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Choi Y, No MH, Heo JW, Cho EJ, Park DH, Kang JH, Kim CJ, Seo DY, Han J, Kwak HB. Resveratrol attenuates aging-induced mitochondrial dysfunction and mitochondria-mediated apoptosis in the rat heart. Nutr Res Pract 2025; 19:186-199. [PMID: 40226768 PMCID: PMC11982693 DOI: 10.4162/nrp.2025.19.2.186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/03/2024] [Accepted: 10/15/2024] [Indexed: 04/15/2025] Open
Abstract
BACKGROUD/OBJECTIVES Resveratrol, a natural polyphenolic compound, has potent antioxidant and anti-inflammatory properties, leading to beneficial effects against cardiovascular diseases. The purpose of this study was to determine whether resveratrol induces protective effects against aging-induced cardiac remodeling, mitochondrial dysfunction, and mitochondria-mediated apoptosis in the heart. MATERIALS/METHODS Thirty-two male Fischer 344 rats were divided into 4 groups: 2 groups that were orally treated with resveratrol (50 mg/kg/day) for 6 weeks (young and old resveratrol groups), and 2 control groups (young and old control groups). Mitochondrial function and mitochondria-mediated apoptotic pathway were analyzed in cardiac muscle fibers from the left ventricle. RESULTS Resveratrol significantly reduced cardiac hypertrophy and remodeling in aging hearts. In addition, resveratrol significantly ameliorated aging-induced mitochondrial dysfunction (e.g., decreased oxygen respiration and increased hydrogen peroxide emission) and mitochondria-dependent apoptotic signaling (the Bax/Bcl-2 ratio, mitochondrial permeability transition pore opening sensitivity, and cleaved caspase-3 protein levels). Resveratrol also significantly attenuated aging-induced apoptosis (determined via cleaved caspase-3 staining and TUNEL-positive myonuclei) in cardiac muscles. CONCLUSION This study demonstrates that resveratrol treatment has a beneficial effect on aging-induced cardiac remodeling by ameliorating mitochondrial dysfunction and inhibiting mitochondria-mediated apoptosis in the heart.
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Affiliation(s)
- Youngju Choi
- Institute of Sports and Arts Convergence (ISAC), Inha University, Incheon 22212, Korea
- Institute for Specialized Teaching and Research, Inha University, Incheon 22212, Korea
- Department of Kinesiology, Inha University, Incheon 22212, Korea
| | - Mi-Hyun No
- Institute of Sports and Arts Convergence (ISAC), Inha University, Incheon 22212, Korea
| | - Jun-Won Heo
- Department of Biomedical Science and Engineering, Inha University, Incheon 22212, Korea
| | - Eun-Jeong Cho
- Department of Biomedical Science and Engineering, Inha University, Incheon 22212, Korea
| | - Dong-Ho Park
- Institute of Sports and Arts Convergence (ISAC), Inha University, Incheon 22212, Korea
- Department of Kinesiology, Inha University, Incheon 22212, Korea
- Department of Biomedical Science and Engineering, Inha University, Incheon 22212, Korea
| | - Ju-Hee Kang
- Institute of Sports and Arts Convergence (ISAC), Inha University, Incheon 22212, Korea
- Department of Biomedical Science and Engineering, Inha University, Incheon 22212, Korea
- Department of Pharmacology, College of Medicine, Inha University, Incheon 22212, Korea
| | - Chang-Ju Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Dae Yun Seo
- National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan 47392, Korea
| | - Jin Han
- National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan 47392, Korea
| | - Hyo-Bum Kwak
- Institute of Sports and Arts Convergence (ISAC), Inha University, Incheon 22212, Korea
- Department of Kinesiology, Inha University, Incheon 22212, Korea
- Department of Biomedical Science and Engineering, Inha University, Incheon 22212, Korea
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Derafshpour L, Niazi M, Pourheydar B, Roshan-Milani S, Asghariehahari M, Chodari L. Aging and voluntary exercise's effects on Aβ1-42 levels, endoplasmic reticulum stress factors, and apoptosis in the hippocampus of old male rats. Brain Res 2025; 1850:149447. [PMID: 39761746 DOI: 10.1016/j.brainres.2025.149447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 12/21/2024] [Accepted: 01/03/2025] [Indexed: 01/14/2025]
Abstract
Within the aging cortex, amyloid beta peptide (Aβ) is a crucial element of the senile plaques, a hallmark feature often observed in cases of Alzheimer's disease (AD). The UPR (unfolded protein response), a cellular mechanism for protein folding, is switched on by Aβ accumulation. Endoplasmic reticulum (ER) stress has been identified as playing a role in aging and the development of neurodegenerative diseases. The exact molecular pathways leading to perishing of cells from Aβ-induced ER stress, as well as the impact of voluntary exercise on these mechanisms, are still subjects awaiting a definitive answer yet. In the current study, 18 male Wistar rats were included: 6 young rats (3 months old; 200-250 g) in the Young Control group, and 12 old rats (18 months old; 400-430 g) randomly allocated to the Old Control and Old Exercise groups. The rat cages had running wheels for them to voluntarily run on for 8 weeks. This was followed by Western blotting, immunohistochemical staining, biochemical as well as morphological analyses. Voluntary exercise reduced Aβ1-42 deposition (P < 0.001) and inhibited the activation of caspase-8 (P < 0.001) and caspase-12 (P < 0.01), and on top of that down-regulated the expression of ATF6 (P < 0.001), CHOP (P < 0.01), and p-PERK (P < 0.05) proteins in the hippocampus of old male rats. Exercise amplified the population of Bcl-2-expressing cells and decreased the population of Bax-expressing cells in the hippocampus of the Old Exercise group (P < 0.001). Voluntary exercise inhibited the apoptotic pathways and suppressed the activation of UPR signaling pathways. Hence, voluntary exercise may be a therapeutic strategy and a promising approach to prevent AD through modulation of Aβ-induced ER stress.
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Affiliation(s)
- Leila Derafshpour
- Neuroscience, Ottawa Hospital Research Institue, Ottawa, ONK1H 8M5, Canada
| | - Mona Niazi
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Bagher Pourheydar
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Anatomical Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Shiva Roshan-Milani
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran; Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Morteza Asghariehahari
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Leila Chodari
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran; Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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Arroum T, Hish GA, Burghardt KJ, Ghamloush M, Bazzi B, Mrech A, Morse PT, Britton SL, Koch LG, McCully JD, Hüttemann M, Malek MH. Mitochondria Transplantation: Rescuing Innate Muscle Bioenergetic Impairment in a Model of Aging and Exercise Intolerance. J Strength Cond Res 2024; 38:1189-1199. [PMID: 38900170 PMCID: PMC11192236 DOI: 10.1519/jsc.0000000000004793] [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] [Indexed: 06/21/2024]
Abstract
ABSTRACT Arroum, T, Hish, GA, Burghardt, KJ, Ghamloush, M, Bazzi, B, Mrech, A, Morse, PT, Britton, SL, Koch, LG, McCully, JD, Hüttemann, M, and Malek, MH. Mitochondria transplantation: Rescuing innate muscle bioenergetic impairment in a model of aging and exercise intolerance. J Strength Cond Res 38(7): 1189-1199, 2024-Mitochondria, through oxidative phosphorylation, are crucial for energy production. Disease, genetic impairment, or deconditioning can harm muscle mitochondria, affecting energy production. Endurance training enhances mitochondrial function but assumes mobility. Individuals with limited mobility lack effective treatments for mitochondrial dysfunction because of disease or aging. Mitochondrial transplantation replaces native mitochondria that have been damaged with viable, respiration-competent mitochondria. Here, we used a rodent model selectively bred for low-capacity running (LCR), which exhibits innate mitochondrial dysfunction in the hind limb muscles. Hence, the purpose of this study was to use a distinct breed of rats (i.e., LCR) that display hereditary skeletal muscle mitochondrial dysfunction to evaluate the consequences of mitochondrial transplantation. We hypothesized that the transplantation of mitochondria would effectively alleviate mitochondrial dysfunction in the hind limb muscles of rats when compared with placebo injections. In addition, we hypothesized that rats receiving the mitochondrial transplantation would experience an improvement in their functional capacity, as evaluated through incremental treadmill testing. Twelve aged LCR male rats (18 months old) were randomized into 2 groups (placebo or mitochondrial transplantation). One LCR rat of the same age and sex was used as the donor to isolate mitochondria from the hindlimb muscles. Isolated mitochondria were injected into both hindlimb muscles (quadriceps femoris, tibialis anterior (TA), and gastrocnemius complex) of a subset LCR (n = 6; LCR-M) rats. The remaining LCR (n = 5; LCR-P) subset received a placebo injection containing only the vehicle without the isolated mitochondria. Four weeks after mitochondrial transplantation, rodents were euthanized and hindlimb muscles harvested. The results indicated a significant (p < 0.05) increase in mitochondrial markers for glycolytic (plantaris and TA) and mixed (quadricep femoris) muscles, but not oxidative muscle (soleus). Moreover, we found significant (p < 0.05) epigenetic changes (i.e., hypomethylation) at the global and site-specific levels for a key mitochondrial regulator (transcription factor A mitochondrial) between the placebo and mitochondrial transplantation groups. To our knowledge, this is the first study to examine the efficacy of mitochondrial transplantation in a rodent model of aging with congenital skeletal muscle dysfunction.
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Affiliation(s)
- Tasnim Arroum
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201
| | - Gerald A. Hish
- Unit for Laboratory Animal Medicine (ULAM), University of Michigan, Ann Arbor, Ann Arbor, MI 48109
| | - Kyle J. Burghardt
- Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201
| | - Mohamed Ghamloush
- Physical Therapy Program, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Health Care Sciences, Detroit, MI 48201
- Integrative Physiology of Exercise Laboratory, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Health Care Sciences, Detroit, MI 48201
| | - Belal Bazzi
- Physical Therapy Program, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Health Care Sciences, Detroit, MI 48201
- Integrative Physiology of Exercise Laboratory, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Health Care Sciences, Detroit, MI 48201
| | - Abdallah Mrech
- Physical Therapy Program, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Health Care Sciences, Detroit, MI 48201
- Integrative Physiology of Exercise Laboratory, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Health Care Sciences, Detroit, MI 48201
| | - Paul T. Morse
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201
| | - Steven L. Britton
- Department of Anesthesiology, University of Michigan, Ann Arbor, Ann Arbor, MI 48109
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Ann Arbor, MI 48109
| | - Lauren G. Koch
- Department of Physiology and Pharmacology, The University of Toledo, College of Medicine and Life Sciences, Toledo, OH 43606
| | - James D. McCully
- Department of Cardiac Surgery, Boston Children’s Hospital Harvard Medical School, Boston, MA 02115
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201
| | - Moh H. Malek
- Physical Therapy Program, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Health Care Sciences, Detroit, MI 48201
- Integrative Physiology of Exercise Laboratory, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Health Care Sciences, Detroit, MI 48201
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El-Akabawy G, El-Kersh SOF, El-Kersh AOFO, Amin SN, Rashed LA, Abdel Latif N, Elshamey A, Abdallah MAAEM, Saleh IG, Hein ZM, El-Serafi I, Eid N. Dental pulp stem cells ameliorate D-galactose-induced cardiac ageing in rats. PeerJ 2024; 12:e17299. [PMID: 38799055 PMCID: PMC11127642 DOI: 10.7717/peerj.17299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 04/03/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND Ageing is a key risk factor for cardiovascular disease and is linked to several alterations in cardiac structure and function, including left ventricular hypertrophy and increased cardiomyocyte volume, as well as a decline in the number of cardiomyocytes and ventricular dysfunction, emphasizing the pathological impacts of cardiomyocyte ageing. Dental pulp stem cells (DPSCs) are promising as a cellular therapeutic source due to their minimally invasive surgical approach and remarkable proliferative ability. AIM This study is the first to investigate the outcomes of the systemic transplantation of DPSCs in a D-galactose (D-gal)-induced rat model of cardiac ageing. Methods. Thirty 9-week-old Sprague-Dawley male rats were randomly assigned into three groups: control, ageing (D-gal), and transplanted groups (D-gal + DPSCs). D-gal (300 mg/kg/day) was administered intraperitoneally daily for 8 weeks. The rats in the transplantation group were intravenously injected with DPSCs at a dose of 1 × 106 once every 2 weeks. RESULTS The transplanted cells migrated to the heart, differentiated into cardiomyocytes, improved cardiac function, upregulated Sirt1 expression, exerted antioxidative effects, modulated connexin-43 expression, attenuated cardiac histopathological alterations, and had anti-senescent and anti-apoptotic effects. CONCLUSION Our results reveal the beneficial effects of DPSC transplantation in a cardiac ageing rat model, suggesting their potential as a viable cell therapy for ageing hearts.
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Affiliation(s)
- Gehan El-Akabawy
- Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman, United Arab Emirates
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
- Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | | | | | - Shaimaa Nasr Amin
- Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Laila Ahmed Rashed
- Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Noha Abdel Latif
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Cairo, Egypt
- Department of Medical Pharmacology, Armed Forces College of Medicine, Cairo, Egypt
| | - Ahmed Elshamey
- Samanoud General Hospital, Samannoud City, Samanoud, Gharbia, Egypt
| | | | - Ibrahim G. Saleh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Sinai University, Kantra, Ismailia, Egypt
| | - Zaw Myo Hein
- Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman, United Arab Emirates
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Ibrahim El-Serafi
- Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman, United Arab Emirates
| | - Nabil Eid
- Department of Anatomy, Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, Malaysia
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Rao S, He Z, Wang Z, Yin H, Hu X, Tan Y, Wan T, Zhu H, Luo Y, Wang X, Li H, Wang Z, Hu X, Hong C, Wang Y, Luo M, Du W, Qian Y, Tang S, Xie H, Chen C. Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1. Acta Pharm Sin B 2024; 14:1166-1186. [PMID: 38487008 PMCID: PMC10935484 DOI: 10.1016/j.apsb.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 03/17/2024] Open
Abstract
Aging increases the risks of various diseases and the vulnerability to death. Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases. This study demonstrates that extracellular vesicles from human urine-derived stem cells (USC-EVs) efficiently inhibit cellular senescence in vitro and in vivo. The intravenous injection of USC-EVs improves cognitive function, increases physical fitness and bone quality, and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice. The anti-aging effects of USC-EVs are not obviously affected by the USC donors' ages, genders, or health status. Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase (PLAU) and tissue inhibitor of metalloproteinases 1 (TIMP1). These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases, cyclin-dependent kinase inhibitor 2A (P16INK4a), and cyclin-dependent kinase inhibitor 1A (P21cip1). These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.
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Affiliation(s)
- Shanshan Rao
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Zehui He
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Zun Wang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
- Xiangya School of Nursing, Central South University, Changsha 410013, China
| | - Hao Yin
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Xiongke Hu
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
- Department of Pediatric Orthopedics, Hunan Children's Hospital, University of South China, Changsha 410007, China
| | - Yijuan Tan
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Tengfei Wan
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Hao Zhu
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Yi Luo
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Xin Wang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Hongming Li
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Zhenxing Wang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Xinyue Hu
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Chungu Hong
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Yiyi Wang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Mingjie Luo
- Xiangya School of Nursing, Central South University, Changsha 410013, China
- School of Nursing, Xinjiang Medical University, Urumqi, Xinjiang 830000, China
| | - Wei Du
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Department of Rehabilitation, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yuxuan Qian
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
| | - Siyuan Tang
- Xiangya School of Nursing, Central South University, Changsha 410013, China
| | - Hui Xie
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Chunyuan Chen
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha 410008, China
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Sassu E, Tumlinson G, Stefanovska D, Fernández MC, Iaconianni P, Madl J, Brennan TA, Koch M, Cameron BA, Preissl S, Ravens U, Schneider-Warme F, Kohl P, Zgierski-Johnston CM, Hortells L. Age-related structural and functional changes of the intracardiac nervous system. J Mol Cell Cardiol 2024; 187:1-14. [PMID: 38103633 DOI: 10.1016/j.yjmcc.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/14/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND Although aging is known to be associated with an increased incidence of both atrial and ventricular arrhythmias, there is limited knowledge about how Schwann cells (SC) and the intracardiac nervous system (iCNS) remodel with age. Here we investigate the differences in cardiac SC, parasympathetic nerve fibers, and muscarinic acetylcholine receptor M2 (M2R) expression in young and old mice. Additionally, we examine age-related changes in cardiac responses to sympathomimetic and parasympathomimetic drugs. METHODS AND RESULTS Lower SC density, lower SC proliferation and fewer parasympathetic nerve fibers were observed in cardiac and, as a control sciatic nerves from old (20-24 months) compared to young mice (2-3 months). In old mice, chondroitin sulfate proteoglycan 4 (CSPG4) was increased in sciatic but not cardiac nerves. Expression of M2R was lower in ventricular myocardium and ventricular conduction system from old mice compared to young mice, while no significant difference was seen in M2R expression in sino-atrial or atrio-ventricular node pacemaker tissue. Heart rate was slower and PQ intervals were longer in Langendorff-perfused hearts from old mice. Ventricular tachycardia and fibrillation were more frequently observed in response to carbachol administration in hearts from old mice versus those from young mice. CONCLUSIONS On the background of reduced presence of SC and parasympathetic nerve fibers, and of lower M2R expression in ventricular cardiomyocytes and conduction system of aged hearts, the propensity of ventricular arrhythmogenesis upon parasympathomimetic drug application is increased. Whether this is caused by an increase in heterogeneity of iCNS structure and function remains to be elucidated.
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Affiliation(s)
- Eliza Sassu
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79110 Freiburg, Germany
| | - Gavin Tumlinson
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Dragana Stefanovska
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79110 Freiburg, Germany
| | - Marbely C Fernández
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Pia Iaconianni
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Josef Madl
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Tomás A Brennan
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Manuel Koch
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Breanne A Cameron
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Sebastian Preissl
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79110 Freiburg, Germany
| | - Ursula Ravens
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Franziska Schneider-Warme
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; CIBSS Centre for Integrative Biological Signalling Studies, and Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Peter Kohl
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; CIBSS Centre for Integrative Biological Signalling Studies, and Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Callum M Zgierski-Johnston
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany.
| | - Luis Hortells
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, University of Freiburg, 79110 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79110 Freiburg, Germany.
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7
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Rancan L, Linillos-Pradillo B, Centeno J, Paredes SD, Vara E, Tresguerres JAF. Protective Actions of Cannabidiol on Aging-Related Inflammation, Oxidative Stress and Apoptosis Alterations in Liver and Lung of Long Evans Rats. Antioxidants (Basel) 2023; 12:1837. [PMID: 37891916 PMCID: PMC10604065 DOI: 10.3390/antiox12101837] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/04/2023] [Accepted: 10/08/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Aging is characterised by the progressive accumulation of oxidative damage which leads to inflammation and apoptosis in cells. This affects all tissues in the body causing the deterioration of several organs. Previous studies observed that cannabidiol (CBD) could extend lifespan and health span by its antioxidant, anti-inflammatory and autophagy properties. However, research on the anti-aging effect of CBD is still in the beginning stages. This study aimed to investigate the role of cannabidiol (CBD) in the prevention of age-related alterations in liver and lung using a murine model. METHODS 15-month-old Long Evans rats were treated with 10 mg/kg b.w./day of CBD for 10 weeks and compared to animals of the same age as old control and 2-month-old animals as young control. Gene and/or protein expressions, by RT-qPCR and Western blotting, respectively, were assessed in terms of molecules related to oxidative stress (GST, GPx, GR and HO-1d), inflammation (NFκB, IL-1β and TNF-α) and apoptosis (BAX, Bcl-2, AIF, and CASP-1). In addition, MDA and MPO levels were measured by colorimetric assay. Results were analysed by ANOVA followed by Tukey-Kramer test, considering statistically significant a p < 0.05. RESULTS GST, GPx and GR expressions were significantly reduced (p < 0.01) in liver samples from old animals compared to young ones and CBD treatment was able to revert it. A significant increase was observed in old animals compared to young ones in relation to oxidative stress markers (MDA and HO-1d), proinflammatory molecules (NFκB, IL-1β and TNF-α), MPO levels and proapoptotic molecules (BAX, AIF and CASP-1), while no significant alterations were observed in the antiapoptotic molecules (Bcl-2). All these changes were more noticeable in the liver, while the lung seemed to be less affected. In almost all the measured parameters, CBD treatment was able to revert the alterations caused by age restoring the levels to those observed in the group of young animals. CONCLUSIONS Chronic treatment with CBD in 15-month-old rats showed beneficial effects in lung and more significantly in liver by reducing the levels of inflammatory, oxidative and apoptotic mediators, and hence the cell damage associated with these three processes inherent to aging.
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Affiliation(s)
- Lisa Rancan
- Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (L.R.); (B.L.-P.); (E.V.)
| | - Beatriz Linillos-Pradillo
- Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (L.R.); (B.L.-P.); (E.V.)
| | - Julia Centeno
- Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (L.R.); (B.L.-P.); (E.V.)
| | - Sergio D. Paredes
- Department of Physiology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Elena Vara
- Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (L.R.); (B.L.-P.); (E.V.)
| | - Jesús A. F. Tresguerres
- Department of Physiology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain;
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8
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Ho Shon I, Hogg PJ. Imaging of cell death in malignancy: Targeting pathways or phenotypes? Nucl Med Biol 2023; 124-125:108380. [PMID: 37598518 DOI: 10.1016/j.nucmedbio.2023.108380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/06/2023] [Accepted: 08/10/2023] [Indexed: 08/22/2023]
Abstract
Cell death is fundamental in health and disease and resisting cell death is a hallmark of cancer. Treatment of malignancy aims to cause cancer cell death, however current clinical imaging of treatment response does not specifically image cancer cell death but assesses this indirectly either by changes in tumor size (using x-ray computed tomography) or metabolic activity (using 2-[18F]fluoro-2-deoxy-glucose positron emission tomography). The ability to directly image tumor cell death soon after commencement of therapy would enable personalised response adapted approaches to cancer treatment that is presently not possible with current imaging, which is in many circumstances neither sufficiently accurate nor timely. Several cell death pathways have now been identified and characterised that present multiple potential targets for imaging cell death including externalisation of phosphatidylserine and phosphatidylethanolamine, caspase activation and La autoantigen redistribution. However, targeting one specific cell death pathway carries the risk of not detecting cell death by other pathways and it is now understood that cancer treatment induces cell death by different and sometimes multiple pathways. An alternative approach is targeting the cell death phenotype that is "agnostic" of the death pathway. Cell death phenotypes that have been targeted for cell death imaging include loss of plasma membrane integrity and dissipation of the mitochondrial membrane potential. Targeting the cell death phenotype may have the advantage of being a more sensitive and generalisable approach to cancer cell death imaging. This review describes and summarises the approaches and radiopharmaceuticals investigated for imaging cell death by targeting cell death pathways or cell death phenotype.
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Affiliation(s)
- Ivan Ho Shon
- Department of Nuclear Medicine and PET, Prince of Wales Hospital, Sydney, Australia; School of Clinical Medicine, UNSW Medicine & Health, Randwick Clinical Campus, UNSW Sydney, Australia.
| | - Philip J Hogg
- The Centenary Institute, University of Sydney, Sydney, Australia
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9
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Abaquita TAL, Damulewicz M, Tylko G, Pyza E. The dual role of heme oxygenase in regulating apoptosis in the nervous system of Drosophila melanogaster. Front Physiol 2023; 14:1060175. [PMID: 36860519 PMCID: PMC9969482 DOI: 10.3389/fphys.2023.1060175] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
Accumulating evidence from mammalian studies suggests the dual-faced character of heme oxygenase (HO) in oxidative stress-dependent neurodegeneration. The present study aimed to investigate both neuroprotective and neurotoxic effects of heme oxygenase after the ho gene chronic overexpression or silencing in neurons of Drosophila melanogaster. Our results showed early deaths and behavioral defects after pan-neuronal ho overexpression, while survival and climbing in a strain with pan-neuronal ho silencing were similar over time with its parental controls. We also found that HO can be pro-apoptotic or anti-apoptotic under different conditions. In young (7-day-old) flies, both the cell death activator gene (hid) expression and the initiator caspase Dronc activity increased in heads of flies when ho expression was changed. In addition, various expression levels of ho produced cell-specific degeneration. Dopaminergic (DA) neurons and retina photoreceptors are particularly vulnerable to changes in ho expression. In older (30-day-old) flies, we did not detect any further increase in hid expression or enhanced degeneration, however, we still observed high activity of the initiator caspase. In addition, we used curcumin to further show the involvement of neuronal HO in the regulation of apoptosis. Under normal conditions, curcumin induced both the expression of ho and hid, which was reversed after exposure to high-temperature stress and when supplemented in flies with ho silencing. These results indicate that neuronal HO regulates apoptosis and this process depends on ho expression level, age of flies, and cell type.
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Affiliation(s)
- Terence Al L. Abaquita
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Cracow, Poland
| | - Milena Damulewicz
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Cracow, Poland
| | - Grzegorz Tylko
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Cracow, Poland
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10
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Zilio E, Piano V, Wirth B. Mitochondrial Dysfunction in Spinal Muscular Atrophy. Int J Mol Sci 2022; 23:10878. [PMID: 36142791 PMCID: PMC9503857 DOI: 10.3390/ijms231810878] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by recessive mutations in the SMN1 gene, globally affecting ~8-14 newborns per 100,000. The severity of the disease depends on the residual levels of functional survival of motor neuron protein, SMN. SMN is a ubiquitously expressed RNA binding protein involved in a plethora of cellular processes. In this review, we discuss the effects of SMN loss on mitochondrial functions in the neuronal and muscular systems that are the most affected in patients with spinal muscular atrophy. Our aim is to highlight how mitochondrial defects may contribute to disease progression and how restoring mitochondrial functionality may be a promising approach to develop new therapies. We also collected from previous studies a list of transcripts encoding mitochondrial proteins affected in various SMA models. Moreover, we speculate that in adulthood, when motor neurons require only very low SMN levels, the natural deterioration of mitochondria associated with aging may be a crucial triggering factor for adult spinal muscular atrophy, and this requires particular attention for therapeutic strategies.
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Affiliation(s)
- Eleonora Zilio
- Institute of Human Genetics, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
| | - Valentina Piano
- Institute of Human Genetics, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
- Institute for Genetics, University of Cologne, 50674 Cologne, Germany
- Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
| | - Brunhilde Wirth
- Institute of Human Genetics, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
- Institute for Genetics, University of Cologne, 50674 Cologne, Germany
- Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
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11
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Jujuboside A inhibits oxidative stress damage and enhances immunomodulatory capacity of human umbilical cord mesenchymal stem cells through up-regulating IDO expression. Chin J Nat Med 2022; 20:494-505. [DOI: 10.1016/s1875-5364(22)60176-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Indexed: 11/23/2022]
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12
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Vougioukalaki M, Demmers J, Vermeij WP, Baar M, Bruens S, Magaraki A, Kuijk E, Jager M, Merzouk S, Brandt RM, Kouwenberg J, van Boxtel R, Cuppen E, Pothof J, Hoeijmakers JHJ. Different responses to DNA damage determine ageing differences between organs. Aging Cell 2022; 21:e13562. [PMID: 35246937 PMCID: PMC9009128 DOI: 10.1111/acel.13562] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 12/17/2021] [Accepted: 01/05/2022] [Indexed: 12/13/2022] Open
Abstract
Organs age differently, causing wide heterogeneity in multimorbidity, but underlying mechanisms are largely elusive. To investigate the basis of organ-specific ageing, we utilized progeroid repair-deficient Ercc1Δ /- mouse mutants and systematically compared at the tissue, stem cell and organoid level two organs representing ageing extremes. Ercc1Δ /- intestine shows hardly any accelerated ageing. Nevertheless, we found apoptosis and reduced numbers of intestinal stem cells (ISCs), but cell loss appears compensated by over-proliferation. ISCs retain their organoid-forming capacity, but organoids perform poorly in culture, compared with WT. Conversely, liver ages dramatically, even causing early death in Ercc1-KO mice. Apoptosis, p21, polyploidization and proliferation of various (stem) cells were prominently elevated in Ercc1Δ /- liver and stem cell populations were either largely unaffected (Sox9+), or expanding (Lgr5+), but were functionally exhausted in organoid formation and development in vitro. Paradoxically, while intestine displays less ageing, repair in WT ISCs appears inferior to liver as shown by enhanced sensitivity to various DNA-damaging agents, and lower lesion removal. Our findings reveal organ-specific anti-ageing strategies. Intestine, with short lifespan limiting time for damage accumulation and repair, favours apoptosis of damaged cells relying on ISC plasticity. Liver with low renewal rates depends more on repair pathways specifically protecting the transcribed compartment of the genome to promote sustained functionality and cell preservation. As shown before, the hematopoietic system with intermediate self-renewal mainly invokes replication-linked mechanisms, apoptosis and senescence. Hence, organs employ different genome maintenance strategies, explaining heterogeneity in organ ageing and the segmental nature of DNA-repair-deficient progerias.
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Affiliation(s)
- Maria Vougioukalaki
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Joris Demmers
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Wilbert P. Vermeij
- Princess Máxima Center for Pediatric Oncology Oncode Institute Utrecht The Netherlands
| | - Marjolein Baar
- Center for Molecular Medicine University Medical Center Utrecht Utrecht The Netherlands
| | - Serena Bruens
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Aristea Magaraki
- Department of Developmental Biology Oncode Institute Rotterdam The Netherlands
| | - Ewart Kuijk
- Division Biomedical Genetics Center for Molecular Medicine and Cancer Genomics Netherlands University Medical Center Utrecht Utrecht University Utrecht The Netherlands
| | - Myrthe Jager
- Department of Genetics Center for Molecular Medicine University Medical Center Utrecht Utrecht University Utrecht The Netherlands
| | - Sarra Merzouk
- Department of Developmental Biology Oncode Institute Rotterdam The Netherlands
| | - Renata M.C. Brandt
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Janneke Kouwenberg
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Ruben van Boxtel
- Princess Máxima Center for Pediatric Oncology Oncode Institute Utrecht The Netherlands
| | - Edwin Cuppen
- Division Biomedical Genetics Center for Molecular Medicine and Cancer Genomics Netherlands University Medical Center Utrecht Utrecht University Utrecht The Netherlands
- Hartwig Medical Foundation Amsterdam Netherlands
| | - Joris Pothof
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Jan H. J. Hoeijmakers
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
- Princess Máxima Center for Pediatric Oncology Oncode Institute Utrecht The Netherlands
- Institute for Genome Stability in Ageing and Disease Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University Hospital of Cologne Cologne Germany
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13
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Wang Y, Wang D, Yin K, Liu Y, Lu H, Zhao H, Xing M. Lycopene attenuates oxidative stress, inflammation, and apoptosis by modulating Nrf2/NF-κB balance in sulfamethoxazole-induced neurotoxicity in grass carp (Ctenopharyngodon Idella). FISH & SHELLFISH IMMUNOLOGY 2022; 121:322-331. [PMID: 35032680 DOI: 10.1016/j.fsi.2022.01.012] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/06/2022] [Accepted: 01/08/2022] [Indexed: 06/14/2023]
Abstract
All drugs that can penetrate the blood-brain barrier (BBB) may lead to mental state changes, including the widely used anti-infective drug sulfamethoxazole (SMZ). Herein, we investigated whether lycopene (LYC) could ameliorate SMZ-induced brain injury and the postulated mechanisms involved. A total of 120 grass carps were exposed under SMZ (0.3 μg/L, waterborne) or LYC (10 mg/kg fish weight, diet) or their combination for 30 days. Firstly, brain injury induced by SMZ exposure was suggested by the damage of BBB (decreases of Claudins, Occludin and Zonula Occludens), and the decrease of neurotransmitter activity (AChE). Through inducing oxidative stress (elevations of malondialdehyde and 8-hydroxy-2 deoxyguanosine, inhibition of glutathione), SMZ increased the intra-nuclear level of NF-κB and its target genes (TNF-α and interleukins), creating an inflammatory microenvironment. As a positive feed-back mechanism, apoptosis begins with activation of pro-death proteins (Bax/Bcl-2) and activation of caspases (caspase-9 and caspase-3). Meanwhile, a compensatory upregulation of constitutive Nrf2 and its downstream antioxidative gene expression (NAD(P)H Quinone Dehydrogenase 1 and Heme oxygenase 1) and accelerated autophagy (increases of autophagy-related genes and p62 inhibition) were activated as a defense mechanism. Intriguingly, under SMZ stress, LYC co-administration decreased NF-κB/apoptosis cascades and restored Nrf2/autophagy levels. The neuroprotective roles of LYC make this natural compound a valuable agent for prevention SMZ stress in environment. This study suggests that LYC might be developed as a potential candidate for alleviating environmental SMZ stress in aquaculture.
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Affiliation(s)
- Yu Wang
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China
| | - Dongxu Wang
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China
| | - Kai Yin
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China
| | - Yachen Liu
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China
| | - Hongmin Lu
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China
| | - Hongjing Zhao
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
| | - Mingwei Xing
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
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14
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Koagouw W, Hazell RJ, Ciocan C. Induction of apoptosis in the gonads of Mytilus edulis by metformin and increased temperature, via regulation of HSP70, CASP8, BCL2 and FAS. MARINE POLLUTION BULLETIN 2021; 173:113011. [PMID: 34649205 DOI: 10.1016/j.marpolbul.2021.113011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 09/22/2021] [Accepted: 09/26/2021] [Indexed: 06/13/2023]
Abstract
Pharmaceutically active compounds have been considered contaminants of emerging concern, in response to evidence that these substances may adversely affect aquatic organisms. Here we expose mussels for 7 days to metformin, the most commonly prescribed anti-diabetes treatment, at a concentration of 40 μg/L and a high temperature of 20 °C. The apoptosis-related genes HSP70, CASP8, BCL2 and FAS showed variation in expression in gonadal tissue. The results suggest that complex interactions between these genes are modulating the onset of apoptotic changes such as atresia and follicle degeneration. The temperature induced apoptosis may be initiated by overexpression of CASP8. Conversely, metformin may induce apoptosis by suppressing the anti-apoptotic gene BCL2, thus promoting the process. Interestingly, apoptosis and follicle degeneration are likely FAS-mediated, following the synergistic effect of metformin and temperature. The potential of metformin to act as a non-traditional EDC, due to its impact on the reproductive system in mussels is discussed.
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Affiliation(s)
- Wulan Koagouw
- School of Applied Sciences, University of Brighton, Lewes Road, Brighton BN2 4AT, United Kingdom; Centre for Aquatic Environments, University of Brighton, Lewes Road, Brighton BN2 4AT, United Kingdom; National Research and Innovation Agency, Jl. M. H. Thamrin No. 8 Jakarta, Indonesia.
| | - Richard J Hazell
- School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, United Kingdom.
| | - Corina Ciocan
- School of Applied Sciences, University of Brighton, Lewes Road, Brighton BN2 4AT, United Kingdom; Centre for Aquatic Environments, University of Brighton, Lewes Road, Brighton BN2 4AT, United Kingdom.
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15
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Keskin-Aktan A, Akbulut KG, Abdi S, Akbulut H. SIRT2 and FOXO3a expressions in the cerebral cortex and hippocampus of young and aged male rats: antioxidant and anti-apoptotic effects of melatonin. Biol Futur 2021; 73:71-85. [PMID: 34708398 DOI: 10.1007/s42977-021-00102-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 10/17/2021] [Indexed: 12/14/2022]
Abstract
Melatonin has antioxidant, anti-apoptotic and anti-aging effects in the brain. Sirtuin2 (SIRT2) accumulates in the central nervous system with aging, and its inhibition appears to be protective in aging and aging-related neurodegenerative diseases. Forkhead Box-class O3a (FOXO3a) transcription factor is one of the main targets of SIRT2, and SIRT2-mediated FOXO3a deacetylation is closely related to aging, oxidative stress, and apoptosis. This study aimed to investigate the effects of melatonin on SIRT2 and FOXO3a expressions in the cerebral cortex and hippocampus of aged rats. Young (3 months, n = 18) and aged (22 months, n = 18) male Wistar rats were divided into control (4% DMSO-PBS, sc, for 21 days), melatonin (10 mg/kg, sc, for 21 days) and salermide (1 mM; 25 μl/100 g bw, ip, for 21 days) groups. SIRT2, FOXO3a, Bcl-2, Bax and Bim expressions in the cerebral cortex and hippocampus were demonstrated by Western blotting. SIRT2 and FOXO3a protein levels were also measured by a sandwich ELISA method. Oxidative stress index (OSI) was calculated by measuring total oxidant status (TOS) and total antioxidant status (TAS). Aging increased SIRT2, FOXO3a, Bim (only in the cerebral cortex), Bax (only in the hippocampus), TOS, and OSI, while decreasing Bcl-2, Bcl-2/Bax and TAS in both brain regions. Melatonin decreased SIRT2, FOXO3a, oxidative stress parameters and pro-apoptotic proteins, while increasing TAS, Bcl-2 and Bcl-2/Bax, more specifically in the hippocampus of the aged brain. Our results indicate that inhibition of SIRT2 and FOXO3a expressions appears to be involved in the protective effects of melatonin in the hippocampus of aged rats.
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Affiliation(s)
- Arzu Keskin-Aktan
- Department of Physiology, School of Medicine, Afyonkarahisar Health Sciences University, Afyonkarahisar, 03200, Turkey.
| | | | - Samira Abdi
- Department of Basic Oncology, Institute of Cancer Research, Ankara University, Ankara, Turkey
| | - Hakan Akbulut
- Department of Basic Oncology, Institute of Cancer Research, Ankara University, Ankara, Turkey
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16
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Ferreira WAS, Burbano RR, do Ó Pessoa C, Harada ML, do Nascimento Borges B, de Oliveira EHC. Pisosterol Induces G2/M Cell Cycle Arrest and Apoptosis via the ATM/ATR Signaling Pathway in Human Glioma Cells. Anticancer Agents Med Chem 2021; 20:734-750. [PMID: 32013837 DOI: 10.2174/1871520620666200203160117] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 11/05/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Pisosterol, a triterpene derived from Pisolithus tinctorius, exhibits potential antitumor activity in various malignancies. However, the molecular mechanisms that mediate the pisosterol-specific effects on glioma cells remain unknown. OBJECTIVE This study aimed to evaluate the antitumoral effects of pisosterol on glioma cell lines. METHODS The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue exclusion assays were used to evaluate the effect of pisosterol on cell proliferation and viability in glioma cells. The effect of pisosterol on the distribution of the cells in the cell cycle was performed by flow cytometry. The expression and methylation pattern of the promoter region of MYC, ATM, BCL2, BMI1, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, MDM2, p14ARF and TP53 was analyzed by RT-qPCR, western blotting and bisulfite sequencing PCR (BSP-PCR). RESULTS Here, it has been reported that pisosterol markedly induced G2/M arrest and apoptosis and decreased the cell viability and proliferation potential of glioma cells in a dose-dependent manner by increasing the expression of ATM, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, p14ARF and TP53 and decreasing the expression of MYC, BCL2, BMI1 and MDM2. Pisosterol also triggered both caspase-independent and caspase-dependent apoptotic pathways by regulating the expression of Bcl-2 and activating caspase-3 and p53. CONCLUSION It has been, for the first time, confirmed that the ATM/ATR signaling pathway is a critical mechanism for G2/M arrest in pisosterol-induced glioma cell cycle arrest and suggests that this compound might be a promising anticancer candidate for further investigation.
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Affiliation(s)
- Wallax A S Ferreira
- Laboratorio de Cultura de Tecidos e Citogenetica, SAMAM, Instituto Evandro Chagas, Ananindeua, Para, Brazil
| | - Rommel R Burbano
- Laboratório de Citogenética Humana, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Pará, Brazil.,Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Belém, Pará, Brazil.,Laboratório de Biologia Molecular, Hospital Ophir Loyola, Belém, Pará, Brazil
| | - Claudia do Ó Pessoa
- Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceara, Fortaleza, Ceara, Brazil
| | - Maria L Harada
- Laboratorio de Biologia Molecular Francisco Mauro Salzano, Instituto de Ciencias Biologicas, Universidade Federal do Para, Belem, Para, Brazil
| | - Bárbara do Nascimento Borges
- Laboratorio de Biologia Molecular Francisco Mauro Salzano, Instituto de Ciencias Biologicas, Universidade Federal do Para, Belem, Para, Brazil
| | - Edivaldo H Correa de Oliveira
- Laboratorio de Cultura de Tecidos e Citogenetica, SAMAM, Instituto Evandro Chagas, Ananindeua, Para, Brazil.,Instituto de Ciências Exatas e Naturais, Faculdade de Ciências Naturais, Universidade Federal do Pará, Belém, Pará, Brazil
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17
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Qin S, Tang H, Li W, Gong Y, Li S, Huang J, Fang Y, Yuan W, Liu Y, Wang S, Guo Y, Guo Y, Xu Z. AMPK and its Activator Berberine in the Treatment of Neurodegenerative Diseases. Curr Pharm Des 2021; 26:5054-5066. [PMID: 32445451 DOI: 10.2174/1381612826666200523172334] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/14/2020] [Indexed: 12/11/2022]
Abstract
Neurodegenerative disorders are heterogeneous diseases associated with either acute or progressive neurodegeneration, causing the loss of neurons and axons in the central nervous system (CNS), showing high morbidity and mortality, and there are only a few effective therapies. Here, we summarized that the energy sensor adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and its agonist berberine can combat the common underlying pathological events of neurodegeneration, including oxidative stress, neuroinflammation, mitochondrial disorder, glutamate excitotoxicity, apoptosis, autophagy disorder, and disruption of neurovascular units. The abovementioned effects of berberine may primarily depend on activating AMPK and its downstream targets, such as the mammalian target of rapamycin (mTOR), sirtuin1 (SIRT1), nuclear factor erythroid-2 related factor-2 (Nrf2), nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), nicotinamide adenine dinucleotide (NAD+), and p38 mitogen-activated protein kinase (p38 MAPK). It is hoped that this review will provide a strong basis for further scientific exploration and development of berberine's therapeutic potential against neurodegeneration.
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Affiliation(s)
- Siru Qin
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Huiling Tang
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wei Li
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yinan Gong
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shanshan Li
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jin Huang
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuxin Fang
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China,Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenjuan Yuan
- The First people’s hospital of Lanzhou city, Gansu, China
| | - Yangyang Liu
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China,Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shenjun Wang
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China,Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yongming Guo
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China,Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yi Guo
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhifang Xu
- Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China,Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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18
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Seyedaghamiri F, Farajdokht F, Vatandoust SM, Mahmoudi J, Khabbaz A, Sadigh-Eteghad S. Sericin modulates learning and memory behaviors by tuning of antioxidant, inflammatory, and apoptotic markers in the hippocampus of aged mice. Mol Biol Rep 2021; 48:1371-1382. [PMID: 33523373 DOI: 10.1007/s11033-021-06195-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 01/28/2021] [Indexed: 01/01/2023]
Abstract
Sericin is a protein derived from silkworm cocoons and identified as an anti-aging agent. This study aimed to examine the effects of sericin administration on episodic and avoidance memories, social interaction behavior, and molecular mechanisms including oxidative stress, inflammation, and apoptosis in the hippocampus of aged mice. Sericin was administered at 250 mg/kg/day (oral gavage) to 2-year-old BALB/c mice for a duration of 21 consecutive days. Lashley III Maze and Shuttle-Box tests were performed to assess episodic and avoidance memories, respectively. Subjects also underwent social interaction test to reveal any changes in their social behavior. Besides, markers of oxidative stress (TAC, SOD, GPx, and MDA) and neuroinflammation mediators (TNF-α, IL-1β, and IL-10) were measured in the hippocampus. The extent of apoptosis in the hippocampal tissue was further determined by TUNEL assay and histological assessment. The obtained results suggest that sericin promotes episodic and avoidance memories and social behaviors in aged mice. As of the molecular assay outcomes, it was noted that sericin regulates hippocampal inflammation by inhibiting the pro-inflammatory cytokines, TNF-α and IL-1β, and by increasing the anti-inflammatory factor IL-10. Moreover, sericin suppressed oxidative stress by enhancing antioxidant markers (TAC, SOD, and GPx) and inhibiting MDA. It was also identified that sericin can substantially suppress the apoptosis in the hippocampal tissue. Overall, sericin modulates memory and sociability behavior by tuning hippocampal antioxidant, inflammatory, and apoptotic markers in the aged mice.
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Affiliation(s)
| | - Fereshteh Farajdokht
- Neurosciences Research Center, Tabriz University of Medical Sciences, 5166614756, Tabriz, Iran
| | - Seyed Mehdi Vatandoust
- Neurosciences Research Center, Tabriz University of Medical Sciences, 5166614756, Tabriz, Iran
| | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, 5166614756, Tabriz, Iran
| | - Aytak Khabbaz
- Neurosciences Research Center, Tabriz University of Medical Sciences, 5166614756, Tabriz, Iran
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center, Tabriz University of Medical Sciences, 5166614756, Tabriz, Iran.
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19
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Pandey T, Shukla A, Trivedi M, Khan F, Pandey R. Swertiamarin from Enicostemma littorale, counteracts PD associated neurotoxicity via enhancement α-synuclein suppressive genes and SKN-1/NRF-2 activation through MAPK pathway. Bioorg Chem 2021; 108:104655. [PMID: 33548732 DOI: 10.1016/j.bioorg.2021.104655] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 01/05/2021] [Accepted: 01/12/2021] [Indexed: 11/30/2022]
Abstract
The elusive targets and the multifactorial etiology of Parkinson's disease (PD) have hampered the discovery of a potent drug for PD. Furthermore, the presently available medications provide only symptomatic relief and have failed to mitigate the pathogenesis associated with PD. Therefore, the current study was aimed to evaluate the prospective of swertiamarin (SW), a secoiridoid glycoside isolated from a traditional medicinal plant, Enicostemma littorale Blume to ameliorate the characteristic features of PD in Caenorhabditis elegans. SW (25 μM) administration decreased the α-synuclein (α-syn) deposition, inhibited apoptosis and increased dopamine level mediated through upregulating the expression of genes linked to ceramide synthesis, mitochondrial morphology and function regulation, fatty acid desaturase genes along with stress responsive MAPK (mitogen-activated protein kinase) pathway genes. The neuroprotective effect of SW was evident from the robust reduction of 6-hydroxydopamine (6-OHDA) induced dopaminergic neurodegeneration independent of dopamine transporter (dat-1). SW mediated translational regulation of MAPK pathway genes was observed through increase expression of SKN-1 and GST-4. Further, in-silico molecular docking analysis of SW with C. elegans MEK-1 showed a promising binding affinity affirming the in-vivo results. Overall, these novel finding supports that SW is a possible lead for drug development against the multi- factorial PD pathologies.
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Affiliation(s)
- Taruna Pandey
- Aging Biology Lab, Microbial Technology and Nematology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India
| | - Aparna Shukla
- Department of Molecular and Structural Biology, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India
| | - Mashu Trivedi
- Aging Biology Lab, Microbial Technology and Nematology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India
| | - Feroz Khan
- Department of Molecular and Structural Biology, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India
| | - Rakesh Pandey
- Aging Biology Lab, Microbial Technology and Nematology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
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20
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Rodrigues FS, França AP, Broetto N, Furian AF, Oliveira MS, Santos ARS, Royes LFF, Fighera MR. Sustained glial reactivity induced by glutaric acid may be the trigger to learning delay in early and late phases of development: Involvement of p75 NTR receptor and protection by N-acetylcysteine. Brain Res 2020; 1749:147145. [PMID: 33035499 DOI: 10.1016/j.brainres.2020.147145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 09/28/2020] [Accepted: 10/01/2020] [Indexed: 11/17/2022]
Abstract
Degeneration of striatal neurons and cortical atrophy are pathological characteristics of glutaric acidemia type I (GA-I), a disease characterized by accumulation of glutaric acid (GA). The mechanisms that lead to neuronal loss and cognitive impairment are still unclear. The purpose of this study was to verify if acute exposure to GA during the neonatal period is sufficient to trigger apoptotic processes and lead to learning delay in early and late period. Besides, whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Pups mice received a dose of GA (2.5 μmol/ g) or saline, 12 hs after birth, and were treated with NAC (250 mg/kg) or saline, up to 21th day of life. Although GA exhibited deficits in the procedural and working memories in 21 and 40-day-old mice, NAC protected against cognitive impairment. In striatum and cortex, NAC prevented glial cells activation (GFAP and Iba-1), decreased NGF, Bcl-2 and NeuN, the increase of lipid peroxidation and PARP induced by GA in both ages. NAC protected against increased p75NTR induced by GA, but not in cortex of 21-day-old mice. Thus, we showed that the integrity of striatal and cortical pathways has an important role for learning and suggested that sustained glial reactivity in neonatal period can be an initial trigger for delay of cognitive development. Furthermore, NAC protected against cognitive impairment induced by GA. This work shows that early identification of the alterations induced by GA is important to avoid future clinical complications and suggest that NAC could be an adjuvant treatment for this acidemia.
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Affiliation(s)
- Fernanda Silva Rodrigues
- Centro de Ciências da Saúde, Departamento de Neuropsiquiatria, Laboratório de Neuropsiquiatria Experimental e Clínico, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil; Centro de Educação Física e Desportos, Departamento de Métodos e Técnicas Desportivas, Laboratório de Bioquímica do Exercício (BIOEX), Universidade Federal de Santa Maria, Santa Maria, RS, Brazil; Centro de Ciências Biológicas, Laboratório de Neurobiologia da Dor e Inflamação, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Angela Patrícia França
- Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Núbia Broetto
- Centro de Ciências da Saúde, Departamento de Neuropsiquiatria, Laboratório de Neuropsiquiatria Experimental e Clínico, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil; Centro de Educação Física e Desportos, Departamento de Métodos e Técnicas Desportivas, Laboratório de Bioquímica do Exercício (BIOEX), Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Ana Flávia Furian
- Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmacologia, Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria, Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Mauro Schneider Oliveira
- Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmacologia, Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria, Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Adair Roberto Soares Santos
- Centro de Ciências Biológicas, Laboratório de Neurobiologia da Dor e Inflamação, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Luiz Fernando Freire Royes
- Centro de Ciências Naturais e Exatas, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil; Centro de Educação Física e Desportos, Departamento de Métodos e Técnicas Desportivas, Laboratório de Bioquímica do Exercício (BIOEX), Universidade Federal de Santa Maria, Santa Maria, RS, Brazil; Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Michele Rechia Fighera
- Centro de Ciências da Saúde, Departamento de Neuropsiquiatria, Laboratório de Neuropsiquiatria Experimental e Clínico, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil; Centro de Ciências Naturais e Exatas, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil; Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil; Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmacologia, Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria, Santa Maria, 97105-900 Santa Maria, RS, Brazil.
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21
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Yang X, Jia J, Ding L, Yu Z, Qu C. The Role of Nrf2 in D-Galactose-Induced Cardiac Aging in Mice: Involvement of Oxidative Stress. Gerontology 2020; 67:91-100. [PMID: 33271531 DOI: 10.1159/000510470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 07/27/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Cardiac aging is the major risk factor for advanced heart disease, which is the leading cause of death in developed countries, accounting for >30% of deaths worldwide. OBJECTIVE To discover the detailed mechanism of cardiac aging and develop an effective therapeutic candidate drug to treat or delay cardiac aging. METHODS We used D-galactose to induce cardiac aging in Nrf2+/+ and Nrf2-/- mice, and then treated these mice with vehicle or the Nrf2 activator, CDDO-imidazolide (CDDO-Im). RESULTS AND CONCLUSIONS D-galactose injection significantly induced cardiac aging, cell apoptosis, and oxidative stress in Nrf2+/+ mice, all of which were further exacerbated in Nrf2-/- mice. CDDO-Im treatment can effectively weaken oxidative stress and enhance the activities of antioxidant enzymes, but CDDO-Im lost its antioxidative effect in the Nrf2-/- mice. Nrf2 activator CDDO-Im could therefore effectively protect against D-galactose-induced cardiac aging by inhibiting oxidative stress, suggesting that CDDO-Im might be a potential and promising therapeutic candidate drug to treat cardiac aging.
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Affiliation(s)
- Xilan Yang
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Jia
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ling Ding
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhen Yu
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chen Qu
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China,
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22
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Teruya T, Goga H, Yanagida M. Aging markers in human urine: A comprehensive, non-targeted LC-MS study. FASEB Bioadv 2020; 2:720-733. [PMID: 33336159 PMCID: PMC7734427 DOI: 10.1096/fba.2020-00047] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/04/2020] [Accepted: 09/28/2020] [Indexed: 12/25/2022] Open
Abstract
Metabolites in human biofluids document the physiological status of individuals. We conducted comprehensive, non-targeted, non-invasive metabolomic analysis of urine from 27 healthy human subjects, comprising 13 young adults (30 ± 3 years) and 14 seniors (76 ± 4 years). Quantitative analysis of 99 metabolites revealed 55 that displayed significant differences in abundance between the two groups. Forty-four did not show a statistically significant relationship with age. These include 13 standard amino acids, 5 methylated, 4 acetylated, and 9 other amino acids, 6 nucleosides, nucleobases, and derivatives, 4 sugar derivatives, 5 sugar phosphates, 4 carnitines, 2 hydroxybutyrates, 1 choline, and 1 ethanolamine derivative, and glutathione disulfide. Abundances of 53 compounds decreased, while 2 (glutathione disulfide, myo-inositol) increased in elderly people. The great majority of age-linked markers were highly correlated with creatinine. In contrast, 44 other urinary metabolites, including urate, carnitine, hippurate, and betaine, were not age-linked, neither declining nor increasing in elderly subjects. As metabolite profiles of urine and blood are quite different, age-related information in urine offers additional valuable insights into aging mechanisms of endocrine system. Correlation analysis of urinary metabolites revealed distinctly inter-related groups of compounds.
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Affiliation(s)
- Takayuki Teruya
- G0 Cell UnitOkinawa Institute of Science and Technology Graduate UniversityOkinawaJapan
| | - Haruhisa Goga
- G0 Cell UnitOkinawa Institute of Science and Technology Graduate UniversityOkinawaJapan
- Forensic Laboratory, Department of Criminal InvestigationOkinawa Prefectural Police HQOkinawaJapan
| | - Mitsuhiro Yanagida
- G0 Cell UnitOkinawa Institute of Science and Technology Graduate UniversityOkinawaJapan
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23
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Linial M, Stern A, Weinstock M. Effect of ladostigil treatment of aging rats on gene expression in four brain areas associated with regulation of memory. Neuropharmacology 2020; 177:108229. [PMID: 32738309 DOI: 10.1016/j.neuropharm.2020.108229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/17/2020] [Accepted: 07/01/2020] [Indexed: 02/09/2023]
Abstract
Episodic and spatial memory decline in aging and are controlled by the hippocampus, perirhinal, frontal and parietal cortices and the connections between them. Ladostigil, a drug with antioxidant and anti-inflammatory activity, was shown to prevent the loss of episodic and spatial memory in aging rats. To better understand the molecular effects of aging and ladostigil on these brain regions we characterized the changes in gene expression using RNA-sequencing technology in rats aged 6 and 22 months. We found that the changes induced by aging and chronic ladostigil treatment were brain region specific. In the hippocampus, frontal and perirhinal cortex, ladostigil decreased the overexpression of genes regulating calcium homeostasis, ion channels and those adversely affecting synaptic function. In the parietal cortex, ladostigil increased the expression of several genes that provide neurotrophic support, while reducing that of pro-apoptotic genes and those encoding pro-inflammatory cytokines and their receptors. Ladostigil also decreased the expression of axonal growth inhibitors and those impairing mitochondrial function. Together, these actions could explain the protection by ladostigil against age-related memory decline.
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Affiliation(s)
- Michal Linial
- Department of Biological Chemistry, Life Science Institute, Israel; The Rachel and Selim Benin School of Computer Science and Engineering, Israel
| | - Amos Stern
- Department of Biological Chemistry, Life Science Institute, Israel
| | - Marta Weinstock
- Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Israel.
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24
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Xiao H, Li H, Song H, Kong L, Yan X, Li Y, Deng Y, Tai H, Wu Y, Ni Y, Li W, Chen J, Yang J. Shenzao jiannao oral liquid, an herbal formula, ameliorates cognitive impairments by rescuing neuronal death and triggering endogenous neurogenesis in AD-like mice induced by a combination of Aβ42 and scopolamine. JOURNAL OF ETHNOPHARMACOLOGY 2020; 259:112957. [PMID: 32416248 DOI: 10.1016/j.jep.2020.112957] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 04/28/2020] [Accepted: 05/07/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE According to the theory of traditional Chinese medicine (TCM), Alzheimer's disease (AD) is identified as "forgetfulness" or "dementia", and is mainly caused by "kidney essence deficiency" which ultimately induces "encephala reduction". Therefore, herbal formulas possessing the efficacy of nourishing kidney essence or replenishing brain marrow are commonly served as effective strategies for AD treatment. Shenzao jiannao oral liquid (SZJN), a traditional Chinese preparation approved by the China Food and Drug Administration (CFDA), is used for the treatment of insomnia and mind fatigue at present for its efficacy of nourishing kidneys. In present study, we found that SZJN could improve cognitive function of AD-like mice. AIMS OF STUDY This study aims to investigate the effects of SJZN on ameliorating cognitive deficits of AD-like mouse model, and to illuminate the underlying mechanisms from the perspective of neuroprotection and neurogenesis. MATERIALS AND METHODS Kunming mice (28 ± 2 g) were randomly allocated into seven groups: control, sham, model, donepezil and SZJN groups (low, middle and high). The AD mouse model was established by Aβ42 combined with scopolamine. SZJN were intragastrically administrated at doses of 0.3, 1.5 and 7.5 g/kg for 28 days. Morris water maze (MWM) test was applied to determine the cognitive function. Hematoxylin eosin (HE) and Nissl staining were carried out to evaluate pathological damages in the cortex and hippocampal tissues. To explore the protective effects of SZJN on multiple pathogenic factors of AD, protein levels of Aβ42, glial fibrillary acidic protein (GFAP), Bax, Bcl-2, Caspase-3, synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), and neurogenesis related proteins were assessed using Immunofluorescence (IF) and western blot analysis. In vitro, the AD cell model was established by transduction of APP695swe genes into Neural stem cells (NSCs) isolated from the hippocampal tissues of neonatal C57BL/6 mice. Cell viability assay and neurosphere formation assay were carried out to verify the efficacy of SZJN on proliferation of NSCs. RESULTS Our results demonstrated that SZJN (1.5 g/kg and 7.5 g/kg) treatment significantly ameliorated cognitive deficits of AD-like mice. SZJN (7.5 g/kg) treatment significantly retarded the pathological damages including neuronal degeneration, neuronal apoptosis, Aβ peptides aggregation and reaction of astrocytes in AD-like mice. In addition, SZJN (7.5 g/kg) increased the expression of BDNF and SYP, and restored the abnormal level of MDA and SOD in the brain of AD-like mice. Furthermore, SZJN treatment for 28 days remarkably increased the proliferation of NSCs evidenced by more Nestin+ and BrdU+ cells in the hippocampal DG regions, and increased the amount of mature neurons marked by NeuN both in the cortex and hippocampal DG regions. In vitro, SZJN treatement (16, 32, 64 mg/ml) promoted the proliferation of NSCs evidenced by the increased amount and enlarged size of the neurospheres (p < 0.05). CONCLUSIONS Our findings indicated that SZJN could ameliorate cognitive deficits by protecting neurons from death and triggering endogenous neurogenesis. Therefore, SZJN may be considered as a promising agent to restore neuronal loss and deter the deterioration in AD patients.
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Affiliation(s)
- Honghe Xiao
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China.
| | - Hongyan Li
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China
| | - Huipeng Song
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China
| | - Liang Kong
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China
| | - Xin Yan
- Diaoyutai Pharmaceutical Group Jilin Tianqiang Pharmaceutical co. LTD, 309 Renmin Street, Tonghua, 135300, PR China
| | - Yan Li
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China
| | - Yan Deng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China
| | - He Tai
- Key Laboratory of Ministry of Education for Traditional Chinese Medicine Visera-State Theory and Application, Liaoning University of Traditional Chinese Medicine, Huanggu District Chongshan Road No. 79, Shenyang, Liaoning, 110847, PR China
| | - Yutong Wu
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China
| | - Yingnan Ni
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China
| | - Wanyi Li
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China
| | - Jicong Chen
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China
| | - Jingxian Yang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77 Life One Road, DD Port, Dalian, 116600, PR China.
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25
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Hirano T, Doi K, Matsunaga K, Takahashi S, Donishi T, Suga K, Oishi K, Yasuda K, Mimura Y, Harada M, Suizu S, Murakawa K, Chikumoto A, Ohteru Y, Matsuda K, Uehara S, Hamada K, Ohata S, Murata Y, Yamaji Y, Asami-Noyama M, Edakuni N, Kakugawa T. A Novel Role of Growth Differentiation Factor (GDF)-15 in Overlap with Sedentary Lifestyle and Cognitive Risk in COPD. J Clin Med 2020; 9:E2737. [PMID: 32847145 PMCID: PMC7565594 DOI: 10.3390/jcm9092737] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/19/2020] [Accepted: 08/21/2020] [Indexed: 12/18/2022] Open
Abstract
Sedentary behavior and cognitive impairment have a direct impact on patients' outcomes. An energy metabolic disorder may be involved in the overlap of these comorbid conditions (motoric cognitive risk (MCR)) in patients with chronic obstructive pulmonary disease (COPD). We aimed to explore the linkage between a proapoptotic protein, growth differentiation factor (GDF)-15, and MCR. Physical activity (PA), cognitive function (Japanese version of the Montreal Cognitive Assessment: MOCA-J), and the serum GDF-15 levels were assessed in healthy subjects (n = 14), asthmatics (n = 22), and COPD patients (n = 28). In the entire cohort, serum GDF-15 had negative correlations with exercise (Ex) (ρ = -0.43, p < 0.001) and MoCA-J (ρ = -0.44, p < 0.001), and Ex and MOCA-J showed a positive correlation (ρ = 0.52, p < 0.0001). Compared to healthy subjects and asthmatics, COPD patients showed the highest serum GDF-15 levels and had a significantly higher proportion of subjects with MCR (both sedentary lifestyle (EX < 1.5) and cognitive risk (MoCA-J ≤ 25)). Also, we found that serum GDF-15 has a screening potential (100% sensitivity) greater than aging (67% sensitivity) for detecting MCR in COPD patients. In conclusion, higher serum GDF-15 had interrelationships with a sedentary lifestyle and cognitive risk. This protein was not disease-specific but could be a screening biomarker to detect MCR related to poor health outcomes of COPD patients.
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Affiliation(s)
- Tsunahiko Hirano
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Keiko Doi
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Kazuto Matsunaga
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Shun Takahashi
- Department of Neuropsychiatry, Wakayama Medical University, Wakayama 641-8510, Japan; (S.T.); (K.Y.)
| | - Tomohiro Donishi
- Department of System Neurophysiology, Graduate School of Wakayama Medical University, Wakayama 641-8510, Japan;
| | - Kazuyoshi Suga
- Department of Radiology, Semui PET Screening and Radiatiotherapeutic Site, St. Hill Hospital, Ube 755-0155, Japan;
| | - Keiji Oishi
- Department of Medicine and Clinical Science, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.O.); (Y.M.)
| | - Kasumi Yasuda
- Department of Neuropsychiatry, Wakayama Medical University, Wakayama 641-8510, Japan; (S.T.); (K.Y.)
| | - Yusuke Mimura
- Department of Clinical Research, National Hospital Organization Yamaguchi Ube Medical Center, Ube 755-0241, Japan;
| | - Misa Harada
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Sumiteru Suizu
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Keita Murakawa
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Ayumi Chikumoto
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Yuichi Ohteru
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Kazuki Matsuda
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Sho Uehara
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Kazuki Hamada
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Shuichiro Ohata
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Yoriyuki Murata
- Department of Medicine and Clinical Science, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.O.); (Y.M.)
| | - Yoshikazu Yamaji
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Maki Asami-Noyama
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Nobutaka Edakuni
- Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan; (K.D.); (K.M.); (M.H.); (S.S.); (K.M.); (A.C.); (Y.O.); (K.M.); (S.U.); (K.H.); (S.O.); (Y.Y.); (M.A.-N.); (N.E.)
| | - Tomoyuki Kakugawa
- Department of Pulmonology and Gerontology Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan;
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Farzanegi P, Abbaszadeh H, Farokhi F, Rahmati-Ahmadabad S, Hosseini SA, Ahmad A, Mazandarani MR, Rezaei I, Shokrie M, Vizvari E, Alinejad H, Azarbayjani MA. Attenuated Renal and Hepatic Cells Apoptosis Following Swimming Exercise Supplemented with Garlic Extract in Old Rats. Clin Interv Aging 2020; 15:1409-1418. [PMID: 32884250 PMCID: PMC7443438 DOI: 10.2147/cia.s250321] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 07/08/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND/OBJECTIVE One of the problems associated with aging is the development of apoptosis in different tissues. There is evidence that physical activity and herbal remedies can be useful. This study aimed to determine the effect of swimming training (SW) alone or combined with garlic extract on renal and hepatic cells apoptosis, as wellas on the liver and kidney function biomarkers in old rats. METHODS A total of 35 old rats (aged 40-50 weeks) were randomly divided into 5 groups including control, saline (S), exercise training (ET), garlic (G) and exercise training+ garlic (ET.G) groups. Exercise was started for 5 min/day and then gradually extended to 60 min/day and the G and E+G groups received 1 mL/kg of this mixture by gavage. Twenty-four hours after completion of 8 weeks training, liver, kidney and blood samples were collected for histopathological examinations, liver and kidney functions, oxidative stress and apoptosis biomarkers. RESULTS The tissue sections of the SW exercise, control and saline groups showed some mild histopathological changes in liver and kidney, while SW supplemented with garlic prevented these damages. The SW alone or supplemented with garlic significantly increased the Bcl-2 value and declined the BAX level in both liver and kidney (p<0.05). The activities of catalase (CAT) and superoxide dismutase (SOD) in the liver and kidney of the control and saline groups were lower than those in E, G and G+E groups, while a significant increase for malondialdehyde (MDA) value was found in the control and saline groups. Furthermore, the E+G significantly declined the activity of hepatic (ALT, AST and ALP) and renal damage (uric acid, urea and creatinine) biomarkers compared to the control and saline groups (p<0.05). DISCUSSION Swimming exercise supplemented with garlic extract not only improves antioxidant capacity but also declines oxidative damages and apoptosis through reducing Bax levels and enhancing Bcl-2 value.
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Affiliation(s)
- Parvin Farzanegi
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
| | - Hajar Abbaszadeh
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
| | - Farzaneh Farokhi
- Department of Biology, Faculty of Basic Sciences, Sari Branch, Islamic Azad University, Sari, Iran
| | | | - Seyed Ali Hosseini
- Department of Sport Physiology, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
| | - Abdi Ahmad
- Department of Physical Education, Faculty of Physical Education, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
| | | | - Iraj Rezaei
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
| | - Mohammad Shokrie
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
| | - Exir Vizvari
- Department of Exercise Physiology, Faculty of Humanities, Shams Institute of Higher Education, Gonbad Kavous, Iran
| | - Hadi Alinejad
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
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Kidera H, Hatabu T, Takahashi KH. Apoptosis inhibition mitigates aging effects in Drosophila melanogaster. Genetica 2020; 148:69-76. [PMID: 32219590 DOI: 10.1007/s10709-020-00088-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 02/14/2020] [Indexed: 11/30/2022]
Abstract
Aging is a natural biological process that results in progressive loss of cell, tissue, and organ function. One of the causing factors of the aging process is the decrease in muscle mass, which has not been fully verified in Drosophila. Apoptotic cell death may result in aberrant cell loss and can eventually diminish tissue function and muscle atrophy. If so, inhibition of apoptosis may prolong longevity and reduce motor function and muscle mass decline with age in Drosophila flies. Here, we used Drosophila melanogaster as study material, and induced the overexpression of Drosophila inhibitor of apoptosis protein 1 gene to inhibit apoptosis, and investigated the effect of apoptosis inhibition on the longevity and age-related declines in flight and climbing ability and muscle mass. As a result, the inhibition of apoptosis tended to mitigate the aging effects and prolonged longevity and reduced climbing ability decline with age. The current study suggests that apoptosis inhibition could mitigate the aging effects in D. melanogaster. Although such effects have already been known in mammals, the current results suggest that the apoptosis may play a similar role in insects as well.
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Affiliation(s)
- Hiroaki Kidera
- Graduate School of Environmental Science, Okayama University, Tsushima-naka 1-1-1, Kita-ku, Okayama, 700-8530, Japan
| | - Toshimitsu Hatabu
- Graduate School of Environmental Science, Okayama University, Tsushima-naka 1-1-1, Kita-ku, Okayama, 700-8530, Japan
| | - Kazuo H Takahashi
- Graduate School of Environmental Science, Okayama University, Tsushima-naka 1-1-1, Kita-ku, Okayama, 700-8530, Japan.
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28
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Aceros H, Der Sarkissian S, Borie M, Pinto Ribeiro RV, Maltais S, Stevens LM, Noiseux N. Novel heat shock protein 90 inhibitor improves cardiac recovery in a rodent model of donation after circulatory death. J Thorac Cardiovasc Surg 2020; 163:e187-e197. [PMID: 32354629 DOI: 10.1016/j.jtcvs.2020.03.042] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 02/29/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Organ donation after circulatory death (DCD) is a potential solution for the shortage of suitable organs for transplant. Heart transplantation using DCD donors is not frequently performed due to the potential myocardial damage following warm ischemia. Heat shock protein (HSP) 90 has recently been investigated as a novel target to reduce ischemia/reperfusion injury. The objective of this study is to evaluate an innovative HSP90 inhibitor (HSP90i) as a cardioprotective agent in a model of DCD heart. METHODS A DCD protocol was initiated in anesthetized Lewis rats by discontinuation of ventilation and confirmation of circulatory death by invasive monitoring. Following 15 minutes of warm ischemia, cardioplegia was perfused for 5 minutes at physiological pressure. DCD hearts were mounted on a Langendorff ex vivo heart perfusion system for reconditioning and functional assessment (60 minutes). HSP90i (0.01 μmol/L) or vehicle was perfused in the cardioplegia and during the first 10 minutes of ex vivo heart perfusion reperfusion. Following assessment, pro-survival pathway signaling was evaluated by western blot or polymerase chain reaction. RESULTS Treatment with HSP90i preserved left ventricular contractility (maximum + dP/dt, 2385 ± 249 vs 1745 ± 150 mm Hg/s), relaxation (minimum -dP/dt, -1437 ± 97 vs 1125 ± 85 mm Hg/s), and developed pressure (60.7 ± 5.6 vs 43.9 ± 4.0 mm Hg), when compared with control DCD hearts (All P = .001). Treatment abrogates ischemic injury as demonstrated by a significant reduction of infarct size (2,3,5-triphenyl-tetrazolium chloride staining) of 7 ± 3% versus 19 ± 4% (P = .03), troponin T release, and mRNA expression of Bax/Bcl-2 (P < .05). CONCLUSIONS The cardioprotective effects of HSP90i when used following circulatory death might improve transplant organ availability by expanding the use of DCD hearts.
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Affiliation(s)
- Henry Aceros
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Shant Der Sarkissian
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Canada
| | - Mélanie Borie
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Roberto Vanin Pinto Ribeiro
- Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Simon Maltais
- Division of Cardiovascular Surgery, Mayo Clinic, Rochester, Minn
| | - Louis-Mathieu Stevens
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Canada
| | - Nicolas Noiseux
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Canada.
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29
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Cheng SM, Ho YJ, Yu SH, Liu YF, Lin YY, Huang CY, Ou HC, Huang HL, Lee SD. Anti-Apoptotic Effects of Diosgenin in D-Galactose-Induced Aging Brain. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2020; 48:391-406. [PMID: 32138534 DOI: 10.1142/s0192415x20500202] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The purpose of this study was to evaluate the effects of diosgenin on the D-galactose-induced cerebral cortical widely dispersed apoptosis. Male 12-week-old Wistar rats were divided into four groups: Control (1mg/kg/day of saline, i.p.), DD0 (150mg/kg/day of D-galactose, i.p.), DD10, and DD50 (D-galactose+10 or 50mg/kg/day of diosgenin orally). After eight weeks, histopathological analysis, positive TUNEL and Western blotting assays were performed on the excised cerebral cortex from all four groups. The TUNEL-positive apoptotic cells, the components of Fas pathway (Fas, FADD, active caspase-8 and active caspase-3), and mitochondria pathway (t-Bid, Bax, cytochrome c, active caspase-9 and active caspase-3) were increased in the DD0 group compared with the control group, whereas they were decreased in the DD50 group. The components of survival pathway (p-Bad, Bcl-2, Bcl-xL, IGF-1, p-PI3K and p-AKT) were increased in the DD50 group compared to the control group, whereas the levels of Bcl-xL, p-PI3K, and p-AKT were also compensatorily increased in the DD0 group compared to the control group. Taken together, diosgenin suppressed D-galactose-induced neuronal Fas-dependent and mitochondria-dependent apoptotic pathways and enhanced the Bcl-2 family associated pro-survival and IGF-1-PI3K-AKT survival pathways, which might provide neuroprotective effects of diosgenin for prevention of the D-galactose-induced aging brain.
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Affiliation(s)
- Shiu-Min Cheng
- Department of HealthCare Administration, Asia University, Taichung, Taiwan
| | - Ying-Jui Ho
- Department of Psychology, Chung Shan Medical University, Taichung, Taiwan
| | - Shao-Hong Yu
- College of Rehabilitation, Shandong University of Traditional Chinese Medicine, Shandong, P. R. China
| | - Yi-Fan Liu
- Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan
| | - Yi-Yuan Lin
- Department of Physical Therapy, Asia University, Taichung, Taiwan.,Department of Rehabilitation, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Chih-Yang Huang
- Department of Biotechnology, Asia University, Taichung, Taiwan.,Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Hsiu-Chung Ou
- Department of Physical Therapy, Asia University, Taichung, Taiwan
| | - Hai-Liang Huang
- College of Rehabilitation, Shandong University of Traditional Chinese Medicine, Shandong, P. R. China
| | - Shin-Da Lee
- Department of Physical Therapy, Asia University, Taichung, Taiwan.,College of Rehabilitation, Shandong University of Traditional Chinese Medicine, Shandong, P. R. China.,Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan
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30
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Chen K, Chen L, Ouyang Y, Zhang L, Li X, Li L, Si J, Wang L, Ma K. Pirfenidone attenuates homocysteine‑induced apoptosis by regulating the connexin 43 pathway in H9C2 cells. Int J Mol Med 2020; 45:1081-1090. [PMID: 32124965 PMCID: PMC7053877 DOI: 10.3892/ijmm.2020.4497] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 01/23/2020] [Indexed: 12/15/2022] Open
Abstract
Pirfenidone (PFD) is an anti-fibrotic agent that is clinically used in the treatment of idiopathic pulmonary fibrosis. PFD has been shown to exert protective effects against damage to orbital fibroblasts, endothelial cells, liver cells and renal proximal tubular cells; however, its effect on myocardial cell apoptosis remains unclear. The present study aimed to characterize the effects of PFD on homocysteine (Hcy)-induced cardiomyocyte apoptosis and investigated the underlying mechanisms. H9C2 rat cardiomyocytes were pre-treated with PFD for 30 min followed by Hcy exposure for 24 h. The effects of PFD on cell cytotoxicity were evaluated by CCK-8 assay. The apoptosis rate of each group was determined by flow cytometry. The protein and mRNA levels of connexin 43 (Cx43), Bax, B-cell lymphoma-2 (Bcl-2) and caspase-3 were measured by western blot analysis and reverse transcription-quantitative PCR, respectively. The present results demonstrated that the apoptotic rate increased following Hcy exposure, whereas the apoptotic rate significantly decreased following PFD pre-treatment. Furthermore, the ratio of Bax/Bcl2 was upregulated following Hcy exposure, and Hcy upregulated the expression levels of cleaved caspase-3 and Cx43. Notably, these effects were prevented by PFD. Additionally, the effects of PFD were inhibited by the Cx43 agonist, AAP10. In summary, the findings of the present study demonstrate that PFD protects H9C2 rat cardiomyocytes against Hcy-induced apoptosis by modulating the Cx43 signaling pathway.
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Affiliation(s)
- Kai Chen
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Medicine School of Shihezi University, Shihezi, Xinjiang 832008, P.R. China
| | - Ling Chen
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Medicine School of Shihezi University, Shihezi, Xinjiang 832008, P.R. China
| | - Yuanshuo Ouyang
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Medicine School of Shihezi University, Shihezi, Xinjiang 832008, P.R. China
| | - Liang Zhang
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Medicine School of Shihezi University, Shihezi, Xinjiang 832008, P.R. China
| | - Xinzhi Li
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Medicine School of Shihezi University, Shihezi, Xinjiang 832008, P.R. China
| | - Li Li
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Medicine School of Shihezi University, Shihezi, Xinjiang 832008, P.R. China
| | - Junqiang Si
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Medicine School of Shihezi University, Shihezi, Xinjiang 832008, P.R. China
| | - Li Wang
- The Third Department of Cardiology, The First Affiliated Hospital of The Medical College, Shihezi University, Shihezi, Xinjiang 832008, P.R. China
| | - Ketao Ma
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Medicine School of Shihezi University, Shihezi, Xinjiang 832008, P.R. China
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31
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Martini F, Régis Leite M, Gonçalves Rosa S, Pregardier Klann I, Wayne Nogueira C. Strength exercise suppresses STZ-induced spatial memory impairment and modulates BDNF/ERK-CAMKII/CREB signalling pathway in the hippocampus of mice. Cell Biochem Funct 2020; 38:213-221. [PMID: 31978253 DOI: 10.1002/cbf.3470] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 09/11/2019] [Accepted: 10/28/2019] [Indexed: 12/22/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has generated scientific interest because of its prevalence in the population. Studies indicate that physical exercise promotes neuroplasticity and improves cognitive function in animal models and in human beings. The aim of the present study was to investigate the effects of strength exercise on the hippocampal protein contents and memory performance in mice subjected to a model of sporadic AD induced by streptozotocin (STZ). Swiss mice received two injections of STZ (3 mg/kg, intracerebroventricular). After 21 days, they began physical training using a ladde. Mice performed this protocol for 4 weeks. After the last exercise training session, mice performed the Morris Water Maze test. The samples of hippocampus were excised and used to determine protein contents of brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase-Ca2+ (ERK), calmodulin-dependent protein kinase (CAMKII) and cAMP-response element-binding protein (CREB) signalling pathway. Strength exercise was effective against the decrease in the time spent and distance travelled in the target quadrant by STZ-injected mice. Strength exercise was also effective against the reduction of mature BDNF, tropomyosin receptor kinase B and neuronal nuclear antigen (NeuN) hippocampal protein levels in STZ mice. The decrease in the hippocampal ratio of pERK/ERK, pCAMKII/CAMKII and pCREB/CREB induced by STZ was reversed by strength exercise. Strength exercise decreased Bax/Bcl2 ratio in the hippocampus of STZ-injected mice. The present study demonstrates that strength exercise modulated the hippocampal BDNF/ERK-CAMKII/CREB signalling pathway and suppressed STZ-induced spatial memory impairment in mice.
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Affiliation(s)
- Franciele Martini
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
| | - Marlon Régis Leite
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
| | - Suzan Gonçalves Rosa
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
| | - Isabella Pregardier Klann
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
| | - Cristina Wayne Nogueira
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
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Li ML, Wu SH, Zhang JJ, Tian HY, Shao Y, Wang ZB, Irwin DM, Li JL, Hu XT, Wu DD. 547 transcriptomes from 44 brain areas reveal features of the aging brain in non-human primates. Genome Biol 2019; 20:258. [PMID: 31779658 PMCID: PMC6883628 DOI: 10.1186/s13059-019-1866-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 10/26/2019] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Brain aging is a complex process that depends on the precise regulation of multiple brain regions; however, the underlying molecular mechanisms behind this process remain to be clarified in non-human primates. RESULTS Here, we explore non-human primate brain aging using 547 transcriptomes originating from 44 brain areas in rhesus macaques (Macaca mulatta). We show that expression connectivity between pairs of cerebral cortex areas as well as expression symmetry between the left and right hemispheres both decrease after aging. Although the aging mechanisms across different brain areas are largely convergent, changes in gene expression and alternative splicing vary at diverse genes, reinforcing the complex multifactorial basis of aging. Through gene co-expression network analysis, we identify nine modules that exhibit gain of connectivity in the aged brain and uncovered a hub gene, PGLS, underlying brain aging. We further confirm the functional significance of PGLS in mice at the gene transcription, molecular, and behavioral levels. CONCLUSIONS Taken together, our study provides comprehensive transcriptomes on multiple brain regions in non-human primates and provides novel insights into the molecular mechanism of healthy brain aging.
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Affiliation(s)
- Ming-Li Li
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
- Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
| | - Shi-Hao Wu
- Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
| | - Jin-Jin Zhang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
- Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
| | - Hang-Yu Tian
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
- Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
| | - Yong Shao
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
- Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
| | - Zheng-Bo Wang
- Yunnan Key Laboratory of Primate Biomedicine Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - David M Irwin
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Jia-Li Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China
| | - Xin-Tian Hu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China.
- Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
- National Research Facility for Phenotypic and Genetic Analysis of Model Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China.
| | - Dong-Dong Wu
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China.
- National Research Facility for Phenotypic and Genetic Analysis of Model Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China.
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China.
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Fatty Acid Profile and Antioxidant Status Fingerprint in Sarcopenic Elderly Patients: Role of Diet and Exercise. Nutrients 2019; 11:nu11112569. [PMID: 31653011 PMCID: PMC6893529 DOI: 10.3390/nu11112569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023] Open
Abstract
Plasma fatty acids (FAs) and oxidant status contribute to the etiology of sarcopenia in the elderly concurring to age-related muscle loss and elderly frailty through several mechanisms including changes in FA composition within the sarcolemma, promotion of chronic low-grade inflammation, and insulin resistance. The aim of this study was to determine the FA profile and pro-antioxidant status in sarcopenic frail elderly patients enrolled in a nutritional and physical activity program and to evaluate their correlation with clinical markers. Moreover, the possible changes, produced after a short-term clinical protocol, were evaluated. Plasma and erythrocyte FA composition and pro-antioxidant status were analyzed in sarcopenic elderly subjects recruited for the randomized clinical study and treated with a placebo or dietary supplement, a personalized diet, and standardized physical activity. Subjects were tested before and after 30 days of treatment. Pearson correlations between biochemical parameters and patients’ characteristics at recruitment indicate interesting features of sarcopenic status such as negative correlation among the plasma FA profile, age, and physical characteristics. Physical activity and dietetic program alone for 30 days induced a decrease of saturated FA concentration with a significant increase of dihomo-gamma-linolenic acid. Supplementation plus physical activity induced a significant decrease of linoleic acid, omega-6 polyunsaturated FAs, and an increase of stearic and oleic acid concentration. Moreover, glutathione reductase activity, which is an indicator of antioxidant status, significantly increased in erythrocytes. Changes over time between groups indicate significant differences for saturated FAs, which suggest that the amino acid supplementation restores FA levels that are consumed during physical activity. A relationship between FA and clinical/metabolic status revealed unique correlations and a specific metabolic and lipidomic fingerprint in sarcopenic elderly. The results indicate the positive beneficial role of supplementation and physical activity on plasma FA status and the antioxidant system as a co-adjuvant approach in sarcopenic, frail, elderly patients.
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Darband SG, Sadighparvar S, Yousefi B, Kaviani M, Mobaraki K, Majidinia M. Combination of exercise training and L-arginine reverses aging process through suppression of oxidative stress, inflammation, and apoptosis in the rat heart. Pflugers Arch 2019; 472:169-178. [PMID: 31624955 DOI: 10.1007/s00424-019-02311-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 08/31/2019] [Accepted: 09/11/2019] [Indexed: 12/22/2022]
Abstract
Aging-induced progressive decline of molecular and metabolic factors in the myocardium is suggested to be related with heart dysfunction and cardiovascular disease. Therefore, we evaluated the effects of exercise training and L-arginine supplementation on oxidative stress, inflammation, and apoptosis in ventricle of the aging rat heart. Twenty-four 24-month-aged Wistar rats were randomly divided into four groups: the aged control, aged exercise, aged L-arginine (orally administered with 150 mg/kg for 12 weeks), and aged exercise + L-arginine groups. Six 4-month-old rats were also considered the young control. Animals with training program performed exercise on a treadmill 5 days/week for 12 weeks. After 12 weeks, protein levels of Bax, Bcl-2, pro-caspase-3/cleaved caspase-3, cytochrome C, and heat shock protein (HSP)-70 were assessed. Tissue contents of total anti-oxidant capacity, superoxide dismutase, catalase, and levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 were analyzed. Histological and fibrotic changes were also evaluated. Treadmill exercise and L-arginine supplementation significantly alleviated aging-induced apoptosis with enhancing HSP-70 expression, increasing anti-oxidant enzyme activity, and suppressing inflammatory markers in the cardiac myocytes. Potent attenuation in apoptosis, inflammation, and oxidative stress was indicated in the rats with the combination of L-arginine supplementation and exercise program in comparison with each group (p < 0.05). In addition, fibrosis percentage and collagen accumulation were significantly lower in the rats with the combination treatment of L-arginine and exercise (p < 0.05). Treadmill exercise and L-arginine supplementation provided protection against age-induced increase in the myocyte loss and formation of fibrosis in the ventricle through potent suppression of oxidative stress, inflammations, and apoptosis pathways.
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Affiliation(s)
- Saber Ghazizadeh Darband
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran.,Department of Exercise Physiology, Faculty of Sport Sciences, Urmia University, Urmia, Iran
| | - Shirin Sadighparvar
- Neurophysiology Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Mojtaba Kaviani
- School of Nutrition and Dietetics, Acadia University, Wolfville, Nova Scotia, Canada
| | - Kazhal Mobaraki
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran.
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35
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Wu G, Tan J, Li J, Sun X, Du L, Tao S. miRNA-145-5p induces apoptosis after ischemia-reperfusion by targeting dual specificity phosphatase 6. J Cell Physiol 2019; 234:16281-16289. [PMID: 30883744 DOI: 10.1002/jcp.28291] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 12/04/2018] [Accepted: 12/07/2018] [Indexed: 01/24/2023]
Abstract
Disorders mainly caused by ischemia-reperfusion (I/R), including stroke and myocardial infarction, is linked to debilitating health conditions and death. Recent research indicates that microRNAs (miRNAs) mediate the process of ischemic pathology. This study investigated the effects of miR-145-5p in regulating myocardial ischemic injury. The I/R models were established in rat cardiomyocytes H9C2 and rats. Western blot analysis and quantitative polymerase chain reaction was performed to analyze protein expression. Annexin V-FITC/PI staining was conducted to evaluate cell apoptosis. The application of miR-145-5p mimics and inhibitor revealed that miR-145-5p promoted apoptosis in cardiomyocytes. Furthermore, we found that miR-145-5p directly inhibited dual specificity phosphatase 6 (DUSP6) by luciferase reporter assay. The results indicated that DUSP6 was beneficial against I/R injury through inhibiting c-Jun N-terminal kinase pathways. In conclusion, the essential roles of miR-145-5p and DUSP6 in I/R provide a novel therapeutic target to develop future intervention strategies.
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Affiliation(s)
- Gang Wu
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jiaying Tan
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Junping Li
- Department of Obstetrics and Gynecology, Huashan Hospital North, Fudan University, Shanghai, People's Republic of China
| | - Xiaoli Sun
- Department of Cardiology, Karamay Central Hospital, Karamay, People's Republic of China
| | - Lei Du
- Department of Cardiology, Karamay Central Hospital, Karamay, People's Republic of China
| | - Sun Tao
- Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
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36
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Pandey T, Sammi SR, Nooreen Z, Mishra A, Ahmad A, Bhatta RS, Pandey R. Anti-ageing and anti-Parkinsonian effects of natural flavonol, tambulin from Zanthoxyllum aramatum promotes longevity in Caenorhabditis elegans. Exp Gerontol 2019; 120:50-61. [DOI: 10.1016/j.exger.2019.02.016] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 01/12/2019] [Accepted: 02/25/2019] [Indexed: 12/01/2022]
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The natural involution of the sheep proximal sesamoidean ligament is due to depletion of satellite cells and simultaneous proliferation of fibroblasts: Ultrastructural evidence. Res Vet Sci 2019; 124:106-111. [PMID: 30877991 DOI: 10.1016/j.rvsc.2019.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/11/2019] [Accepted: 03/07/2019] [Indexed: 01/08/2023]
Abstract
The rapid involution that happens in some muscles of ungulate fetlock joints has never been investigated at an ultrastructural level. In this study, the proximal sesamoidean ligament (PSL) of sheep was chosen as a model to investigate, at the cellular level, the transition from muscle to connective structures that occurs during early development. In particular, we were interested in observing the presence of satellite cells and fibroblasts, detecting fluctuations in their numbers in the postnatal developing PSL, and evaluating putative apoptotic mechanisms. Interestingly, some features were shared by both PSL involution and muscle ageing; the most relevant being the significant and rapid decrease in the number of satellite cells together with a quick proliferation of fibroblasts in the muscle-connective transitional area (MCT-TA). Electron microscopy and immunohistochemical analyses revealed putative cellular mechanisms that led to a progressive involution of the muscle portion of the PSL during postnatal growth. Our findings showed a fast transition from muscle to connective tissue due to the depletion of satellite cells, apoptosis of some muscle fibres, and simultaneous proliferation of fibroblasts originating from mesenchymal progenitors or from differentiation of satellite cells typically located at the border between muscle and connective tissue of the PSL.
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38
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Sovran B, Hugenholtz F, Elderman M, Van Beek AA, Graversen K, Huijskes M, Boekschoten MV, Savelkoul HFJ, De Vos P, Dekker J, Wells JM. Age-associated Impairment of the Mucus Barrier Function is Associated with Profound Changes in Microbiota and Immunity. Sci Rep 2019; 9:1437. [PMID: 30723224 PMCID: PMC6363726 DOI: 10.1038/s41598-018-35228-3] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 10/16/2018] [Indexed: 02/07/2023] Open
Abstract
Aging significantly increases the vulnerability to gastrointestinal (GI) disorders but there are few studies investigating the key factors in aging that affect the GI tract. To address this knowledge gap, we used 10-week- and 19-month-old litter-mate mice to investigate microbiota and host gene expression changes in association with ageing. In aged mice the thickness of the colonic mucus layer was reduced about 6-fold relative to young mice, and more easily penetrable by luminal bacteria. This was linked to increased apoptosis of goblet cells in the upper part of the crypts. The barrier function of the small intestinal mucus was also compromised and the microbiota were frequently observed in contact with the villus epithelium. Antimicrobial Paneth cell factors Ang4 and lysozyme were expressed in significantly reduced amounts. These barrier defects were accompanied by major changes in the faecal microbiota and significantly decreased abundance of Akkermansia muciniphila which is strongly and negatively affected by old age in humans. Transcriptomics revealed age-associated decreases in the expression of immunity and other genes in intestinal mucosal tissue, including decreased T cell-specific transcripts and T cell signalling pathways. The physiological and immunological changes we observed in the intestine in old age, could have major consequences beyond the gut.
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Affiliation(s)
- Bruno Sovran
- Top Institute Food and Nutrition, Wageningen, The Netherlands.,Cell Biology and Immunology Group, Wageningen University and Research Center, Wageningen, The Netherlands
| | - Floor Hugenholtz
- Laboratory of Microbiology, Wageningen University and Research Center, Wageningen, The Netherlands
| | - Marlies Elderman
- Top Institute Food and Nutrition, Wageningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Adriaan A Van Beek
- Top Institute Food and Nutrition, Wageningen, The Netherlands.,Cell Biology and Immunology Group, Wageningen University and Research Center, Wageningen, The Netherlands
| | - Katrine Graversen
- Host-Microbe Interactomics Group, Wageningen University and Research Center, Wageningen, The Netherlands
| | - Myrte Huijskes
- Host-Microbe Interactomics Group, Wageningen University and Research Center, Wageningen, The Netherlands
| | - Mark V Boekschoten
- Top Institute Food and Nutrition, Wageningen, The Netherlands.,Division of Human Nutrition, Wageningen University and Research Center, Wageningen, The Netherlands
| | - Huub F J Savelkoul
- Top Institute Food and Nutrition, Wageningen, The Netherlands.,Cell Biology and Immunology Group, Wageningen University and Research Center, Wageningen, The Netherlands
| | - Paul De Vos
- Top Institute Food and Nutrition, Wageningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan Dekker
- Top Institute Food and Nutrition, Wageningen, The Netherlands.,Host-Microbe Interactomics Group, Wageningen University and Research Center, Wageningen, The Netherlands
| | - Jerry M Wells
- Top Institute Food and Nutrition, Wageningen, The Netherlands. .,Host-Microbe Interactomics Group, Wageningen University and Research Center, Wageningen, The Netherlands.
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Teo YV, Capri M, Morsiani C, Pizza G, Faria AMC, Franceschi C, Neretti N. Cell-free DNA as a biomarker of aging. Aging Cell 2019; 18:e12890. [PMID: 30575273 PMCID: PMC6351822 DOI: 10.1111/acel.12890] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/12/2018] [Accepted: 11/10/2018] [Indexed: 12/18/2022] Open
Abstract
Cell-free DNA (cfDNA) is present in the circulating plasma and other body fluids and is known to originate mainly from apoptotic cells. Here, we provide the first in vivo evidence of global and local chromatin changes in human aging by analyzing cfDNA from the blood of individuals of different age groups. Our results show that nucleosome signals inferred from cfDNA are consistent with the redistribution of heterochromatin observed in cellular senescence and aging in other model systems. In addition, we detected a relative cfDNA loss at several genomic locations, such as transcription start and termination sites, 5'UTR of L1HS retrotransposons and dimeric AluY elements with age. Our results also revealed age and deteriorating health status correlate with increased enrichment of signals from cells in different tissues. In conclusion, our results show that the sequencing of circulating cfDNA from human blood plasma can be used as a noninvasive methodology to study age-associated changes to the epigenome in vivo.
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Affiliation(s)
- Yee Voan Teo
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island
| | - Miriam Capri
- CIG Interdepartmental Centre "Galvani", University of Bologna, Bologna, Italy
- DIMES-Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Cristina Morsiani
- DIMES-Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Grazia Pizza
- DIMES-Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Imperial College London, London, UK
| | - Ana Maria Caetano Faria
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Nicola Neretti
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island
- Center for Computational Molecular Biology, Brown University, Providence, Rhode Island
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40
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Martini F, Rosa SG, Klann IP, Fulco BCW, Carvalho FB, Rahmeier FL, Fernandes MC, Nogueira CW. A multifunctional compound ebselen reverses memory impairment, apoptosis and oxidative stress in a mouse model of sporadic Alzheimer's disease. J Psychiatr Res 2019; 109:107-117. [PMID: 30521994 DOI: 10.1016/j.jpsychires.2018.11.021] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 10/24/2018] [Accepted: 11/21/2018] [Indexed: 01/08/2023]
Abstract
Alzheimer 's disease (AD) is characterized by progressive cognitive decline including memory impairment, cortical dysfunction, and neuropsychiatric disturbances. The drug discovery to treat AD consists to develop compounds able to act in multiple molecular targets involved in the pathogenesis of the disease and the repositioning of old drugs for new application. This way, the intracerebroventricular (icv) injection of streptozotocin (STZ) has been used as a metabolic model of sporadic AD. The aim of the present study was to investigate whether ebselen (1-10 mg/kg), a multifunctional selenoorganic compound, ameliorates memory impairment, hippocampal oxidative stress, apoptosis and cell proliferation in a mouse model of sporadic AD induced by icv STZ (3 mg/kg, 1 μl/min). The administration of ebselen (10 mg/kg, i.p.) reversed memory impairment and hippocampal oxidative stress, by increasing the activities of antioxidant enzymes and the level of a non-enzymatic antioxidant defense, in Swiss mice administered with icv STZ. The anti-apoptotic property of ebselen was demonstrated by its effectiveness against the increase in the ratios of Bax/Bcl-2, cleaved PARP/PARP and the cleaved caspase-3 levels in the hippocampus of icv STZ mice. Although ebselen reversed memory impairment, it was ineffective against the reduction in the number of BrdU positive cells induced by icv STZ. In conclusion, the multifunctional selenoorganic compound ebselen was effective to reverse memory impairment, hippocampal oxidative stress and apoptosis in a mouse model of sporadic AD induced by icv STZ.
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Affiliation(s)
- Franciele Martini
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil
| | - Suzan Gonçalves Rosa
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil
| | - Isabella Pregardier Klann
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil
| | - Bruna Cruz Weber Fulco
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil
| | - Fabiano Barbosa Carvalho
- Laboratório de Patologia da Fundação, Universidade Federal de Ciências da Saúde de Porto Alegre, CEP 90050-170, Porto Alegre, Rio Grande do Sul, Brazil
| | - Francine Luciano Rahmeier
- Laboratório de Patologia da Fundação, Universidade Federal de Ciências da Saúde de Porto Alegre, CEP 90050-170, Porto Alegre, Rio Grande do Sul, Brazil
| | - Marilda Cruz Fernandes
- Laboratório de Patologia da Fundação, Universidade Federal de Ciências da Saúde de Porto Alegre, CEP 90050-170, Porto Alegre, Rio Grande do Sul, Brazil
| | - Cristina Wayne Nogueira
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil.
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Relat J, Come J, Perez B, Camps P, Muñoz-Torrero D, Badia A, Gimenez-Llort L, Clos MV. Neuroprotective Effects of the Multitarget Agent AVCRI104P3 in Brain of Middle-Aged Mice. Int J Mol Sci 2018; 19:ijms19092615. [PMID: 30181440 PMCID: PMC6165152 DOI: 10.3390/ijms19092615] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 08/14/2018] [Accepted: 08/15/2018] [Indexed: 11/16/2022] Open
Abstract
Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3β, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3β in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia.
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Affiliation(s)
- Julia Relat
- Neuroscience Institute, Autonomous University of Barcelona, 08193 Barcelona, Spain.
- Department of Pharmacology, Therapeutic and Toxicology, Autonomous University of Barcelona, 08193 Barcelona, Spain.
| | - Julio Come
- Neuroscience Institute, Autonomous University of Barcelona, 08193 Barcelona, Spain.
- Department of Pharmacology, Therapeutic and Toxicology, Autonomous University of Barcelona, 08193 Barcelona, Spain.
| | - Belen Perez
- Neuroscience Institute, Autonomous University of Barcelona, 08193 Barcelona, Spain.
- Department of Pharmacology, Therapeutic and Toxicology, Autonomous University of Barcelona, 08193 Barcelona, Spain.
| | - Pelayo Camps
- Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, Spain.
| | - Diego Muñoz-Torrero
- Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, Spain.
| | - Albert Badia
- Neuroscience Institute, Autonomous University of Barcelona, 08193 Barcelona, Spain.
- Department of Pharmacology, Therapeutic and Toxicology, Autonomous University of Barcelona, 08193 Barcelona, Spain.
| | - Lydia Gimenez-Llort
- Neuroscience Institute, Autonomous University of Barcelona, 08193 Barcelona, Spain.
- Department of Psychiatry and Forensic Medicine, Autonomous University of Barcelona, 08193 Barcelona, Spain.
| | - M Victòria Clos
- Neuroscience Institute, Autonomous University of Barcelona, 08193 Barcelona, Spain.
- Department of Pharmacology, Therapeutic and Toxicology, Autonomous University of Barcelona, 08193 Barcelona, Spain.
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Dietary magnesium deficiency impaired intestinal structural integrity in grass carp (Ctenopharyngodon idella). Sci Rep 2018; 8:12705. [PMID: 30139942 PMCID: PMC6107577 DOI: 10.1038/s41598-018-30485-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 07/30/2018] [Indexed: 02/07/2023] Open
Abstract
Grass carp (223.85–757.33 g) were fed diets supplemented with magnesium (73.54–1054.53 mg/kg) for 60 days to explore the impacts of magnesium deficiency on the growth and intestinal structural integrity of the fish. The results demonstrated that magnesium deficiency suppressed the growth and damaged the intestinal structural integrity of the fish. We first demonstrated that magnesium is partly involved in (1) attenuating antioxidant ability by suppressing Nrf2 signalling to decrease antioxidant enzyme mRNA levels and activities (except CuZnSOD mRNA levels and activities); (2) aggravating apoptosis by activating JNK (not p38MAPK) signalling to upregulate proapoptotic protein (Apaf-1, Bax and FasL) and caspase-2, -3, -7, -8 and -9 gene expression but downregulate antiapoptotic protein (Bcl-2, IAP and Mcl-1b) gene expression; (3) weakening the function of tight junctional complexes (TJs) by promoting myosin light chain kinase (MLCK) signalling to downregulate TJ gene expression [except claudin-7, ZO-2b and claudin-15 gene expression]. Additionally, based on percent weight gain (PWG), against reactive oxygen species (ROS), against caspase-9 and claudin-3c in grass carp, the optimal dietary magnesium levels were calculated to be 770.38, 839.86, 856.79 and 811.49 mg/kg, respectively.
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Metabonomics and Molecular Biology-based Effects of Sugemule-3 in an Isoproterenol-induced Cardiovascular Disease Rat Model. Chem Res Chin Univ 2018. [DOI: 10.1007/s40242-018-7307-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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44
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Majdi A, Sadigh-Eteghad S, Talebi M, Farajdokht F, Erfani M, Mahmoudi J, Gjedde A. Nicotine Modulates Cognitive Function in D-Galactose-Induced Senescence in Mice. Front Aging Neurosci 2018; 10:194. [PMID: 30061821 PMCID: PMC6055060 DOI: 10.3389/fnagi.2018.00194] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 06/08/2018] [Indexed: 01/21/2023] Open
Abstract
Here, we tested the claim that nicotine attenuates the signs of brain dysfunction in the model of brain aging induced by D-galactose (DGal) in mice. We administered nicotine at doses of 0.1, 0.5 and 1 mg/kg by the subcutaneous (s.c.) or at 0.1 mg/kg by the intranasal (i.n.) routes in mice that had received DGal at the dose of 500 mg/kg subcutaneous (s.c.) for 6 weeks. We assessed animal withdrawal signs as the number of presented somatic signs, thermal hyperalgesia, elevated plus maze (EPM) and open field tests. We evaluated spatial memory and recognition with Barnes maze and novel object recognition (NOR) tests. We tested brain tissue for reactive oxygen species (ROS), mitochondrial membrane potential, caspase-3, Bax, Bcl-2, cytochrome C, brain-derived neurotrophic factor and nerve growth factor levels. Nicotine administration in model groups (0.5 mg/kg s.c. and 0.1 mg/kg i.n. doses) significantly attenuated impairment of spatial and episodic memories in comparison to normal saline-received model group. These doses also reduced mito-oxidative damage as well as apoptosis and raised neurotrophic factors level in model groups in comparison to normal saline-received model group. The 1 mg/kg s.c. dose nicotine revealed withdrawal signs compared with the other nicotine-received groups. Nicotine at specific doses and routes has the potential to attenuate age-related cognitive impairment, mito-oxidative damage, and apoptosis. The doses raise neurotrophic factors without producing withdrawal signs.
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Affiliation(s)
- Alireza Majdi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahnaz Talebi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fereshteh Farajdokht
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marjan Erfani
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Albert Gjedde
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Departments of Clinical Research and Nuclear Medicine, Odense University Hospital, University of Southern Denmark, Odense, Denmark
- Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States
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45
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Zhang D, Han J, Li Y, Yuan B, Zhou J, Cheong L, Li Y, Lu C, Su X. Tuna Oil Alleviates d-Galactose Induced Aging in Mice Accompanied by Modulating Gut Microbiota and Brain Protein Expression. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:5510-5520. [PMID: 29656644 DOI: 10.1021/acs.jafc.8b00446] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
To discern whether tuna oil modulates the expression of brain proteins and the gut microbiota structure during aging induced by d-galactose, we generated an aging mouse model with d-galactose treatment, and the mice showed aging and memory deterioration symptoms according to physiological and biochemical indices. Treatment with different doses of tuna oil alleviated the symptoms; the high dose showed a better effect. Subsequently, brain proteomic analysis showed the differentially expressed proteins were involved in damaged synaptic system repairment and signal transduction system enhancement. In addition, tuna oil treatment restored the diversity of gut microbiota, 27 key operational taxonomic units, which were identified using a redundancy analysis and were significantly correlated with at least one physiological index and three proteins or genes. These findings suggest that the combination of proteomics and gut microbiota is an effective strategy to gain novel insights regarding the effect of tuna oil treatment on the microbiota-gut-brain axis.
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Affiliation(s)
- Dijun Zhang
- School of Marine Science , Ningbo University , Ningbo 315211 , China
| | - Jiaojiao Han
- School of Marine Science , Ningbo University , Ningbo 315211 , China
| | - Yanyan Li
- Department of Food Science , Cornell University , Ithaca , New York 14853 , United States
| | - Bei Yuan
- School of Marine Science , Ningbo University , Ningbo 315211 , China
| | - Jun Zhou
- School of Marine Science , Ningbo University , Ningbo 315211 , China
| | - Lingzhi Cheong
- School of Marine Science , Ningbo University , Ningbo 315211 , China
| | - Ye Li
- School of Marine Science , Ningbo University , Ningbo 315211 , China
| | - Chenyang Lu
- School of Marine Science , Ningbo University , Ningbo 315211 , China
| | - Xiurong Su
- School of Marine Science , Ningbo University , Ningbo 315211 , China
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46
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Gao H, Wu B, Le Y, Zhu Z. Homeobox protein VentX induces p53-independent apoptosis in cancer cells. Oncotarget 2018; 7:39719-39729. [PMID: 27175592 PMCID: PMC5129965 DOI: 10.18632/oncotarget.9238] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 04/24/2016] [Indexed: 01/24/2023] Open
Abstract
Identifying novel tumor suppressors holds promise for improving cancer treatment. Our recent studies identified VentX, a homeobox transcriptional factor, as a putative tumor suppressor. Here we demonstrate that VentX exerts strong inhibitory effects on the proliferation and survival of cancer cells, but not primary transformed cells, such as 293T cells. Mechanistically, both in vitro and in vivo data showed that VentX induces apoptosis of cancer cells in a p53-independent manner. We found that VentX expression can be induced by chemotherapeutic agents. Taken together, our findings suggest that VentX may function as a novel therapeutic target in cancer treatment.
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Affiliation(s)
- Hong Gao
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA.,Current address: Department of Medicine, Tufts Medical Center, Boston, 02115, Massachusetts, USA
| | - Bin Wu
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA.,Current address: Department of Gastroenterology, Third Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Yi Le
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA
| | - Zhenglun Zhu
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA
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47
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Mehdizadeh H, Pourahmad J, Taghizadeh G, Vousooghi N, Yoonessi A, Naserzadeh P, Behzadfar L, Rouini MR, Sharifzadeh M. Mitochondrial impairments contribute to spatial learning and memory dysfunction induced by chronic tramadol administration in rat: Protective effect of physical exercise. Prog Neuropsychopharmacol Biol Psychiatry 2017; 79:426-433. [PMID: 28757160 DOI: 10.1016/j.pnpbp.2017.07.022] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 07/06/2017] [Accepted: 07/26/2017] [Indexed: 01/15/2023]
Abstract
Despite the worldwide use of tramadol, few studies have been conducted about its effects on memory and mitochondrial function, and controversial results have been reported. Recently, there has been an increasing interest in physical exercise as a protective approach to neuronal and cognitive impairments. Therefore, the aim of this study was to investigate the effects of physical exercise on spatial learning and memory and brain mitochondrial function in tramadol-treated rats. After completion of 2-week (short-term) and 4-week (long-term) treadmill exercise regimens, male Wistar rats received tramadol (20, 40, 80mg/kg/day) intraperitoneally for 30days. Then spatial learning and memory was assessed by Morris water maze test (MWM). Moreover, brain mitochondrial function was evaluated by determination of mitochondrial reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release from mitochondria. Chronic administration of tramadol impaired spatial learning and memory as well as brain mitochondrial function as indicated by increased ROS level, MMP collapse, increased mitochondrial swelling and cytochrome c release from mitochondria. Conversely, treadmill exercise significantly attenuated the impairments of spatial learning and memory and brain mitochondrial dysfunction induced by tramadol. The results revealed that chronic tramadol treatment caused memory impairments through induction of brain mitochondrial dysfunction. Furthermore, pre-exposure to physical exercise markedly mitigated these impairments through its positive effects on brain mitochondrial function.
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Affiliation(s)
- Hajar Mehdizadeh
- Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Jalal Pourahmad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghorban Taghizadeh
- Department of Occupational Therapy, Faculty of Rehabilitation, Iran University of Medical Sciences, Tehran, Iran; Rehabilitation Research Center, Faculty of Rehabilitation, Iran University of Medical Sciences, Tehran, Iran
| | - Nasim Vousooghi
- Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Yoonessi
- Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parvaneh Naserzadeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ladan Behzadfar
- Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Rouini
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Sharifzadeh
- Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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48
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Dong F, Wang S, Wang Y, Yang X, Jiang J, Wu D, Qu X, Fan H, Yao R. Quercetin ameliorates learning and memory via the Nrf2-ARE signaling pathway in d-galactose-induced neurotoxicity in mice. Biochem Biophys Res Commun 2017; 491:636-641. [DOI: 10.1016/j.bbrc.2017.07.151] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 07/27/2017] [Indexed: 12/28/2022]
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49
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Wang Y, Gong GH, Xu YN, Yu LJ, Wei CX. Sugemule-3 Protects against Isoprenaline-induced Cardiotoxicity In vitro. Pharmacogn Mag 2017; 13:517-522. [PMID: 28839382 PMCID: PMC5551375 DOI: 10.4103/0973-1296.211018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/19/2016] [Indexed: 12/25/2022] Open
Abstract
Background: Sugemule-3 (SD) is a traditional Chinese medicine with protective effect of myocardium. However, the underlying mechanisms of the effect had not been elucidated. Materials and Methods: In the present study, the serum of SD was prepared. A model of β-adrenergic agonist isoprenaline (ISO)-induced H9c2 cardiomyocytes injury was established in vitro. The changes in cell viability were examined to determine the available concentration of ISO and serum of SD. ELISA, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, and flow cytometry were used to detect the effect of serum of SD on oxidative stress and apoptosis. The expression levels of the mitochondria-dependent apoptotic pathway and mitogen-activated protein kinase signalling-related proteins were analyzed. Results: Incubation with different dose of ISO (0.015, 0.01, 0.005, and 0.0025 mol/L) for 24 h caused dose-dependent loss of cell viability and 0.01 mol/L of ISO approximately reduced the cell viability to 50%. Pretreatment with 50 μ mol/L serum of SD effectively decreased the levels of ISO-induced cell toxicity. Serum of SD relived ISO-induced oxidative stress and apoptosis in H9c2 cardiomyocytes. A further mechanism study indicated that serum of SD inhibited the mitochondria-dependent apoptotic pathways and regulated the expression levels of Bcl-2 family. ISO activated ERK and P38, whereas serum of SD inhibited their activation. Conclusion: Serum of SD inhibits the ISO-induced activation of the mitochondria-dependent apoptotic pathway, oxidative stress, and ERK, P38 inactivation. Serum of SD is used for the treatment of ISO-induced cardiomyopathy. SUMMARY
The serum of SD pretreatment significantly ameliorated ISO-induced H9c2 cardiomyocytes injuries. The protective effect related with apoptosis and oxidative stress Inhibition of MAPK pathway was involed in serum of SD induced cardioprotection. The serum of SD is used for the treatment of ISO-induced cardiomyopathy. Abbreviations used: ELISA: Enzyme-linked Immunosorbent Assay; TUNEL: TdT-mediated dUTP nick end labeling; MTT: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, DMSO: dimethyl sulfoxide; MDA: Malondialdehyde; SOD: Superoxide Dismutase; GSH-Px: Glutathione peroxidase.
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Affiliation(s)
- Yu Wang
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for The Nationalities, Tongliao.,Inner Mongolia Autonomous Region Key laboratory of Mongolian medicine pharmacology for cardio-cerebral vascular system, Tongliao, Inner Mongolia, P. R. China
| | - Guo-Hua Gong
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for The Nationalities, Tongliao.,Inner Mongolia Autonomous Region Key laboratory of Mongolian medicine pharmacology for cardio-cerebral vascular system, Tongliao, Inner Mongolia, P. R. China
| | - Ya-Nan Xu
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for The Nationalities, Tongliao.,Inner Mongolia Autonomous Region Key laboratory of Mongolian medicine pharmacology for cardio-cerebral vascular system, Tongliao, Inner Mongolia, P. R. China
| | - Li-Jun Yu
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for The Nationalities, Tongliao.,Inner Mongolia Autonomous Region Key laboratory of Mongolian medicine pharmacology for cardio-cerebral vascular system, Tongliao, Inner Mongolia, P. R. China
| | - Cheng-Xi Wei
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for The Nationalities, Tongliao.,Inner Mongolia Autonomous Region Key laboratory of Mongolian medicine pharmacology for cardio-cerebral vascular system, Tongliao, Inner Mongolia, P. R. China
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50
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Salehpour F, Ahmadian N, Rasta SH, Farhoudi M, Karimi P, Sadigh-Eteghad S. Transcranial low-level laser therapy improves brain mitochondrial function and cognitive impairment in D-galactose-induced aging mice. Neurobiol Aging 2017; 58:140-150. [PMID: 28735143 DOI: 10.1016/j.neurobiolaging.2017.06.025] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 05/11/2017] [Accepted: 06/29/2017] [Indexed: 12/11/2022]
Abstract
Mitochondrial function plays a key role in the aging-related cognitive impairment, and photoneuromodulation of mitochondria by transcranial low-level laser therapy (LLLT) may contribute to its improvement. This study focused on the transcranial LLLT effects on the D-galactose (DG)-induced mitochondrial dysfunction, apoptosis, and cognitive impairment in mice. For this purpose, red and near-infrared (NIR) laser wavelengths (660 and 810 nm) at 2 different fluencies (4 and 8 J/cm2) at 10-Hz pulsed wave mode were administrated transcranially 3 d/wk in DG-received (500 mg/kg/subcutaneous) mice model of aging for 6 weeks. Spatial and episodic-like memories were assessed by the Barnes maze and What-Where-Which (WWWhich) tasks. Brain tissues were analyzed for mitochondrial function including active mitochondria, adenosine triphosphate, and reactive oxygen species levels, as well as membrane potential and cytochrome c oxidase activity. Apoptosis-related biomarkers, namely, Bax, Bcl-2, and caspase-3 were evaluated by Western blotting method. Laser treatments at wavelengths of 660 and 810 nm at 8 J/cm2 attenuated DG-impaired spatial and episodic-like memories. Also, results showed an obvious improvement in the mitochondrial function aspects and modulatory effects on apoptotic markers in aged mice. However, same wavelengths at the fluency of 4 J/cm2 had poor effect on the behavioral and molecular indexes in aging model. This data indicates that transcranial LLLT at both of red and NIR wavelengths at the fluency of 8 J/cm2 has a potential to ameliorate aging-induced mitochondrial dysfunction, apoptosis, and cognitive impairment.
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Affiliation(s)
- Farzad Salehpour
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Physics, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nahid Ahmadian
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Hossein Rasta
- Department of Medical Physics, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Bioengineering, Tabriz University of Medical Sciences, Tabriz, Iran; School of Medical Sciences, University of Aberdeen, Aberdeen, UK
| | - Mehdi Farhoudi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pouran Karimi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran.
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