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He L, Zhang L, Meng F, Wei J, Chen F, Qin S, Jin G, Cao H. Dietary emulsifier Polysorbate 80-induced lipotoxicity promotes intestinal senescence. Food Res Int 2025; 209:116165. [PMID: 40253120 DOI: 10.1016/j.foodres.2025.116165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 02/11/2025] [Accepted: 03/09/2025] [Indexed: 04/21/2025]
Abstract
Intestinal senescence, often characterized by increased oxidative stress, is linked to gastrointestinal disorders such as inflammatory bowel disease and colorectal cancer. While previous studies have suggested that diets rich in food additives, such as the emulsifier Polysorbate 80 (P80), may influence gut health, the impact of P80 exposure on intestinal senescence remains unclear. This study aimed to explore the effects of P80 on intestinal senescence in a senescence-accelerated mouse prone model. The results revealed that P80 exposure could damage the intestinal barrier, induce oxidative stress, and accelerate intestinal senescence. Mechanistically, P80 activated the peroxisome proliferator-activated receptor-α (PPARα) and fatty acid-binding protein 1 (FABP1) axis, increasing intestinal fatty acid absorption and triggering lipotoxicity, which promoted senescence. Additionally, P80 exacerbated D-galactose-induced epithelial cell senescence and lipid accumulation via the PPARα signalling pathway. Importantly, the PPARα antagonist GW6471 mitigated fatty acid uptake and reduced senescence in the intestine. In conclusion, the emulsifier P80 accelerated intestinal senescence by regulating the PPARα-FABP1 axis to induce intestinal fatty acid uptake and lipotoxicity, suggesting new insights into the adverse effects of food additives on gut health.
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Affiliation(s)
- Linlin He
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Lan Zhang
- Department of Infective disease, Tianjin First Central Hospital, Tianjin, China
| | - Fanyi Meng
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Jingge Wei
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Fei Chen
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Siqi Qin
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Ge Jin
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China..
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China..
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Zarroug SHO. Caenorhabditis elegans as in vivo model for the screening of natural plants-derived novel anti-aging compounds: a short introduction. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2025; 27:577-590. [PMID: 39404185 DOI: 10.1080/10286020.2024.2414189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 09/30/2024] [Accepted: 10/01/2024] [Indexed: 03/18/2025]
Abstract
The global aging population highlights the need for effective anti-aging treatments. Natural products show promise, but thorough evaluation requires in vivo models due to the complexity of aging. Ethical concerns are driving a shift from traditional models like rabbits and mice to alternatives such as Caenorhabditis elegans. This microscopic nematode, with its short life cycle, genetic similarities to humans, and cost-effectiveness, is ideal for testing anti-aging compounds. We review studies using C. elegans to assess natural products, suggesting it could serve as a primary model for -evaluating the safety and efficacy of plant-derived anti-aging compounds.
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Affiliation(s)
- Samah H O Zarroug
- Department of Pharmacology, College of Medicine, Alfaisal University, Riyadh11533, Saudi Arabia
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3
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De Bartolo A, Angelone T, Rocca C. Elucidating emerging signaling pathways driving endothelial dysfunction in cardiovascular aging. Vascul Pharmacol 2025; 158:107462. [PMID: 39805379 DOI: 10.1016/j.vph.2025.107462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/24/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025]
Abstract
The risk for developing cardiovascular diseases dramatically increases in older individuals, and aging vasculature plays a crucial role in determining their morbidity and mortality. Aging disrupts endothelial balance between vasodilators and vasoconstrictors, impairing function and promoting pathological vascular remodeling. In this Review, we discuss the impact of key and emerging molecular pathways that transduce aberrant inflammatory signals (i.e., chronic low-grade inflammation-inflammaging), oxidative stress, and mitochondrial dysfunction in aging vascular compartment. We focus on the interplay between these events, which contribute to generating a vicious cycle driving the progressive alterations in vascular structure and function during cardiovascular aging. We also discuss the primary role of senescent endothelial cells and vascular smooth muscle cells, and the potential link between vascular and myeloid cells, in impairing plaque stability and promoting the progression of atherosclerosis. The aim of this summary is to provide potential novel insights into targeting these processes for therapeutic benefit.
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Affiliation(s)
- Anna De Bartolo
- Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory, Department of Biology, E. and E. S. (DiBEST), University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Tommaso Angelone
- Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory, Department of Biology, E. and E. S. (DiBEST), University of Calabria, Arcavacata di Rende, Cosenza, Italy; National Institute of Cardiovascular Research (INRC), Bologna, Italy.
| | - Carmine Rocca
- Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory, Department of Biology, E. and E. S. (DiBEST), University of Calabria, Arcavacata di Rende, Cosenza, Italy; National Institute of Cardiovascular Research (INRC), Bologna, Italy.
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Ding X, Wang G, Lin Y, Hu W, Chen C, Gao J, Wu Y, Zhou C. A novel SIRT1 activator attenuates neuropathic pain by inhibiting spinal neuronal activation via the SIRT1-mGluR1/5 pathway. Cell Biol Toxicol 2025; 41:24. [PMID: 39779529 PMCID: PMC11711878 DOI: 10.1007/s10565-024-09970-6] [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: 07/07/2024] [Accepted: 12/21/2024] [Indexed: 01/11/2025]
Abstract
Neuropathic pain is a type of pain caused by an injury or disease of the somatosensory nervous system. Currently, there is still absence of effective therapeutic drugs for neuropathic pain, so developing new therapeutic drugs is urgently needed. In the present study, we observed the effect of Comp 6d, a novel silent information regulator 1 (SIRT1) activator synthesized in our laboratory, on neuropathic pain and investigated the mechanisms involved. We found that both intrathecal and intraperitoneal injections of Comp 6d effectively alleviated neuropathic pain induced by chronic constriction injury (CCI) or spared nerve injury (SNI). However, the effect of Comp 6d on neuropathic pain was abolished in SIRT1 knockout mice. These results demonstrated that Comp 6d alleviated neuropathic pain by specifically activating SIRT1 in the spinal cord. Moreover, long-term intraperitoneal injection of Comp 6d had no significant side effects on heart, liver and kidney in SNI mice. Further study showed that the improvement of neuropathic pain by Comp 6d was mediated by the downregulation of mGluR1/5 levels and the subsequent inhibition of spinal neuronal activation. Taken together, the present findings suggest that the novel SIRT1 activator Comp 6d inhibits the activation of spinal cord neurons via the SIRT1-mGluR1/5 pathway, thereby attenuating neuropathic pain. Comp 6d is expected to be an effective therapeutic agent for neuropathic pain.
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Affiliation(s)
- Xiaobao Ding
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Guizhi Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yuwen Lin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Wenli Hu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Chen Chen
- Jiangsu Province Key Laboratory of Anesthesiology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China
| | - Jian Gao
- School of Medicine, Anhui University of Science and Technology, Huainan, China.
| | - Yuqing Wu
- Jiangsu Province Key Laboratory of Anesthesiology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China.
| | - Chenghua Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
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Ungvari Z, Kunutsor SK. Coffee consumption and cardiometabolic health: a comprehensive review of the evidence. GeroScience 2024; 46:6473-6510. [PMID: 38963648 PMCID: PMC11493900 DOI: 10.1007/s11357-024-01262-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 06/21/2024] [Indexed: 07/05/2024] Open
Abstract
This review provides a comprehensive synthesis of longitudinal observational and interventional studies on the cardiometabolic effects of coffee consumption. It explores biological mechanisms, and clinical and policy implications, and highlights gaps in the evidence while suggesting future research directions. It also reviews evidence on the causal relationships between coffee consumption and cardiometabolic outcomes from Mendelian randomization (MR) studies. Findings indicate that while coffee may cause short-term increases in blood pressure, it does not contribute to long-term hypertension risk. There is limited evidence indicating that coffee intake might reduce the risk of metabolic syndrome and non-alcoholic fatty liver disease. Furthermore, coffee consumption is consistently linked with reduced risks of type 2 diabetes (T2D) and chronic kidney disease (CKD), showing dose-response relationships. The relationship between coffee and cardiovascular disease is complex, showing potential stroke prevention benefits but ambiguous effects on coronary heart disease. Moderate coffee consumption, typically ranging from 1 to 5 cups per day, is linked to a reduced risk of heart failure, while its impact on atrial fibrillation remains inconclusive. Furthermore, coffee consumption is associated with a lower risk of all-cause mortality, following a U-shaped pattern, with the largest risk reduction observed at moderate consumption levels. Except for T2D and CKD, MR studies do not robustly support a causal link between coffee consumption and adverse cardiometabolic outcomes. The potential beneficial effects of coffee on cardiometabolic health are consistent across age, sex, geographical regions, and coffee subtypes and are multi-dimensional, involving antioxidative, anti-inflammatory, lipid-modulating, insulin-sensitizing, and thermogenic effects. Based on its beneficial effects on cardiometabolic health and fundamental biological processes involved in aging, moderate coffee consumption has the potential to contribute to extending the healthspan and increasing longevity. The findings underscore the need for future research to understand the underlying mechanisms and refine health recommendations regarding coffee consumption.
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Affiliation(s)
- Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral College/Department of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary
| | - Setor K Kunutsor
- Leicester Real World Evidence Unit, Diabetes Research Centre, University of Leicester, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4WP, UK.
- Section of Cardiology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Saint Boniface Hospital, Winnipeg, MB, R2H 2A6, Canada.
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Chen L, Chen S, Bai Y, Zhang Y, Li X, Wang Y, Xiao Y, Wan J, Sun K. Electroacupuncture improves cognitive impairment after ischemic stroke based on regulation of mitochondrial dynamics through SIRT1/PGC-1α pathway. Brain Res 2024; 1844:149139. [PMID: 39111521 DOI: 10.1016/j.brainres.2024.149139] [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: 12/06/2023] [Revised: 07/20/2024] [Accepted: 08/03/2024] [Indexed: 08/21/2024]
Abstract
In recent years, the mechanism of acupuncture in the treatment of post-stroke cognitive impairment (PSCI) has not been fully elucidated. The balance between mitochondrial fission and fusion is important for PSCI. Our previous research demonstrated that electroacupuncture can improve learning and memory in middle cerebral artery ischemia reperfusion (MCAO/R) rats. However, the specific mechanism by which electroacupuncture improves learning and memory in MCAO/R rats by regulating mitochondrial fission and fusion needs to be further investigated. The MCAO/R rats was developed using the line-bolt method. The rats were randomly divided into sham-operated (Sham), model (MCAO/R), electroacupuncture (MCAO/R + EA) and sham-electroacupuncture (MCAO/R + sham EA) groups. Investigating the effects of EA on the expression of Sirtuin1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), Optic atrophy 1R + (OPA1) and Dynamin-related protein 1 (DRP1) in hippocampal neurons and on the morphology and function of hippocampal neurons and mitochondria. EA was able to reduce neurologic deficit scores and cerebral infarct volume and improve new object discrimination in MCAO/R rats, but there were no significant changes in these indices in the sham-electroacupuncture group. Moreover, EA increased the expression of SIRT1, PGC-1α, and OPA1 in hippocampal tissues, inhibited the expression of DRP1, attenuated neuronal and mitochondrial damage, and reduced mitochondrial fragmentation. The mechanism by which EA improves learning memory deficits in MCAO/R rats may be related to the inhibition of SIRT1/PGC-1α expression, the enhancement of mitochondrial fusion and the obstruction of its fission, and the reduction of hippocampal neuronal damage.
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Affiliation(s)
- Limin Chen
- Rehabilitation Medicine School of Henan University of Chinese Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, People's Hospital of Henan University of Chinese Medicine, Department of Rehabilitation Medicine of Zhengzhou People's Hospital (South Hospital), Zhengzhou, Henan, China
| | - Shuying Chen
- Rehabilitation Medicine School of Henan University of Chinese Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yanjie Bai
- Rehabilitation Centre of the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China.
| | - Yongchuang Zhang
- Rehabilitation Medicine School of Henan University of Chinese Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xiaoxiao Li
- Rehabilitation Medicine School of Henan University of Chinese Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yan Wang
- Rehabilitation Centre of the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yuqian Xiao
- Rehabilitation Medicine School of Henan University of Chinese Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Jun Wan
- Rehabilitation Medicine School of Henan University of Chinese Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Kexin Sun
- Rehabilitation Medicine School of Henan University of Chinese Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
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7
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Yang G, Xiang J, Yang X, Liu X, Li Y, Li L, Kang L, Liang Z, Yang S. Nuclear translocation of SIRT4 mediates deacetylation of U2AF2 to modulate renal fibrosis through alternative splicing-mediated upregulation of CCN2. eLife 2024; 13:RP98524. [PMID: 39495216 PMCID: PMC11534337 DOI: 10.7554/elife.98524] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2024] Open
Abstract
TGF-β stimulates CCN2 expression which in turn amplifies TGF-β signaling. This process promotes extracellular matrix production and accelerates the pathological progression of fibrotic diseases. Alternative splicing plays an important role in multiple disease development, while U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential factor in the early steps of pre-mRNA splicing. However, the molecular mechanism underlying abnormal CCN2 expression upon TGF-β stimulation remains unclear. This study elucidates that SIRT4 acts as a master regulator for CCN2 expression in response to TGF-β by modulating U2AF2-mediated alternative splicing. Analyses of renal biopsy specimens from patients with CKD and mouse fibrotic kidney tissues revealed marked nuclear accumulation of SIRT4. The tubulointerstitial fibrosis was alleviated by global deletion or tubular epithelial cell (TEC)-specific knockout of Sirt4, and aggravated by adeno-associated virus-mediated SIRT4 overexpression in TECs. Furthermore, SIRT4 was found to translocate from the mitochondria to the cytoplasm through the BAX/BAK pore under TGF-β stimulation. In the cytoplasm, TGF-β activated the ERK pathway and induced the phosphorylation of SIRT4 at Ser36, which further promoted its interaction with importin α1 and subsequent nuclear translocation. In the nucleus, SIRT4 was found to deacetylate U2AF2 at K413, facilitating the splicing of CCN2 pre-mRNA to promote CCN2 protein expression. Importantly, exosomes containing anti-SIRT4 antibodies were found to effectively mitigate the UUO-induced kidney fibrosis in mice. Collectively, these findings indicated that SIRT4 plays a role in kidney fibrosis by regulating CCN2 expression via the pre-mRNA splicing.
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Affiliation(s)
- Guangyan Yang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
| | - Jiaqing Xiang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
| | - Xiaoxiao Yang
- Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of TechnologyHefeiChina
| | - Xiaomai Liu
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
| | - Yanchun Li
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
| | - Lixing Li
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
| | - Lin Kang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
| | - Zhen Liang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
| | - Shu Yang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)GuangdongChina
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Liu K, Liu J, Xu A, Ding J. The role of polydatin in inhibiting oxidative stress through SIRT1 activation: A comprehensive review of molecular targets. JOURNAL OF ETHNOPHARMACOLOGY 2024; 331:118322. [PMID: 38729537 DOI: 10.1016/j.jep.2024.118322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 04/26/2024] [Accepted: 05/07/2024] [Indexed: 05/12/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Reynoutria japonica Houtt is a medicinal plant renowned for its diverse pharmacological properties, including heat-clearing, toxin-removing, blood circulation promotion, blood stasis removal, diuretic action, and pain relief. The plant is commonly utilized in Traditional Chinese Medicine (TCM), and its major bioactive constituents consist of polydatin (PD) and resveratrol (RES). AIM OF THE STUDY To summarize the relevant targets of PD in various oxidative stress-related diseases through the activation of Silence information regulator1 (SIRT1). Furthermore, elucidating the pharmacological effects and signaling mechanisms to establish the basis for PD's secure clinical implementation and expanded range of application. MATERIALS AND METHODS Literature published before November 2023 on the structural analysis and pharmacological activities of PD was collected using online databases such as Google Scholar, PubMed, and Web of Science. The keywords were "polydatin", "SIRT1" and "oxidative stress". The inclusion criteria were research articles published in English, including in vivo and in vitro experiments and clinical studies. Non-research articles such as reviews, meta-analyses, and letters were excluded. RESULTS PD has been found to have significantly protective and curative effects on diseases associated with oxidative stress by regulating SIRT1-related targets including peroxisome proliferator-activated receptor γ coactivator 1-alpha (PGC-1α), nuclear factor erythroid2-related factor 2 (Nrf2), high mobility group box 1 protein (HMGB1), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), p38/p53, as well as endothelial nitric oxide synthase (eNOs), among others. Strong evidence suggests that PD is an effective natural product for treating diseases related to oxidative stress. CONCLUSION PD holds promise as an effective treatment for a wide range of diseases, with SIRT1-mediated oxidative stress as its potential pathway.
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Affiliation(s)
- Ke Liu
- Beijing Institute of Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Jiaxi Liu
- Beijing University of Chinese Medicine, Beijing, China
| | - Anjian Xu
- Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Junying Ding
- Beijing Institute of Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
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Waykar TR, Mandlik SK, Mandlik DS. Sirtuins: exploring next-gen therapeutics in the pathogenesis osteoporosis and associated diseases. Immunopharmacol Immunotoxicol 2024; 46:277-301. [PMID: 38318808 DOI: 10.1080/08923973.2024.2315418] [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: 06/05/2023] [Accepted: 01/30/2024] [Indexed: 02/07/2024]
Abstract
OBJECTIVE Osteoporosis poses a substantial public health challenge due to an ageing population and the lack of adequate treatment options. The condition is marked by a reduction in bone mineral density, resulting in an elevated risk of fractures. The reduction in bone density and strength, as well as musculoskeletal issues that come with aging, present a significant challenge for individuals impacted by these conditions, as well as the healthcare system worldwide. METHODS Literature survey was conducted until May 2023 using databases such as Web of Science, PubMed, Scopus, and Google Scholar. RESULT Sirtuins 1-7 (SIRT1-SIRT7), which are a group of Nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, possess remarkable capabilities to increase lifespan and combat diseases related to aging. Research has demonstrated that these proteins play an important role in regular skeletal development and maintenance by directly impacting bone cells. Their dysfunction could be a factor in various bone conditions. Studies conducted on animals before clinical trials have shown that administering Sirtuins agonists to mice provides a safeguard against osteoporosis resulting from aging, menopause, and immobilization. These findings imply that Sirtuins may be a viable target for addressing the irregularity in bone remodeling and treating osteoporosis and other skeletal ailments. CONCLUSION The purpose of this review was to present a thorough and current evaluation of the existing knowledge on Sirtuins biology, with a particular emphasis on their involvement in maintaining bone homeostasis and contributing to osteoporosis. Additionally, the review examines potential pharmacological interventions targeting Sirtuins for the treatment of osteoporosis.
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Affiliation(s)
- Tejal R Waykar
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Satish K Mandlik
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Deepa S Mandlik
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, India
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10
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Tanaka K, Kawakami S, Mori S, Yamaguchi T, Saito E, Setoguchi Y, Matsui Y, Nishimura E, Ebihara S, Kawama T. Piceatannol Upregulates SIRT1 Expression in Skeletal Muscle Cells and in Human Whole Blood: In Vitro Assay and a Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Trial. Life (Basel) 2024; 14:589. [PMID: 38792610 PMCID: PMC11122325 DOI: 10.3390/life14050589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/19/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
Piceatannol (PIC), a polyphenol abundant in passion fruit seeds, is reported to promote fat metabolism. This study investigated whether PIC affects sirtuin 1 (SIRT1) expression and metabolic factors in C2C12 skeletal muscle cells. C2C12 myotubes were stimulated with PIC, and alterations in gene expression, protein levels, mitochondrial DNA content, and fatty acid levels were assessed using real-time PCR, Western blotting, and Nile red staining. Furthermore, we examined changes in SIRT1 expression following the consumption of a test food containing 100 mg PIC for 2 weeks among adults with varying age and body mass index ranges. Both PIC and passion fruit seed extract induced SIRT1 expression in C2C12 myotubes to a greater extent than resveratrol. PIC also increased the expression of genes associated with mitochondrial biogenesis and fatty acid utilization, increased mitochondrial DNA content, and suppressed oleic acid-induced fat accumulation. Moreover, participants who consumed PIC exhibited significantly higher SIRT1 mRNA expression in whole blood compared to those in the placebo group. These findings suggest that PIC induces SIRT1 expression both in vitro and in the human body, which may promote mitochondrial biosynthesis and fat metabolism.
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Affiliation(s)
- Kenta Tanaka
- R&D Institute, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan; (K.T.); (S.K.); (S.M.); (T.Y.); (E.S.); (Y.S.); (Y.M.); (E.N.)
| | - Shinpei Kawakami
- R&D Institute, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan; (K.T.); (S.K.); (S.M.); (T.Y.); (E.S.); (Y.S.); (Y.M.); (E.N.)
| | - Sadao Mori
- R&D Institute, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan; (K.T.); (S.K.); (S.M.); (T.Y.); (E.S.); (Y.S.); (Y.M.); (E.N.)
| | - Takumi Yamaguchi
- R&D Institute, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan; (K.T.); (S.K.); (S.M.); (T.Y.); (E.S.); (Y.S.); (Y.M.); (E.N.)
| | - Eriko Saito
- R&D Institute, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan; (K.T.); (S.K.); (S.M.); (T.Y.); (E.S.); (Y.S.); (Y.M.); (E.N.)
| | - Yuko Setoguchi
- R&D Institute, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan; (K.T.); (S.K.); (S.M.); (T.Y.); (E.S.); (Y.S.); (Y.M.); (E.N.)
| | - Yuko Matsui
- R&D Institute, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan; (K.T.); (S.K.); (S.M.); (T.Y.); (E.S.); (Y.S.); (Y.M.); (E.N.)
| | - Eisaku Nishimura
- R&D Institute, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan; (K.T.); (S.K.); (S.M.); (T.Y.); (E.S.); (Y.S.); (Y.M.); (E.N.)
| | - Shukuko Ebihara
- Chiyoda Paramedical Care Clinic, 3-3-10 Hongokucyo, Nihonbashi, Cyuo-ku, Tokyo 103-0021, Japan
| | - Toshihiro Kawama
- R&D Institute, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan; (K.T.); (S.K.); (S.M.); (T.Y.); (E.S.); (Y.S.); (Y.M.); (E.N.)
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11
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Chen M, Tan J, Jin Z, Jiang T, Wu J, Yu X. Research progress on Sirtuins (SIRTs) family modulators. Biomed Pharmacother 2024; 174:116481. [PMID: 38522239 DOI: 10.1016/j.biopha.2024.116481] [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: 02/02/2024] [Revised: 03/15/2024] [Accepted: 03/19/2024] [Indexed: 03/26/2024] Open
Abstract
Sirtuins (SIRTs) represent a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that exert a crucial role in cellular signal transduction and various biological processes. The mammalian sirtuins family encompasses SIRT1 to SIRT7, exhibiting therapeutic potential in counteracting cellular aging, modulating metabolism, responding to oxidative stress, inhibiting tumors, and improving cellular microenvironment. These enzymes are intricately linked to the occurrence and treatment of diverse pathological conditions, including cancer, autoimmune diseases, and cardiovascular disorders. Given the significance of histone modification in gene expression and chromatin structure, maintaining the equilibrium of the sirtuins family is imperative for disease prevention and health restoration. Mounting evidence suggests that modulators of SIRTs play a crucial role in treating various diseases and maintaining physiological balance. This review delves into the molecular structure and regulatory functions of the sirtuins family, reviews the classification and historical evolution of SIRTs modulators, offers a systematic overview of existing SIRTs modulation strategies, and elucidates the regulatory mechanisms of SIRTs modulators (agonists and inhibitors) and their clinical applications. The article concludes by summarizing the challenges encountered in SIRTs modulator research and offering insights into future research directions.
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Affiliation(s)
- Mingkai Chen
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China; School of Medicine Jiangsu University, Zhenjiang, Jiangsu, China
| | - Junfei Tan
- School of Medicine Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zihan Jin
- Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou City, China
| | - Tingting Jiang
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Jiabiao Wu
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Xiaolong Yu
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China; The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China.
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12
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Jiang YZ, Huang XR, Chang J, Zhou Y, Huang XT. SIRT1: An Intermediator of Key Pathways Regulating Pulmonary Diseases. J Transl Med 2024; 104:102044. [PMID: 38452903 DOI: 10.1016/j.labinv.2024.102044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 02/07/2024] [Accepted: 02/21/2024] [Indexed: 03/09/2024] Open
Abstract
Silent information regulator type-1 (SIRT1), a nicotinamide adenine dinucleotide+-dependent deacetylase, is a member of the sirtuins family and has unique protein deacetylase activity. SIRT1 participates in physiological as well as pathophysiological processes by targeting a wide range of protein substrates and signalings. In this review, we described the latest progress of SIRT1 in pulmonary diseases. We have introduced the basic information and summarized the prominent role of SIRT1 in several lung diseases, such as acute lung injury, acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung cancer, and aging-related diseases.
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Affiliation(s)
- Yi-Zhu Jiang
- Xiangya Nursing School, Central South University, Changsha, China; Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Xin-Ran Huang
- Xiangya Nursing School, Central South University, Changsha, China; Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Jing Chang
- Xiangya Nursing School, Central South University, Changsha, China; Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Yong Zhou
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Xiao-Ting Huang
- Xiangya Nursing School, Central South University, Changsha, China.
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13
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Pei MQ, Xu LM, Yang YS, Chen WC, Chen XL, Fang YM, Lin S, He HF. Latest advances and clinical application prospects of resveratrol therapy for neurocognitive disorders. Brain Res 2024; 1830:148821. [PMID: 38401770 DOI: 10.1016/j.brainres.2024.148821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/13/2024] [Accepted: 02/21/2024] [Indexed: 02/26/2024]
Abstract
Neurocognitive disorders, such as Alzheimer's disease, vascular dementia, and postoperative cognitive dysfunction, are non-psychiatric brain syndromes in which a significant decline in cognitive function causes great trauma to the mental status of the patient. The lack of effective treatments for neurocognitive disorders imposes a considerable burden on society, including a substantial economic impact. Over the past few decades, the identification of resveratrol, a natural plant compound, has provided researchers with an opportunity to formulate novel strategies for the treatment of neurocognitive disorders. This is because resveratrol effectively protects the brain of those with neurocognitive disorders by targeting some mechanisms such as inflammation and oxidative stress. This article reviews the status of recent research investigating the use of resveratrol for the treatment of different neurocognitive disorders. By examining the possible mechanisms of action of resveratrol and the shared mechanisms of different neurocognitive disorders, treatments for neurocognitive disorders may be further clarified.
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Affiliation(s)
- Meng-Qin Pei
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, China
| | - Li-Ming Xu
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, China
| | - Yu-Shen Yang
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, China
| | - Wei-Can Chen
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, China
| | - Xin-Li Chen
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, China
| | - Yu-Ming Fang
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, China
| | - Shu Lin
- Center of Neurological and Metabolic Research, the Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, China; Neuroendocrinology Group, Garvan Institute of Medical Research, 384 Victoria St, Sydney, Australia.
| | - He-Fan He
- Department of Anesthesiology, the Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, China.
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14
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Zeng Q, Qi Z, He X, Luo C, Wen J, Wei J, Yue F, Zhao X, Wei H, Chen T. Bifidobacterium pseudocatenulatum NCU-08 ameliorated senescence via modulation of the AMPK/Sirt1 signaling pathway and gut microbiota in mice. Food Funct 2024; 15:4095-4108. [PMID: 38563760 DOI: 10.1039/d3fo04575g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Aging is a degenerative disease in which organisms and neurological functions decline. Emerging research has underscored the vital role of the gut microbiota in age-related processes. However, the identification of aging-associated core microbiota remains limited. In this investigation, we isolated a strain of B. pseudocatenulatum NCU-08 from the feces of centenarians and assessed its impact on aging using a mouse model induced by D-gal. Our study revealed the exceptional probiotic attributes of B. pseudocatenulatum NCU-08. Administration of B. pseudocatenulatum NCU-08 significantly ameliorated age-related memory impairment, motor dysfunction, and anxiety-like behaviors in aging mice (p < 0.01). Moreover, tissue staining analysis demonstrated that B. pseudocatenulatum NCU-08 reduced the intensity of SA-β-gal-positive in the hippocampus of aging mice. It also reversed pathological damage and structural abnormalities in brain and intestinal tissue. B. pseudocatenulatum NCU-08 inhibited neuroinflammation induced by TLR4/NF-κB (p < 0.01) and preserved the blood-brain barrier integrity by activating the AMPK/Sirt1 pathway (p < 0.05). Furthermore, it mitigated neuronal apoptosis and oxidative stress by upregulating the PI3K/AKT signaling pathway (p < 0.01) and enhancing the activities of antioxidant enzymes, including GSH-Px (p < 0.01), SOD (p < 0.01), and CAT (p < 0.01). Besides, analysis of 16S rRNA sequencing data demonstrated that treatment with B. pseudocatenulatum NCU-08 restored intestinal microbiota homeostasis after senescence. It enhanced the abundance of beneficial bacteria while suppressing the growth of pathogenic microorganisms. In summary, our study unveiled that this novel strain of B. pseudocatenulatum NCU-08 exerts anti-aging effects through regulating the AMPK/Sirt1 pathway and intestinal microbiota. It holds promise as a functional food for promoting anti-aging effects and offers a novel approach to address aging and associated metabolic disorders.
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Affiliation(s)
- Qingwei Zeng
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, P. R. China.
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang 330006, P. R. China
| | - Zhanghua Qi
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, P. R. China.
| | - Xia He
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, P. R. China.
| | - Chuanlin Luo
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, P. R. China.
| | - Jianing Wen
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, P. R. China.
| | - Jing Wei
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, P. R. China.
| | - Fenfang Yue
- School of Life Sciences, Nanchang University, Nanchang 330031, China
| | - Xuanqi Zhao
- School of Life Sciences, Nanchang University, Nanchang 330031, China
| | - Hong Wei
- The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhong Shan Er Lu, Guangzhou 510080, P. R. China.
| | - Tingtao Chen
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, P. R. China.
- School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang 330006, P. R. China
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15
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Faakye J, Nyúl-Tóth Á, Muranyi M, Gulej R, Csik B, Shanmugarama S, Tarantini S, Negri S, Prodan C, Mukli P, Yabluchanskiy A, Conley S, Toth P, Csiszar A, Ungvari Z. Preventing spontaneous cerebral microhemorrhages in aging mice: a novel approach targeting cellular senescence with ABT263/navitoclax. GeroScience 2024; 46:21-37. [PMID: 38044400 PMCID: PMC10828142 DOI: 10.1007/s11357-023-01024-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 11/20/2023] [Indexed: 12/05/2023] Open
Abstract
Emerging evidence from both clinical and preclinical studies underscores the role of aging in potentiating the detrimental effects of hypertension on cerebral microhemorrhages (CMHs, or cerebral microbleeds). CMHs progressively impair neuronal function and contribute to the development of vascular cognitive impairment and dementia. There is growing evidence showing accumulation of senescent cells within the cerebral microvasculature during aging, which detrimentally affects cerebromicrovascular function and overall brain health. We postulated that this build-up of senescent cells renders the aged cerebral microvasculature more vulnerable, and consequently, more susceptible to CMHs. To investigate the role of cellular senescence in CMHs' pathogenesis, we subjected aged mice, both with and without pre-treatment with the senolytic agent ABT263/Navitoclax, and young control mice to hypertension via angiotensin-II and L-NAME administration. The aged cohort exhibited a markedly earlier onset, heightened incidence, and exacerbated neurological consequences of CMHs compared to their younger counterparts. This was evidenced through neurological examinations, gait analysis, and histological assessments of CMHs in brain sections. Notably, the senolytic pre-treatment wielded considerable cerebromicrovascular protection, effectively delaying the onset, mitigating the incidence, and diminishing the severity of CMHs. These findings hint at the potential of senolytic interventions as a viable therapeutic avenue to preempt or alleviate the consequences of CMHs linked to aging, by counteracting the deleterious effects of senescence on brain microvasculature.
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Affiliation(s)
- Janet Faakye
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Ádám Nyúl-Tóth
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Mihaly Muranyi
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Rafal Gulej
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Boglarka Csik
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Santny Shanmugarama
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Stefano Tarantini
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
| | - Sharon Negri
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Calin Prodan
- Veterans Affairs Medical Center, Oklahoma City, OK, USA
- Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Peter Mukli
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Andriy Yabluchanskiy
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Shannon Conley
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Peter Toth
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary
| | - Anna Csiszar
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary.
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA.
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
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16
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Duan C, Liu H, Yang X, Liu J, Deng Y, Wang T, Xing J, Hu Z, Xu H. Sirtuin1 inhibits calcium oxalate crystal-induced kidney injury by regulating TLR4 signaling and macrophage-mediated inflammatory activation. Cell Signal 2023; 112:110887. [PMID: 37717713 DOI: 10.1016/j.cellsig.2023.110887] [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: 06/21/2023] [Revised: 08/27/2023] [Accepted: 09/10/2023] [Indexed: 09/19/2023]
Abstract
Sirtuin1 (Sirt1) activation significantly attenuated calcium oxalate (CaOx) crystal deposition and renal inflammatory injury by regulating renal immune microenvironment. Here, to elucidate the molecular mechanism underlying the therapeutic effects of Sirt1 on macrophage related inflammation and tubular epithelial cells (TECs) necrosis, we constructed a macrophage and CaOx monohydrate (COM)-stimulated tubular cell co-culture system to mimic immune microenvironment in kidney and established a mouse model of CaOx nephrocalcinosis in wild-type and myeloid-specific Sirt1 knockout mice. Target prediction analyses of Gene Expression Omnibus Datasets showed that only miR-34b-5p is regulated by lipopolysaccharides and upregulated by SRT1720 and targets the TLR4 3'-untranslated region. In vitro, SRT1720 suppressed TLR4 expression and M1 macrophage polarization and decreased reactive oxygen species (ROS) production and mitochondrial damage in COM-stimulated TECs by targeting miR-34b-5p. Mechanically, Sirt1 promoted miR-34b-5p expression by suppressing the tri-methylation of H3K27, which directly bound to the miR-34b-5p promoter and abolished the miR-34b-5p transcription. Furthermore, loss of Sirt1 aggravated CaOx nephrocalcinosis-induced inflammatory and oxidative kidney injury, while AgomiR-34b reversed these effects. Therefore, our data suggested that Sirt1 inhibited TLR4 signaling and M1 macrophage polarization and decreased inflammatory and oxidative injury of TECs in vitro and in vivo.
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Affiliation(s)
- Chen Duan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430000 Wuhan, China
| | - Haoran Liu
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, 230000 Hefei, China
| | - Xiaoqi Yang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430000 Wuhan, China
| | - Jianhe Liu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, 650000 Kunming, China
| | - Yaoliang Deng
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, 530000 Nanning, China
| | - Tao Wang
- Department of Urology, The First Affiliated Hospital of Xiamen University, 361000 Xiamen, China
| | - Jinchun Xing
- Department of Urology, The First Affiliated Hospital of Xiamen University, 361000 Xiamen, China
| | - Zhiquan Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430000 Wuhan, China.
| | - Hua Xu
- Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research Center, 430000 Wuhan, China; Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 430000 Wuhan, China; Department of Urology, Zhongnan Hospital of Wuhan University, 430000 Wuhan, China.; Taikang Center for Life and Medical Sciences, Wuhan University, 430000 Wuhan, China.
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17
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Ungvari Z, Fazekas-Pongor V, Csiszar A, Kunutsor SK. The multifaceted benefits of walking for healthy aging: from Blue Zones to molecular mechanisms. GeroScience 2023; 45:3211-3239. [PMID: 37495893 PMCID: PMC10643563 DOI: 10.1007/s11357-023-00873-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 07/11/2023] [Indexed: 07/28/2023] Open
Abstract
Physical activity, including walking, has numerous health benefits in older adults, supported by a plethora of observational and interventional studies. Walking decreases the risk or severity of various health outcomes such as cardiovascular and cerebrovascular diseases, type 2 diabetes mellitus, cognitive impairment and dementia, while also improving mental well-being, sleep, and longevity. Dose-response relationships for walking duration and intensity are established for adverse cardiovascular outcomes. Walking's favorable effects on cardiovascular risk factors are attributed to its impact on circulatory, cardiopulmonary, and immune function. Meeting current physical activity guidelines by walking briskly for 30 min per day for 5 days can reduce the risk of several age-associated diseases. Additionally, low-intensity physical exercise, including walking, exerts anti-aging effects and helps prevent age-related diseases, making it a powerful tool for promoting healthy aging. This is exemplified by the lifestyles of individuals in Blue Zones, regions of the world with the highest concentration of centenarians. Walking and other low-intensity physical activities contribute significantly to the longevity of individuals in these regions, with walking being an integral part of their daily lives. Thus, incorporating walking into daily routines and encouraging walking-based physical activity interventions can be an effective strategy for promoting healthy aging and improving health outcomes in all populations. The goal of this review is to provide an overview of the vast and consistent evidence supporting the health benefits of physical activity, with a specific focus on walking, and to discuss the impact of walking on various health outcomes, including the prevention of age-related diseases. Furthermore, this review will delve into the evidence on the impact of walking and low-intensity physical activity on specific molecular and cellular mechanisms of aging, providing insights into the underlying biological mechanisms through which walking exerts its beneficial anti-aging effects.
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Affiliation(s)
- Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary.
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
| | | | - Anna Csiszar
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Setor K Kunutsor
- Diabetes Research Centre, University of Leicester, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4WP, UK.
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18
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Bouhamida E, Chaudhry HW. A new strategy for cardiac protection. eLife 2023; 12:e93239. [PMID: 37917118 PMCID: PMC10622142 DOI: 10.7554/elife.93239] [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] [Indexed: 11/03/2023] Open
Abstract
It may be possible to treat cardiac hypertrophy and injury by using drugs that inhibit a protein called SIRT2.
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Affiliation(s)
- Esmaa Bouhamida
- Cardiac Regenerative Medicine Laboratory and the Department of Cardiology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Hina W Chaudhry
- Cardiac Regenerative Medicine Laboratory and the Department of Cardiology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
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19
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Yang X, Chang HC, Tatekoshi Y, Mahmoodzadeh A, Balibegloo M, Najafi Z, Wu R, Chen C, Sato T, Shapiro J, Ardehali H. SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury. eLife 2023; 12:e85571. [PMID: 37728319 PMCID: PMC10558204 DOI: 10.7554/elife.85571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 09/19/2023] [Indexed: 09/21/2023] Open
Abstract
Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria, and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.
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Affiliation(s)
- Xiaoyan Yang
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Hsiang-Chun Chang
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Yuki Tatekoshi
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Amir Mahmoodzadeh
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Maryam Balibegloo
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Zeinab Najafi
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Rongxue Wu
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Chunlei Chen
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Tatsuya Sato
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Jason Shapiro
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
| | - Hossein Ardehali
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of MedicineChicagoUnited States
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20
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Han J, Li S, Wang W, Jiang X, Liu C, Lei L, Li Y, Sheng R, Zhang Y, Wu Y, Zhang J, Zhang Y, Xu Y, Si S. SIRT1 Activator E1231 Alleviates Nonalcoholic Fatty Liver Disease by Regulating Lipid Metabolism. Curr Issues Mol Biol 2023; 45:5052-5070. [PMID: 37367070 DOI: 10.3390/cimb45060321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/11/2023] [Accepted: 05/16/2023] [Indexed: 06/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Silencing information regulator 1 (SIRT1) was demonstrated to modulate cholesterol and lipid metabolism in NAFLD. Here, a novel SIRT1 activator, E1231, was studied for its potential improvement effects on NAFLD. C57BL/6J mice were fed a high-fat and high-cholesterol diet (HFHC) for 40 weeks to create a NAFLD mouse model, and E1231 was administered by oral gavage (50 mg/kg body weight, once/day) for 4 weeks. Liver-related plasma biochemistry parameter tests, Oil Red O staining, and hematoxylin-eosin staining results showed that E1231 treatment ameliorated plasma dyslipidemia, plasma marker levels of liver damage (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), liver total cholesterol (TC) and triglycerides (TG) contents, and obviously decreased hepatic steatosis score and NAFLD Activity Score (NAS) in the NAFLD mouse model. Western blot results showed that E1231 treatment significantly regulated lipid-metabolism-related protein expression. In particular, E1231 treatment increased SIRT1, PGC-1α, and p-AMPKα protein expression but decreased ACC and SCD-1 protein expression. Additionally, in vitro studies demonstrated that E1231 inhibited lipid accumulation and improved mitochondrial function in free-fatty-acid-challenged hepatocytes, and required SIRT1 activation. In conclusion, this study illustrated that the SIRT1 activator E1231 alleviated HFHC-induced NAFLD development and improved liver injury by regulating the SIRT1-AMPKα pathway, and might be a promising candidate compound for NAFLD treatment.
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Affiliation(s)
- Jiangxue Han
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Shunwang Li
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Weizhi Wang
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Xinhai Jiang
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Chao Liu
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Lijuan Lei
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Yining Li
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Ren Sheng
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Yuyan Zhang
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Yexiang Wu
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Jing Zhang
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Yuhao Zhang
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Yanni Xu
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Shuyi Si
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
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Fang J, Chen W, Hou P, Liu Z, Zuo M, Liu S, Feng C, Han Y, Li P, Shi Y, Shao C. NAD + metabolism-based immunoregulation and therapeutic potential. Cell Biosci 2023; 13:81. [PMID: 37165408 PMCID: PMC10171153 DOI: 10.1186/s13578-023-01031-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/14/2023] [Indexed: 05/12/2023] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD+ bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD+ biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD+ research in the development of therapeutics for inflammatory diseases, such as COVID-19.
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Affiliation(s)
- Jiankai Fang
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Wangwang Chen
- Laboratory Animal Center, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Pengbo Hou
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Zhanhong Liu
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Muqiu Zuo
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Shisong Liu
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Chao Feng
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Yuyi Han
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Peishan Li
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
| | - Yufang Shi
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - Changshun Shao
- Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
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22
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He L, Liu Q, Cheng J, Cao M, Zhang S, Wan X, Li J, Tu H. SIRT4 in ageing. Biogerontology 2023; 24:347-362. [PMID: 37067687 DOI: 10.1007/s10522-023-10022-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 01/31/2023] [Indexed: 04/18/2023]
Abstract
Ageing is a phenomenon in which cells, tissues and organs undergo systemic pathological changes as individuals age, leading to the occurrence of ageing-related diseases and the end of life. It is associated with many phenotypes known as ageing characteristics, such as genomic instability, nutritional imbalance, mitochondrial dysfunction, cell senescence, stem cell depletion, and an altered microenvironment. The sirtuin family (SIRT), known as longevity proteins, is thought to delay ageing and prolong life, and mammals, including humans, have seven family members (SIRT1-7). SIRT4 has been studied less among the sirtuin family thus far, but it has been reported that it has important physiological functions in organisms, such as promoting DNA damage repair, participating in the energy metabolism of three substances, inhibiting inflammatory reactions and apoptosis, and regulating mitochondrial function. Recently, some studies have demonstrated the involvement of SIRT4 in age-related processes, but knowledge in this field is still scarce. Therefore, this review aims to analyse the relationship between SIRT4 and ageing characteristics as well as some age-related diseases (e.g., cardiovascular diseases, metabolic diseases, neurodegenerative diseases and cancer).
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Affiliation(s)
- Ling He
- The Department of Geratology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, China
| | - Qingcheng Liu
- The Department of Geratology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, China
| | - Jielong Cheng
- The Department of Geratology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, China
| | - Mei Cao
- The Department of Geratology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, China
| | - Shuaimei Zhang
- The Department of Geratology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, China
| | - Xiaolin Wan
- The Department of Geratology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, China
| | - Jian Li
- The Key Laboratory of Hematology of Jiangxi Province, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, China.
| | - Huaijun Tu
- The Department of Geratology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, China.
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Yang X, Chang HC, Tatekoshi Y, Balibegloo M, Wu R, Chen C, Sato T, Shapiro J, Ardehali H. SIRT2 inhibition protects against cardiac hypertrophy and heart failure. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.25.525524. [PMID: 36747794 PMCID: PMC9900849 DOI: 10.1101/2023.01.25.525524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of heart failure (HF) and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 ( Sirt2 -/- ) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2 -/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitors reduces cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in the progression of HF and cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of this disorder.
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24
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DiNicolantonio JJ, McCarty MF, O'Keefe JH. Nutraceutical activation of Sirt1: a review. Open Heart 2022; 9:openhrt-2022-002171. [PMID: 36522127 PMCID: PMC9756291 DOI: 10.1136/openhrt-2022-002171] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
The deacetylase sirtuin 1 (Sirt1), activated by calorie restriction and fasting, exerts several complementary effects on cellular function that are favourable to healthspan; it is often thought of as an 'anti-aging' enzyme. Practical measures which might boost Sirt1 activity are therefore of considerable interest. A number of nutraceuticals have potential in this regard. Nutraceuticals reported to enhance Sirt1 synthesis or protein expression include ferulic acid, tetrahydrocurcumin, urolithin A, melatonin, astaxanthin, carnosic acid and neochlorogenic acid. The half-life of Sirt1 protein can be enhanced with the natural nicotinamide catabolite N1-methylnicotinamide. The availability of Sirt1's obligate substrate NAD+ can be increased in several ways: nicotinamide riboside and nicotinamide mononucleotide can function as substrates for NAD+ synthesis; activators of AMP-activated kinase-such as berberine-can increase expression of nicotinamide phosphoribosyltransferase, which is rate limiting for NAD+ synthesis; and nutraceutical quinones such as thymoquinone and pyrroloquinoline quinone can boost NAD+ by promoting oxidation of NADH. Induced ketosis-as via ingestion of medium-chain triglycerides-can increase NAD+ in the brain by lessening the reduction of NAD+ mediated by glycolysis. Post-translational modifications of Sirt1 by O-GlcNAcylation or sulfonation can increase its activity, suggesting that administration of glucosamine or of agents promoting hydrogen sulfide synthesis may aid Sirt1 activity. Although resveratrol has poor pharmacokinetics, it can bind to Sirt1 and activate it allosterically-as can so-called sirtuin-activating compound drugs. Since oxidative stress can reduce Sirt1 activity in multiple ways, effective antioxidant supplementation that blunts such stress may also help preserve Sirt1 activity in some circumstances. Combination nutraceutical regimens providing physiologically meaningful doses of several of these agents, capable of activating Sirt1 in complementary ways, may have considerable potential for health promotion. Such measures may also amplify the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in non-diabetic disorders, as these benefits appear to reflect upregulation of Sirt1 and AMP-activated protein kinase activities.
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Affiliation(s)
- James J DiNicolantonio
- Department of Preventive Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
| | - Mark F McCarty
- Catalytic Longevity Foundation, Encinitas, California, USA
| | - James H O'Keefe
- Department of Preventive Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
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Zhang Z, Fang J, Sun D, Zheng Y, Liu X, Li H, Hu Y, Liu Y, Zhang M, Liu W, Zhang X, Liu X. Study on the Mechanism of Radix Astragali against Renal Aging Based on Network Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:6987677. [PMID: 36561604 PMCID: PMC9767736 DOI: 10.1155/2022/6987677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 11/17/2022] [Accepted: 11/26/2022] [Indexed: 12/15/2022]
Abstract
Radix Astragali is widely used in the traditional Chinese medicine with the effect of antiaging. The purpose of this study is to explore the main active ingredients and targets of Radix Astragali against renal aging by network pharmacology and further to verify the mechanism of the main active ingredients in vitro. TCMSP, ETCM, and TCMID databases were used to screen active ingredients of Radix Astragali. Targets of active ingredients were predicted using BATMAN-TCM and cross validated using kidney aging-related genes obtained from GeneCards and NCBI database. Pathways enrichment and protein-protein interaction (PPI) analysis were performed on core targets. Additionally, a pharmacological network was constructed based on the active ingredients-targets-pathways. HK-2 cell was treated with D-galactose to generate a cell model of senescence. CCK-8 and β-galactosidase were used to detect the effect of Radix Astragali active components on cell proliferation and aging. ELISA was used to detect the expression of senescence-associated secreted protein (TGF-β and IL-6) in the cell culture supernatant. Western blot was used to detect the expression of key proteins in the SIRT1/p53 pathway. Five active ingredients (Astragaloside I, II, III, IV and choline) were identified from Radix Astragali, and all these active ingredients target a total of 128 genes. Enrichment analysis showed these genes were implicated in 153 KEGG pathways, including the p53, FoxO, and AMPK pathway. 117 proteins and 572 interactions were found in PPI network. TP53 and SIRT1 were two hub genes in PPI network, which interacted with each other. The pharmacological network showed that the five main active ingredients target on some coincident genes, including TP53 and SIRT1. These targeted genes were involved in the p53, FoxO, and AMPK pathway. Proliferation of HK-2 cells was increased by Astragaloside IV treatment compared with that of the D-Gal treatment group. However, the proliferation of the SA-β-gal positive cells were inhibited. The expression of TGF-β and IL-6 in the D-Gal group was higher than that in the normal group, and the treatment of Astragaloside IV could significantly reduce the expression of TGF-β and IL-6. The expression of SIRT1 in the Astragaloside IV group was higher than that in the D-Gal group. However, the expression of p53 and p21 was less in the Astragaloside IV group than that in the D-Gal group. This study suggested that Astragaloside IV is an important active ingredient of Radix Astragali in the treatment of kidney aging via the SITR1-p53 pathway.
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Affiliation(s)
- Ziyuan Zhang
- Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province 030001, China
- Department of Nephrology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province 030001, China
| | - Jingai Fang
- Department of Nephrology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province 030001, China
| | - Dalin Sun
- Department of Nephrology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province 030001, China
| | - Yaqin Zheng
- Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province 030001, China
| | - Xinhui Liu
- Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province 030001, China
| | - Hui Li
- Department of Nephrology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province 030001, China
| | - Yaling Hu
- Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province 030001, China
- Department of Nephrology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province 030001, China
| | - Yuxiang Liu
- Department of Nephrology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province 030001, China
| | - Mingyu Zhang
- Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi Province 030001, China
| | - Wenyuan Liu
- Department of Nephrology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province 030001, China
| | - Xiaodong Zhang
- Department of Nephrology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province 030001, China
| | - Xuejun Liu
- Department of Geriatrics, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province 030001, China
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26
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Urban VS, Cegledi A, Mikala G. Multiple myeloma, a quintessential malignant disease of aging: a geroscience perspective on pathogenesis and treatment. GeroScience 2022; 45:727-746. [PMID: 36508077 PMCID: PMC9742673 DOI: 10.1007/s11357-022-00698-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 11/18/2022] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy, which is predominantly a disease of older adults (the median age at diagnosis is 70 years). The slow progression from asymptomatic stages and the late-onset of MM suggest fundamental differences compared to many other hematopoietic system-related malignancies. The concept discussed in this review is that age-related changes at the level of terminally differentiated plasma cells act as the main risk factors for the development of MM. Epigenetic and genetic changes that characterize both MM development and normal aging are highlighted. The relationships between cellular aging processes, genetic mosaicism in plasma cells, and risk for MM and the stochastic processes contributing to clonal selection and expansion of mutated plasma cells are investigated. In line with the DNA damage accumulation theory of aging, in this review, the evolution of monoclonal gammopathy to symptomatic MM is considered. Therapeutic consequences of age-dependent comorbidities that lead to frailty and have fundamental influence on treatment outcome are described. The importance of considering geriatric states when planning the life-long treatment course of an elderly MM patient in order to achieve maximal therapeutic benefit is emphasized.
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Affiliation(s)
- Veronika S. Urban
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
| | - Andrea Cegledi
- Department of Hematology and Stem Cell Transplantation, South Pest Central Hospital–National Institute for Hematology and Infectious Diseases, Budapest, Hungary
| | - Gabor Mikala
- Department of Hematology and Stem Cell Transplantation, South Pest Central Hospital-National Institute for Hematology and Infectious Diseases, Budapest, Hungary.
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Dong K, Jiang Z, Zhang J, Qin H, Chen J, Chen Q. The role of SIRT1 in the process of Toxoplasma gondii infection of RAW 264.7 macrophages. Front Microbiol 2022; 13:1017696. [PMID: 36466662 PMCID: PMC9713941 DOI: 10.3389/fmicb.2022.1017696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/18/2022] [Indexed: 08/24/2023] Open
Abstract
Toxoplasma gondii is an opportunistic pathogenic protozoan that can infect almost all kinds of warm-blooded animals, including humans. T. gondii can evade the host's immune response, a process known as immune evasion. Our main objective was to evaluate the role played by Sirtuin1 (SIRT1) [one of the sirtuins (SIRTs) that are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs)] in the T. gondii infection of RAW264.7 macrophages. In this study, we evaluated and observed alterations in the activity, expression, and localization of SIRT1 and assessed its involvement in the CD154/IFN-γ (CD40 ligand/interferon gamma) killing pathway and in autophagy during T. gondii infection. The inhibition of SIRT1 in host cells effectively reduced the number of intracellular tachyzoites, and the mechanism behind this effect might be the upregulation of IRGM1 [murine ortholog of IRGM (immunity-related GTPase family M)] and the initiation of autophagy. To the best of our knowledge, our study is the first to prove that T. gondii infection upregulates SIRT1 in RAW264.7 cells and that the inhibition of SIRT1 reduces the number of intracellular tachyzoites. Moreover, the upregulation of IRGM1 and the activation of autophagy may contribute to the intracellular inhibition of T. gondii caused by SIRT1 inhibition.
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Affiliation(s)
- Kai Dong
- Department of Parasitology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Ziyang Jiang
- Department of Parasitology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Jianhui Zhang
- Department of Parasitology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Hanxiao Qin
- Department of Parasitology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Jianping Chen
- Department of Parasitology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
- Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, Chengdu, China
| | - Qiwei Chen
- Department of Parasitology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
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Suenkel B, Valente S, Zwergel C, Weiss S, Di Bello E, Fioravanti R, Aventaggiato M, Amorim JA, Garg N, Kumar S, Lombard DB, Hu T, Singh PK, Tafani M, Palmeira CM, Sinclair D, Mai A, Steegborn C. Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5. J Med Chem 2022; 65:14015-14031. [PMID: 36228194 PMCID: PMC9653166 DOI: 10.1021/acs.jmedchem.2c01215] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Sirtuins are NAD+-dependent protein deacylases involved in metabolic regulation and aging-related diseases. Specific activators for seven human Sirtuin isoforms would be important chemical tools and potential therapeutic drugs. Activators have been described for Sirt1 and act via a unique N-terminal domain of this isoform. For most other Sirtuin isoforms, including mitochondrial Sirt3-5, no potent and specific activators have yet been identified. We here describe the identification and characterization of 1,4-dihydropyridine-based compounds that either act as pan Sirtuin activators or specifically stimulate Sirt3 or Sirt5. The activators bind to the Sirtuin catalytic cores independent of NAD+ and acylated peptides and stimulate turnover of peptide and protein substrates. The compounds also activate Sirt3 or Sirt5 in cellular systems regulating, e.g., apoptosis and electron transport chain. Our results provide a scaffold for potent Sirtuin activation and derivatives specific for Sirt3 and Sirt5 as an excellent basis for further drug development.
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Affiliation(s)
- Benjamin Suenkel
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Sandra Weiss
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Elisabetta Di Bello
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Michele Aventaggiato
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - João A. Amorim
- Department of Life Sciences, University of Coimbra, 3004-504 Coimbra, Portugal
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- Genetics Department, Blavatnik Institute, Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA 02115, USA
| | - Neha Garg
- Genetics Department, Blavatnik Institute, Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA 02115, USA
| | - Surinder Kumar
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109-2800, USA
| | - David B. Lombard
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109-2800, USA
- Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109-2800, USA
| | - Tuo Hu
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
| | - Pankaj K. Singh
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
| | - Marco Tafani
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Carlos M. Palmeira
- Department of Life Sciences, University of Coimbra, 3004-504 Coimbra, Portugal
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - David Sinclair
- Genetics Department, Blavatnik Institute, Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA 02115, USA
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
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29
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Teng M, Young DW, Tan Z. The Pursuit of Enzyme Activation: A Snapshot of the Gold Rush. J Med Chem 2022; 65:14289-14304. [PMID: 36265019 DOI: 10.1021/acs.jmedchem.2c01291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A range of enzymes drive human physiology, and their activities are tightly regulated through numerous signaling pathways. Depending on the context, these pathways may activate or inhibit an enzyme as a way to ensure proper execution of cellular functions. From a drug discovery and development perspective, pharmacological inhibition of enzymes has been a focus of interest, as many diseases are associated with the upregulation of enzyme function. On the other hand, however, pharmacological activation of enzymes such as kinases and phosphatases has been of increasing interest. In this review, we discuss seven case studies that highlight pharmacological activation strategy, describe the binding modes and pharmacology of the activators, and comment on how this on-demand activation strategy complements the commonly pursued inhibition strategy, thus jointly enabling bidirectional modulation of specific target of interest. Going forward, we expect activators to play important roles as chemical probes and drug leads.
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Affiliation(s)
- Mingxing Teng
- Department of Pathology & Immunology, and Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Damian W Young
- Department of Pathology & Immunology, and Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Zhi Tan
- Department of Pathology & Immunology, and Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States
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30
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Satyam SM, Bairy LK. Neuronutraceuticals Combating Neuroinflammaging: Molecular Insights and Translational Challenges—A Systematic Review. Nutrients 2022; 14:nu14153029. [PMID: 35893883 PMCID: PMC9330442 DOI: 10.3390/nu14153029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 11/16/2022] Open
Abstract
Neuropathologies, such as neuroinflammaging, have arisen as a serious concern for preserving the quality of life due to the global increase in neurodegenerative illnesses. Nowadays, neuronutraceuticals have gained remarkable attention. It is necessary to investigate the bioavailability, off-target effects, and mechanism of action of neuronutraceuticals. To comprehend the comprehensive impact on brain health, well-designed randomized controlled trials testing combinations of neuronutraceuticals are also necessary. Although there is a translational gap between basic and clinical research, the present knowledge of the molecular perspectives of neuroinflammaging and neuronutraceuticals may be able to slow down brain aging and to enhance cognitive performance. The present review also highlights the key emergent issues, such as regulatory and scientific concerns of neuronutraceuticals, including bioavailability, formulation, blood–brain permeability, safety, and efficacy.
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31
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Yu SL, Lee SI, Park HW, Lee SK, Kim TH, Kang J, Park SR. SIRT1 suppresses in vitro decidualization of human endometrial stromal cells through the downregulation of forkhead box O1 expression. Reprod Biol 2022; 22:100672. [PMID: 35839571 DOI: 10.1016/j.repbio.2022.100672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 06/03/2022] [Accepted: 07/03/2022] [Indexed: 11/29/2022]
Abstract
SIRT1 regulates survival, DNA repair, and metabolism in human cells and has pleiotropic effects on age-related diseases through either deacetylating target proteins or inhibiting gene transcription. Forkhead box O1 (FOXO1) is one of the most important transcription factors during decidualization. Prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1) are well-known FOXO1-dependent genes in decidualizing cells. To determine whether SIRT1 plays a role in decidualization, we investigated morphological changes in cells following artificially stimulated decidualization and expression levels of PRL, IGFBP1, and FOXO1 in the immortalized non-neoplastic human endometrial stromal cell line T HESCs. SIRT1 expression decreased in the decidualization condition and SIRT1 inhibited morphological changes caused by decidualization of T HESCs. SIRT1 suppressed PRL, IGFBP1, and FOXO1 expression; inhibited FOXO1, PRL, and IGFBP1 promoter activity; and decreased histone protein acetylation of the FOXO1 promoter. We found that FOXO1 expression increased in the secretory phase compared with the proliferative phase, whereas SIRT1 expression decreased in the secretory phase in the human endometrium. We also revealed that SIRT1 may inhibit embryo implantation according to the blastocyst-like spheroid implantation assay. Collectively, these results indicate that SIRT1 suppresses decidualization of human endometrial stromal cells by inhibiting FOXO1 expression.
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Affiliation(s)
- Seong-Lan Yu
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
| | - Se-In Lee
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
| | - Hwan-Woo Park
- Department of Cell Biology, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
| | - Sung Ki Lee
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
| | - Tae-Hyun Kim
- Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
| | - Jaeku Kang
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
| | - Seok-Rae Park
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; Department of Microbiology, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea.
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SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway. Int J Mol Sci 2022; 23:ijms23126790. [PMID: 35743232 PMCID: PMC9223775 DOI: 10.3390/ijms23126790] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/24/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), a condition strongly associated with obesity and insulin resistance, is characterized by hepatic lipid accumulation and activation of the endoplasmic reticulum (ER) stress response. The sirtuin 2 (SIRT2) protein deacetylase is emerging as a new player in metabolic homeostasis, but its role in the development of hepatic steatosis and its link with ER stress activation remains unknown. SIRT2-knockout (SIRT2-KO) and wild-type mice were fed either a control or a high-fat diet (HFD) for 4 weeks. Genetic manipulation of SIRT2 levels was performed in human hepatic cells. Although apparently normal under a control diet, SIRT2-KO mice showed accelerated body weight gain and adiposity on a HFD, accompanied by severe insulin resistance. Importantly, SIRT2-KO mice exhibited worsened hepatic steatosis independently from diet, consistent with upregulated gene expression of lipogenic enzymes and increased expression of ER stress markers. Exposure of hepatic cells to palmitate induced lipid accumulation, increased ER stress, and decreased SIRT2 expression. Moreover, SIRT2-silenced cells showed enhanced lipid accumulation and ER stress activation under basal conditions, whereas SIRT2 overexpression abrogated palmitate-induced lipid deposition and ER stress activation. Our findings reveal a role for SIRT2 in the regulation of hepatic lipid homeostasis, potentially through the ER stress response, suggesting that SIRT2 activation might constitute a therapeutic strategy against obesity and its metabolic complications.
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33
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Chen J, Chen S, Cai D, Wang Q, Qin J. The role of Sirt6 in osteoarthritis and its effect on macrophage polarization. Bioengineered 2022; 13:9677-9689. [PMID: 35443857 PMCID: PMC9161952 DOI: 10.1080/21655979.2022.2059610] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Osteoarthritis (OA), the commonest arthritis type, features irreversible cartilage loss and synovitis. It was reported that macrophages have an important function in synovial inflammation, and our team revealed that the amounts of Sirt6, a nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylase, decrease during synovial inflammation and osteoarthritis. This work aimed to examine the anti-inflammatory properties of Sirt6 in synovial inflammation. Firstly, we compared Sirt6 amounts in acute meniscus injury and OA human knee synovial tissue samples by immunofluorescence and immunoblot. Secondly, Sirt6ʹs suppressive effects on inflammatory markers and macrophage polarization were evaluated. Finally, OA mice were histologically evaluated, and serum inflammatory factors were detected for assessing the impact of Sirt6 overexpression on the mouse synovium. We found significantly lower interleukin-4 (IL-4) amounts and M2 polarization in OA patients compared with control individuals. The expression of Sirt6 was lower in RAW264.7 cells of the lipopolysaccharides (LPS) + interferon-gamma (IFN-γ) group compared with the phosphate buffer saline (PBS) group, but higher than in the IL-4 group. The polarization of macrophages affected Sirt6 expression, which was reduced and elevated in M1 and M2 macrophages, respectively. Sirt6 inhibition could promote the release of proinflammatory cytokines by macrophages in the synovial membrane, induce M1 polarization in macrophages and inhibit M2 polarization in vitro, and Sirt6 overexpression alleviated osteoarthritis in vivo. These data strongly suggested that Sirt6 could inhibit synovial inflammation. Thus, this study provides a novel therapeutic target in osteoarthritis.
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Affiliation(s)
- Jinwei Chen
- Department of Orthopaedics Trauma Center, Shanghai General Hospital of Nanjing Medical University, Shanghai China.,Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Sichun Chen
- Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Dawei Cai
- Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Qiugen Wang
- Department of Orthopaedics Trauma Center, Shanghai General Hospital of Nanjing Medical University, Shanghai China
| | - Jian Qin
- Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
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Domi E, Hoxha M, Kolovani E, Tricarico D, Zappacosta B. The Importance of Nutraceuticals in COVID-19: What's the Role of Resveratrol? MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27082376. [PMID: 35458574 PMCID: PMC9030369 DOI: 10.3390/molecules27082376] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/26/2022] [Accepted: 03/29/2022] [Indexed: 12/21/2022]
Abstract
Since COVID-19 has affected global public health, there has been an urgency to find a solution to limit both the number of infections, and the aggressiveness of the disease once infected. The main characteristic of this infection is represented by a strong alteration of the immune system which, day by day, increases the risk of mortality, and can lead to a multiorgan dysfunction. Because nutritional profile can influence patient’s immunity, we focus our interest on resveratrol, a polyphenolic compound known for its immunomodulating and anti-inflammatory properties. We reviewed all the information concerning the different roles of resveratrol in COVID-19 pathophysiology using PubMed and Scopus as the main databases. Interestingly, we find out that resveratrol may exert its role through different mechanisms. In fact, it has antiviral activity inhibiting virus entrance in cells and viral replication. Resveratrol also improves autophagy and decreases pro-inflammatory agents expression acting as an anti-inflammatory agent. It regulates immune cell response and pro-inflammatory cytokines and prevents the onset of thrombotic events that usually occur in COVID-19 patients. Since resveratrol acts through different mechanisms, the effect could be enhanced, making a totally natural agent particularly effective as an adjuvant in anti COVID-19 therapy.
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Affiliation(s)
- Elisa Domi
- Department for Chemical-Toxicological and Pharmacological Evaluation of Drugs, Faculty of Pharmacy, Catholic University Our Lady of Good Counsel, Rruga Dritan Hoxha, 1000 Tirana, Albania; (E.D.); (M.H.)
| | - Malvina Hoxha
- Department for Chemical-Toxicological and Pharmacological Evaluation of Drugs, Faculty of Pharmacy, Catholic University Our Lady of Good Counsel, Rruga Dritan Hoxha, 1000 Tirana, Albania; (E.D.); (M.H.)
| | - Entela Kolovani
- Infectious Diseases Department, Faculty of Medicine, University of Medicine, Tirana, Rruga e Dibrës, 1005 Tirana, Albania;
| | - Domenico Tricarico
- Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari, Via Orabona 4, 70125 Bari, Italy;
| | - Bruno Zappacosta
- Department for Chemical-Toxicological and Pharmacological Evaluation of Drugs, Faculty of Pharmacy, Catholic University Our Lady of Good Counsel, Rruga Dritan Hoxha, 1000 Tirana, Albania; (E.D.); (M.H.)
- Correspondence: ; Tel.: +355-42-273-290
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35
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Optimization of the ultrasonic-assisted extraction of trans-resveratrol and its glucoside from grapes followed by UPLC-MS/MS using the response surface methodology. JOURNAL OF FOOD MEASUREMENT AND CHARACTERIZATION 2022. [DOI: 10.1007/s11694-021-01236-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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36
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Essential Oils Derived from Cistus Species Activate Mitochondria by Inducing SIRT1 Expression in Human Keratinocytes, Leading to Senescence Inhibition. Molecules 2022; 27:molecules27072053. [PMID: 35408452 PMCID: PMC9000612 DOI: 10.3390/molecules27072053] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/16/2022] [Accepted: 03/20/2022] [Indexed: 11/26/2022] Open
Abstract
Cistus L. is a genus of dicotyledonous perennial herbaceous plants. Cistus species have been commonly used in folk medicine in the Mediterranean region. In the present study, the biological activities of essential oils derived from Cistus species (Cistus laurifolius, C. monspeliensis, C. creticus, and C. salviifolius) were evaluated. Essential oils derived from C. laurifolius and C. monspeliensis were found to augment the expression of SIRT1, an anti-aging gene, in the normal culture of HaCaT cells. Furthermore, these essential oils increased the number and size of mitochondria and augmented their activity. These effects were thought to be caused by the up- and downregulated expression of MITOL and Drp1 in HaCaT cells, respectively, in response to the essential oil treatment. In addition, these essential oils were found to attenuate ultraviolet-B-induced mitochondrial damage and cellular senescence in HaCaT cells. These findings indicate that essential oils derived from C. laurifolius and C. monspeliensis may inhibit skin aging through mitochondrial regulation via SIRT1 activation.
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37
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Li LR, Sethi G, Zhang X, Liu CL, Huang Y, Liu Q, Ren BX, Tang FR. The neuroprotective effects of icariin on ageing, various neurological, neuropsychiatric disorders, and brain injury induced by radiation exposure. Aging (Albany NY) 2022; 14:1562-1588. [PMID: 35165207 PMCID: PMC8876913 DOI: 10.18632/aging.203893] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 02/08/2022] [Indexed: 11/25/2022]
Abstract
Epimedium brevicornum Maxim, a Traditional Chinese Medicine, has been used for the treatment of impotence, sinew and bone disorders, “painful impediment caused by wind-dampness,” numbness, spasms, hypertension, coronary heart disease, menopausal syndrome, bronchitis, and neurasthenia for many years in China. Recent animal experimental studies indicate that icariin, a major bioactive component of epimedium may effectively treat Alzheimer’s disease, cerebral ischemia, depression, Parkinson’s disease, multiple sclerosis, as well as delay ageing. Our recent study also suggested that epimedium extract could exhibit radio-neuro-protective effects and prevent ionizing radiation-induced impairment of neurogenesis. This paper reviewed the pharmacodynamics of icariin in treating different neurodegenerative and neuropsychiatric diseases, ageing, and radiation-induced brain damage. The relevant molecular mechanisms and its anti-neuroinflammatory, anti-apoptotic, anti-oxidant, as well as pro-neurogenesis roles were also discussed.
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Affiliation(s)
- Ling Rui Li
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Xing Zhang
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Cui Liu Liu
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Yan Huang
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Qun Liu
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Bo Xu Ren
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Feng Ru Tang
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, Singapore 138602, Singapore
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38
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Hu C, Zhang X, Teng T, Ma ZG, Tang QZ. Cellular Senescence in Cardiovascular Diseases: A Systematic Review. Aging Dis 2022; 13:103-128. [PMID: 35111365 PMCID: PMC8782554 DOI: 10.14336/ad.2021.0927] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Aging is a prominent risk factor for cardiovascular diseases, which is the leading cause of death around the world. Recently, cellular senescence has received potential attention as a promising target in preventing cardiovascular diseases, including acute myocardial infarction, atherosclerosis, cardiac aging, pressure overload-induced hypertrophy, heart regeneration, hypertension, and abdominal aortic aneurysm. Here, we discuss the mechanisms underlying cellular senescence and describe the involvement of senescent cardiovascular cells (including cardiomyocytes, endothelial cells, vascular smooth muscle cells, fibroblasts/myofibroblasts and T cells) in age-related cardiovascular diseases. Then, we highlight the targets (SIRT1 and mTOR) that regulating cellular senescence in cardiovascular disorders. Furthermore, we review the evidence that senescent cells can exert both beneficial and detrimental implications in cardiovascular diseases on a context-dependent manner. Finally, we summarize the emerging pro-senescent or anti-senescent interventions and discuss their therapeutic potential in preventing cardiovascular diseases.
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Affiliation(s)
- Can Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Xin Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Teng Teng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Zhen-Guo Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
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39
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Zhao Y, Liu YS. Longevity Factor FOXO3: A Key Regulator in Aging-Related Vascular Diseases. Front Cardiovasc Med 2022; 8:778674. [PMID: 35004893 PMCID: PMC8733402 DOI: 10.3389/fcvm.2021.778674] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/06/2021] [Indexed: 12/11/2022] Open
Abstract
Forkhead box O3 (FOXO3) has been proposed as a homeostasis regulator, capable of integrating multiple upstream signaling pathways that are sensitive to environmental changes and counteracting their adverse effects due to external changes, such as oxidative stress, metabolic stress and growth factor deprivation. FOXO3 polymorphisms are associated with extreme human longevity. Intriguingly, longevity-associated single nucleotide polymorphisms (SNPs) in human FOXO3 correlate with lower-than-average morbidity from cardiovascular diseases in long-lived people. Emerging evidence indicates that FOXO3 plays a critical role in vascular aging. FOXO3 inactivation is implicated in several aging-related vascular diseases. In experimental studies, FOXO3-engineered human ESC-derived vascular cells improve vascular homeostasis and delay vascular aging. The purpose of this review is to explore how FOXO3 regulates vascular aging and its crucial role in aging-related vascular diseases.
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Affiliation(s)
- Yan Zhao
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Aging and Age-Related Disease Research, Central South University, Changsha, China
| | - You-Shuo Liu
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Aging and Age-Related Disease Research, Central South University, Changsha, China
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40
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Kaur MM, Sharma DS. Mitochondrial repair as potential pharmacological target in cerebral ischemia. Mitochondrion 2022; 63:23-31. [PMID: 34999014 DOI: 10.1016/j.mito.2022.01.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/31/2021] [Accepted: 01/03/2022] [Indexed: 12/19/2022]
Abstract
Cerebral ischemia and its consequences like transient ischemic attack, aneurysm and stroke are the common and devastating conditions which remain the leading cause of mortality after coronary heart disease in developed countries and are the greatest cause of disability, leaving 50% of survivors permanently disabled. Despite recognition of risk factors and mechanisms involved in the pathology of the disease, treatment of ischemic disorders is limited to thrombolytic drugs like recombinant tissue plasminogen activator (rt-PA) and clinical rendition of the neuroprotective agents have not been so successful. Recent studies evidenced the role of mitochondrial dysfunction in neuronal damage that occurred after cerebral ischemia. This review article will focus on the various fundamental mechanisms responsible for neuronal damage because of mitochondrial dysfunction including cell signaling pathways, autophagy, apoptosis/necrosis, generation of reactive oxygen species, calcium overload, the opening of membrane permeability transition pore (mPTP), mitochondrial dynamics and biogenesis. Recent studies have concerned the significant role of mitochondrial biogenesis in mitochondrial repair and transfer of healthy mitochondria from astrocytes to the damaged neurons, providing neuroprotection and neural recovery following ischemia. Novel and influential studies have evidenced the significant role of mitochondria transfer and mitochondrial transplantation in reviving cell energy and in replacement of impaired or dysfunctional mitochondria with healthy mitochondria after ischemic episode. This review article will focus on recent advances in mitochondrial interventions and exogenous therapeutic modalities like mitochondria transfer technique, employment of stem cells, mitochondrial transplantation, miRNA inhibition and mitochondrial-targeted Sirtuin1 activator for designing novel and promising treatment for cerebral ischemia induced pathological states.
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Affiliation(s)
- Ms Mandeep Kaur
- Research Scholar, Department of Pharmacology, School of Pharmaceutical Sciences, CT University, Ludhiana, Punjab, India.
| | - Dr Saurabh Sharma
- Principal and Head, School of Pharmaceutical Sciences, CT University, Ludhiana, Punjab, India.
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41
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Zhang N, Zhang C, Liu J, Fan C, Yin J, Wu T. An oral hydrogel carrier for delivering resveratrol into intestine-specific target released with high encapsulation efficiency and loading capacity based on structure-selected alginate and pectin. Food Funct 2022; 13:12051-12066. [DOI: 10.1039/d2fo01889f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Resveratrol (RES) has many beneficial effects on the human body, but it is always unstable, resulting in low oral bioavailability, especially in the gastrointestinal tract.
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Affiliation(s)
- Nan Zhang
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Chuanbo Zhang
- College of Chemical Engineering and Materials Science, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Jiaming Liu
- College of Chemical Engineering and Materials Science, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Chaozhong Fan
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Jinjin Yin
- College of Chemical Engineering and Materials Science, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Tao Wu
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, 300457, China
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42
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Mesenchymal Stem Cell Senescence and Osteogenesis. Medicina (B Aires) 2021; 58:medicina58010061. [PMID: 35056369 PMCID: PMC8779043 DOI: 10.3390/medicina58010061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/25/2021] [Accepted: 12/27/2021] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are stem cells with the potential ability to differentiate into various cells and the ability to self-renew and resemble fibroblasts. These cells can adhere to plastic to facilitate the culture process. MSCs can be used in research into tissue biotechnology and rejuvenation medicine. MSCs are also beneficial in recipient tissue and differentiate as a breakthrough strategy through paracrine activity. Many databases have shown MSC-based treatment can be beneficial in the reduction of osteogenesis induced by senescence. In this article, we will discuss the potential effect of MSCs in senescence cells related to osteogenesis.
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43
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Yamada C, Hattori T, Ohnishi S, Takeda H. Ghrelin Enhancer, the Latest Evidence of Rikkunshito. Front Nutr 2021; 8:761631. [PMID: 34957179 PMCID: PMC8702727 DOI: 10.3389/fnut.2021.761631] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Rikkunshito is a Japanese herbal medicine (Kampo) that has been attracting attention and researched by many researchers not only in Japan but also worldwide. There are 214 rikkunshito articles that can be searched on PubMed by August 2021. The reason why rikkunshito has attracted so much attention is due to an epoch-making report (Gastroenterology, 2008) discovered that rikkunshito promotes the secretion of the orexigenic peptide ghrelin. Since then, many researchers have discovered that rikkunshito has a direct effect on the ghrelin receptor, GHS-R1a, and an effect of enhancing the ghrelin signal to the brain. Additionally, a lot of evidence that rikkunshito is expected to be effective for various gastrointestinal diseases have also been demonstrated. Numerous basic and clinical studies have suggested that rikkunshito affects (i) various discomforts caused by anticancer drugs, gastroesophageal reflux disease, functional dyspepsia, (ii) various stress-induced anorexia, (iii) hypophagia in the elderly, and (iv) healthy lifespan. In this review, as one who discovered the ghrelin enhancer effect of rikkunshito, we will review the research of rikkunshito so far and report on the latest research results.
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Affiliation(s)
- Chihiro Yamada
- Tsumura Kampo Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - Tomohisa Hattori
- Tsumura Kampo Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Hiroshi Takeda
- Gastroenterology, Tokeidai Memorial Hospital, Sapporo, Japan.,Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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44
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Isaacs-Ten A, Moreno-Gonzalez M, Bone C, Martens A, Bernuzzi F, Ludwig T, Hellmich C, Hiller K, Rushworth SA, Beraza N. Metabolic Regulation of Macrophages by SIRT1 Determines Activation During Cholestatic Liver Disease in Mice. Cell Mol Gastroenterol Hepatol 2021; 13:1019-1039. [PMID: 34952202 PMCID: PMC8873616 DOI: 10.1016/j.jcmgh.2021.12.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Inflammation is the hallmark of chronic liver disease. Metabolism is a key determinant to regulate the activation of immune cells. Here, we define the role of sirtuin 1 (SIRT1), a main metabolic regulator, in controlling the activation of macrophages during cholestatic liver disease and in response to endotoxin. METHODS We have used mice overexpressing SIRT1, which we treated with intraperitoneal lipopolysaccharides or induced cholestasis by bile duct ligation. Bone marrow-derived macrophages were used for mechanistic in vitro studies. Finally, PEPC-Boy mice were used for adoptive transfer experiments to elucidate the impact of SIRT1-overexpressing macrophages in contributing to cholestatic liver disease. RESULTS We found that SIRT1 overexpression promotes increased liver inflammation and liver injury after lipopolysaccharide/GalN and bile duct ligation; this was associated with an increased activation of the inflammasome in macrophages. Mechanistically, SIRT1 overexpression associated with the activation of the mammalian target of rapamycin (mTOR) pathway that led to increased activation of macrophages, which showed metabolic rewiring with increased glycolysis and broken tricarboxylic acid cycle in response to endotoxin in vitro. Activation of the SIRT1/mTOR axis in macrophages associated with the activation of the inflammasome and the attenuation of autophagy. Ultimately, in an in vivo model of cholestatic disease, the transplantation of SIRT1-overexpressing myeloid cells contributed to liver injury and fibrosis. CONCLUSIONS Our study provides novel mechanistic insights into the regulation of macrophages during cholestatic disease and the response to endotoxin, in which the SIRT1/mTOR crosstalk regulates macrophage activation controlling the inflammasome, autophagy and metabolic rewiring.
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Affiliation(s)
- Anna Isaacs-Ten
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Mar Moreno-Gonzalez
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Caitlin Bone
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Andre Martens
- Department of Bioinfomatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Braunschweig, Germany
| | - Federico Bernuzzi
- Food Innovation and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Tobias Ludwig
- Department of Bioinfomatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Braunschweig, Germany
| | - Charlotte Hellmich
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom; Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom
| | - Karsten Hiller
- Department of Bioinfomatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Braunschweig, Germany; Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Stuart A Rushworth
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
| | - Naiara Beraza
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, United Kingdom; Food Innovation and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, United Kingdom.
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Abdelnabi ALSM, Esmayel IM, Hussein S, Ali RM, AbdelAal AA. Sirtuin-1 in Egyptian patients with coronary artery disease. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2021. [DOI: 10.1186/s43088-021-00164-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Coronary artery disease (CAD) represents the leading cause of death worldwide. Animal and human studies have demonstrated that silent information regulator 1 (SIRT1) is involved in a wide range of physiological and pathological processes. This study aimed to measure the plasma level of SIRT1 in patients with CAD and explore its correlation with cardiovascular risk factors.
Results
Plasma SIRT1 was significantly lower in patients with chronic coronary syndrome (CCS) than in those in the control group and was significantly lower in patients with both acute myocardial infarction and unstable angina than in those in the control group and with CCS. Moreover, plasma SIRT1 was positively correlated with platelet count and negatively correlated with cholesterol and triglyceride levels.
Conclusions
The plasma level of SIRT1 is lower in patients with CAD compared to control and it could be a possible marker for this disease. Multi-center studies with follow-up measurements are recommended for further investigation.
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46
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Alì S, Davinelli S, Accardi G, Aiello A, Caruso C, Duro G, Ligotti ME, Pojero F, Scapagnini G, Candore G. Healthy ageing and Mediterranean diet: A focus on hormetic phytochemicals. Mech Ageing Dev 2021; 200:111592. [PMID: 34710375 DOI: 10.1016/j.mad.2021.111592] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 10/06/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022]
Abstract
Mediterranean diet (MedDiet) is rich in fruits and vegetables associated with longevity and a reduced risk of several age-related diseases. It is demonstrated that phytochemicals in these plant products enhance the positive effects of MedDiet by acting on the inflammatory state and reducing oxidative stress. Evidence support that these natural compounds act as hormetins, triggering one or more adaptive stress-response pathways at low doses. Activated stress-response pathways increase the expression of cytoprotective proteins and multiple genes that act as lifespan regulators, essential for the ageing process. In these ways, the hormetic response by phytochemicals such as resveratrol, ferulic acid, and several others in MedDiet might enhance cells' ability to cope with more severe challenges, resist diseases, and promote longevity. This review discusses the role of MedDiet phytochemicals in healthy ageing and the prevention of age-related diseases.
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Affiliation(s)
- Sawan Alì
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Sergio Davinelli
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Giulia Accardi
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy
| | - Anna Aiello
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy
| | - Calogero Caruso
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy.
| | - Giovanni Duro
- Institute for Research and Biomedical Innovation, National Research Council, Palermo, Italy
| | - Mattia Emanuela Ligotti
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy; Institute for Research and Biomedical Innovation, National Research Council, Palermo, Italy
| | - Fanny Pojero
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy
| | - Giovanni Scapagnini
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Giuseppina Candore
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Italy
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47
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Zhang M, Chen S, Dai Y, Duan T, Xu Y, Li X, Yang J, Zhu X. Aspartame and sucralose extend the lifespan and improve the health status of C. elegans. Food Funct 2021; 12:9912-9921. [PMID: 34486601 DOI: 10.1039/d1fo01579f] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aspartame (ASP) and sucralose (SUC) are non-nutritive sweeteners which are widely consumed worldwide. They are considered safe for human consumption, but their effects on certain physiological aspects, such as the lifespan or health status, of the organism have not yet been studied in depth and only limited data are available in the literature. The objectives of this study were to evaluate the effects of ASP and SUC on the lifespan and health indexes using Caenorhabditis elegans (C. elegans) as a model system. Interestingly, it was shown that at the concentrations tested, ASP (0.03-3 mg mL-1) showed an increasing trend of the mean lifespan of C. elegans, with a significant increase of 27.6% compared to the control at 3 mg mL-1. Similarly, SUC (ranging from 0.03 to 10 mg mL-1) also significantly increased the mean lifespan by 20.3% and 22.3% at 0.03 and 0.3 mg mL-1, respectively. However, 10 mg mL-1 SUC had a negative effect on the lifespan, though it did not reach a statistically significant level. In addition, ASP and SUC decreased lipofuscin accumulation and transiently improved motility, indicating improved health status. Nonetheless, they had different effects on food intake and intestinal fat deposition (IFD) at different intervals of time. Taken together, our findings revealed that ASP and SUC can prolong the lifespan and improve the health status of C. elegans.
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Affiliation(s)
- Mohan Zhang
- Wenzhou Center for Disease Control and Prevention, Wenzhou, Zhejiang 325000, China.,Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
| | - Shuai Chen
- Wenzhou Center for Disease Control and Prevention, Wenzhou, Zhejiang 325000, China
| | - Yuhua Dai
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China.
| | - Ting Duan
- Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
| | - Yuying Xu
- Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
| | - Xiaolin Li
- Technical Center for Animal, Plant and Food Inspection and Quarantine of Shanghai Customs district, Shanghai 200135, China
| | - Jun Yang
- Department of Toxicology, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 311121, China. .,Zhejiang Provincial Center for Uterine Cancer Diagnosis and Therapy Research, The Affiliated Women's Hospital, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Xinqiang Zhu
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China. .,Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
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48
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Fang D, Wang Y, Zhang Z, Yang D, Gu D, He B, Zhang X, He D, Wang H, Jose PA, Han Y, Zeng C. Calorie Restriction Protects against Contrast-Induced Nephropathy via SIRT1/GPX4 Activation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2999296. [PMID: 34712381 PMCID: PMC8548166 DOI: 10.1155/2021/2999296] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 08/05/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022]
Abstract
Calorie restriction (CR) extends lifespan and increases resistance to multiple forms of stress, including renal ischemia-reperfusion (I/R) injury. However, whether CR has protective effects on contrast-induced nephropathy (CIN) remains to be determined. In this study, we evaluated the therapeutic effects of CR on CIN and investigated the potential mechanisms. CIN was induced by the intravenous injection of iodinated contrast medium (CM) iopromide (1.8 g/kg) into Sprague Dawley rats with normal food intake or 40% reduced food intake, 4 weeks prior to iopromide administration. We found that CR was protective of CIN, assessed by renal structure and function. CM increased apoptosis, reactive oxygen species (ROS), and inflammation in the renal outer medulla, which were decreased by CR. The silent information regulator 1 (SIRT1) participated in the protective effect of CR on CIN, by upregulating glutathione peroxidase 4 (GPX4), a regulator of ferroptosis, because this protective effect was reversed by EX527, a specific SIRT1 antagonist. Our study showed that CR protected CIN via SIRT1/GPX4 activation. CR may be used to mitigate CIN.
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Affiliation(s)
- Dandong Fang
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - Yongbin Wang
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - Ziyue Zhang
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - Donghai Yang
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - Daqian Gu
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - Bo He
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - Xiaoqun Zhang
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - Duofen He
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - HongYong Wang
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - Pedro A. Jose
- Cardiovascular Research Center of Chongqing College, Department of Cardiology of Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China
| | - Yu Han
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
- Chongqing Institute of Cardiology& Chongqing Key Laboratory of Hypertension Research, Chongqing, China
- Division of Renal Disease & Hypertension, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA
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Zhang J, Zou L, Shi D, Liu J, Zhang J, Zhao R, Wang G, Zhang L, Ouyang L, Liu B. Structure-Guided Design of a Small-Molecule Activator of Sirtuin-3 that Modulates Autophagy in Triple Negative Breast Cancer. J Med Chem 2021; 64:14192-14216. [PMID: 34605238 DOI: 10.1021/acs.jmedchem.0c02268] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Sirtuin-3 (SIRT3) is an NAD+-dependent protein deacetylase localized primarily in the mitochondria with many links to different types of human cancers. Autophagy, which is a highly conserved lysosomal degradation process in eukaryotic cells, has been recently reported to be positively regulated by SIRT3 in cancer; therefore, activating SIRT3-modulated autophagy may be a promising strategy for drug discovery. In this study, we discovered a small-molecule activator of SIRT3 compound 33c (ADTL-SA1215) with specific SIRT3 deacetylase activity by structure-guided design and high-throughput screening. Subsequently, compound 33c inhibited the proliferation and migration of human breast carcinoma MDA-MB-231 cells by SIRT3-driven autophagy/mitophagy signaling pathways in vitro and in vivo. Collectively, these results demonstrate that pharmacological activation of SIRT3 is a potential therapeutic approach of triple negative breast cancer (TNBC). More importantly, compound 33c may be a first-in-class specific small-molecule activator of SIRT3 that would be utilized for future cancer drug development.
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Affiliation(s)
- Jin Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.,School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Ling Zou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Danfeng Shi
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.,Warshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Jifa Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Rongyan Zhao
- School of Life Science and Engineering, Southwest Jiaotong University Chengdu, Chengdu 610031, China
| | - Guan Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Lan Zhang
- School of Life Science and Engineering, Southwest Jiaotong University Chengdu, Chengdu 610031, China
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
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50
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Kocabas Ş, Sanlier N. A comprehensive overview of the complex relationship between epigenetics, bioactive components, cancer, and aging. Crit Rev Food Sci Nutr 2021:1-13. [PMID: 34623201 DOI: 10.1080/10408398.2021.1986803] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Among age-related diseases, the incidence of cancer increases significantly due to the overlap of some molecular pathways between cancer and aging. While the genetic influence on the human lifespan is estimated to be about 20-25%, epigenetic changes play an important role in modulating individual health status, aging. Aging and age-related conditions are processes that can be modified by both genetic, environmental factors, including dietary habits. Epigenetics is a new discipline has significant potential to be applied for the prevention, management of certain carcinomas and diseases. Epigenetic modifications may play an important role in disease occurrence and pathogenesis. Some nutritional components can be significantly effective in the prevention of breast, skin, esophagus, colorectal, prostate, pancreatic, lung cancers. It contains minerals, vitamins, and some bioactive components (curcumin, indole 3 carbinol, di-indolylmethane, sulforaphane, epigallocatechin-3-gallate, genistein, resveratrol, pterostilbene, apigenin, etc.) regulatory processes. However, compelling evidence suggests that dietary habits can manipulate the aging process and/or its consequences, have health benefits. Aging processes become complex when combined with the relational role of bioactive nutritional components on gene expression. In this review, the relationship between epigenetic processes caused by DNA methylylation, histone modification, non-coding m-RNA, and telomerase activity, the risk of aging and cancer is discussed.
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Affiliation(s)
- Şule Kocabas
- Department of Nutrition and Dietetics, School of Health Sciences, Ankara Medipol University, Altındağ, Ankara, Turkey
| | - Nevin Sanlier
- Department of Nutrition and Dietetics, School of Health Sciences, Ankara Medipol University, Altındağ, Ankara, Turkey
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