PMCID: PMC10812742 DOI: 10.3390/antiox13010109] [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: 12/12/2023] [Revised: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 01/23/2024] Open
Abstract
The process of cellular senescence, which is characterized by stable cell cycle arrest, is strongly associated with dysfunctional cellular metabolism and circadian rhythmicity, both of which are reported to result from and also be causal to cellular senescence. As a result, modifying any of them-senescence, metabolism, or the circadian clock-may affect all three simultaneously. Obesity accelerates aging by disrupting the homeostasis of reactive oxygen species (ROS) via an increased mitochondrial burden of fatty acid oxidation. As a result, if senescence, metabolism, and circadian rhythm are all linked, anti-obesity treatments may improve metabolic regulation while also alleviating senescence and circadian rhythm. Vutiglabridin is a small molecule in clinical trials that improves obesity by enhancing mitochondrial function. We found that chronic treatment of senescent primary human dermal fibroblasts (HDFs) with vutiglabridin alleviates all investigated markers of cellular senescence (SA-β-gal, CDKN1A, CDKN2A) and dysfunctional cellular circadian rhythm (BMAL1) while remarkably preventing the alterations of mitochondrial function and structure that occur during the process of cellular senescence. Our results demonstrate the significant senescence-alleviating effects of vutiglabridin, specifically with the restoration of cellular circadian rhythmicity and metabolic regulation. These data support the potential development of vutiglabridin against aging-associated diseases and corroborate the intricate link between cellular senescence, metabolism, and the circadian clock.
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Affiliation(s)
- Jin-Woong Heo
- School of Undergraduate Studies, Daegu Gyeongbuk Institute of Science and Technology, College of Transdisciplinary Studies, Daegu 42988, Republic of Korea; (J.-W.H.); (J.L.)
- Aging and Immunity Laboratory, Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea
| | - Hye-Eun Lee
- School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea;
- Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea;
| | - Jimin Lee
- School of Undergraduate Studies, Daegu Gyeongbuk Institute of Science and Technology, College of Transdisciplinary Studies, Daegu 42988, Republic of Korea; (J.-W.H.); (J.L.)
| | - Leo Sungwong Choi
- Glaceum Incorporation, Research Department, Suwon 16675, Republic of Korea; (L.S.C.); (J.S.); (H.-S.P.)
| | - Jaejin Shin
- Glaceum Incorporation, Research Department, Suwon 16675, Republic of Korea; (L.S.C.); (J.S.); (H.-S.P.)
| | - Ji-Young Mun
- Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea;
| | - Hyung-Soon Park
- Glaceum Incorporation, Research Department, Suwon 16675, Republic of Korea; (L.S.C.); (J.S.); (H.-S.P.)
| | - Sang-Chul Park
- Future Life and Society Research Center, Advanced Institute of Aging Science, Chonnam National University, Gwangju 61186, Republic of Korea;
| | - Chang-Hoon Nam
- Aging and Immunity Laboratory, Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea
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12
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Kapoor N, Bhattacharjee A, Chakraborty S, Katti DS. Piperlongumine mediates amelioration of osteoarthritis via inhibition of chondrocyte senescence and inflammation in a goat ex vivo model. Eur J Pharmacol 2023; 961:176136. [PMID: 37944845 DOI: 10.1016/j.ejphar.2023.176136] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 10/06/2023] [Accepted: 10/18/2023] [Indexed: 11/12/2023]
Abstract
In osteoarthritis (OA), chondrocytes manifest senescence, which results in a vicious signaling loop that aids the progression of the disease. More specifically, inflammation-associated senescence is one of the major regulators of the initiation and progression of OA. Therefore, we targeted senescence through inflammation with a pharmacological approach for OA amelioration. In this study, we first confirmed the suitability of the IL1β-induced goat ex vivo OA model (emphasizing 3R's principle) for the screening of senotherapeutics, namely, ABT-263, ABT-737, and Piperlongumine (PL), wherein PL showed a positive outcome in the preliminary studies. Thereafter, we determined the cytocompatible concentrations of PL using live/dead staining. Further, treatment of ex vivo OA cartilage with PL exhibited a concentration-dependent increase in the retention of key cartilage matrix components. We then examined the effect of PL on chondrocyte senescence and observed a decreased expression of major senescence markers in the PL-treated groups. Interestingly, PL treatment reduced the expression of major downstream effectors of the chondrocyte senescence pathway in a concentration-dependent manner at both gene and protein levels. Moreover, IL1β-induced elevated levels of oxidative stress and DNA damage in cartilage explants were rescued by all the tested concentrations of PL. In addition, PL also reduced the expression of major inflammatory markers of OA in the goat ex vivo OA model. Finally, we proposed a model for the mechanism of action of PL in the treatment of OA. Overall, PL showed a promising outcome as a senotherapeutic for the amelioration of OA in the goat ex vivo OA model.
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Affiliation(s)
- Nindiya Kapoor
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India; The Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India
| | - Arijit Bhattacharjee
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India; The Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India
| | - Saptomee Chakraborty
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India; The Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India
| | - Dhirendra S Katti
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India; The Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India.
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13
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Wang S, Heng K, Song X, Zhai J, Zhang H, Geng Q. Lycopene Improves Bone Quality in SAMP6 Mice by Inhibiting Oxidative Stress, Cellular Senescence, and the SASP. Mol Nutr Food Res 2023; 67:e2300330. [PMID: 37880898 DOI: 10.1002/mnfr.202300330] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 09/17/2023] [Indexed: 10/27/2023]
Abstract
SCOPE Cellular senescence (CS) is closely related to tissue ageing including bone ageing. CS and the senescence-associated secretory phenotype (SASP) have emerged as critical pathogenesis elements of senile osteoporosis. This study aims to investigate the effect of lycopene on senile osteoporosis. METHODS AND RESULTS The senescence-accelerated mouse prone 6 (SAMP6) strain of mice is used as the senile osteoporosis model. Daily ingestion of lycopene for 8 weeks preserves the bone mass, density, strength, and microarchitecture in the SAMP6 mice. Moreover, these alterations are associated with a decrease in oxidative stress in the senile osteoporosis model. In addition, there is a reduction in osteoblast and osteocyte senescence and the SASP in the bone tissues of the SAMP6 mice. Lycopene improves bone health likely due to its antioxidant properties that may be linked with the regulation of CS and SASP in the SAMP6 mice. CONCLUSION These results suggest that lycopene may be beneficial for the management of senile osteoporosis by inhibiting oxidative stress, CS, and the SASP.
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Affiliation(s)
- Shen Wang
- Key Laboratory of Clinical Research of Osteoporosis, Xuzhou Medical University, Xuzhou, 221300, China
- Central Lab, Pizhou Hospital, Xuzhou Medical University, Xuzhou, 221300, China
- Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing, 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education, Beijing, 100044, China
- National Center for Trauma Medicine, Beijing, 100044, China
| | - Ke Heng
- Department of Orthopedics, Changzhou Second Hospital, Nanjing Medical University, Changzhou, 213000, China
| | - Xingchen Song
- Key Laboratory of Clinical Research of Osteoporosis, Xuzhou Medical University, Xuzhou, 221300, China
- Central Lab, Pizhou Hospital, Xuzhou Medical University, Xuzhou, 221300, China
| | - Juan Zhai
- Key Laboratory of Clinical Research of Osteoporosis, Xuzhou Medical University, Xuzhou, 221300, China
- Central Lab, Pizhou Hospital, Xuzhou Medical University, Xuzhou, 221300, China
| | - Huanyu Zhang
- Key Laboratory of Clinical Research of Osteoporosis, Xuzhou Medical University, Xuzhou, 221300, China
- Central Lab, Pizhou Hospital, Xuzhou Medical University, Xuzhou, 221300, China
| | - Qinghe Geng
- Key Laboratory of Clinical Research of Osteoporosis, Xuzhou Medical University, Xuzhou, 221300, China
- Central Lab, Pizhou Hospital, Xuzhou Medical University, Xuzhou, 221300, China
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14
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He H, Zeng B, Wu X, Hou J, Wang Y, Wang Y, Lin Y, Wu P, Zheng C, Yin H, Wang N. Higher matrix stiffness promotes VSMC senescence by affecting mitochondria-ER contact sites and mitochondria/ER dysfunction. FASEB J 2023; 37:e23318. [PMID: 37997545 DOI: 10.1096/fj.202301198rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 10/17/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023]
Abstract
Abdominal aortic aneurysm (AAA) is a prevalent condition characterized by the weakening and bulging of the abdominal aorta. This study aimed to investigate the impact of a stiff matrix on vascular smooth muscle cells (VSMCs) in AAA development. Bioinformatics analysis revealed that differentially expressed genes (DEGs) in VSMCs of an AAA mouse model were enriched in cellular senescence and related pathways. To simulate aging-related changes, VSMCs were cultured on stiff matrices, and compared to those on soft matrices, the VSMCs cultured on stiff matrices exhibited cellular senescence. Furthermore, the mutual distance between mitochondria and endoplasmic reticulum (ER) in VSMCs was increased, indicating altered mitochondria-endoplasmic reticulum contacts (MERCs). The observed upregulation of reactive oxygen species (ROS) levels, antioxidant gene expression, and decreased mitochondrial membrane potential suggested the presence of mitochondrial dysfunction in VSMCs cultured on a stiff matrix. Additionally, the induction of ER stress-related genes indicated ER dysfunction. These findings collectively indicated impaired functionality of both mitochondria and ER in VSMCs cultured on a stiff matrix. Moreover, our data revealed that high lipid levels exacerbated the effects of high matrix stiffness on VSMCs senescence, MERC sites, and mitochondria/ER dysfunction. Importantly, treatment with the antilipemic agent CI-981 effectively reversed these detrimental effects. These findings provide insights into the role of matrix stiffness, mitochondrial dysfunction, ER stress, and lipid metabolism in AAA development, suggesting potential therapeutic targets for intervention.
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Affiliation(s)
- Haipeng He
- Department of Vascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Baozhu Zeng
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xinxiang Wu
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jianfeng Hou
- Department of Joint and Trauma Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yannan Wang
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-Sen University, Shenzhen, China
| | - Yanheng Wang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Yuqing Lin
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-Sen University, Shenzhen, China
| | - Peng Wu
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-Sen University, Shenzhen, China
| | - Changyu Zheng
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-Sen University, Shenzhen, China
| | - Henghui Yin
- Department of Vascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Nan Wang
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-Sen University, Shenzhen, China
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15
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Mas-Bargues C. Mitochondria pleiotropism in stem cell senescence: Mechanisms and therapeutic approaches. Free Radic Biol Med 2023; 208:657-671. [PMID: 37739140 DOI: 10.1016/j.freeradbiomed.2023.09.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/10/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
Aging is a complex biological process characterized by a progressive decline in cellular and tissue function, ultimately leading to organismal aging. Stem cells, with their regenerative potential, play a crucial role in maintaining tissue homeostasis and repair throughout an organism's lifespan. Mitochondria, the powerhouses of the cell, have emerged as key players in the aging process, impacting stem cell function and contributing to age-related tissue dysfunction. Here are discuss the mechanisms through which mitochondria influence stem cell fate decisions, including energy production, metabolic regulation, ROS signalling, and epigenetic modifications. Therefore, this review highlights the role of mitochondria in driving stem cell senescence and the subsequent impact on tissue function, leading to overall organismal aging and age-related diseases. Finally, we explore potential anti-aging therapies targeting mitochondrial health and discuss their implications for promoting healthy aging. This comprehensive review sheds light on the critical interplay between mitochondrial function, stem cell senescence, and organismal aging, offering insights into potential strategies for attenuating age-related decline and promoting healthy longevity.
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Affiliation(s)
- Cristina Mas-Bargues
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010, Valencia, Spain.
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16
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Gupta A, Carnazza M, Jones M, Darzynkiewicz Z, Halicka D, O’Connell T, Zhao H, Dadafarin S, Shin E, Schwarcz MD, Moscatello A, Tiwari RK, Geliebter J. Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells. Cancers (Basel) 2023; 15:2198. [PMID: 37190127 PMCID: PMC10137266 DOI: 10.3390/cancers15082198] [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: 12/21/2022] [Revised: 03/30/2023] [Accepted: 03/30/2023] [Indexed: 05/17/2023] Open
Abstract
Thyroid cancer (TC) is the most common endocrine malignancy, with an approximately three-fold higher incidence in women. TCGA data indicate that androgen receptor (AR) RNA is significantly downregulated in PTC. In this study, AR-expressing 8505C (anaplastic TC) (84E7) and K1 (papillary TC) cells experienced an 80% decrease in proliferation over 6 days of exposure to physiological levels of 5α-dihydrotestosterone (DHT). In 84E7, continuous AR activation resulted in G1 growth arrest, accompanied by a flattened, vacuolized cell morphology, with enlargement of the cell and the nuclear area, which is indicative of senescence; this was substantiated by an increase in senescence-associated β-galactosidase activity, total RNA and protein content, and reactive oxygen species. Additionally, the expression of tumor suppressor proteins p16, p21, and p27 was significantly increased. A non-inflammatory senescence-associated secretory profile was induced, significantly decreasing inflammatory cytokines and chemokines such as IL-6, IL-8, TNF, RANTES, and MCP-1; this is consistent with the lower incidence of thyroid inflammation and cancer in men. Migration increased six-fold, which is consistent with the clinical observation of increased lymph node metastasis in men. Proteolytic invasion potential was not significantly altered, which is consistent with unchanged MMP/TIMP expression. Our studies provide evidence that the induction of senescence is a novel function of AR activation in thyroid cancer cells, and may underlie the protective role of AR activation in the decreased incidence of TC in men.
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Affiliation(s)
- Anvita Gupta
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
| | - Michelle Carnazza
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
| | - Melanie Jones
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
| | - Zbigniew Darzynkiewicz
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
- Department of Medicine, New York Medical College, Valhalla, NY 10595, USA
| | - Dorota Halicka
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
| | - Timmy O’Connell
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
| | - Hong Zhao
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
| | - Sina Dadafarin
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
- Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA 98195, USA
| | - Edward Shin
- Department of Otolaryngology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY 10003, USA
| | - Monica D. Schwarcz
- Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | | | - Raj K. Tiwari
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
| | - Jan Geliebter
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
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17
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Osman AG, Avula B, Katragunta K, Ali Z, Chittiboyina AG, Khan IA. Elderberry Extracts: Characterization of the Polyphenolic Chemical Composition, Quality Consistency, Safety, Adulteration, and Attenuation of Oxidative Stress- and Inflammation-Induced Health Disorders. Molecules 2023; 28:molecules28073148. [PMID: 37049909 PMCID: PMC10096080 DOI: 10.3390/molecules28073148] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/24/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Elderberry is highly reputed for its health-improving effects. Multiple pieces of evidence indicate that the consumption of berries is linked to enhancing human health and preventing or delaying the onset of chronic medical conditions. Compared with other fruit, elderberry is a very rich source of anthocyanins (approximately 80% of the polyphenol content). These polyphenols are the principals that essentially contribute to the high antioxidant and anti-inflammatory capacities and the health benefits of elderberry fruit extract. These health effects include attenuation of cardiovascular, neurodegenerative, and inflammatory disorders, as well as anti-diabetic, anticancer, antiviral, and immuno-stimulatory effects. Sales of elderberry supplements skyrocketed to $320 million over the year 2020, according to an American Botanical Council (ABC) report, which is attributable to the purported immune-enhancing effects of elderberry. In the current review, the chemical composition of the polyphenolic content of the European elderberry (Sambucus nigra) and the American elderberry (Sambucus canadensis), as well as the analytical techniques employed to analyze, characterize, and ascertain the chemical consistency will be addressed. Further, the factors that influence the consistency of the polyphenolic chemical composition, and hence, the consistency of the health benefits of elderberry extracts will be presented. Additionally, adulteration and safety as factors contributing to consistency will be covered. The role of elderberry in enhancing human health alone with the pharmacological basis, the cellular pathways, and the molecular mechanisms underlying the observed health benefits of elderberry fruit extracts will be also reviewed.
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Affiliation(s)
- Ahmed G. Osman
- National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA
| | - Bharathi Avula
- National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA
| | - Kumar Katragunta
- National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA
| | - Zulfiqar Ali
- National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA
| | - Amar G. Chittiboyina
- National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA
| | - Ikhlas A. Khan
- National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA
- Division of Pharmacognosy, Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA
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18
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Lyamina S, Baranovskii D, Kozhevnikova E, Ivanova T, Kalish S, Sadekov T, Klabukov I, Maev I, Govorun V. Mesenchymal Stromal Cells as a Driver of Inflammaging. Int J Mol Sci 2023; 24:6372. [PMID: 37047346 PMCID: PMC10094085 DOI: 10.3390/ijms24076372] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/03/2023] [Accepted: 03/22/2023] [Indexed: 03/31/2023] Open
Abstract
Life expectancy and age-related diseases burden increased significantly over the past few decades. Age-related conditions are commonly discussed in a very limited paradigm of depleted cellular proliferation and maturation with exponential accumulation of senescent cells. However, most recent evidence showed that the majority of age-associated ailments, i.e., diabetes mellitus, cardiovascular diseases and neurodegeneration. These diseases are closely associated with tissue nonspecific inflammation triggered and controlled by mesenchymal stromal cell secretion. Mesenchymal stromal cells (MSCs) are known as the most common type of cells for therapeutic approaches in clinical practice. Side effects and complications of MSC-based treatments increased interest in the MSCs secretome as an alternative concept for validation tests in regenerative medicine. The most recent data also proposed it as an ideal tool for cell-free regenerative therapy and tissue engineering. However, senescent MSCs secretome was shown to hold the role of 'key-driver' in inflammaging. We aimed to review the immunomodulatory effects of the MSCs-secretome during cell senescence and provide eventual insight into the interpretation of its beneficial biological actions in inflammaging-associated diseases.
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Affiliation(s)
- Svetlana Lyamina
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Delegatskaya Str., 20/1, 127473 Moscow, Russia
- Scientific Research Institute for Systems Biology and Medicine, Nauchniy Proezd, 18, 117246 Moscow, Russia
| | - Denis Baranovskii
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Delegatskaya Str., 20/1, 127473 Moscow, Russia
- Research and Educational Resource Center for Cellular Technologies, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
- National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia
| | - Ekaterina Kozhevnikova
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Delegatskaya Str., 20/1, 127473 Moscow, Russia
| | - Tatiana Ivanova
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Delegatskaya Str., 20/1, 127473 Moscow, Russia
| | - Sergey Kalish
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Delegatskaya Str., 20/1, 127473 Moscow, Russia
- Scientific Research Institute for Systems Biology and Medicine, Nauchniy Proezd, 18, 117246 Moscow, Russia
| | - Timur Sadekov
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Delegatskaya Str., 20/1, 127473 Moscow, Russia
| | - Ilya Klabukov
- Research and Educational Resource Center for Cellular Technologies, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
- National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia
| | - Igor Maev
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Delegatskaya Str., 20/1, 127473 Moscow, Russia
| | - Vadim Govorun
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Delegatskaya Str., 20/1, 127473 Moscow, Russia
- Scientific Research Institute for Systems Biology and Medicine, Nauchniy Proezd, 18, 117246 Moscow, Russia
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19
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Hypoxia-Induced GST1 Exerts Protective Effects on Trophoblasts via Inhibiting Reactive Oxygen Species (ROS) Accumulation. Anal Cell Pathol (Amst) 2023. [DOI: 10.1155/2023/9391252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Hypoxic conditions are a typical extrinsic factor for the modification of trophoblast biological functions, including cell proliferation, migration, and invasion. Hypoxia-induced reactive oxygen species (ROS) accumulation causes chronic trophoblast injury and contributes to preeclampsia (PE). Glutathione-S-transferase P (GSTP1) is a main regulator of ROS. However, it is still unknown whether GSTP1 is involved in ROS regulation under hypoxic conditions. Here, we investigated the expression level of GSTP1 in first-trimester villi placentas compared with full-term placentas and the effect of hypoxic conditions on GSTP1. GSTP1 expression in first-trimester villi placentas was much higher than that in full-term placentas. After hypoxia exposure, GSTP1 was significantly upregulated in JEG3 cells, a trophoblast-like cell line. Hypoxic-induced GSTP1 scavenged ROS accumulated by hypoxia exposure, potentially by promoting GST activity. The inhibitory effects of hypoxia exposure on cell proliferation, migration, and invasion induced by hypoxia exposure were obviously reversed by overexpression of GSTP1. Hypoxia-induced cell apoptosis was also reversed by GSTP1 overexpression, indicating the protective effects of GSTP1 against ROS-induced cell injury. Moreover, overexpressed GSTP1 markedly promoted the cell proliferation, migration, invasion, and colony formation abilities in JEG3 cells, demonstrating that GSP1 also exerts promoting effects under normoxic conditions. These data show that hypoxia-induced GSTP1 expression facilitates trophoblast cell proliferation, migration, and invasion and exerts protective effects under hypoxic conditions, which may play an important role during the increase in PE.
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20
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Yuan S, Dong PY, Ma HH, Liang SL, Li L, Zhang XF. Antioxidant and Biological Activities of the Lotus Root Polysaccharide-Iron (III) Complex. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27207106. [PMID: 36296700 PMCID: PMC9611182 DOI: 10.3390/molecules27207106] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/16/2022] [Accepted: 10/18/2022] [Indexed: 11/05/2022]
Abstract
In this study, the synthesis parameters of the lotus root polysaccharide iron complex (LRPF) were determined and optimized by response surface methodology. Under the optimum preparation conditions, the pH of the solution was 9, the ratio of M (trisodium citrate): m (lotus root polysaccharide) was 0.45, the reaction time was 3 h. UV spectroscopy, thermogravimetry, FT-IR spectroscopy, X-ray diffraction, CD, and NMR were used for the characterization of the LRPF. LRPF has good stability and easily releases iron ions under artificial gastrointestinal conditions. LRPF exhibited antioxidant activity in vitro and can significantly improve the antioxidant activity in vivo. In addition, LRPF has a good effect in the treatment of iron deficiency anemia in model mice, impacts the gut microbiome, and reduces the iron deficiency-induced perniciousness by regulating steroid hormone biosynthesis. Therefore, LRPF can be used as a nutritional supplement to treat and prevent iron-deficiency anemia and improve human immunity.
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21
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Wang T, Huang S, He C. Senescent cells: A therapeutic target for osteoporosis. Cell Prolif 2022; 55:e13323. [DOI: 10.1111/cpr.13323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 07/21/2022] [Accepted: 07/25/2022] [Indexed: 11/30/2022] Open
Affiliation(s)
- Tiantian Wang
- Department of Rehabilitation Medicine, Key Laboratory of Rehabilitation Medicine, West China Hospital Sichuan University Chengdu Sichuan China
- Institute of Rehabilitation Medicine, West China Hospital Sichuan University Chengdu Sichuan China
| | - Shishu Huang
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital and West China School of Medicine Sichuan University Chengdu Sichuan China
| | - Chengqi He
- Department of Rehabilitation Medicine, Key Laboratory of Rehabilitation Medicine, West China Hospital Sichuan University Chengdu Sichuan China
- Institute of Rehabilitation Medicine, West China Hospital Sichuan University Chengdu Sichuan China
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22
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Baek M, Jang W, Kim C. Dual Oxidase, a Hydrogen-Peroxide-Producing Enzyme, Regulates Neuronal Oxidative Damage and Animal Lifespan in Drosophila melanogaster. Cells 2022; 11:cells11132059. [PMID: 35805145 PMCID: PMC9265666 DOI: 10.3390/cells11132059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 02/04/2023] Open
Abstract
Reducing the oxidative stress in neurons extends lifespan in Drosophila melanogaster, highlighting the crucial role of neuronal oxidative damage in lifespan determination. However, the source of the reactive oxygen species (ROS) that provoke oxidative stress in neurons is not clearly defined. Here, we identify dual oxidase (duox), a calcium-activated ROS-producing enzyme, as a lifespan determinant. Due to the lethality of duox homozygous mutants, we employed a duox heterozygote that exhibited normal appearance and movement. We found that duox heterozygous male flies, which were isogenized with control flies, demonstrated extended lifespan. Neuronal knockdown experiments further suggested that duox is crucial to oxidative stress in neurons. Our findings suggest duox to be a source of neuronal oxidative stress associated with animal lifespan.
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23
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Meqbel BRM, Gomes M, Omer A, Gallouzi IE, Horn HF. LINCing Senescence and Nuclear Envelope Changes. Cells 2022; 11:1787. [PMID: 35681483 PMCID: PMC9179861 DOI: 10.3390/cells11111787] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 01/27/2023] Open
Abstract
The nuclear envelope (NE) has emerged as a nexus for cellular organization, signaling, and survival. Beyond its role as a barrier to separate the nucleoplasm from the cytoplasm, the NE's role in supporting and maintaining a myriad of other functions has made it a target of study in many cellular processes, including senescence. The nucleus undergoes dramatic changes in senescence, many of which are driven by changes in the NE. Indeed, Lamin B1, a key NE protein that is consistently downregulated in senescence, has become a marker for senescence. Other NE proteins have also been shown to play a role in senescence, including LINC (linker of nucleoskeleton and cytoskeleton) complex proteins. LINC complexes span the NE, forming physical connections between the cytoplasm to the nucleoplasm. In this way, they integrate nuclear and cytoplasmic mechanical signals and are essential not only for a variety of cellular functions but are needed for cell survival. However, LINC complex proteins have been shown to have a myriad of functions in addition to forming a LINC complex, often existing as nucleoplasmic or cytoplasmic soluble proteins in a variety of isoforms. Some of these proteins have now been shown to play important roles in DNA repair, cell signaling, and nuclear shape regulation, all of which are important in senescence. This review will focus on some of these roles and highlight the importance of LINC complex proteins in senescence.
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Affiliation(s)
- Bakhita R. M. Meqbel
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar;
| | - Matilde Gomes
- KAUST Smart-Health Initiative and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah 21589, Saudi Arabia; (M.G.); (I.E.G.)
| | - Amr Omer
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada;
| | - Imed E. Gallouzi
- KAUST Smart-Health Initiative and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah 21589, Saudi Arabia; (M.G.); (I.E.G.)
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada;
| | - Henning F. Horn
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar;
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Abstract
Macropinocytosis is an evolutionarily conserved endocytic pathway that mediates the nonselective acquisition of extracellular material via large endocytic vesicles known as macropinosomes. In addition to other functions, this uptake pathway supports cancer cell metabolism through the uptake of nutrients. Cells harboring oncogene or tumor suppressor mutations are known to display heightened macropinocytosis, which confers to the cancer cells the ability to survive and proliferate despite the nutrient-scarce conditions of the tumor microenvironment. Thus, macropinocytosis is associated with cancer malignancy. Macropinocytic uptake can be induced in cancer cells by different stress stimuli, acting as an adaptive mechanism for the cells to resist stresses in the tumor milieu. Here, we review the cellular stresses that are known to promote macropinocytosis, as well as the underlying molecular mechanisms that drive this process.
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Affiliation(s)
- Guillem Lambies
- Cell and Molecular Biology of Cancer Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Cosimo Commisso
- Cell and Molecular Biology of Cancer Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
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25
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Repetitive Bathing and Skin Poultice with Hydrogen-Rich Water Improve Wrinkles and Blotches Together with Modulation of Skin Oiliness and Moisture. HYDROGEN 2022. [DOI: 10.3390/hydrogen3020011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Hydrogen-rich warm water (HW) has not been verified yet for skin anti-aging effects. Daily 10 min HW (dissolved hydrogen: 338–682 μg/mL, 41 °C) bathing and skin poultice with HW-impregnated towels for 11–61 days were demonstrated to improve wrinkle degrees (29 skin-loci) from 3.14 ± 0.52 to 1.52 ± 0.74 (p < 0.001) and blotch degrees (23 loci) from 3.48 ± 0.67 to 1.74 ± 0.86 (p < 0.001) in five healthy subjects (49–66 years old), by densito-/planimetrically evaluating with an Image-J software, and ranked into six hierarchies (0, 1–5). Meanwhile, skin oiliness was evaluated to increase for the oil-poor skins, but inversely decrease for excessively oily skins, suggesting the HW’s function as skin-oiliness modulation, with an appreciably negative correlation in prior oiliness contents versus change after HW application (r = −0.345, 23 loci). Skin moisture increased upon HW application, with a negative correlation (r = −0.090, 23 loci) in prior moisture contents versus post-HW-application moisture-changing rates, meaning that HW application compensated moisture for water-deficient skins (27.5–40% moisture), but not for wet skins (>41% moisture). Thus, the HW bath together with HW poultice exerted beneficial effects on skin appearances such as wrinkles, blotches and moisture/oiliness, some of which might ensue from enhanced antioxidant ability in blood, as was previously demonstrated for the HW bath.
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26
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Muresanu C, Khalchitsky S. Updated Understanding of the Causes of Cancer, and a New Theoretical Perspective of Combinational Cancer Therapies, a Hypothesis. DNA Cell Biol 2022; 41:342-355. [PMID: 35262416 DOI: 10.1089/dna.2021.1118] [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] [Indexed: 12/12/2022] Open
Abstract
We present an integrative understanding of cancer as a metabolic multifactorial, multistage disease. We focus on underlying genetics-environmental interactions, evidenced by telomere changes. A range of genetic and epigenetic factors, including physical agents and predisposing factors such as diet and lifestyle are included. We present a structured model of the causes of cancer, methods of investigations, approaches to cancer prevention, and polypharmaceutical multidisciplinary complex treatment within a framework of personalized medicine. We searched PubMed, National Cancer Institute online, and other databases for publications regarding causes of cancer, reports of novel mitochondrial reprogramming, epigenetic, and telomerase therapies and state-of-the-art investigations. We focused on multistep treatment protocols to enhance early detection of cancer, and elimination or neutralization of the causes and factors associated with cancer formation and progression.Our aim is to suggest a model therapeutic protocol that incorporates the patient's genome, metabolism, and immune system status; stage of tumor development; and comorbidity(ies), if any. Investigation and treatment of cancer is a challenge that requires further holistic studies that improve the quality of life and survival rates, but are most likely to aid prevention.
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Affiliation(s)
- Cristian Muresanu
- Research Center for Applied Biotechnology in Diagnosis and Molecular Therapies, Cluj-Napoca, Romania.,Department of Ecology, Taxonomy and Nature Conservation, Institute of Biology, Romanian Academy, Bucharest, Romania
| | - Sergei Khalchitsky
- H. Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Ministry of Health of the Russian Federation, Saint-Petersburg, Russia
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DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction. Int J Mol Sci 2022; 23:ijms23052877. [PMID: 35270019 PMCID: PMC8911374 DOI: 10.3390/ijms23052877] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/25/2022] [Accepted: 03/02/2022] [Indexed: 12/14/2022] Open
Abstract
Endothelial cell senescence is involved in endothelial dysfunction and vascular diseases. However, the detailed mechanisms of endothelial senescence are not fully understood. Here, we demonstrated that deficiency of developmentally regulated GTP-binding protein 2 (DRG2) induces senescence and dysfunction of endothelial cells. DRG2 knockout (KO) mice displayed reduced cerebral blood flow in the brain and lung blood vessel density. We also determined, by Matrigel plug assay, aorta ring assay, and in vitro tubule formation of primary lung endothelial cells, that deficiency in DRG2 reduced the angiogenic capability of endothelial cells. Endothelial cells from DRG2 KO mice showed a senescence phenotype with decreased cell growth and enhanced levels of p21 and phosphorylated p53, γH2AX, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence-associated secretory phenotype (SASP) cytokines. DRG2 deficiency in endothelial cells upregulated arginase 2 (Arg2) and generation of reactive oxygen species. Induction of SA-β-gal activity was prevented by the antioxidant N-acetyl cysteine in endothelial cells from DRG2 KO mice. In conclusion, our results suggest that DRG2 is a key regulator of endothelial senescence, and its downregulation is probably involved in vascular dysfunction and diseases.
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Sharma R. Emerging Interrelationship Between the Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: Perspectives and Therapeutic Opportunities. Probiotics Antimicrob Proteins 2022; 14:648-663. [PMID: 34985682 PMCID: PMC8728710 DOI: 10.1007/s12602-021-09903-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2021] [Indexed: 12/12/2022]
Abstract
The significance of diversity, composition, and functional attributes of the gut microbiota in shaping human health is well recognized. Studies have shown that gut microbiota is closely linked to human aging, and changes in the gut microbiome can predict human survival and longevity. In addition, a causal relationship between gut microbiota dysbiosis and chronic age-related disorders is also becoming apparent. Recent advances in our understanding of the cellular and molecular aspects of biological aging have revealed a cellular senescence-centric view of the aging process. However, the association between the gut microbiome and cellular senescence is only beginning to be understood. The present review provides an integrative view of the evolving relationship between the gut microbiome and cellular senescence in aging and disease. Evidence relating to microbiome-mediated modulation of senescent cells, as well as senescent cells-mediated changes in intestinal homeostasis and diseases, have been discussed. Unanswered questions and future research directions have also been deliberated to truly ascertain the relationship between the gut microbiome and cellular senescence for developing microbiome-based age-delaying and longevity-promoting therapies.
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Affiliation(s)
- Rohit Sharma
- Faculty of Applied Sciences & Biotechnology, Shoolini University, Solan, 173229, India.
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Santos ALDC, Ferreira ACA, Figueiredo JRD. Potential use of bacterial pigments as anticancer drugs and female reproductive toxicity: a review. CIÊNCIA ANIMAL BRASILEIRA 2022. [DOI: 10.1590/1809-6891v23e-72911e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Abstract Natural bioactive compounds obtained from microorganisms, have awakened particular interest in the industry nowadays. This attention comes when natural resources depletion is pronounced, and the acquisition of both new plant origin resources and bioactive products, represents a challenge for the next generations. In this sense, prospecting for large-scale production and use of bacterial pigments is a necessary strategy for the development of novel products. A wide variety of properties have been attributed to these substances and, among them, their therapeutic potential against important diseases, such as cancer. There is consensus that available chemotherapy protocols are known to detrimentally affect cancer patients fertility. Hence, considerable part of the deleterious effects of chemotherapy is related to the drugs cytotoxicity, which, in addition to cancer cells, also affect normal cells. Therefore, the intrinsic properties of bacterial pigments associated with low cytotoxicity and relevant cell selectivity, certified them as potential anticancer drugs. However, little information is available about reproductive toxicity of these new and promising compounds. Thus, the present review aims to address the main bacterial pigments, their potential uses as anticancer drugs and their possible toxic effects, especially on the female gonad.
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Santos ALDC, Ferreira ACA, Figueiredo JRD. Uso potencial de pigmentos bacterianos como drogas anticâncer e toxicidade reprodutiva feminina: uma revisão. CIÊNCIA ANIMAL BRASILEIRA 2022. [DOI: 10.1590/1809-6891v23e-72911p] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Resumo Os compostos bioativos naturais obtidos de microrganismos têm despertado especial interesse da indústria nos últimos anos. Esta atenção ocorre em um momento em que o esgotamento de recursos naturais é pronunciado, e a aquisição de novos insumos e produtos bioativos de origem vegetal representa um desafio para as próximas gerações. Neste sentido, a prospecção para a produção e uso em larga escala dos pigmentos bacterianos tem representado uma importante estratégia para o desenvolvimento de novos produtos. Uma grande variedade de propriedades foi atribuída a estas substâncias, entre elas, o potencial terapêutico contra doenças importantes, como o câncer. Existe um consenso de que os protocolos quimioterápicos disponíveis são conhecidos por afetarem negativamente a fertilidade de pacientes com câncer. Grande parte dos efeitos deletérios da quimioterapia está relacionado à citotoxicidade das drogas usadas para este fim, que além das células cancerosas, afetam as células normais. Nesse sentido, as propriedades naturais atribuídas aos pigmentos bacterianos associadas à baixa citotoxicidade e relevante seletividade, os qualificaram como potenciais drogas anticâncer. No entanto, pouco se tem de informação a respeito da toxicidade reprodutiva destes novos e promissores compostos. Dessa forma, a presente revisão tem o objetivo de abordar os principais pigmentos bacterianos, suas utilizações potenciais como drogas anticâncer, bem como os seus possíveis efeitos tóxicos, sobretudo, sobre a gônada feminina.
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Roger L, Tomas F, Gire V. Mechanisms and Regulation of Cellular Senescence. Int J Mol Sci 2021; 22:ijms222313173. [PMID: 34884978 PMCID: PMC8658264 DOI: 10.3390/ijms222313173] [Citation(s) in RCA: 195] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/25/2021] [Accepted: 12/02/2021] [Indexed: 12/23/2022] Open
Abstract
Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.
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Affiliation(s)
- Lauréline Roger
- Structure and Instability of Genomes Laboratory, Muséum National d’Histoire Naturelle (MNHN), CNRS-UMR 7196/INSERM U1154, 43 Rue Cuvier, 75005 Paris, France;
| | - Fanny Tomas
- Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier, CNRS UMR 5237, 1919 Route de Mende, 34293 Montpellier, France;
| | - Véronique Gire
- Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier, CNRS UMR 5237, 1919 Route de Mende, 34293 Montpellier, France;
- Correspondence: ; Tel.: +33-(0)-434359513; Fax: +33-(0)-434359410
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Leser JM, Harriot A, Buck HV, Ward CW, Stains JP. Aging, Osteo-Sarcopenia, and Musculoskeletal Mechano-Transduction. FRONTIERS IN REHABILITATION SCIENCES 2021; 2:782848. [PMID: 36004321 PMCID: PMC9396756 DOI: 10.3389/fresc.2021.782848] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/10/2021] [Indexed: 11/13/2022]
Abstract
The decline in the mass and function of bone and muscle is an inevitable consequence of healthy aging with early onset and accelerated decline in those with chronic disease. Termed osteo-sarcopenia, this condition predisposes the decreased activity, falls, low-energy fractures, and increased risk of co-morbid disease that leads to musculoskeletal frailty. The biology of osteo-sarcopenia is most understood in the context of systemic neuro-endocrine and immune/inflammatory alterations that drive inflammation, oxidative stress, reduced autophagy, and cellular senescence in the bone and muscle. Here we integrate these concepts to our growing understanding of how bone and muscle senses, responds and adapts to mechanical load. We propose that age-related alterations in cytoskeletal mechanics alter load-sensing and mechano-transduction in bone osteocytes and muscle fibers which underscores osteo-sarcopenia. Lastly, we examine the evidence for exercise as an effective countermeasure to osteo-sarcopenia.
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Affiliation(s)
| | | | | | | | - Joseph P. Stains
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, United States
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33
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Mahajan AS, Arikatla VS, Thyagarajan A, Zhelay T, Sahu RP, Kemp MG, Spandau DF, Travers JB. Creatine and Nicotinamide Prevent Oxidant-Induced Senescence in Human Fibroblasts. Nutrients 2021; 13:4102. [PMID: 34836359 PMCID: PMC8622652 DOI: 10.3390/nu13114102] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/15/2021] [Accepted: 11/15/2021] [Indexed: 01/20/2023] Open
Abstract
Dermal fibroblasts provide structural support by producing collagen and other structural/support proteins beneath the epidermis. Fibroblasts also produce insulin-like growth factor-1 (IGF-1), which binds to the IGF-1 receptors (IGF-1Rs) on keratinocytes to activate signaling pathways that regulate cell proliferation and cellular responses to genotoxic stressors like ultraviolet B radiation. Our group has determined that the lack of IGF-1 expression due to fibroblast senescence in the dermis of geriatric individuals is correlated with an increased incidence of skin cancer. The present studies tested the hypothesis that pro-energetics creatine monohydrate (Cr) and nicotinamide (NAM) can protect normal dermal human fibroblasts (DHF) against experimentally induced senescence. To that end, we used an experimental model of senescence in which primary DHF are treated with hydrogen peroxide (H2O2) in vitro, with senescence measured by staining for beta-galactosidase activity, p21 protein expression, and senescence associated secretory phenotype cytokine mRNA levels. We also determined the effect of H2O2 on IGF-1 mRNA and protein expression. Our studies indicate that pretreatment with Cr or NAM protects DHF from the H2O2-induced cell senescence. Treatment with pro-energetics post-H2O2 had no effect. Moreover, these agents also inhibited reactive oxygen species generation from H2O2 treatment. These studies suggest a potential strategy for protecting fibroblasts in geriatric skin from undergoing stress-induced senescence, which may maintain IGF-1 levels and therefore limit carcinogenesis in epidermal keratinocytes.
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Affiliation(s)
- Avinash S. Mahajan
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton Ohio, OH 45435, USA; (A.S.M.); (V.S.A.); (A.T.); (T.Z.); (R.P.S.); (M.G.K.)
| | - Venkata S. Arikatla
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton Ohio, OH 45435, USA; (A.S.M.); (V.S.A.); (A.T.); (T.Z.); (R.P.S.); (M.G.K.)
| | - Anita Thyagarajan
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton Ohio, OH 45435, USA; (A.S.M.); (V.S.A.); (A.T.); (T.Z.); (R.P.S.); (M.G.K.)
| | - Tetyana Zhelay
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton Ohio, OH 45435, USA; (A.S.M.); (V.S.A.); (A.T.); (T.Z.); (R.P.S.); (M.G.K.)
| | - Ravi P. Sahu
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton Ohio, OH 45435, USA; (A.S.M.); (V.S.A.); (A.T.); (T.Z.); (R.P.S.); (M.G.K.)
| | - Michael G. Kemp
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton Ohio, OH 45435, USA; (A.S.M.); (V.S.A.); (A.T.); (T.Z.); (R.P.S.); (M.G.K.)
- Dayton Veterans Administration Medical Center, Dayton Ohio, OH 45428, USA
| | - Dan F Spandau
- Departments of Dermatology and Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46223, USA;
- Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202, USA
| | - Jeffrey B. Travers
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton Ohio, OH 45435, USA; (A.S.M.); (V.S.A.); (A.T.); (T.Z.); (R.P.S.); (M.G.K.)
- Dayton Veterans Administration Medical Center, Dayton Ohio, OH 45428, USA
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Chuenwisad K, More-Krong P, Tubsaeng P, Chotechuang N, Srisa-Art M, Storer RJ, Boonla C. Premature Senescence and Telomere Shortening Induced by Oxidative Stress From Oxalate, Calcium Oxalate Monohydrate, and Urine From Patients With Calcium Oxalate Nephrolithiasis. Front Immunol 2021; 12:696486. [PMID: 34745087 PMCID: PMC8566732 DOI: 10.3389/fimmu.2021.696486] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 09/24/2021] [Indexed: 01/29/2023] Open
Abstract
Oxidative stress, a well-known cause of stress-induced premature senescence (SIPS), is increased in patients with calcium oxalate (CaOx) kidney stones (KS). Oxalate and calcium oxalate monohydrate (COM) induce oxidative stress in renal tubular cells, but to our knowledge, their effect on SIPS has not yet been examined. Here, we examined whether oxalate, COM, or urine from patients with CaOx KS could induce SIPS and telomere shortening in human kidney (HK)-2 cells, a proximal tubular renal cell line. Urine from age- and sex-matched individuals without stones was used as a control. In sublethal amounts, H2O2, oxalate, COM, and urine from those with KS evoked oxidative stress in HK-2 cells, indicated by increased protein carbonyl content and decreased total antioxidant capacity, but urine from those without stones did not. The proportion of senescent HK-2 cells, as indicated by SA-βgal staining, increased after treatment with H2O2, oxalate, COM, and urine from those with KS. Expression of p16 was higher in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS than it was in cells treated with urine from those without stones and untreated controls. p16 was upregulated in the SA-βgal positive cells. Relative telomere length was shorter in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS than that in cells treated with urine from those without stones and untreated controls. Transcript expression of shelterin components (TRF1, TRF2 and POT1) was decreased in HK-2 cells treated with H2O2, oxalate, COM, and urine from those with KS, in which case the expression was highest. Urine from those without KS did not significantly alter TRF1, TRF2, and POT1 mRNA expression in HK-2 cells relative to untreated controls. In conclusion, oxalate, COM, and urine from patients with CaOx KS induced SIPS and telomere shortening in renal tubular cells. SIPS induced by a lithogenic milieu may result from upregulation of p16 and downregulation of shelterin components, specifically POT1, and might contribute, at least in part, to the development of CaOx KS.
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Affiliation(s)
- Kamonchanok Chuenwisad
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pimkanya More-Krong
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Praween Tubsaeng
- Division of Urology, Mahasarakham Hospital, Mahasarakham, Thailand
| | - Nattida Chotechuang
- Department of Food Technology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Monpichar Srisa-Art
- Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Robin James Storer
- Office of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Chanchai Boonla
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Li BS, Jin AL, Zhou Z, Seo JH, Choi BM. DRG2 Accelerates Senescence via Negative Regulation of SIRT1 in Human Diploid Fibroblasts. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:7301373. [PMID: 34777693 PMCID: PMC8580627 DOI: 10.1155/2021/7301373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 10/04/2021] [Indexed: 11/21/2022]
Abstract
Accumulating evidence suggests that developmentally regulated GTP-binding protein 2 (DRG2), an evolutionarily conserved GTP-binding protein, plays an important role in regulating cell growth, inflammation, and mitochondria dynamics. However, the effect of DRG2 in aging remains unclear. In this study, we found that endogenous DRG2 protein expression is upregulated in oxidative stress-induced premature senescence models and tissues of aged mice. Ectopic expression of DRG2 significantly promoted senescence-associated β-galactosidase (SA-β-gal) activity and inhibited cell growth, concomitant with increase in levels of acetyl (ac)-p53 (Lys382), ac-nuclear factor-kB (NF-κB) p65 (Lys310), p21 Waf1/Cip1 , and p16 Ink4a and a decrease in cyclin D1. In this process, reactive oxygen species (ROS) and phosphorylation of H2A histone family member X (H2A.X), forming γ-H2A.X, were enhanced. Mechanistically, ectopic expression of DRG2 downregulated Sirtuin-1 (SIRT1), resulting in augmented acetylation of p53 and NF-κB p65. Additionally, DRG2 knockdown significantly abolished oxidative stress-induced premature senescence. Our results provide a possible molecular mechanism for investigation of cellular senescence and aging regulated by DRG2.
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Affiliation(s)
- Bing Si Li
- Department of Biochemistry, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
| | - Ai Lin Jin
- Department of Biochemistry, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
| | - ZiQi Zhou
- Department of Herbology, Wonkwang University School of Korean Medicine, Iksan, Jeonbuk 54538, Republic of Korea
| | - Jae Ho Seo
- Department of Biochemistry, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
- Sarcopenia Total Solution Center, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
| | - Byung-Min Choi
- Department of Biochemistry, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
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Alqahtani SA, Schattenberg JM. NAFLD in the Elderly. Clin Interv Aging 2021; 16:1633-1649. [PMID: 34548787 PMCID: PMC8448161 DOI: 10.2147/cia.s295524] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/12/2021] [Indexed: 12/25/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent disease globally. Current estimates are that 24% of the adult population, thus, one billion individuals worldwide, are affected. Interestingly, the prevalence of fatty liver seems to peak between 40─50 years of age in males and 60─69 years in females, often slightly decreasing in older (>70 years) cohorts. Furthermore, several risk factors for NAFLD development, such as hypertension, diabetes, hyperlipidemia, and obesity are higher in older adults. The diagnosis and management strategies in older adults are sometimes challenging, and certain age-specific factors have to be taken into account by healthcare professionals. In this review, we provide an overview of considerations relevant to the management and diagnosis of NAFLD in older adults (age >65 years) and discuss the types of pharmacological interventions available for the management of non-alcoholic steatohepatitis (NASH) in the aging population.
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Affiliation(s)
- Saleh A Alqahtani
- Liver Transplantation Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.,Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center, Mainz, Germany
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Zhao S, Wang X, Zheng X, Liang X, Wang Z, Zhang J, Zhao X, Zhuang S, Pan Q, Sun F, Shang W, Barasch J, Qiu A. Iron deficiency exacerbates cisplatin- or rhabdomyolysis-induced acute kidney injury through promoting iron-catalyzed oxidative damage. Free Radic Biol Med 2021; 173:81-96. [PMID: 34298093 PMCID: PMC9482792 DOI: 10.1016/j.freeradbiomed.2021.07.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/17/2021] [Accepted: 07/19/2021] [Indexed: 02/05/2023]
Abstract
Iron deficiency is the most common micronutrient deficiency worldwide. While iron deficiency is known to suppress embryonic organogenesis, its effect on the adult organ in the context of clinically relevant damage has not been considered. Here we report that iron deficiency is a risk factor for nephrotoxic intrinsic acute kidney injury of the nephron (iAKI). Iron deficiency exacerbated cisplatin-induced iAKI by markedly increasing non-heme catalytic iron and Nox4 protein which together catalyze production of hydroxyl radicals followed by protein and DNA oxidation, apoptosis and ferroptosis. Crosstalk between non-heme catalytic iron/Nox4 and downstream oxidative damage generated a mutual amplification cycle that facilitated rapid progression of cisplatin-induced iAKI. Iron deficiency also exacerbated a second model of iAKI, rhabdomyolysis, via increasing catalytic heme-iron. Heme-iron induced lipid peroxidation and DNA oxidation by interacting with Nox4-independent mechanisms, promoting p53/p21 activity and cellular senescence. Our data suggests that correcting iron deficiency and/or targeting specific catalytic iron species are strategies to mitigate iAKI in a wide range of patients with diverse forms of kidney injury.
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Affiliation(s)
- Shifeng Zhao
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xueqiao Wang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xiaoqing Zheng
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xiu Liang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zhigang Wang
- Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Juanlian Zhang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xudong Zhao
- Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Shougang Zhuang
- Division of Nephrology, Department of Medicine, Brown University, Providence, USA
| | - Qiuhui Pan
- Department of Clinical Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Fenyong Sun
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Wenjun Shang
- Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Jonathan Barasch
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA.
| | - Andong Qiu
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
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38
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Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis. Proc Natl Acad Sci U S A 2021; 118:2003193118. [PMID: 33468664 DOI: 10.1073/pnas.2003193118] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
We have shown previously that phosphorylation of Mdm2 by ATM and c-Abl regulates Mdm2-p53 signaling and alters the effects of DNA damage in mice, including bone marrow failure and tumorigenesis induced by ionizing radiation. Here, we examine the physiological effects of Mdm2 phosphorylation by Akt, another DNA damage effector kinase. Surprisingly, Akt phosphorylation of Mdm2 does not alter the p53-mediated effects of ionizing radiation in cells or mice but regulates the p53 response to oxidative stress. Akt phosphorylation of Mdm2 serine residue 183 increases nuclear Mdm2 stability, decreases p53 levels, and prevents senescence in primary cells exposed to reactive oxidative species (ROS). Using multiple mouse models of ROS-induced cancer, we show that Mdm2 phosphorylation by Akt reduces senescence to promote KrasG12D-driven lung cancers and carcinogen-induced papilloma and hepatocellular carcinomas. Collectively, we document a unique physiologic role for Akt-Mdm2-p53 signaling in regulating cell growth and tumorigenesis in response to oxidative stress.
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Li BS, Zhu RZ, Lim SH, Seo JH, Choi BM. Apigenin Alleviates Oxidative Stress-Induced Cellular Senescence via Modulation of the SIRT1-NAD[Formula: see text]-CD38 Axis. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2021; 49:1235-1250. [PMID: 34049472 DOI: 10.1142/s0192415x21500592] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Oxidative stress-induced cellular senescence is now regarded as an important driving mechanism in chronic lung diseases-particularly chronic obstructive pulmonary disease (COPD). 4[Formula: see text],5,7-trihydroxyflavone (Apigenin) is a natural flavonoid product abundantly present in fruits, vegetables, and Chinese medicinal herbs. It has been known that apigenin has anti-oxidant, anti-inflammatory and liver-protecting effects. The efficacy of apigenin for lung aging, however, has not been reported. In this study, we selected the hydrogen peroxide (H2O[Formula: see text]- or doxorubicin (DOXO)-induced senescence model in WI-38 human embryonic lung fibroblast cells to determine the potential anti-aging effects of apigenin in vitro and associated molecular mechanisms. We found that apigenin reduced senescence-associated [Formula: see text]-galactosidase (SA-[Formula: see text]-gal) activity and promoted cell growth, concomitant with a decrease in levels of Acetyl (ac)-p53, p21[Formula: see text], and p16[Formula: see text] and an increase in phospho (p)-Rb. Apigenin also increased the activation ratio of silent information regulator 1 (SIRT1), nicotinamide adenine dinucleotide (NAD[Formula: see text], and NAD[Formula: see text]/NADH and inhibited cluster of differentiation 38 (CD38) activity in a concentration-dependent manner. SIRT1 inhibition by SIRT1 siRNA abolished the anti-aging effect of apigenin. In addition, CD38 inhibition by CD38 siRNA or apigenin increased the SIRT1 level and reduced H2O2-induced senescence. Our findings suggest that apigenin is a promising phytochemical for reducing the impact of senescent cells in age-related lung diseases such as COPD.
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Affiliation(s)
- Bing Si Li
- Department of Biochemistry, Wonkwang University School of Medicine, 460 Iksandaero, Iksan, Jeonbuk 54538, Republic of Korea
| | - Ri Zhe Zhu
- Department of Biochemistry, Wonkwang University School of Medicine, 460 Iksandaero, Iksan, Jeonbuk 54538, Republic of Korea
| | - Seok-Hee Lim
- Department of Biochemistry, Wonkwang University School of Medicine, 460 Iksandaero, Iksan, Jeonbuk 54538, Republic of Korea
| | - Jae Ho Seo
- Department of Biochemistry, Wonkwang University School of Medicine, 460 Iksandaero, Iksan, Jeonbuk 54538, Republic of Korea
| | - Byung-Min Choi
- Department of Biochemistry, Wonkwang University School of Medicine, 460 Iksandaero, Iksan, Jeonbuk 54538, Republic of Korea
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40
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Dey DK, Kang SC. CopA3 peptide induces permanent cell-cycle arrest in colorectal cancer cells. Mech Ageing Dev 2021; 196:111497. [PMID: 33957217 DOI: 10.1016/j.mad.2021.111497] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 12/23/2022]
Abstract
Cell-cycle arrest reflects an accumulation of responses to DNA damage that sequentially affects cell growth and division. Herein, we analyzed the effect of the 9-mer dimer defensin-like peptide, CopA3, against colorectal cancer cell growth and proliferation in a dose-dependent manner upon 96 h of treatment. As observed, CopA3 treatment significantly affected cancer cell growth, reduced colony formation ability, increased the number of SA-β-Gal positive cells, and remarkably reduced Ki67 protein expression. Notably, in HCT-116 cells, CopA3 (5 μM) treatment effectively increased oxidative stress and, as a result, amplified the endogenous ROS, mitochondrial ROS, and NO content in the cells, which further activated the DNA damage response and caused cell-cycle arrest at the G1 phase. The prolonged cell-cycle arrest elevated the release of inflammatory cytokines in the cell supernatant. Nevertheless, mechanistically, NAC treatment effectively reversed the CopA3 effect and significantly reduced the oxidative stress; subsequently rescuing the cells from G1 phase arrest. Overall, CopA3 treatment can inhibit the growth and proliferation of colorectal cancer cells by inducing cell-cycle arrest through the ROS-mediated pathway.
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Affiliation(s)
- Debasish Kumar Dey
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea.
| | - Sun Chul Kang
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea.
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Differential role of melatonin in healthy brain aging: a systematic review and meta-analysis of the SAMP8 model. Aging (Albany NY) 2021; 13:9373-9397. [PMID: 33811754 PMCID: PMC8064193 DOI: 10.18632/aging.202894] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 03/14/2021] [Indexed: 12/16/2022]
Abstract
The relationship between oxidative stress (OS) and cellular senescence (CS) is an important research topic because of the rapidly aging global population. Melatonin (MT) is associated with aging and plays a pivotal role in redox homeostasis, but its role in maintaining physiological stability in the brain (especially in OS-induced senescence) remains elusive. Here, we systematically reviewed the differential role of MT on OS-induced senescence in the SAMP8 mouse model. Major electronic databases were searched for relevant studies. Pooled mean differences (MDs)/standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to estimate the effect size. Overall, 10 studies met the inclusion criteria. MT treatment was associated with the reduction of lipid peroxidation (SMD = -2.00, 95% CI [-2.91, -1.10]; p < 0.0001) and carbonylated protein (MD = -5.74, 95% CI [-11.03, -0.44]; p = 0.03), and with enhancement of the reduced-glutathione/oxidized-glutathione ratio (MD = 1.12, 95% CI [0.77, 1.47]; p < 0.00001). No differences were found in catalase and superoxide dismutase activities between MT-treated and vehicle-treated groups. Furthermore, nuclear-factor-κB, cyclin-dependent kinase-5, and p53 were regulated by MT administration. MT may improve physiological stability during aging by regulating interactions in brain senescence, but acts differentially on the antioxidant system.
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Salunkhe S, Mishra SV, Nair J, Shah S, Gardi N, Thorat R, Sarkar D, Rajendra J, Kaur E, Dutt S. Nuclear localization of p65 reverses therapy-induced senescence. J Cell Sci 2021; 134:jcs.253203. [PMID: 33526713 DOI: 10.1242/jcs.253203] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 01/21/2021] [Indexed: 01/07/2023] Open
Abstract
Senescence is the arrest of cell proliferation and is a tumor suppressor phenomenon. In a previous study, we have shown that therapy-induced senescence of glioblastoma multiforme (GBM) cells can prevent relapse of GBM tumors. Here, we demonstrate that ciprofloxacin-induced senescence in glioma-derived cell lines and primary glioma cultures is defined by SA-β-gal positivity, a senescence-associated secretory phenotype (SASP), a giant cell (GC) phenotype, increased levels of reactive oxygen species (ROS), γ-H2AX and a senescence-associated gene expression signature, and has three stages of senescence -initiation, pseudo-senescence and permanent senescence. Ciprofloxacin withdrawal during initiation and pseudo-senescence reinitiated proliferation in vitro and tumor formation in vivo Importantly, prolonged treatment with ciprofloxacin induced permanent senescence that failed to reverse following ciprofloxacin withdrawal. RNA-seq revealed downregulation of the p65 (RELA) transcription network, as well as incremental expression of SMAD pathway genes from initiation to permanent senescence. Ciprofloxacin withdrawal during initiation and pseudo-senescence, but not permanent senescence, increased the nuclear localization of p65 and escape from ciprofloxacin-induced senescence. By contrast, permanently senescent cells showed loss of nuclear p65 and increased apoptosis. Pharmacological inhibition or genetic knockdown of p65 upheld senescence in vitro and inhibited tumor formation in vivo Our study demonstrates that levels of nuclear p65 define the window of reversibility of therapy-induced senescence and that permanent senescence can be induced in GBM cells when the use of senotherapeutics is coupled with p65 inhibitors.
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Affiliation(s)
- Sameer Salunkhe
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400 094, India
| | - Saket V Mishra
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400 094, India
| | - Jyothi Nair
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400 094, India
| | - Sanket Shah
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400 094, India
| | - Nilesh Gardi
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400 094, India.,Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Navi Mumbai, Maharashtra 410210, India
| | - Rahul Thorat
- Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer Kharghar, Navi Mumbai, Maharashtra 410210, India
| | - Debashmita Sarkar
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400 094, India
| | - Jacinth Rajendra
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400 094, India
| | - Ekjot Kaur
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400 094, India
| | - Shilpee Dutt
- Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India .,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400 094, India
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Barbouti A, Lagopati N, Veroutis D, Goulas V, Evangelou K, Kanavaros P, Gorgoulis VG, Galaris D. Implication of Dietary Iron-Chelating Bioactive Compounds in Molecular Mechanisms of Oxidative Stress-Induced Cell Ageing. Antioxidants (Basel) 2021; 10:491. [PMID: 33800975 PMCID: PMC8003849 DOI: 10.3390/antiox10030491] [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: 02/22/2021] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023] Open
Abstract
One of the prevailing perceptions regarding the ageing of cells and organisms is the intracellular gradual accumulation of oxidatively damaged macromolecules, leading to the decline of cell and organ function (free radical theory of ageing). This chemically undefined material known as "lipofuscin," "ceroid," or "age pigment" is mainly formed through unregulated and nonspecific oxidative modifications of cellular macromolecules that are induced by highly reactive free radicals. A necessary precondition for reactive free radical generation and lipofuscin formation is the intracellular availability of ferrous iron (Fe2+) ("labile iron"), catalyzing the conversion of weak oxidants such as peroxides, to extremely reactive ones like hydroxyl (HO•) or alcoxyl (RO•) radicals. If the oxidized materials remain unrepaired for extended periods of time, they can be further oxidized to generate ultimate over-oxidized products that are unable to be repaired, degraded, or exocytosed by the relevant cellular systems. Additionally, over-oxidized materials might inactivate cellular protection and repair mechanisms, thus allowing for futile cycles of increasingly rapid lipofuscin accumulation. In this review paper, we present evidence that the modulation of the labile iron pool distribution by nutritional or pharmacological means represents a hitherto unappreciated target for hampering lipofuscin accumulation and cellular ageing.
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Affiliation(s)
- Alexandra Barbouti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | - Nefeli Lagopati
- Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Faculty of Medicine, School of Health Science, National and Kapodistrian University of Athens, 75, Mikras Asias Str., Goudi, 11527 Athens, Greece; (N.L.); (D.V.); (K.E.); (V.G.G.)
| | - Dimitris Veroutis
- Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Faculty of Medicine, School of Health Science, National and Kapodistrian University of Athens, 75, Mikras Asias Str., Goudi, 11527 Athens, Greece; (N.L.); (D.V.); (K.E.); (V.G.G.)
| | - Vlasios Goulas
- Department of Agricultural Sciences, Biotechnology and Food Science, Cyprus University of Technology, 3036 Lemesos, Cyprus;
| | - Konstantinos Evangelou
- Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Faculty of Medicine, School of Health Science, National and Kapodistrian University of Athens, 75, Mikras Asias Str., Goudi, 11527 Athens, Greece; (N.L.); (D.V.); (K.E.); (V.G.G.)
| | - Panagiotis Kanavaros
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | - Vassilis G. Gorgoulis
- Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Faculty of Medicine, School of Health Science, National and Kapodistrian University of Athens, 75, Mikras Asias Str., Goudi, 11527 Athens, Greece; (N.L.); (D.V.); (K.E.); (V.G.G.)
- Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
- Faculty of Biology, Medicine and Health Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, UK
- Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Galaris
- Laboratory of Biological Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
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Garbern JC, Lee RT. Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes. Stem Cell Res Ther 2021; 12:177. [PMID: 33712058 PMCID: PMC7953594 DOI: 10.1186/s13287-021-02252-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/28/2021] [Indexed: 12/13/2022] Open
Abstract
Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.
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Affiliation(s)
- Jessica C Garbern
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA, 02138, USA
- Department of Cardiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Richard T Lee
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA, 02138, USA.
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA.
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45
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Mechanisms of Cisplatin in Combination with Repurposed Drugs against Human Endometrial Carcinoma Cells. Life (Basel) 2021; 11:life11020160. [PMID: 33669781 PMCID: PMC7922822 DOI: 10.3390/life11020160] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/10/2021] [Accepted: 02/16/2021] [Indexed: 12/18/2022] Open
Abstract
Although endometrial carcinoma is one of the most common gynecological malignancies worldwide, its precise etiology remains unknown. Moreover, no novel adjuvant and/or targeted therapies are currently being developed to achieve greater efficacy for endometrial cancer patients who develop chemotherapeutic drug resistance. In this study, we used three human endometrial cancer cell lines, RL95-2, HEC-1-A, and KLE, to investigate the responsiveness of cisplatin alone and in combination with potential repurposed drugs. We first found that RL95-2 cells were more sensitive to cisplatin than HEC-1-A or KLE cells. The cytotoxicity of cisplatin in RL95-2 cells may reflect its ability to perturb the cell cycle, reactive oxygen species production and autophagy as well as to induce senescence and DNA damage. Similar effects, although not DNA damage, were also observed in HEC-1-A and KLE cells. In addition, downregulation of p53 and/or cyclin D1 may also impact the responsiveness of HEC-1-A and KLE cells to cisplatin. We also observed that resveratrol, trichostatin A (TSA), caffeine, or digoxin increased the apoptotic process of cisplatin toward RL95-2 cells, while amiodarone or TSA increased its apoptotic process toward HEC-1-A cells. The combination index supported the assertion that the combination of cisplatin with caffeine, amiodarone, resveratrol, metformin, digoxin, or TSA increases the cytotoxicity of cisplatin in HEC-1-A cells. These findings suggest potential strategies for enhancing the efficacy of cisplatin to overcome drug resistance in endometrial carcinoma patients.
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Guo Z, Wang G, Wu B, Chou WC, Cheng L, Zhou C, Lou J, Wu D, Su L, Zheng J, Ting JPY, Wan YY. DCAF1 regulates Treg senescence via the ROS axis during immunological aging. J Clin Invest 2021; 130:5893-5908. [PMID: 32730228 DOI: 10.1172/jci136466] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
As a hallmark of immunological aging, low-grade, chronic inflammation with accumulation of effector memory T cells contributes to increased susceptibility to many aging-related diseases. While the proinflammatory state of aged T cells indicates a dysregulation of immune homeostasis, whether and how aging drives regulatory T cell (Treg) aging and alters Treg function are not fully understood owing to a lack of specific aging markers. Here, by a combination of cellular, molecular, and bioinformatic approaches, we discovered that Tregs senesce more severely than conventional T (Tconv) cells during aging. We found that Tregs from aged mice were less efficient than young Tregs in suppressing Tconv cell function in an inflammatory bowel disease model and in preventing Tconv cell aging in an irradiation-induced aging model. Furthermore, we revealed that DDB1- and CUL4-associated factor 1 (DCAF1) was downregulated in aged Tregs and was critical to restrain Treg aging via reactive oxygen species (ROS) regulated by glutathione-S-transferase P (GSTP1). Importantly, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Tregs. Therefore, our studies uncover an important role of the DCAF1/GSTP1/ROS axis in Treg senescence, which leads to uncontrolled inflammation and immunological aging.
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Affiliation(s)
- Zengli Guo
- Lineberger Comprehensive Cancer Center and.,Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Gang Wang
- Lineberger Comprehensive Cancer Center and.,Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China
| | - Bing Wu
- Lineberger Comprehensive Cancer Center and.,Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Wei-Chun Chou
- Lineberger Comprehensive Cancer Center and.,Department of Genetics
| | - Liang Cheng
- Lineberger Comprehensive Cancer Center and.,Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | - Jitong Lou
- Department of Biostatistics, Gillings School of Global Public Health, and
| | - Di Wu
- Department of Biostatistics, Gillings School of Global Public Health, and.,Department of Periodontology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Lishan Su
- Lineberger Comprehensive Cancer Center and.,Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Junnian Zheng
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China
| | - Jenny P-Y Ting
- Lineberger Comprehensive Cancer Center and.,Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Genetics
| | - Yisong Y Wan
- Lineberger Comprehensive Cancer Center and.,Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Wang B, Ke W, Wang K, Li G, Ma L, Lu S, Xiang Q, Liao Z, Luo R, Song Y, Hua W, Wu X, Zhang Y, Zeng X, Yang C. Mechanosensitive Ion Channel Piezo1 Activated by Matrix Stiffness Regulates Oxidative Stress-Induced Senescence and Apoptosis in Human Intervertebral Disc Degeneration. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8884922. [PMID: 33628392 PMCID: PMC7889339 DOI: 10.1155/2021/8884922] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 01/10/2021] [Accepted: 01/16/2021] [Indexed: 02/06/2023]
Abstract
Mechanical stimulation plays a crucial part in the development of intervertebral disc degeneration (IDD). Extracellular matrix (ECM) stiffness, which is a crucial mechanical microenvironment of the nucleus pulposus (NP) tissue, contributes to the pathogenesis of IDD. The mechanosensitive ion channel Piezo1 mediates mechanical transduction. This study purposed to investigate the function of Piezo1 in human NP cells under ECM stiffness. The expression of Piezo1 and the ECM elasticity modulus increased in degenerative NP tissues. Stiff ECM activated the Piezo1 channel and increased intracellular Ca2+ levels. Moreover, the activation of Piezo1 increased intracellular reactive oxygen species (ROS) levels and the expression of GRP78 and CHOP, which contribute to oxidative stress and endoplasmic reticulum (ER) stress. Furthermore, stiff ECM aggravated oxidative stress-induced senescence and apoptosis in human NP cells. Piezo1 inhibition alleviated oxidative stress-induced senescence and apoptosis, caused by the increase in ECM stiffness. Finally, Piezo1 silencing ameliorated IDD in an in vivo rat model and decreased the elasticity modulus of rat NP tissues. In conclusion, we identified the mechanosensitive ion channel Piezo1 in human NP cells as a mechanical transduction mediator for stiff ECM stimulation. Our results provide novel insights into the mechanism of mechanical transduction in NP cells, with potential for treating IDD.
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Affiliation(s)
- Bingjin Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wencan Ke
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kun Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Gaocai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Liang Ma
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Saideng Lu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qian Xiang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhiwei Liao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Rongjin Luo
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yu Song
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wenbin Hua
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xinghuo Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yukun Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xianlin Zeng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Cao Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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48
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Feng G, Zhang XF. Production of a codonopsis polysaccharide iron complex and evaluation of its properties. Int J Biol Macromol 2020; 162:1227-1240. [PMID: 32615228 DOI: 10.1016/j.ijbiomac.2020.06.210] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 06/14/2020] [Accepted: 06/22/2020] [Indexed: 11/20/2022]
Abstract
A water extraction and alcohol precipitation method was applied to extract polysaccharides from Codonopsis pilosula (CPP), response surface methodology was used to optimize the extraction conditions and synthesis of C. pilosula polysaccharide iron (CPPI), and the properties of CPPI were evaluated. The optimum extraction conditions for CPP were as follows: liquid-solid ratio of 29.39 mL/g, time of 1.25 h and temperature of 62.84 °C. The optimum synthesis conditions for CPPI were pH 8.9, temperature 70.30 °C and the ratio of citric acid to CPP1 of 2.95. An HPSEC-MALLS-RID system, UV spectroscopy, FT-IR spectroscopy and NMR were used for characterization of the polysaccharide. CPPI exhibited antioxidant activity in vitro and a relatively strong inhibitory effect on A2780 cells growth. After CPPI treatment, the reactive oxygen species increased, the mitochondrial membrane potential decreased, and DNA damage was observed in A2780 cells. Therefore, CPPI should be explored as a potential antioxidant and an antitumor drug in a clinical setting.
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Affiliation(s)
- Ge Feng
- College of Veterinary medicine, Qingdao Agricultural University, Qingdao, People's Republic of China; College of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, People's Republic of China
| | - Xi-Feng Zhang
- College of Veterinary medicine, Qingdao Agricultural University, Qingdao, People's Republic of China; Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, People's Republic of China.
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49
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Comparative Assessment of the Antioxidant Activities among the Extracts of Different Parts of Clausena lansium (Lour.) Skeels in Human Gingival Fibroblast Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:3958098. [PMID: 33082823 PMCID: PMC7563039 DOI: 10.1155/2020/3958098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 09/08/2020] [Accepted: 09/22/2020] [Indexed: 12/29/2022]
Abstract
Clausena lansium (Lour.) Skeels (wampee) is an outstanding natural plant with medicinal properties. The aim of this study was to compare the cytoprotective effects of four parts of wampee under oxidative stress. The aqueous extracts of leaf, peel, pulp, and seed were tested for the proliferation effects on human gingival fibroblast (HGF) cells and the protective effects in the hydrogen peroxide-induced HGF model. Furthermore, the total glutathione assay and identification of rutin by high-performance liquid chromatography were carried out to attempt to determine whether the cytoprotective effects were related to the total glutathione (GSH) stability and rutin content. The results showed that all of the extracts had no cytotoxicity to HGF at tested concentrations ranging from 50 to 5000 μg/ml during 24 h, and the leaf, pulp, and seed extracts increased proliferation of HGF at relatively high concentrations. All the extracts except for the seed extract significantly decreased the production of reactive oxygen species, and the peel extracts exhibited the most effective antioxidant effect. The leaf extract had the highest anticytotoxicity and GSH stabilization effect in the HGF challenged with hydrogen peroxide. In addition, the relative content of rutin in peel and leaf extracts was higher than that in pulp and seed. The results of GSH assay and rutin identification suggest that different cellular protective effects among the four parts of wampee are partially related to the GSH stabilization and rutin content. These findings provide a scientific basis for the antioxidant effect-related biological activities of wampee extracts.
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50
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Ribeiro FM, de Oliveira MM, Singh S, Sakthivel TS, Neal CJ, Seal S, Ueda-Nakamura T, Lautenschlager SDOS, Nakamura CV. Ceria Nanoparticles Decrease UVA-Induced Fibroblast Death Through Cell Redox Regulation Leading to Cell Survival, Migration and Proliferation. Front Bioeng Biotechnol 2020; 8:577557. [PMID: 33102462 PMCID: PMC7546350 DOI: 10.3389/fbioe.2020.577557] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
Exposure to ultraviolet radiation is a major contributor to premature skin aging and carcinogenesis, which is mainly driven by overproduction of reactive oxygen species (ROS). There is growing interest for research on new strategies that address photoaging prevention, such as the use of nanomaterials. Cerium oxide nanoparticles (nanoceria) show enzyme-like activity in scavenging ROS. Herein, our goal was to study whether under ultraviolet A rays (UVA)-induced oxidative redox imbalance, a low dose of nanoceria induces protective effects on cell survival, migration, and proliferation. Fibroblasts cells (L929) were pretreated with nanoceria (100 nM) and exposed to UVA radiation. Pretreatment of cells with nanoceria showed negligible cytotoxicity and protected cells from UVA-induced death. Nanoceria also inhibited ROS production immediately after irradiation and for up to 48 h and restored the superoxide dismutase (SOD) activity and GSH level. Additionally, the nanoceria pretreatment prevented apoptosis by decreasing Caspase 3/7 levels and the loss of mitochondrial membrane potential. Nanoceria significantly improved the cell survival migration and increased proliferation, over a 5 days period, as compared with UVA-irradiated cells, in wound healing assay. Furthermore, it was observed that nanoceria decreased cellular aging and ERK 1/2 phosphorylation. Our study suggests that nanoceria might be a potential ally to endogenous, antioxidant enzymes, and enhancing the redox potentials to fight against UVA-induced photodamage and consequently modulating the cells survival, migration, and proliferation.
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Affiliation(s)
- Fabianne Martins Ribeiro
- Programa de Pós-Graduação em Ciências Biológicas, Universidade Estadual de Maringá, Maringá, Brazil
| | | | - Sushant Singh
- Advanced Materials Processing and Analysis Center, Nanoscience Technology Center, University of Central Florida, Orlando, FL, United States
| | - Tamil S Sakthivel
- Advanced Materials Processing and Analysis Center, Nanoscience Technology Center, University of Central Florida, Orlando, FL, United States
| | - Craig J Neal
- Advanced Materials Processing and Analysis Center, Nanoscience Technology Center, University of Central Florida, Orlando, FL, United States
| | - Sudipta Seal
- Advanced Materials Processing and Analysis Center, Nanoscience Technology Center, University of Central Florida, Orlando, FL, United States
| | - Tânia Ueda-Nakamura
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Brazil
| | | | - Celso Vataru Nakamura
- Programa de Pós-Graduação em Ciências Biológicas, Universidade Estadual de Maringá, Maringá, Brazil.,Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Brazil
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