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Wang J, Ren Y, Qu S. Modulation of Sirtuins to address aging related disorders through the use of selected phytochemicals. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156648. [PMID: 40359853 DOI: 10.1016/j.phymed.2025.156648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 03/08/2025] [Accepted: 03/14/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Aging is a complex phenomenon involving oxidative stress, inflammation, and cellular damage subsequently leading to various disorders, such as cardiovascular diseases, neurodegenerative disorders, diabetes, and cancer. Sirtuin (SIRT) proteins are one of the major molecular factors that affect human aging. Sirtuins are a class of NAD+-dependent enzymes that control oxidative stress response, DNA damage repair, inflammation and metabolism, all of which are involved in aging and age-related diseases. PURPOSE The objective of this review is to elucidate the potential role of SIRT in the aging process and modulation of SIRT pathway through selected phytochemicals like Curcumin, Resveratrol, Quercetin, and Kaempferol. RESULTS Studies convincedly revealed that SIRT pathway represents a promising avenue for extending the human health span and addressing age-related conditions. Phytochemicals like Curcumin, Resveratrol, Quercetin, and Kaempferol have shown excellent potential to mediate aging effects through their potent antioxidant, anti-inflammatory, and regulatory activities. These potent bioactive compounds enhance oxidative stress response, genomic integrity, neuroprotective and anti-inflammatory activities through SIRT pathway modulation. Furthermore, in addition to antiaging effects, other therapeutic benefits are also associated with each compound including nervous disorders, cancer, and metabolic disorders are also briefly highlighted. Studies reported convincing evidence that Curcumin, Resveratrol, Quercetin, and Kaempferol, effectively modulate SIRT expression/activity leading to improved cell stress tolerance, reduced oxidation and enhanced metabolic state. CONCLUSIONS Collectively, studies revealed the comprehensive nutraceutical significance of Curcumin, Resveratrol, Quercetin, and Kaempferol as anti-aging therapeutics and warrant future studies to exploit the full potential of these natural compounds.
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Affiliation(s)
- Jing Wang
- Department of Ophthalmology, Shengjing Hospital of China Medical University. 36 Sanhao Street, Heping District, 110004 Shenyang, Liaoning, PR China.
| | - Yaoyao Ren
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, 110004 Shenyang, Liaoning, PR China.
| | - Shengtao Qu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, No. 36 Sanhao St, Shenyang 110004, PR China.
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Wang Z, Liang G, Peng J, Gu Y, Zhang X, Ding C, Yu T, Li Z. Sirtuin 7 Promotes Alcohol-Associated Liver Injury via Modulating Myeloid Cell Chemokine (C-C Motif) Ligand 2 Secretion through the NF-κB Signaling Pathway. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:575-588. [PMID: 39746506 DOI: 10.1016/j.ajpath.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 12/07/2024] [Accepted: 12/18/2024] [Indexed: 01/04/2025]
Abstract
The pathogenesis of alcohol-associated liver disease (ALD) involves ethanol-induced enhancement of gut permeability, bacterial products released from intestine and intrahepatic inflammation, and liver damage. Hepatic macrophages play a crucial role in mediating inflammatory response by alcohol. Sirtuin 7 (SIRT7), a NAD+-dependent type III histone deacetylase, is being recognized as a therapeutic target in various human diseases. Emerging evidence shows that SIRT7 participates in immune regulation, but whether it is involved in ALD remains elusive. In the present study, myeloid cell-specific Sirt7 knockout mice (Lyz2-Sirt7-/-) were used to show that knockout Sirt7 in myeloid cells significantly ameliorated alcohol-induced liver injury, inflammation, and cell infiltration, while only mildly affecting lipid metabolism pathways. Chemokine (C-C motif) ligand 2 (CCL2) was identified as the main target impaired by Sirt7 knockout after alcohol. In vitro studies confirmed that Sirt7 knockout impaired macrophages' ability of CCL2 secretion and monocyte recruiting, and exogenous CCL2 reversed this impairment. At the molecular level, knockout of Sirt7 significantly impaired lipopolysaccharide-induced p65 phosphorylation and nuclear localization. More importantly, the SIRT7 inhibitor 40569 sufficiently decreased alcohol-induced liver injury and hepatic inflammation via preventing CCL2 in vivo. The current data thus uncovered a previously undescribed role of myeloid SIRT7 in mediating ALD via promoting CCL2 secretion through the NF-κB signaling pathway. Targeting SIRT7 might offer novel mechanism-based therapeutic options for ALD.
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Affiliation(s)
- Zhiqiang Wang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China; Human Anatomy Teaching and Experimental Center, School of Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Gaoshuang Liang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Jinying Peng
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Yiying Gu
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Xiangwen Zhang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Cong Ding
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Tingzi Yu
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Zhuan Li
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China.
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Wang W, Yuan G, Li G, Zhao T, Chen Y, Xu Y. Cigarette smoking extract induces mitochondrial dysfunction and apoptosis in HUVECs via the Sirt1-SHH axis. Hum Exp Toxicol 2025; 44:9603271251332251. [PMID: 40170556 DOI: 10.1177/09603271251332251] [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: 04/03/2025]
Abstract
IntroductionCigarette smoking extract (CSE) can cause endothelial cell (EC) dysfunction, and then promote the occurrence and development of atherosclerosis. However, the molecular mechanisms underlying CSE-induced EC dysfunction are unknown. Sirt1, as a deacetylase, is involved in various biological processes of ECs. Therefore, this study investigated whether CSE induces apoptosis and mitochondrial dysfunction in human umbilical vein endothelial cells (HUVECs) via Sirt1-dependent mechanisms.MethodsHUVEC activity was assessed using MTT and crystal violet staining following treatment with different concentrations of CSE. Lentiviral transfection technology was used to generate HUVECs overexpressing Sirt1. Apoptosis was detected by Tunnel staining. MitoTracker™ Deep Red FM and JC-1 were used to assess mitochondrial structure and membrane potential. ELISA was used to detect the expression of superoxide dismutase (SOD) and malondialdehyde (MDA). qPCR was used to determine mRNA expression. Atherosclerosis was evaluated by oil red O staining in ApoE-KO mice after cigarette smoke exposure.ResultsCSE decreased Sirt1 and sonic hedgehog (SHH) expression, leading to mitochondrial dysfunction and apoptosis in HUVECs. Overexpressing Sirt1 or activating the SHH signaling pathway attenuated CSE-induced apoptosis and mitochondrial dysfunction. However, inhibiting the SHH signaling axis attenuated the protective effect of Sirt1 overexpression on CSE-induced apoptosis and mitochondrial dysfunction. In vivo studies also showed that cigarette smoke exacerbated atherosclerosis in ApoE-KO mice, downregulating Sirt1, SHH, and Gli1 expression in the aorta. Additionally, cigarette smoke increased Bax expression and decreased Bcl-2 expression in ApoE-KO mice aortas.DiscussionsSmoking can affect all stages of the atherosclerosis process, and the specific mechanism remains unclear. This study confirms that CSE can induce mitochondrial dysfunction and apoptosis of HUVECs by reducing Sirt1 expression and inhibiting SHH signaling activation. These findings provide new insights into the prevention and treatment of smoking-induced atherosclerosis.
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Affiliation(s)
- Weiming Wang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, China
- Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Gang Yuan
- Department of Intervention Radiology, Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, China
| | - Guang Li
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Tingting Zhao
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, China
| | - Yue Chen
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Youhua Xu
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, China
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Sharma R, Wu K, Han K, Russo AC, Dagur PK, Combs CA, Yao X, Levine SJ, Sack MN. BLOC1S1 Control of Vacuolar Organelle Fidelity Modulates Murine T H2 Cell Immunity and Allergy Susceptibility. Allergy 2024. [PMID: 39737471 DOI: 10.1111/all.16461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/15/2024] [Accepted: 12/09/2024] [Indexed: 01/01/2025]
Abstract
BACKGROUND The levels of biogenesis of lysosome organelles complex 1 subunit 1 (BLOC1S1) control mitochondrial and endolysosome organelle homeostasis and function. Reduced fidelity of these vacuolar organelles is increasingly being recognized as important in instigating cell-autonomous immune cell activation. We reasoned that exploring the role of BLOC1S1 in CD4+ T cells may further advance our understanding of regulatory events linked to mitochondrial and/or endolysosomal function in adaptive immunity. METHODS CD4+ T cells were analyzed from control and CD4+ T-cell-specific BLOC1S1 knockout mice. Polarization profiles were assayed using biochemical and molecular signatures, and signaling pathways were disrupted pharmacologically or via siRNA. Mouse models of airway and skin inflammation were generated by Ovalbumin and MC903 exposure, respectively. RESULTS TH2 regulator GATA3 and phosphorylated STAT6 were preferentially induced in BLOC1S1-depleted primary CD4+ T (TKO) cells. The levels of IL-4, IL-5, and IL-13 were markedly induced in the absence of BLOC1S1. At the organelle level, mitochondrial DNA leakage evoked cGAS-STING and NF-κB pathway activation with subsequent TH2 polarization. The induction of autophagy with rapamycin reduced cytosolic mtDNA and reversed these TH2 signatures. Furthermore, genetic knockdown of STING and NF-κB inhibition ameliorated this immune regulatory cascade in TKO cells. Finally, at a functional level, TKO mice displayed an increased susceptibility to allergic conditions, including dermatitis and allergic asthma. CONCLUSIONS BLOC1S1 depletion in mouse CD4+ T cells mediated disruption of mitochondrial integrity to initiate a predominant TH2-responsive phenotype via STING-NF-κB-driven signaling of the canonical TH2 regulatory program.
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Affiliation(s)
- Rahul Sharma
- Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, Maryland, USA
| | - Kaiyuan Wu
- Cardiovascular Branch, NHLBI, NIH, Bethesda, Maryland, USA
| | - Kim Han
- Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, Maryland, USA
| | - Anna Chiara Russo
- Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, Maryland, USA
| | | | | | - Xianglan Yao
- Critical Care Medicine and Pulmonary Branch, Bethesda, Maryland, USA
| | - Stewart J Levine
- Critical Care Medicine and Pulmonary Branch, Bethesda, Maryland, USA
| | - Michael N Sack
- Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, Maryland, USA
- Cardiovascular Branch, NHLBI, NIH, Bethesda, Maryland, USA
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Guo YB, Wu YM, Lin ZZ. Enhancing the radiosensitivity of colorectal cancer cells by reducing spermine synthase through promoting autophagy and DNA damage. World J Gastrointest Oncol 2024; 16:4716-4727. [PMID: 39678812 PMCID: PMC11577379 DOI: 10.4251/wjgo.v16.i12.4716] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/03/2024] [Accepted: 10/18/2024] [Indexed: 11/12/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC), the third most common cancer worldwide, has increasingly detrimental effects on human health. Radiotherapy resistance diminishes treatment efficacy. Studies suggest that spermine synthase (SMS) may serve as a potential target to enhance the radiosensitivity. AIM To investigate the association between SMS and radiosensitivity in CRC cells, along with a detailed elucidation of the underlying mechanisms. METHODS Western blot was adopted to assess SMS expression in normal colonic epithelial cells and CRC cell lines. HCT116 cells were transfected with control/SMS-specific shRNA or control/pcDNA3.1-SMS plasmids. Assessments included cell viability, colony formation, and apoptosis via MTT assays, colony formation assays, and flow cytometry. Radiosensitivity was studied in SMS-specific shRNA-transfected HCT116 cells post-4 Gy radiation, evaluating cell viability, colony formation, apoptosis, DNA damage (comet assays), autophagy (immunofluorescence), and mammalian target of rapamycin (mTOR) pathway protein expression (western blot). RESULTS Significant up-regulation of SMS expression levels was observed in the CRC cell lines. Upon down-regulation of SMS expression, cellular viability and colony-forming ability were markedly suppressed, concomitant with a notable increase in apoptotic indices. Furthermore, attenuation of SMS expression significantly augmented the sensitivity of HCT116 cells to radiation therapy, evidenced by a pronounced elevation in levels of cellular DNA damage and autophagy. Importantly, down-regulation of SMS corresponded with a marked reduction in the expression levels of proteins associated with the mTOR signaling pathway. CONCLUSION Knocking down SMS attenuates the mTOR signaling pathway, thereby promoting cellular autophagy and DNA damage to enhance the radiosensitivity of CRC cells.
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Affiliation(s)
- Yu-Bin Guo
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yue-Ming Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Zhi-Zhao Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Reid MV, Fredickson G, Mashek DG. Mechanisms coupling lipid droplets to MASLD pathophysiology. Hepatology 2024:01515467-990000000-01067. [PMID: 39475114 DOI: 10.1097/hep.0000000000001141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/17/2024] [Indexed: 01/03/2025]
Abstract
Hepatic steatosis, the buildup of neutral lipids in lipid droplets (LDs), is commonly referred to as metabolic dysfunction-associated steatotic liver disease when alcohol or viral infections are not involved. Metabolic dysfunction-associated steatotic liver disease encompasses simple steatosis and the more severe metabolic dysfunction-associated steatohepatitis, characterized by inflammation, hepatocyte injury, and fibrosis. Previously viewed as inert markers of disease, LDs are now understood to play active roles in disease etiology and have significant nonpathological and pathological functions in cell signaling and function. These dynamic properties of LDs are tightly regulated by hundreds of proteins that coat the LD surface, controlling lipid metabolism, trafficking, and signaling. The following review highlights various facets of LD biology with the primary goal of discussing key mechanisms through which LDs promote the development of advanced liver diseases, including metabolic dysfunction-associated steatohepatitis.
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Affiliation(s)
- Mari V Reid
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Gavin Fredickson
- Department of Integrated Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Douglas G Mashek
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
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Haque MA, Yoshimoto A, Nakagawa H, Nishimura K. Effect of long-term inorganic arsenic exposure on erythropoietin production in vitro. Toxicol In Vitro 2024; 99:105877. [PMID: 38876227 DOI: 10.1016/j.tiv.2024.105877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 05/28/2024] [Accepted: 06/10/2024] [Indexed: 06/16/2024]
Abstract
Arsenic is widely present in the environment in trivalent and pentavalent forms; long-term arsenic exposure due to environmental pollution has become a problem. Previous reports have shown that 24-h exposure to arsenate (as pentavalent arsenic) potentiates erythropoietin (EPO) production via reactive oxygen species (ROS) in EPO-producing HepG2 cells. However, the effects of long-term arsenate exposure on EPO production remain unclear. In HepG2 cells subcultured for 3 weeks in the presence of arsenate, EPO mRNA levels were lower than those in untreated cells. Levels of ARSENITE METHYLTRANSFERASE mRNA, as well as those of Nuclear factor erythroid 2-related factor 2, glutathione, and superoxide dismutase proteins, were increased compared to untreated cells, but levels of malondialdehyde were not significantly altered. Thus, long-term exposure to arsenate enhances ROS scavenging, suggesting that the ROS-induced accumulation of EPO mRNA is attenuated by arsenate exposure. The induction of EPO accumulation by hypoxia also was attenuated by long-term arsenate exposure, suggesting an impairment in responsivity of EPO production. Furthermore, mRNA levels of SIRTUIN-1, which affects EPO transcription, were potentiated by long-term arsenate exposure. These results suggest that long-term arsenate exposure has multiple, distinct effects on EPO production in vitro.
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Affiliation(s)
- Md Anamul Haque
- Laboratory of Toxicology, Graduate School of Life and Environmental Sciences, Faculty of Veterinary Medicine, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka 598-853, Japan
| | - Akari Yoshimoto
- Laboratory of Toxicology, Graduate School of Life and Environmental Sciences, Faculty of Veterinary Medicine, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka 598-853, Japan
| | - Hiroshi Nakagawa
- Laboratory of Toxicology, Graduate School of Life and Environmental Sciences, Faculty of Veterinary Medicine, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka 598-853, Japan
| | - Kazuhiko Nishimura
- Laboratory of Toxicology, Graduate School of Life and Environmental Sciences, Faculty of Veterinary Medicine, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka 598-853, Japan.
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Kealy L, Runting J, Thiele D, Scheer S. An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system. Front Immunol 2024; 15:1385319. [PMID: 38962004 PMCID: PMC11219580 DOI: 10.3389/fimmu.2024.1385319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 04/04/2024] [Indexed: 07/05/2024] Open
Abstract
The immune system comprises a complex yet tightly regulated network of cells and molecules that play a critical role in protecting the body from infection and disease. The activity and development of each immune cell is regulated in a myriad of ways including through the cytokine milieu, the availability of key receptors, via tailored intracellular signalling cascades, dedicated transcription factors and even by directly modulating gene accessibility and expression; the latter is more commonly known as epigenetic regulation. In recent years, epigenetic regulators have begun to emerge as key players involved in modulating the immune system. Among these, the lysine methyltransferase DOT1L has gained significant attention for its involvement in orchestrating immune cell formation and function. In this review we provide an overview of the role of DOT1L across the immune system and the implications of this role on health and disease. We begin by elucidating the general mechanisms of DOT1L-mediated histone methylation and its impact on gene expression within immune cells. Subsequently, we provide a detailed and comprehensive overview of recent studies that identify DOT1L as a crucial regulator of immune cell development, differentiation, and activation. Next, we discuss the potential mechanisms of DOT1L-mediated regulation of immune cell function and shed light on how DOT1L might be contributing to immune cell homeostasis and dysfunction. We then provide food for thought by highlighting some of the current obstacles and technical limitations precluding a more in-depth elucidation of DOT1L's role. Finally, we explore the potential therapeutic implications of targeting DOT1L in the context of immune-related diseases and discuss ongoing research efforts to this end. Overall, this review consolidates the current paradigm regarding DOT1L's role across the immune network and emphasises its critical role in governing the healthy immune system and its potential as a novel therapeutic target for immune-related diseases. A deeper understanding of DOT1L's immunomodulatory functions could pave the way for innovative therapeutic approaches which fine-tune the immune response to enhance or restore human health.
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Affiliation(s)
- Liam Kealy
- Immunity Program, The Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Jessica Runting
- Immunity Program, The Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Daniel Thiele
- Immunity Program, The Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Sebastian Scheer
- Immunity Program, The Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
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Kang Y, Kim D, Lee S, Kim H, Kim T, Cho JA, Lee T, Choi EY. Innate Immune Training Initiates Efferocytosis to Protect against Lung Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308978. [PMID: 38279580 PMCID: PMC11005705 DOI: 10.1002/advs.202308978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Indexed: 01/28/2024]
Abstract
Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with β-glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin-induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. β-Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with β-glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of β-glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury-mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury-mediated disorders.
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Affiliation(s)
- Yoon‐Young Kang
- Department of Biomedical SciencesUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
- Department of MicrobiologyUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
| | - Dong‐Young Kim
- Department of Biomedical SciencesUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
- Present address:
Institute for Clinical Chemistry and Laboratory MedicineFaculty of MedicineTechnische Universität Dresden01307DresdenGermany
| | - Sang‐Yong Lee
- Department of Biomedical SciencesUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
- Department of MicrobiologyUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
| | - Hee‐Joong Kim
- Department of Biomedical SciencesUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
- Department of MicrobiologyUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
| | - Taehawn Kim
- Department of Biomedical SciencesUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
| | - Jeong A. Cho
- Department of Biomedical SciencesUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
| | - Taewon Lee
- Division of Applied Mathematical SciencesCollege of Science and TechnologyKorea UniversitySejong30019Republic of Korea
| | - Eun Young Choi
- Department of Biomedical SciencesUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
- Department of MicrobiologyUniversity of Ulsan College of MedicineASAN Medical CenterSeoul05505Republic of Korea
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Han K, Meadows AM, Rodman MJ, Russo AC, Sharma R, Singh K, Hassanzadeh S, Dagur PK, Huffstutler RD, Krause FN, Griffin JL, Baumer Y, Powell-Wiley TM, Sack MN. Propionate functions as a feeding state-dependent regulatory metabolite to counter proinflammatory signaling linked to nutrient load and obesity. J Leukoc Biol 2024; 115:738-749. [PMID: 38207130 PMCID: PMC10980352 DOI: 10.1093/jleuko/qiae006] [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] [Received: 06/14/2023] [Revised: 12/18/2023] [Accepted: 12/22/2023] [Indexed: 01/13/2024] Open
Abstract
Generally, fasting and refeeding confer anti- and proinflammatory effects, respectively. In humans, these caloric-load interventions function, in part, via regulation of CD4+ T cell biology. However, mechanisms orchestrating this regulation remain incomplete. We employed integrative bioinformatics of RNA sequencing and high-performance liquid chromatography-mass spectrometry data to measure serum metabolites and gene expression of peripheral blood mononuclear cells isolated from fasting and refeeding in volunteers to identify nutrient-load metabolite-driven immunoregulation. Propionate, a short chain fatty acid (SCFA), and the SCFA-sensing G protein-coupled receptor 43 (ffar2) were coordinately and inversely regulated by fasting and refeeding. Propionate and free fatty acid receptor agonists decreased interferon-γ and interleukin-17 and significantly blunted histone deacetylase activity in CD4+ T cells. Furthermore, propionate blunted nuclear factor κB activity and diminished interleukin-6 release. In parallel, propionate reduced phosphorylation of canonical T helper 1 (TH1) and TH17 regulators, STAT1 and STAT3, respectively. Conversely, knockdown of free fatty acid receptors significantly attenuated the anti-inflammatory role of propionate. Interestingly, propionate recapitulated the blunting of CD4+ TH cell activation in primary cells from obese individuals, extending the role of this metabolite to a disease associated with low-grade inflammation. Together, these data identify a nutrient-load responsive SCFA-G protein-coupled receptor linked pathway to regulate CD4+ TH cell immune responsiveness.
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Affiliation(s)
- Kim Han
- Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Room 5-3342, Bld 10-CRC, 10 Center Drive, Bethesda, MD 20817, United States
| | - Allison M Meadows
- Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Room 5-3342, Bld 10-CRC, 10 Center Drive, Bethesda, MD 20817, United States
- Department of Biochemistry, University of Cambridge, Sanger Bld, 80 Tennis Ct Rd, Cambridge CB2 1GA, United Kingdom
| | - Matthew J Rodman
- Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Room 5-3342, Bld 10-CRC, 10 Center Drive, Bethesda, MD 20817, United States
| | - Anna Chiara Russo
- Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Room 5-3342, Bld 10-CRC, 10 Center Drive, Bethesda, MD 20817, United States
| | - Rahul Sharma
- Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Room 5-3342, Bld 10-CRC, 10 Center Drive, Bethesda, MD 20817, United States
| | - Komudi Singh
- Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Room 5-3342, Bld 10-CRC, 10 Center Drive, Bethesda, MD 20817, United States
| | - Shahin Hassanzadeh
- Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Room 5-3342, Bld 10-CRC, 10 Center Drive, Bethesda, MD 20817, United States
| | - Pradeep K Dagur
- Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, United States
| | - Rebecca D Huffstutler
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, United States
| | - Fynn N Krause
- Department of Biochemistry, University of Cambridge, Sanger Bld, 80 Tennis Ct Rd, Cambridge CB2 1GA, United Kingdom
| | - Julian L Griffin
- Department of Biochemistry, University of Cambridge, Sanger Bld, 80 Tennis Ct Rd, Cambridge CB2 1GA, United Kingdom
- Rowett Institute, School of Medicine, Medical Sciences and Nutrition, Foresterhill Campus, University of Aberdeen, Ashgrove Rd W, Aberdeen AB25 2ZD, United Kingdom
| | - Yvonne Baumer
- Social Determinants of Obesity and Cardiovascular Risk Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, United States
| | - Tiffany M Powell-Wiley
- Social Determinants of Obesity and Cardiovascular Risk Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, United States
| | - Michael N Sack
- Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Room 5-3342, Bld 10-CRC, 10 Center Drive, Bethesda, MD 20817, United States
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, United States
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11
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Sharma R, Wu K, Han K, Russo AC, Dagur PK, Combs CA, Sack MN. BLOC1S1 control of vacuolar organelle fidelity modulates T H2 cell immunity and allergy susceptibility. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.21.586144. [PMID: 39803487 PMCID: PMC11722528 DOI: 10.1101/2024.03.21.586144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
The levels of biogenesis of lysosome organelles complex 1 subunit 1 (BLOC1S1) control mitochondrial and endolysosome organelle homeostasis and function. Reduced fidelity of these vacuolar organelles is increasingly being recognized as important in instigating cell-autonomous immune cell activation. We reasoned that exploring the role of BLOC1S1 in CD4+ T cells, may further advance our understanding of regulatory events linked to mitochondrial and/or endolysosomal function in adaptive immunity. Transcript levels of the canonical transcription factors driving CD4+T cell polarization in response to activation showed that, the TH2 regulator GATA3 and phosphorylated STAT6 were preferentially induced in BLOC1S1 depleted primary CD4+ T (TKO) cells. In parallel, in response to both T cell receptor activation and in response to TH2 polarization the levels of IL-4, IL-5 and IL-13 were markedly induced in the absence of BLOC1S1. At the organelle level, mitochondrial DNA leakage evoked cGAS-STING and NF-kB pathway activation with subsequent TH2 polarization. The induction of autophagy with rapamycin reduced cytosolic mtDNA and reverses these TH2 signatures. Furthermore, genetic knockdown of STING and STING and NF-κB inhibition ameliorated this immune regulatory cascade in TKO cells. Finally, at a functional level, TKO mice displayed increased susceptible to allergic conditions including atopic dermatitis and allergic asthma. In conclusion, BLOC1S1 depletion mediated disruption of mitochondrial integrity to initiate a predominant TH2 responsive phenotype via STING-NF-κB driven signaling of the canonical TH2 regulatory program.
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Affiliation(s)
- Rahul Sharma
- Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Maryland, USA
| | - Kaiyuan Wu
- Cardiovascular Branch, NHLBI, NIH, Maryland, USA
| | - Kim Han
- Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Maryland, USA
| | - Anna Chiara Russo
- Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Maryland, USA
| | | | | | - Michael N. Sack
- Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Maryland, USA
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12
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Nishimura K, Iitaka S, Sakaki T, Tsuji K, Yoshimoto A, Haque MA, Nakagawa H. Effect of long-term treatment with trivalent chromium on erythropoietin production in HepG2 cells. Arch Biochem Biophys 2024; 752:109872. [PMID: 38141908 DOI: 10.1016/j.abb.2023.109872] [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: 10/05/2023] [Revised: 12/13/2023] [Accepted: 12/16/2023] [Indexed: 12/25/2023]
Abstract
Trivalent chromium (Cr(III)) is sometimes taken as a long-term supplement, but its effectiveness is unclear. Recently, Cr(III) reportedly modulates peroxisome proliferator-activated receptor gamma (PPARγ) expression. Our previous study reported that increased PPARγ after 24 h Cr(III) treatment promoted erythropoietin (EPO) production in HepG2 cells. In the current study, we analyzed 4-week Cr(III) treatment effects on PPARγ and EPO production in HepG2 cells. Long-term Cr(III) treatment resulted in significantly elevated mRNA expression levels of PPARγ and EPO compared to controls. Additionally, treatment with a PPARγ inhibitor suppressed EPO mRNA expression. Increased EPO mRNA expression due to stimulation with hypoxia or cobalt was unaffected by long-term Cr(III) treatment. Administration of lipopolysaccharide and pyocyanin which causes oxidative stress, promoted EPO production, but this effect was attenuated in cells treated with Cr(III). Long-term Cr(III) treatment increased hypoxia inducible factor (HIF)-1α and 2α mRNA expression and protein levels. Increased PPARγ, induced by long-term Cr(III) treatment, suppressed sirtuin1 (SIRT1) mRNA expression and increased EPO mRNA expression, suggesting that increased PPARγ attenuated the suppressive effect of SIRT1 on HIF. These results suggest that the sustained increase in PPARγ during long-term Cr(III) treatment maintains increased EPO production through a mechanism different from that observed under hypoxia.
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Affiliation(s)
- Kazuhiko Nishimura
- Laboratory of Bioenvironmental Sciences, Course of Veterinary Science, Graduate School of Veterinary Science, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka, 598-8531, Japan.
| | - Suzuka Iitaka
- Laboratory of Bioenvironmental Sciences, Course of Veterinary Science, Graduate School of Veterinary Science, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka, 598-8531, Japan
| | - Takuya Sakaki
- Laboratory of Bioenvironmental Sciences, Course of Veterinary Science, Graduate School of Veterinary Science, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka, 598-8531, Japan
| | - Keigo Tsuji
- Laboratory of Bioenvironmental Sciences, Course of Veterinary Science, Graduate School of Veterinary Science, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka, 598-8531, Japan
| | - Akari Yoshimoto
- Laboratory of Bioenvironmental Sciences, Course of Veterinary Science, Graduate School of Veterinary Science, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka, 598-8531, Japan
| | - Md Anamul Haque
- Laboratory of Bioenvironmental Sciences, Course of Veterinary Science, Graduate School of Veterinary Science, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka, 598-8531, Japan
| | - Hiroshi Nakagawa
- Laboratory of Bioenvironmental Sciences, Course of Veterinary Science, Graduate School of Veterinary Science, Osaka Metropolitan University, 1-58 Rinku Ohrai-Kita, Izumisano, Osaka, 598-8531, Japan
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13
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Tian X, Wang T, Shen H, Wang S. Tumor microenvironment, histone modifications, and myeloid-derived suppressor cells. Cytokine Growth Factor Rev 2023; 74:108-121. [PMID: 37598011 DOI: 10.1016/j.cytogfr.2023.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/04/2023] [Accepted: 08/09/2023] [Indexed: 08/21/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are important components of the tumor microenvironment (TME), which drive the tumor immune escape by inducing immunosuppression. The expansion and function of MDSCs are tightly associated with signaling pathways induced by molecules from tumor cells, stromal cells, and activated immune cells in the TME. Although these pathways have been well-characterized, the understanding of the epigenetic regulators involved is incomplete. Since histone modifications are the most studied epigenetic changes in MDSCs, we summarize current knowledge on the role of histone modifications in MDSCs within this review. We first discuss the influence of the TME on histone modifications in MDSCs, with an emphasis on histone modifications and modifiers that direct MDSC differentiation and function. Furthermore, we highlight current epigenetic interventions that can reverse MDSC-induced immunosuppression by modulating histone modifications and discuss future research directions to fully appreciate the role of histone modifications in MDSCs.
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Affiliation(s)
- Xinyu Tian
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ting Wang
- Department of Laboratory Medicine, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Han Shen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
| | - Shengjun Wang
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China; Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.
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14
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Zhang L, Xue Y, Yuan C, Du X, Wang X, Guo L, Li B. Decreased SIRT1 mRNA expression in peripheral blood mononuclear cells from patients with neuromyelitis optica spectrum disorders. Acta Neurol Belg 2023; 123:2287-2294. [PMID: 37294424 DOI: 10.1007/s13760-023-02300-3] [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: 02/18/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023]
Abstract
OBJECTIVE Sirtuin (SIRT)1, as a molecular link between immunity and metabolic pathways, is a key immune response regulator. The significance of SIRT1 in peripheral blood mononuclear cells (PBMCs) of neuromyelitis optica spectrum disorder (NMOSD) has not been investigated. Here, we aimed to evaluate the SIRT1 mRNA level in PBMCs of patients with NMOSD and its clinical relevance and explore the potential mechanism of SIRT1 action. METHODS A total of 65 patients with NMOSD and 60 normal controls from North China were enrolled. Using real-time fluorescence quantitative-polymerase chain reaction, mRNA levels were detected in PBMCs, and protein levels were detected using western blotting. RESULTS Compared to the healthy controls and chronic-phase patients with NMOSD, SIRT1 mRNA and protein levels in PBMCs of NMOSD patients with acute attack were significantly downregulated (p < 0.0001). ∆EDSS scores (EDSS scores in the acute phase-EDSS scores before the recent attack) were higher in NMOSD patients with low SIRT1 mRNA level than in patients with high SIRT1 expression (p = 0.042). SIRT1 mRNA level in patients with acute-phase NMSOD was positively correlated with lymphocyte and monocyte counts and negatively correlated with neutrophil counts and the neutrophil-to-lymphocyte ratio. Furthermore, the transcription factor FOXP3 mRNA level was significantly positively correlated with the SIRT1 mRNA level in PBMCs of patients with acute-phase NMOSD. CONCLUSIONS Our study indicated that SIRT1 mRNA expression was downregulated in the PBMCs of patients with acute-phase NMOSD, and its level was correlated with the clinical parameters of the patients, suggesting a potential role of SIRT1 in NMOSD.
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Affiliation(s)
- Lu Zhang
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215, Hepingxi Road, Shijiazhuang, 050000, China
- Key Laboratory of Neurology of Hebei Province, Shijiazhuang, China
| | - Yumei Xue
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215, Hepingxi Road, Shijiazhuang, 050000, China
- Key Laboratory of Neurology of Hebei Province, Shijiazhuang, China
- Department of Pharmacy, Shijiazhuang People's Hospital, Shijiazhuang, China
| | - Congcong Yuan
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215, Hepingxi Road, Shijiazhuang, 050000, China
- Key Laboratory of Neurology of Hebei Province, Shijiazhuang, China
- Department of Neurology, Baoding First Central Hospital, Baoding, China
| | - Xiaochen Du
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215, Hepingxi Road, Shijiazhuang, 050000, China
- Key Laboratory of Neurology of Hebei Province, Shijiazhuang, China
| | - Xuan Wang
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215, Hepingxi Road, Shijiazhuang, 050000, China
- Key Laboratory of Neurology of Hebei Province, Shijiazhuang, China
| | - Li Guo
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215, Hepingxi Road, Shijiazhuang, 050000, China.
- Key Laboratory of Neurology of Hebei Province, Shijiazhuang, China.
| | - Bin Li
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215, Hepingxi Road, Shijiazhuang, 050000, China.
- Key Laboratory of Neurology of Hebei Province, Shijiazhuang, China.
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15
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Zhang Y, Liu A, Kang Huang S, Evans JD, Cook SC, Palmer-Young E, Corona M, Alburaki M, Liu G, Chou Han R, Feng Li W, Hao Y, Lian Li J, Gilligan TM, Smith-Pardo AH, Banmeke O, Posada-Florez FJ, Hui Gao Y, DeGrandi-Hoffman G, Chun Xie H, Sadzewicz AM, Hamilton M, Ping Chen Y. Mediating a host cell signaling pathway linked to overwinter mortality offers a promising therapeutic approach for improving bee health. J Adv Res 2023; 53:99-114. [PMID: 36564001 PMCID: PMC10658305 DOI: 10.1016/j.jare.2022.12.011] [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: 09/01/2022] [Revised: 11/22/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Honey bees provides valuable pollination services for world food crops and wild flowering plants which are habitats of many animal species and remove carbon dioxide from the atmosphere, a powerful tool in the fight against climate change. Nevertheless, the honey bee population has been declining and the majority of colony losses occur during the winter. OBJECTIVES The goal of this study was to understand the mechanisms underlying overwinter colony losses and develop novel therapeutic strategies for improving bee health. METHODS First, pathogen prevalence in overwintering bees were screened between 2015 and 2018. Second, RNA sequencing (RNA-Seq) for transcriptional profiling of overwintering honey bees was conducted and qRT-PCR was performed to confirm the results of the differential expression of selected genes. Lastly, laboratory bioassays were conducted to measure the effects of cold challenges on bee survivorship and stress responses and to assess the effect of a novel medication for alleviating cold stress in honey bees. RESULTS We identified that sirtuin signaling pathway is the most significantly enriched pathway among the down-regulated differentially expressed genes (DEGs) in overwintering diseased bees. Moreover, we showed that the expression of SIRT1 gene, a major sirtuin that regulates energy and immune metabolism, was significantly downregulated in bees merely exposed to cold challenges, linking cold stress with altered gene expression of SIRT1. Furthermore, we demonstrated that activation of SIRT1 gene expression by SRT1720, an activator of SIRT1 expression, could improve the physiology and extend the lifespan of cold-stressed bees. CONCLUSION Our study suggests that increased energy consumption of overwintering bees for maintaining hive temperature reduces the allocation of energy toward immune functions, thus making the overwintering bees more susceptible to disease infections and leading to high winter colony losses. The novel information gained from this study provides a promising avenue for the development of therapeutic strategies for mitigating colony losses, both overwinter and annually.
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Affiliation(s)
- Yi Zhang
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guanzhou 510260, PR China; U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA; School of Chinese Medicinal Resource, Guangdong Pharmaceutical University, Yunfu 527527, PR China
| | - Andrew Liu
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Shao Kang Huang
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA; College of Animal Sciences (Bee Science), Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, PR China
| | - Jay D Evans
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Steve C Cook
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Evan Palmer-Young
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Miguel Corona
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Mohamed Alburaki
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Ge Liu
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Animal Genomics and Improvement Laboratory, Beltsville, MD 20705, USA
| | - Ri Chou Han
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guanzhou 510260, PR China
| | - Wen Feng Li
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Yue Hao
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA; Key Laboratory of Pollinating Insect Biology, Institute of Apicultural Research, Chinese Academy of Agricultural Science, Beijing 100093, PR China
| | - Ji Lian Li
- Key Laboratory of Pollinating Insect Biology, Institute of Apicultural Research, Chinese Academy of Agricultural Science, Beijing 100093, PR China
| | - Todd M Gilligan
- Identification Technology Program (ITP) Molecular Laboratory, USDA-APHIS-PPQ-Science & Technology (S&T), Fort Collins, CO 80526-1825, USA
| | - Allan H Smith-Pardo
- Identification Technology Program (ITP) Molecular Laboratory, USDA-APHIS-PPQ-Science & Technology (S&T), Fort Collins, CO 80526-1825, USA
| | - Olubukola Banmeke
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Francisco J Posada-Florez
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Ya Hui Gao
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Animal Genomics and Improvement Laboratory, Beltsville, MD 20705, USA
| | | | - Hui Chun Xie
- Key Laboratory of Medicinal Animal and Plant Resources of Qinghai-Tibetan Plateau in Qinghai Province, Qinghai Normal University, Xining 810000, China
| | - Alex M Sadzewicz
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Michele Hamilton
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA
| | - Yan Ping Chen
- U.S. Department of Agriculture -Agricultural Research Service (USDA-ARS) Bee Research Laboratory, Beltsville, MD 20705, USA.
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Elsied MA, Sharawi ZW, Al-Amrah H, Hegazy RA, Mohamed AE, Saleh RM, El-kholy SS, Farrag FA, Fayed MH, El-Magd MA. Walnut Kernel Oil and Defatted Extracts Enhance Mesenchymal Stem Cell Stemness and Delay Senescence. Molecules 2023; 28:6281. [PMID: 37687109 PMCID: PMC10488345 DOI: 10.3390/molecules28176281] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Decreased stemness and increased cellular senescence impair the ability of mesenchymal stem cells (MSCs) to renew themselves, change into different cell types, and contribute to regenerative medicine. There is an urgent need to discover new compounds that can boost MSCs' stemness and delay senescence. Therefore, this study aimed to investigate the impact of walnut kernel oil (WKO) and defatted (WKD) extracts on bone marrow (BM)-MSC stemness and senescence. Premature senescence and inflammation were induced in BM-MSCs using H2O2 and LPS, respectively. Phytochemical constituents of WKO and WKD extracts were detected by HPLC. The stemness (proliferation and migration), senescence-related markers (p53, p21, SIRT1, and AMPK), oxidative stress/antioxidant markers, inflammatory cytokines, and cell cycle of BM-MSCs were measured by MTT assay, qPCR, ELISA, and flow cytometry. WKO and WKD extracts improved rat BM-MSC stemness, as evidenced by (1) increased cell viability, (2) decreased apoptosis (low levels of Bax and caspase3 and high levels of Bcl2), (3) upregulated MMP9 and downregulated TIMP1 expression, and (4) cell cycle arrest in the G0/G1 phase and declined cell number in the S and G2/M phases. Additionally, WKO and WKD extracts reduced rat BM-MSC senescence, as indicated by (1) decreased p53 and p21 expression, (2) upregulated expression and levels of SIRT1 and AMPK, (3) reduced levels of ROS and improved antioxidant activity (higher activity of CAT, SOD, and GPx and upregulated expression of NrF2 and HO-1), and (4) declined levels of TNFα, IL1β, and NF-κB. When compared to the WKO extract, the WKD extract had a greater impact on the induction of stemness and reduction of senescence of BM-MSCs due to its stronger antioxidant activity, which could be attributed to its higher levels of flavonoids and phenolic compounds, as detected by HPLC analysis. WKO and WKD extracts enhance rat BM-MSC stemness and protect them from senescence, suggesting their potential use as enhancers to increase MSCs' therapeutic efficacy.
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Affiliation(s)
- Marwa A. Elsied
- Anatomy and Embryology Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt
| | - Zeina W. Sharawi
- Biological Sciences Department, Faculty of Sciences, King AbdulAziz University, Jeddah 21589, Saudi Arabia; (Z.W.S.); (H.A.-A.)
| | - Hadba Al-Amrah
- Biological Sciences Department, Faculty of Sciences, King AbdulAziz University, Jeddah 21589, Saudi Arabia; (Z.W.S.); (H.A.-A.)
| | - Rabab A. Hegazy
- Department of Biology, Al-Darb University College, Jazan University, Jazan 45142, Saudi Arabia;
| | - Amro E. Mohamed
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt;
| | - Rasha M. Saleh
- Department of Physiology, Faculty of Veterinary Medicine, Mansura University, Mansura 35516, Egypt;
| | - Sanad S. El-kholy
- Department of Physiology, Faculty of Medicine, Kafrelsheikh University, Kafr El-Shaikh 33516, Egypt;
| | - Foad A. Farrag
- Anatomy and Embryology Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt
| | - Masoud H. Fayed
- Anatomy and Embryology Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt
| | - Mohammed A. El-Magd
- Anatomy and Embryology Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt
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Lathe R, St Clair D. Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease. Biol Rev Camb Philos Soc 2023; 98:1424-1458. [PMID: 37068798 DOI: 10.1111/brv.12959] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 04/19/2023]
Abstract
The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master 'clock of age' (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial - specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.
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Affiliation(s)
- Richard Lathe
- Division of Infection Medicine, Chancellor's Building, University of Edinburgh Medical School, Little France, Edinburgh, EH16 4SB, UK
| | - David St Clair
- Institute of Medical Sciences, School of Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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18
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Tao Z, Jin Z, Wu J, Cai G, Yu X. Sirtuin family in autoimmune diseases. Front Immunol 2023; 14:1186231. [PMID: 37483618 PMCID: PMC10357840 DOI: 10.3389/fimmu.2023.1186231] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 06/15/2023] [Indexed: 07/25/2023] Open
Abstract
In recent years, epigenetic modifications have been widely researched. As humans age, environmental and genetic factors may drive inflammation and immune responses by influencing the epigenome, which can lead to abnormal autoimmune responses in the body. Currently, an increasing number of studies have emphasized the important role of epigenetic modification in the progression of autoimmune diseases. Sirtuins (SIRTs) are class III nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and SIRT-mediated deacetylation is an important epigenetic alteration. The SIRT family comprises seven protein members (namely, SIRT1-7). While the catalytic core domain contains amino acid residues that have remained stable throughout the entire evolutionary process, the N- and C-terminal regions are structurally divergent and contribute to differences in subcellular localization, enzymatic activity and substrate specificity. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are predominantly found in the nucleus. SIRTs are key regulators of various physiological processes such as cellular differentiation, apoptosis, metabolism, ageing, immune response, oxidative stress, and mitochondrial function. We discuss the association between SIRTs and common autoimmune diseases to facilitate the development of more effective therapeutic strategies.
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Affiliation(s)
- Zhengjie Tao
- Science and Education Section, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Ultrasonics, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Zihan Jin
- Clinical Lab, Changzhou Second People’s Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Jiabiao Wu
- Department of Immunology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Gaojun Cai
- Cardiology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Xiaolong Yu
- Science and Education Section, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Ultrasonics, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
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Chen C, Yan W, Tao M, Fu Y. NAD + Metabolism and Immune Regulation: New Approaches to Inflammatory Bowel Disease Therapies. Antioxidants (Basel) 2023; 12:1230. [PMID: 37371959 DOI: 10.3390/antiox12061230] [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: 03/27/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a multifactorial systemic inflammatory immune response. Nicotinamide adenine dinucleotide (NAD+) is a co-enzyme involved in cell signaling and energy metabolism. Calcium homeostasis, gene transcription, DNA repair, and cell communication involve NAD+ and its degradation products. There is a growing recognition of the intricate relationship between inflammatory diseases and NAD+ metabolism. In the case of IBD, the maintenance of intestinal homeostasis relies on a delicate balance between NAD+ biosynthesis and consumption. Consequently, therapeutics designed to target the NAD+ pathway are promising for the management of IBD. This review discusses the metabolic and immunoregulatory processes of NAD+ in IBD to examine the molecular biology and pathophysiology of the immune regulation of IBD and to provide evidence and theoretical support for the clinical use of NAD+ in IBD.
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Affiliation(s)
- Chaoyue Chen
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Meihui Tao
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yu Fu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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20
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Zhang K, Du X, Gao Y, Liu S, Xu Y. Mesenchymal Stem Cells for Treating Alzheimer's Disease: Cell Therapy and Chemical Reagent Pretreatment. J Alzheimers Dis 2023:JAD221253. [PMID: 37125553 DOI: 10.3233/jad-221253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
As the size of the population aged 65 and older continues to grow, the incidence and mortality rates of Alzheimer's disease (AD) are increasing annually. Unfortunately, current treatments only treat symptoms temporarily and do not alter the patients' life expectancy or course of AD. Mesenchymal stem cells (MSCs) have shown a certain therapeutic potential in neurodegenerative diseases including AD due to their neuroinflammatory regulation and neuroprotective effects. However, the low survival and homing rates of MSCs after transplantation seriously affect their therapeutic effectiveness. Therefore, appropriate in vitro preconditioning is necessary to increase the survival and homing rates of MSCs to improve their effectiveness in treating AD. Here we summarize the therapeutic mechanisms of MSCs in AD and the chemical reagents used for the pretreatment of MSCs.
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Affiliation(s)
- Kexin Zhang
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xinzhe Du
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yao Gao
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Sha Liu
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yong Xu
- Department of Psychiatry, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China
- Department of Mental Health, Shanxi Medical University, Taiyuan, China
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21
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Zhang J, Liu Y, Li H, Hu Y, Yu S, Liu Q, Chen Y. Stellate Ganglion Block Improves Postoperative Cognitive Dysfunction in aged rats by SIRT1-mediated White Matter Lesion Repair. Neurochem Res 2022; 47:3838-3853. [DOI: 10.1007/s11064-022-03800-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/13/2022] [Accepted: 10/16/2022] [Indexed: 12/04/2022]
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22
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Zhang Y, Liang L, Wang Y, Cui Y, Hao C, Xin H. Anti-cancer effects of Shenqishiyiwei granules in gastric cancer are mediated via modulation of the immune system. J Funct Foods 2022; 98:105280. [DOI: 10.1016/j.jff.2022.105280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
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23
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Chen H, Song L, Xu X, Han Z, Peng F, Zhang Q, Liu C, Liang X. The effect of icariin on autoimmune premature ovarian insufficiency via modulation of Nrf2/HO-1/Sirt1 pathway in mice. Reprod Biol 2022; 22:100638. [PMID: 35344846 DOI: 10.1016/j.repbio.2022.100638] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/17/2022] [Accepted: 03/12/2022] [Indexed: 12/21/2022]
Abstract
Primary ovarian insufficiency (POI) is a common gynecological disease. Autoimmunity is a common cause of POI. Icariin (ICA) plays a therapeutic role in many autoimmune diseases. This study aims to investigate the effect of ICA on autoimmune POI mice and its effect on immune regulation. Sixty-three female BALB/c mice were randomized into three groups (control, POI, POI + ICA). POI and POI + ICA group were hypodermically injected with zona pellucida three peptides (pZP3) to induce autoimmune POI. Then the POI + ICA group was gavaged with ICA. A vaginal smear was to observe estrous cycles, hematoxylin-eosin staining was to count follicles. Enzyme-linked immunosorbent analysis determined serum FSH, LH, AMH, and anti-zona pellucida antibody (AZPAb) levels. In addition, flow cytometry detected the expression of Th1 cells and Treg cells, and Western blot was used to detect the expression of Nuclear factor E2 related factor 2(Nrf2), heme oxygenase-1 (HO-1), and Sirtuin-1 (Sirt1) proteins. pZP3 treatment decreased serum AMH levels and increased FSH, LH, and AZPAb levels. Additionally, decreases in the number of healthy follicles at all stages and an increase in the number of atretic follicles. Abnormal ovarian structure and an arrested estrous cycle were also noted. However, ICA rescued POI through up-regulating Nrf2, HO-1, and Sirt1 expressions and up-regulating Treg expressions. ICA treatment improved the structure of the injured ovarian and its function in autoimmune POI mice. The mechanism is achieved by increasing the expression of Nrf2/HO-1/Sirt1 pathway in the ovary and increasing Treg cells' expression.
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Affiliation(s)
- Haoran Chen
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Reproductive & Women-Children Hospital, Chengdu, China
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Reproductive & Women-Children Hospital, Chengdu, China
| | - Xiaofang Xu
- Department of Gynecology, Leping Maternal and Child Health Care Hospital, Leping, China
| | - Zhongyu Han
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Reproductive & Women-Children Hospital, Chengdu, China
| | - Fang Peng
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Reproductive & Women-Children Hospital, Chengdu, China
| | - Qinxiu Zhang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Reproductive & Women-Children Hospital, Chengdu, China
| | - Chi Liu
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China.
| | - Xin Liang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Reproductive & Women-Children Hospital, Chengdu, China.
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Thongchot S, Jirapongwattana N, Luangwattananun P, Chiraphapphaiboon W, Chuangchot N, Sa-nguanraksa D, O-Charoenrat P, Thuwajit P, Yenchitsomanus PT, Thuwajit C. Adoptive Transfer of Anti-Nucleolin T Cells Combined with PD-L1 Inhibition against Triple-Negative Breast Cancer. Mol Cancer Ther 2022; 21:727-739. [PMID: 35313339 PMCID: PMC9377762 DOI: 10.1158/1535-7163.mct-21-0823] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/21/2021] [Accepted: 03/02/2022] [Indexed: 01/18/2023]
Abstract
Dendritic cell (DC)-based T-cell activation is an alternative immunotherapy in breast cancer. The anti-programmed death ligand 1 (PD-L1) can enhance T-cell function. Nucleolin (NCL) is overexpressed in triple-negative breast cancer (TNBC). The regulation of PD-L1 expression through autophagy and the anti-PD-L1 peptide to help sensitize T cells for NCL-positive TNBC cell killing has not been evaluated. Results showed the worst clinical outcome in patients with high NCL and PD-L1. Self-differentiated myeloid-derived antigen-presenting cells reactive against tumors presenting NCL or SmartDCs-NCL producing GM-CSF and IL-4, could activate NCL-specific T cells. SmartDCs-NCL plus recombinant human ribosomal protein substrate 3 (RPS3) successfully induced maturation and activation of DCs characterized by the reduction of CD14 and the induction of CD11c, CD40, CD80, CD83, CD86, and HLA-DR. Interestingly, SmartDCs-NCL plus RPS3 in combination with anti-PD-L1 peptide revealed significant killing activity of the effector NCL-specific T cells against NCLHigh/PD-L1High MDA-MB-231 and NCLHigh/PD-L1High HCC70 TNBC cells at the effector: a target ratio of 5:1 in 2-D and 10:1 in the 3-D culture system; and increments of IFNγ by the ELISpot assay. No killing effect was revealed in MCF-10A normal mammary cells. Mechanistically, NCL-specific T-cell-mediated TNBC cell killing was through both apoptotic and autophagic pathways. Induction of autophagy by curcumin, an autophagic stimulator, inhibited the expression of PD-L1 and enhanced cytolytic activity of NCL-specific T cells. These findings provide the potential clinical approaches targeting NCLHigh/PD-L1High TNBC cells with NCL-specific T cells in combination with a PD-L1 inhibitor or autophagic stimulator.
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Affiliation(s)
- Suyanee Thongchot
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Research Department, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Niphat Jirapongwattana
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Piriya Luangwattananun
- Research Department, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Wannasiri Chiraphapphaiboon
- Research Department, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Department of Biochemistry, International Graduate Program in Medical Biochemistry and Molecular Biology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nisa Chuangchot
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Research Department, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Doonyapat Sa-nguanraksa
- Department of Clinical Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pa-thai Yenchitsomanus
- Research Department, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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25
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Role of Butylphthalide in Immunity and Inflammation: Butylphthalide May Be a Potential Therapy for Anti-Inflammation and Immunoregulation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7232457. [PMID: 35422893 PMCID: PMC9005281 DOI: 10.1155/2022/7232457] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 03/14/2022] [Indexed: 12/14/2022]
Abstract
Inflammation and immunity play an essential role in disease pathogenesis. 3-N-Butylphthalide (NBP), a group of compounds extracted from seeds of Apium graveolens (Chinese celery), has been demonstrated as an efficient and effective therapy for ischemic stroke. The amount of research on NBP protective effect is increasing at pace, such as microcircular reconstruction, alleviating inflammation, ameliorating brain edema and blood-brain barrier (BBB) damage, mitochondrial function protection, antiplatelet aggregation, antithrombosis, decreasing oxidative damage, and reducing neural cell apoptosis. There has been increasing research emphasizing the association between NBP and immunity and inflammation in the past few years. Hence, it is aimed at reviewing the related literature and summarizing the underlying anti-inflammatory and immunoregulatory function of NBP in various disorders.
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26
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Sirtuins are crucial regulators of T cell metabolism and functions. Exp Mol Med 2022; 54:207-215. [PMID: 35296782 PMCID: PMC8979958 DOI: 10.1038/s12276-022-00739-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 12/23/2021] [Indexed: 01/01/2023] Open
Abstract
It is well known that metabolism underlies T cell differentiation and functions. The pathways regulating T cell metabolism and function are interconnected, and changes in T cell metabolic activity directly impact the effector functions and fate of T cells. Thus, understanding how metabolic pathways influence immune responses and ultimately affect disease progression is paramount. Epigenetic and posttranslational modification mechanisms have been found to control immune responses and metabolic reprogramming. Sirtuins are NAD+-dependent histone deacetylases that play key roles during cellular responses to a variety of stresses and have recently been reported to have potential roles in immune responses. Therefore, sirtuins are of significant interest as therapeutic targets to treat immune-related diseases and enhance antitumor immunity. This review aims to illustrate the potential roles of sirtuins in different subtypes of T cells during the adaptive immune response. Sirtuins, enzymes that regulate how cells respond to stress, regulate T cell metabolism and functions, and therefore blocking or boosting sirtuins influences immune responses. As part of the immune system, some types of T cells attack specific targets; others keep the immune response in check. Imene Hamaidi and Sungjune Kim at H. Lee Moffitt Cancer Center, Tampa, USA, have reviewed how sirtuins affect different subsets of T cells to either promote or suppress immune responses. Boosting sirtuins that increase the function of inflammation-suppressing T cells can improve outcomes for transplant recipients or help treat autoimmune diseases. Conversely, stimulating immune-activating sirtuins can help re-energize exhausted antitumor T cells. Understanding the complex web of sirtuin–T cell interactions may help in developing therapeutic strategies for improving transplant outcomes, and for treating autoimmune diseases and cancer.
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Bosch M, Pol A. Eukaryotic lipid droplets: metabolic hubs, and immune first responders. Trends Endocrinol Metab 2022; 33:218-229. [PMID: 35065875 DOI: 10.1016/j.tem.2021.12.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 12/18/2022]
Abstract
As major eukaryotic lipid storage organelles, lipid droplets (LDs) are metabolic hubs coordinating energy flux and building block distribution. Infectious pathogens often promote accumulation and physically interact with LDs. The most accepted view is that host LDs are hijacked by invaders to draw on nutrients for host colonisation. However, unique traits such as biogenesis plasticity, dynamic proteome, signalling capacity, and ability to interact with other organelles endow LDs with competencies to face complex biological challenges. Here, we focus on published data suggesting that LDs are not usurped organelles but innate immunity first responders. By comparison with analogous mechanisms activated on LDs in nutrient-poor environments, our review supports the hypothesis that host LDs actively participate in immunometabolism, immune signalling, and microbial killing.
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Affiliation(s)
- Marta Bosch
- Lipid Trafficking and Disease Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain.
| | - Albert Pol
- Lipid Trafficking and Disease Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona
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28
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Shen P, Deng X, Chen Z, Ba X, Qin K, Huang Y, Huang Y, Li T, Yan J, Tu S. SIRT1: A Potential Therapeutic Target in Autoimmune Diseases. Front Immunol 2021; 12:779177. [PMID: 34887866 PMCID: PMC8650132 DOI: 10.3389/fimmu.2021.779177] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/08/2021] [Indexed: 12/21/2022] Open
Abstract
The morbidity and mortality of autoimmune diseases (Ads) have been increasing worldwide, and the identification of novel therapeutic strategies for prevention and treatment is urgently needed. Sirtuin 1 (SIRT1), a member of the class III family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in the progression of several diseases. SIRT1 also regulates inflammation, oxidative stress, mitochondrial function, immune responses, cellular differentiation, proliferation and metabolism, and its altered functions are likely involved in Ads. Several inhibitors and activators have been shown to affect the development of Ads. SIRT1 may represent a novel therapeutic target in these diseases, and small molecules or natural products that modulate the functions of SIRT1 are potential therapeutic agents. In the present review, we summarize current studies of the biological functions of SIRT1 and its role in the pathogenesis and treatment of Ads.
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Affiliation(s)
- Pan Shen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Xuan Deng
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhe Chen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Xin Ba
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Kai Qin
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Ying Huang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Yao Huang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Li
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Jiahui Yan
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Shenghao Tu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
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29
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Lu J, He X, Zhang L, Zhang R, Li W. Acetylation in Tumor Immune Evasion Regulation. Front Pharmacol 2021; 12:771588. [PMID: 34880761 PMCID: PMC8645962 DOI: 10.3389/fphar.2021.771588] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/05/2021] [Indexed: 12/24/2022] Open
Abstract
Acetylation is considered as one of the most common types of epigenetic modifications, and aberrant histone acetylation modifications are associated with the pathological process of cancer through the regulation of oncogenes and tumor suppressors. Recent studies have shown that immune system function and tumor immunity can also be affected by acetylation modifications. A comprehensive understanding of the role of acetylation function in cancer is essential, which may help to develop new therapies to improve the prognosis of cancer patients. In this review, we mainly discussed the functions of acetylase and deacetylase in tumor, immune system and tumor immunity, and listed the information of drugs targeting these enzymes in tumor immunotherapy.
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Affiliation(s)
- Jun Lu
- Hunan Normal University School of Medicine, Changsha, China.,Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China
| | - Xiang He
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China.,Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China
| | - Lijuan Zhang
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
| | - Ran Zhang
- Hunan Normal University School of Medicine, Changsha, China
| | - Wenzheng Li
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
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30
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Yang C, Wang Z, Li L, Zhang Z, Jin X, Wu P, Sun S, Pan J, Su K, Jia F, Zhang L, Wang H, Yu X, Shao X, Wang K, Qiu F, Yan J, Huang J. Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis. J Immunother Cancer 2021; 9:jitc-2021-002875. [PMID: 34716206 PMCID: PMC8559246 DOI: 10.1136/jitc-2021-002875] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2021] [Indexed: 12/12/2022] Open
Abstract
Background Neutrophils-linked premetastatic niche plays a key role in tumor metastasis, but not much is known about the heterogeneity and diverse role of neutrophils in niche formation. Our study focuses on the existence and biological function of a rarely delved subset of neutrophils, named as tumor-associated aged neutrophils (Naged, CXCR4+CD62Llow), involved in premetastatic niche formation during breast cancer metastasis. Methods We explored the distributions of Naged in 206 patients and mice models (4T1 and MMTV-PyMT) by flow cytometry. The ability of Naged to form neutrophil extracellular traps (NETs) and promote tumor metastasis in patients and mice was determined by polychromatic immunohistochemistry, scanning electron microscopy and real-time video detection. Furthermore, the differences among tumor-associated Naged, Non-Naged and inflammation-associated aged neutrophils were compared by transcriptome, the biological characteristics of Naged were comprehensively analyzed from the perspectives of morphology, the metabolic capacity and mitochondrial function were investigated by Seahorse, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP) and transmission electron microscopy (TEM). Finally, 120 patients’ sample were applied to confirm the acceleration of Naged formation through secreted NAMPT, and the importance of blocking this pathway in mice was evaluated. Results We find that Naged accumulate in the lung premetastatic niche at early stage of breast tumorigenesis in multiple mice models and also exist in peripheral blood and metastatic lung of patients with breast cancer. Naged exhibit distinct cell marker and morphological feature of oversegmented nuclei. Further transcriptome reveals that Naged are completely different from those of Non-Aged or inflammation-associated aged neutrophils and illustrates that the key transcription factor SIRT1 in Naged is the core to maintain their lifespan via mitophagy for their function. The responsible mechanism is that SIRT1 can induce the opening of mitochondrial permeability transition pore channels to release mitochondrial DNA and lead to the mitochondria-dependent vital NETs formation, rather than traditional Cit-Histone H3 dependent fatal-NETs. Further mechanically investigation found tumor derived NAMPT could induce Naged formation. Additionally, therapeutic interventions of Naged and its formation-linked pathways could effectively decrease breast cancer lung metastasis. Conclusions Naged exerts a vital role in breast cancer lung metastasis, and strategies targeting SIRT1-Naged-NETs axis show promise for translational application.
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Affiliation(s)
- Chenghui Yang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Zhen Wang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lili Li
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Zhigang Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Xiaoyan Jin
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Surgical Oncology, Zhejiang Taizhou Municipal Hospital, Taizhou, Zhejiang, People's Republic of China
| | - Pin Wu
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Thoracic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Shanshan Sun
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Jun Pan
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Ke Su
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Fang Jia
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Leyi Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Haijun Wang
- Department of Pathology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Xiuyan Yu
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Xuan Shao
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Ke Wang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Fuming Qiu
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Jun Yan
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
| | - Jian Huang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China .,Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
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Sirtuins as Metabolic Regulators of Immune Cells Phenotype and Function. Genes (Basel) 2021; 12:genes12111698. [PMID: 34828304 PMCID: PMC8618532 DOI: 10.3390/genes12111698] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 12/28/2022] Open
Abstract
Beyond its role on the conversion of nutrients into energy and biomass, cellular metabolism is actively involved in the control of many physiological processes. Among these, it is becoming increasingly evident that specific metabolic pathways are associated with the phenotype of several immune cell types and, importantly, are crucial in controlling their differentiation, proliferation, and effector functions, thus shaping the immune response against pathogens and tumors. In this context, data generated over the last decade have uncovered mammalian sirtuins as important regulators of cellular metabolism, immune cell function, and cancer. Here, we summarize our current knowledge on the roles of this family of protein deacylases on the metabolic control of immune cells and their implications on immune-related diseases and cancer.
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32
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Patrolling human SLE haematopoietic progenitors demonstrate enhanced extramedullary colonisation; implications for peripheral tissue injury. Sci Rep 2021; 11:15759. [PMID: 34344937 PMCID: PMC8333421 DOI: 10.1038/s41598-021-95224-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/06/2021] [Indexed: 12/28/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease where bone-marrow-derived haematopoietic cells have a key role in its pathogenesis with accumulating evidence suggesting an aberrant function of haematopoietic stem/progenitor cells (HSPCs). We examined whether patrolling HSPCs differ from bone-marrow HSPCs both in SLE and healthy individuals, and how they participate in peripheral tissue injury. By employing next-generation RNA sequencing, the transcriptomes of CD34+ HSPCs deriving from the bone marrow and those patrolling the bloodstream of both healthy and individuals with SLE were compared. Patrolling SLE and Healthy human HSPC kinetics were examined through their inoculation into humanised mice. Patrolling and bone-marrow HSPCs have distinct molecular signatures, while patrolling SLE HSPCs showed an enhanced extramedullary gene expression profile. Non-mobilised, SLE-derived circulating HSPCs demonstrated altered homing capacities. Xenotransplantation of circulating HSPCs in humanised mice showed that human peripheral blood HSPCs possess the ability for extramedullary organ colonisation to the kidneys. Circulating and bone marrow-derived HSPCs are distinct in steady and diseased states. Patrolling SLE CD34+ HSPCs are able to home at extramedullary sites such as the spleen and kidneys, potentially participating in peripheral tissue injury.
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33
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Bosch M, Sweet MJ, Parton RG, Pol A. Lipid droplets and the host-pathogen dynamic: FATal attraction? J Cell Biol 2021; 220:e202104005. [PMID: 34165498 PMCID: PMC8240858 DOI: 10.1083/jcb.202104005] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
In the ongoing conflict between eukaryotic cells and pathogens, lipid droplets (LDs) emerge as a choke point in the battle for nutrients. While many pathogens seek the lipids stored in LDs to fuel an expensive lifestyle, innate immunity rewires lipid metabolism and weaponizes LDs to defend cells and animals. Viruses, bacteria, and parasites directly and remotely manipulate LDs to obtain substrates for metabolic energy, replication compartments, assembly platforms, membrane blocks, and tools for host colonization and/or evasion such as anti-inflammatory mediators, lipoviroparticles, and even exosomes. Host LDs counterattack such advances by synthesizing bioactive lipids and toxic nucleotides, organizing immune signaling platforms, and recruiting a plethora of antimicrobial proteins to provide a front-line defense against the invader. Here, we review the current state of this conflict. We will discuss why, when, and how LDs efficiently coordinate and precisely execute a plethora of immune defenses. In the age of antimicrobial resistance and viral pandemics, understanding innate immune strategies developed by eukaryotic cells to fight and defeat dangerous microorganisms may inform future anti-infective strategies.
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Affiliation(s)
- Marta Bosch
- Lipid Trafficking and Disease Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
| | - Matthew J. Sweet
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia
| | - Robert G. Parton
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
- Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, Australia
| | - Albert Pol
- Lipid Trafficking and Disease Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
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34
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Sirtuin 1, Visfatin and IL-27 Serum Levels of Type 1 Diabetic Females in Relation to Cardiovascular Parameters and Autoimmune Thyroid Disease. Biomolecules 2021; 11:biom11081110. [PMID: 34439776 PMCID: PMC8391548 DOI: 10.3390/biom11081110] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/21/2021] [Accepted: 07/24/2021] [Indexed: 12/19/2022] Open
Abstract
The loss of cardioprotection observed in premenopausal, diabetic women may result from the interplay between epigenetic, metabolic, and immunological factors. The aim of this study was to evaluate the concentration of sirtuin 1, visfatin, and IL-27 in relation to cardiovascular parameters and Hashimoto’s disease (HD) in young, asymptomatic women with type 1 diabetes mellitus (T1DM). Thyroid ultrasound, carotid intima-media thickness (cIMT) measurement, electrocardiography, and echocardiography were performed in 50 euthyroid females with T1DM (28 with HD and 22 without concomitant diseases) and 30 controls. The concentrations of serum sirtuin 1, visfatin and IL-27 were assessed using ELISA. The T1DM and HD group had higher cIMT (p = 0.018) and lower left ventricular global longitudinal strain (p = 0.025) compared to females with T1DM exclusively. In women with a double diagnosis, the sirtuin 1 and IL-27 concentrations were non-significantly higher than in other groups and significantly positively correlated with each other (r = 0.445, p = 0.018) and thyroid volume (r = 0.511, p = 0.005; r = 0.482, p = 0.009, respectively) and negatively correlated with relative wall thickness (r = –0.451, p = 0.016; r = –0.387, p = 0.041, respectively). These relationships were not observed in the control group nor for the visfatin concentration. These results suggest that sirtuin 1 and IL-27 contribute to the pathogenesis of early cardiac dysfunction in women with T1DM and HD.
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35
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Xu R, Luo X, Ye X, Li H, Liu H, Du Q, Zhai Q. SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer. Front Oncol 2021; 11:682762. [PMID: 34381712 PMCID: PMC8351465 DOI: 10.3389/fonc.2021.682762] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/30/2021] [Indexed: 12/18/2022] Open
Abstract
Resistance is the major cause of treatment failure and disease progression in non-small cell lung cancer (NSCLC). There is evidence that hypoxia is a key microenvironmental stress associated with resistance to cisplatin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and immunotherapy in solid NSCLCs. Numerous studies have contributed to delineating the mechanisms underlying drug resistance in NSCLC; nevertheless, the mechanisms involved in the resistance associated with hypoxia-induced molecular metabolic adaptations in the microenvironment of NSCLC remain unclear. Studies have highlighted the importance of posttranslational regulation of molecular mediators in the control of mitochondrial function in response to hypoxia-induced metabolic adaptations. Hypoxia can upregulate the expression of sirtuin 1 (SIRT1) in a hypoxia-inducible factor (HIF)-dependent manner. SIRT1 is a stress-dependent metabolic sensor that can deacetylate some key transcriptional factors in both metabolism dependent and independent metabolic pathways such as HIF-1α, peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-gamma coactivator 1-alpha (PGC-1α) to affect mitochondrial function and biogenesis, which has a role in hypoxia-induced chemoresistance in NSCLC. Moreover, SIRT1 and HIF-1α can regulate both innate and adaptive immune responses through metabolism-dependent and -independent ways. The objective of this review is to delineate a possible SIRT1/PGC-1α/PPAR-γ signaling-related molecular metabolic mechanism underlying hypoxia-induced chemotherapy resistance in the NSCLC microenvironment. Targeting hypoxia-related metabolic adaptation may be an attractive therapeutic strategy for overcoming chemoresistance in NSCLC.
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Affiliation(s)
- Rui Xu
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Minhang Branch, Shanghai, China
| | - Xin Luo
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xuan Ye
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Huan Li
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hongyue Liu
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qiong Du
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Minhang Branch, Shanghai, China.,Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qing Zhai
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Minhang Branch, Shanghai, China.,Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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36
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Wang Y, Li N, Zhang X, Horng T. Mitochondrial metabolism regulates macrophage biology. J Biol Chem 2021; 297:100904. [PMID: 34157289 PMCID: PMC8294576 DOI: 10.1016/j.jbc.2021.100904] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 06/16/2021] [Accepted: 06/18/2021] [Indexed: 01/24/2023] Open
Abstract
Mitochondria are critical for regulation of the activation, differentiation, and survival of macrophages and other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes to mitochondrial metabolism and physiology could underlie the corresponding state of macrophage activation. These changes include alterations of oxidative metabolism, mitochondrial membrane potential, and tricarboxylic acid (TCA) cycling, as well as the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) and transformation of the mitochondrial ultrastructure. Here, we provide an updated review of how changes in mitochondrial metabolism and various metabolites such as fumarate, succinate, and itaconate coordinate to guide macrophage activation to distinct cellular states, thus clarifying the vital link between mitochondria metabolism and immunity. We also discuss how in disease settings, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response. Therefore, mitochondria are a vital source of dynamic signals that regulate macrophage biology to fine-tune immune responses.
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Affiliation(s)
- Yafang Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
| | - Na Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Xin Zhang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Tiffany Horng
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
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37
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Qiu Y, Zhou X, Liu Y, Tan S, Li Y. The Role of Sirtuin-1 in Immune Response and Systemic Lupus Erythematosus. Front Immunol 2021; 12:632383. [PMID: 33981300 PMCID: PMC8110204 DOI: 10.3389/fimmu.2021.632383] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 02/19/2021] [Indexed: 12/13/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a potentially fatal multisystem inflammatory chronic disorder, the etiology and pathogenesis of which remain unclear. The loss of immune tolerance in SLE patients contributes to the production of autoantibodies that attack multiple organs and tissues, such as the skin, joints, and kidneys. Immune cells play important roles in the occurrence and progression of SLE through amplified immune responses. Sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase, has been shown to be a pivotal regulator in various physiological processes, including cell differentiation, apoptosis, metabolism, aging, and immune responses, via modulation of different signaling pathways, such as the nuclear factor κ-light-chain-enhancer of activated B cells and activator protein 1 pathways. Recent studies have provided evidence that SIRT1 could be a regulatory element in the immune system, whose altered functions are likely relevant to SLE development. This review aims to illustrate the functions of SIRT1 in different types of immune cells and the potential roles of SIRT1 in the SLE pathogenesis and its therapeutic perspectives.
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Affiliation(s)
- Yueqi Qiu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Xingyu Zhou
- Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Yu Liu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Siqi Tan
- Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Yaping Li
- Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China
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38
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Brahmbhatt HD, Gupta R, Gupta A, Rastogi S, Misri R, Mobeen A, Ghosh A, Kothari P, Sitaniya S, Scaria V, Singh A. The long noncoding RNA MALAT1 suppresses miR-211 to confer protection from ultraviolet-mediated DNA damage in vitiligo epidermis by upregulating sirtuin 1. Br J Dermatol 2020; 184:1132-1142. [PMID: 33152110 DOI: 10.1111/bjd.19666] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND The absence of melanocytes poses a challenge for long-term tissue homeostasis in vitiligo. Surprisingly, while individuals with Fitzpatrick phototypes I-II (low melanin content) have a higher incidence of melanoma and nonmelanoma skin cancer, people with vitiligo are at a decreased risk for the same. OBJECTIVES To understand the molecular mechanisms that protect vitiligo skin from ultraviolet (UV)-induced DNA damage by (i) characterizing differentially expressed microRNAs in lesional vs. nonlesional epidermis and (ii) identifying their upstream regulators and downstream gene targets. METHODS Genome-wide microRNA profiling of nonlesional and lesional epidermis was performed on five individuals with stable nonsegmental vitiligo using next-generation RNA sequencing. The relevance of the upstream regulator and downstream target gene of the most differentially expressed microRNA was studied. RESULTS Our study found sirtuin1 (SIRT1), an NAD-dependent deacetylase, to be a direct target of miR-211 - the most significantly downregulated microRNA in lesional epidermis. Inhibition of SIRT1 with EX-527 downregulated keratin 10 and involucrin, suggesting that SIRT1 promotes keratinocyte differentiation. Overexpression of miR-211 mimic led to a significant increase in γ-H2AX positivity and cyclobutane pyrimidine dimer (CPD) formation, hallmarks of UVB-mediated DNA damage. These effects could be ameliorated by the addition of resveratrol, a SIRT1 activator. Furthermore, a long noncoding RNA, MALAT1, was identified as a negative upstream regulator of miR-211. Overexpression of MALAT1 resulted in increased expression of SIRT1 and a concomitant removal of UVB-induced CPDs in primary keratinocytes. CONCLUSIONS These findings establish a novel MALAT1-miR-211-SIRT1 signalling axis that potentially confers protection to the 'amelanotic' keratinocytes in vitiligo.
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Affiliation(s)
- H D Brahmbhatt
- CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - R Gupta
- CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - A Gupta
- D.Y. Patil Medical College, Dr D.Y. Patil University, Pimpri, Pune, Maharashtra, 411018, India
| | - S Rastogi
- CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India
| | - R Misri
- Hindu Rao Hospital, New Delhi, India
| | - A Mobeen
- CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - A Ghosh
- CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - P Kothari
- D.Y. Patil Medical College, Dr D.Y. Patil University, Pimpri, Pune, Maharashtra, 411018, India
| | - S Sitaniya
- D.Y. Patil Medical College, Dr D.Y. Patil University, Pimpri, Pune, Maharashtra, 411018, India
| | - V Scaria
- CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - A Singh
- CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
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39
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Rasha F, Mims BM, Castro-Piedras I, Barnes BJ, Grisham MB, Rahman RL, Pruitt K. The Versatility of Sirtuin-1 in Endocrinology and Immunology. Front Cell Dev Biol 2020; 8:589016. [PMID: 33330467 PMCID: PMC7717970 DOI: 10.3389/fcell.2020.589016] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022] Open
Abstract
Sirtuins belong to the class III family of NAD-dependent histone deacetylases (HDAC) and are involved in diverse physiological processes that range from regulation of metabolism and endocrine function to coordination of immunity and cellular responses to stress. Sirtuin-1 (SIRT1) is the most well-studied family member and has been shown to be critically involved in epigenetics, immunology, and endocrinology. The versatile roles of SIRT1 include regulation of energy sensing metabolic homeostasis, deacetylation of histone and non-histone proteins in numerous tissues, neuro-endocrine regulation via stimulation of hypothalamus-pituitary axes, synthesis and maintenance of reproductive hormones via steroidogenesis, maintenance of innate and adaptive immune system via regulation of T- and B-cell maturation, chronic inflammation and autoimmune diseases. Moreover, SIRT1 is an appealing target in various disease contexts due to the promise of pharmacological and/or natural modulators of SIRT1 activity within the context of endocrine and immune-related disease models. In this review we aim to provide a broad overview on the role of SIRT1 particularly within the context of endocrinology and immunology.
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Affiliation(s)
- Fahmida Rasha
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Brianyell McDaniel Mims
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Isabel Castro-Piedras
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Betsy J. Barnes
- Laboratory of Autoimmune and Cancer Research, Center for Autoimmune Musculoskeletal and Hematopoietic Disease, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Department of Molecular Medicine and Department of Pediatrics, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, United States
| | - Matthew B. Grisham
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | | | - Kevin Pruitt
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
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40
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Friend or Foe: Lipid Droplets as Organelles for Protein and Lipid Storage in Cellular Stress Response, Aging and Disease. Molecules 2020; 25:molecules25215053. [PMID: 33143278 PMCID: PMC7663626 DOI: 10.3390/molecules25215053] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/20/2020] [Accepted: 10/22/2020] [Indexed: 02/06/2023] Open
Abstract
Lipid droplets (LDs) were considered as a mere lipid storage organelle for a long time. Recent evidence suggests that LDs are in fact distinct and dynamic organelles with a specialized proteome and functions in many cellular roles. As such, LDs contribute to cellular signaling, protein and lipid homeostasis, metabolic diseases and inflammation. In line with the multitude of functions, LDs interact with many cellular organelles including mitochondria, peroxisomes, lysosomes, the endoplasmic reticulum and the nucleus. LDs are highly mobile and dynamic organelles and impaired motility disrupts the interaction with other organelles. The reduction of interorganelle contacts results in a multitude of pathophysiologies and frequently in neurodegenerative diseases. Contacts not only supply lipids for β-oxidation in mitochondria and peroxisomes, but also may include the transfer of toxic lipids as well as misfolded and harmful proteins to LDs. Furthermore, LDs assist in the removal of protein aggregates when severe proteotoxic stress overwhelms the proteasomal system. During imbalance of cellular lipid homeostasis, LDs also support cellular detoxification. Fine-tuning of LD function is of crucial importance and many diseases are associated with dysfunctional LDs. We summarize the current understanding of LDs and their interactions with organelles, providing a storage site for harmful proteins and lipids during cellular stress, aging inflammation and various disease states.
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41
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Khatun MR, Arifuzzaman S. RETRACTED ARTICLE: Selected TLR7/8 agonist and type I interferon (IFN-α) cooperatively redefine the microglia transcriptome. Inflammopharmacology 2020; 31:547. [PMID: 31190206 PMCID: PMC7087773 DOI: 10.1007/s10787-019-00610-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 06/04/2019] [Indexed: 12/12/2022]
Abstract
Background Microglia, the primary immune cells of the central nervous system, exerts multiple functions to mediate many neurological diseases. Upon any detection of invading pathogen products (e.g., TLR agonists) or host-released signaling factors (e.g., interferon/IFN), these cells undergo an activation process to release large numbers of inflammatory substances that participate in inflammation and homeostasis. The profound effects of inflammation associated with TLR7/8 agonist Resiquimod (R848) and type 1 interferon (e.g., IFN-α)-induced macrophage and dendritic cell activation on biological outcomes have long been recognized. However, the underlying mechanisms are not well defined in microglial cells. Methods The present study investigated the molecular signatures of microglia and identified genes that are uniquely or synergistically expressed in R848-, IFN-α- or R848 with IFN-α-treated primary microglial (PM) cells. We used RNA-sequencing, quantitative real-time PCR, and bioinformatics approaches to derive regulatory networks that control the transcriptional response of PM to R848, IFN-α and R848 with IFN-α. Results Our approach revealed that the inflammatory response in R848 with IFN-α-treated PM is faster and more intense than that in R848 or IFN-α-treated PM in terms of the number of differentially expressed genes and the magnitude of induction/repression. In particular, our integrative analysis enabled us to suggest the regulatory functions of TFs, which allowed the construction of a network model that explains how TLR7/8 and IFN-α-sensing pathways achieve specificity. Conclusion In conclusion, the systematic approach presented herein could be important to the understanding microglial activation-mediated molecular signatures induced by inflammatory stimuli related to TLR7/8, IFN-α or co-signaling, and associated transcriptional machinery of microglial functions and neuroinflammatory mechanisms. Electronic supplementary material The online version of this article (10.1007/s10787-019-00610-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mst Reshma Khatun
- Department of Biomedical Science, Ajou University, Suwon, Gyeonggi-do 16499 Republic of Korea
| | - Sarder Arifuzzaman
- Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-do 17546 Republic of Korea
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Sun H, Cai H, Fu Y, Wang Q, Ji K, Du L, Xu C, Tian L, He N, Wang J, Zhang M, Liu Y, Wang Y, Li J, Liu Q. The Protection Effect of Resveratrol Against Radiation-Induced Inflammatory Bowel Disease via NLRP-3 Inflammasome Repression in Mice. Dose Response 2020; 18:1559325820931292. [PMID: 32636719 PMCID: PMC7323307 DOI: 10.1177/1559325820931292] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
With the extensive application of radiotherapy in various cancers, its side effects in tissues adjacent to cancers are garnering much attention. Intestines are sensitive to irradiation due to its rapid proliferation, and irradiation-induced enteric inflammation is common in patients with pelvic peritoneal tumors. Sirt1, class III protein deacetylase, could lead to transcriptional repression of various inflammation-associated genes, and our previous study has proved its relationship with interleukin (IL)-1β. Here we show that resveratrol, the activator of Sirt1, could alleviate the bowel inflammation induced by irradiation and the expression of Sirt1 is consistent with the inflammation level. We further identified in vivo that Sirt1 repress the expression of IL-1β by the repression of NLR Family, Pyrin Domain Containing protein 3 (NLRP3) expression. In conclusion, this study confirms resveratrol acts against radiation-induced inflammatory bowel disease via NLRP-3 inflammasome repression in mice and supports Sirt1 as a potential biomarker and therapy target in intestinal radiation protection.
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Affiliation(s)
- Hao Sun
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Hui Cai
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Yue Fu
- National Accreditation Service for Conformity Assessment, China
| | - Qin Wang
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Kaihua Ji
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Liqing Du
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Chang Xu
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Lifang Tian
- The People's Hospital of Renqiu City Hebei Province, China
| | - Ningning He
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Jinhan Wang
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Manman Zhang
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Yang Liu
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Yan Wang
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Jia Li
- Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Qiang Liu
- Laboratory of Radiation Medicine and radiation injury effects, Tianjin Institute of Radiology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
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Ali D, Chen L, Kowal JM, Okla M, Manikandan M, AlShehri M, AlMana Y, AlObaidan R, AlOtaibi N, Hamam R, Alajez NM, Aldahmash A, Kassem M, Alfayez M. Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells. Bone 2020; 133:115252. [PMID: 31978617 DOI: 10.1016/j.bone.2020.115252] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/13/2020] [Accepted: 01/20/2020] [Indexed: 12/16/2022]
Abstract
Bone marrow adipose tissue (BMAT) is a unique adipose depot originating from bone marrow stromal stem cells (BMSCs) and regulates bone homeostasis and energy metabolism. An increased BMAT volume is observed in several conditions e.g. obesity, type 2 diabetes, osteoporosis and is known to be associated with bone fragility and increased risk for fracture. Therapeutic approaches to decrease the accumulation of BMAT are clinically relevant. In a screening experiment of natural compounds, we identified Resveratrol (RSV), a plant-derived antioxidant mediating biological effects via sirtuin- related mechanisms, to exert significant effects of BMAT formation. Thus, we examined in details the effects RSV on adipocytic and osteoblastic differentiation of tolermerized human BMSCs (hBMSC-TERT). RSV (1.0 μM) enhanced osteoblastic differentiation and inhibited adipocytic differentiation of hBMSC-TERT when compared with control and Sirtinol (Sirtuin inhibitor). Global gene expression profiling and western blot analysis revealed activation of a number of signaling pathways including focal adhesion kinase (FAK). Pharmacological inhibition of FAK using (PF-573228) and AKT inhibitor (LY-294002) (5μM), diminished RSV-induced osteoblast differentiation. In addition, RSV reduced the levels of senescence-associated secretory phenotype (SASP), gene markers associated with senescence (P53, P16, and P21), intracellular ROS levels and increased gene expression of enzymes protecting cells from oxidative damage (HMOX1 and SOD3). In vitro treatment of primary hBMSCs from aged patients characterized with high adipocytic and low osteoblastic differentiation ability with RSV, significantly enhanced osteoblast and decreased adipocyte formation when compared to hBMSCs from young donors. RSV targets hBMSCs and inhibits adipogenic differentiation and senescence-associated phenotype and thus a potential agent for treating conditions of increased BMAT formation.
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Affiliation(s)
- Dalia Ali
- Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology & Metabolism, University Hospital of Odense and University of Southern Denmark, Odense, Denmark.
| | - Li Chen
- Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology & Metabolism, University Hospital of Odense and University of Southern Denmark, Odense, Denmark.
| | - Justyna M Kowal
- Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology & Metabolism, University Hospital of Odense and University of Southern Denmark, Odense, Denmark.
| | - Meshail Okla
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
| | - Muthurangan Manikandan
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Moayad AlShehri
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Yousef AlMana
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Reham AlObaidan
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Najd AlOtaibi
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Rimi Hamam
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Nehad M Alajez
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Abdullah Aldahmash
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Prince Naif Health Research Center, King Saud University, Riyadh, Saudi Arabia.
| | - Moustapha Kassem
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology & Metabolism, University Hospital of Odense and University of Southern Denmark, Odense, Denmark; Department of Cellular and Molecular Medicine, Danish Stem Cell Center (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark.
| | - Musaad Alfayez
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
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Jarc E, Petan T. A twist of FATe: Lipid droplets and inflammatory lipid mediators. Biochimie 2020; 169:69-87. [DOI: 10.1016/j.biochi.2019.11.016] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 11/25/2019] [Indexed: 12/14/2022]
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Ye F, Jiang J, Zong C, Yang X, Gao L, Meng Y, Li R, Zhao Q, Han Z, Wei L. Sirt1-Overexpressing Mesenchymal Stem Cells Drive the Anti-tumor Effect through Their Pro-inflammatory Capacity. Mol Ther 2020; 28:874-888. [PMID: 32027844 DOI: 10.1016/j.ymthe.2020.01.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 01/06/2020] [Accepted: 01/06/2020] [Indexed: 12/11/2022] Open
Abstract
The major obstacles for the efficacy of tumor immunotherapies are their immune-related systemic adverse events. Therefore, tumor tropism property and pro-inflammatory ability of mesenchymal stem cells (MSCs) could be utilized in combination to potentiate local immunity for cancer eradication. We previously observed that MSCs with the type III histone deacetylase silent information regulator 2 homologue 1 (Sirt1) overexpression displayed a pro-inflammatory capacity. However, the anti-tumor effect of Sirt1-overexpressing MSCs and the role of Sirt1 in regulating the pro-inflammatory capacity of MSCs still need to be clarified. In this study, utilizing the hepatic metastasis model of colorectal carcinoma, we demonstrated that Sirt1-overexpressing MSCs significantly exerted anti-tumor activity through increasing the number of CD8+ T cells. Furthermore, Sirt1 did not affect chemokine secretion in MSCs induced by inflammatory cytokines, but impaired the immunosuppressive ability of MSCs through suppressing inflammatory cytokine-stimulated inducible nitric oxide synthase (iNOS) production via deacetylating p65. iNOS overexpression negated the anti-tumor effect of Sirt1-overexpressing MSCs. Collectively, our data defined Sirt1 as the critical regulator for modulating the pro-inflammatory ability of MSCs, and they suggested that Sirt1-overexpressing MSCs secreting chemokines but little iNOS under the inflammatory milieu were capable of attracting immune cells to close proximity without suppressing their proliferation, thereby achieving a potent anti-tumor effect.
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Affiliation(s)
- Fei Ye
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Lu Gao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
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Yang YCS, Li ZL, Shih YJ, Bennett JA, Whang-Peng J, Lin HY, Davis PJ, Wang K. Herbal Medicines Attenuate PD-L1 Expression to Induce Anti-Proliferation in Obesity-Related Cancers. Nutrients 2019; 11:nu11122979. [PMID: 31817534 PMCID: PMC6949899 DOI: 10.3390/nu11122979] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/27/2019] [Accepted: 12/02/2019] [Indexed: 12/12/2022] Open
Abstract
Pro-inflammatory hormones and cytokines (leptin, tumor necrosis factor (TNF)-α, and interleukin (IL)-6) rise in obesity. Elevated levels of hormones and cytokines are linked with several comorbidities such as diabetes, heart disease, and cancer. The checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) plays an important role in obesity and cancer proliferation. L-thyroxine (T4) and steroid hormones up-regulate PD-L1 accumulation and promote inflammation in cancer cells and diabetics. On the other hand, resveratrol and other herbal medicines suppress PD-L1 accumulation and reduce diabetic effects. In addition, they induce anti-cancer proliferation in various types of cancer cells via different mechanisms. In the current review, we discuss new findings and visions into the antagonizing effects of hormones on herbal medicine-induced anti-cancer properties.
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Affiliation(s)
- Yu-Chen S.H. Yang
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 11031, Taiwan;
| | - Zi-Lin Li
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.L.); (Y.-J.S.); (J.W.-P.); (K.W.)
- Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
| | - Ya-Jung Shih
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.L.); (Y.-J.S.); (J.W.-P.); (K.W.)
- Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
| | - James A. Bennett
- Center for Immunology and Microbial Diseases, Albany Medical College, Albany, NY 12208, USA;
| | - Jaqueline Whang-Peng
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.L.); (Y.-J.S.); (J.W.-P.); (K.W.)
- Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
- Cancer Center, Wang-Fan Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Hung-Yun Lin
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.L.); (Y.-J.S.); (J.W.-P.); (K.W.)
- Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
- Cancer Center, Wang-Fan Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence:
| | - Paul J. Davis
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12208, USA;
- Department of Medicine, Albany Medical College, Albany, NY 12208, USA
| | - Kuan Wang
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.L.); (Y.-J.S.); (J.W.-P.); (K.W.)
- Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
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Abstract
Regulatory T cells (Tregs) are important for limiting inflammation-dependent damage in neural tissue. However, Tregs have also been shown to inhibit neural repair associated with type 2 (anti-inflammatory/wound healing) immune responses. Recently, it was demonstrated that Sirtuins, a family of proteins that contribute to the control of cellular responses to metabolic stimuli, influence the functions of Tregs. Specifically, SIRT4 was found to suppress the anti-neuroinflammatory activity of Tregs infiltrating the spinal cord following injury; when SIRT4 expression was genetically suppressed, Tregs made more anti-inflammatory factors, IL-10, FoxP3, and transforming growth factor beta (TGFβ). Thus, understanding how the SIRT4-Treg pathway can be manipulated could provide useful avenues to control both pathogenic and neuroprotective immune responses.
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Affiliation(s)
- Simon Milling
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Julia M Edgar
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
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Karrunanithi S, Ravichandran KA, Hima L, Pratap UP, Vasantharekha R, ThyagaRajan S. Virgin coconut oil enhances neuroprotective and anti‐inflammatory factors in the thymus and mesenteric lymph nodes of rats. ACTA ACUST UNITED AC 2019. [DOI: 10.1111/cen3.12540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Sunil Karrunanithi
- Integrative Medicine Laboratory Department of Biotechnology School of Bioengineering SRM Institute of Science and Technology Kattankulathur India
| | - Kishore A. Ravichandran
- Integrative Medicine Laboratory Department of Biotechnology School of Bioengineering SRM Institute of Science and Technology Kattankulathur India
| | - Lalgi Hima
- Integrative Medicine Laboratory Department of Biotechnology School of Bioengineering SRM Institute of Science and Technology Kattankulathur India
| | - Uday P. Pratap
- Integrative Medicine Laboratory Department of Biotechnology School of Bioengineering SRM Institute of Science and Technology Kattankulathur India
| | - Ramasamy Vasantharekha
- Integrative Medicine Laboratory Department of Biotechnology School of Bioengineering SRM Institute of Science and Technology Kattankulathur India
| | - Srinivasan ThyagaRajan
- Integrative Medicine Laboratory Department of Biotechnology School of Bioengineering SRM Institute of Science and Technology Kattankulathur India
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Audrito V, Managò A, Gaudino F, Sorci L, Messana VG, Raffaelli N, Deaglio S. NAD-Biosynthetic and Consuming Enzymes as Central Players of Metabolic Regulation of Innate and Adaptive Immune Responses in Cancer. Front Immunol 2019; 10:1720. [PMID: 31402913 PMCID: PMC6671870 DOI: 10.3389/fimmu.2019.01720] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 07/09/2019] [Indexed: 12/15/2022] Open
Abstract
Cancer cells, particularly in solid tumors, are surrounded by non-neoplastic elements, including endothelial and stromal cells, as well as cells of immune origin, which can support tumor growth by providing the right conditions. On the other hand, local hypoxia, and lack of nutrients induce tumor cells to reprogram their metabolism in order to survive, proliferate, and disseminate: the same conditions are also responsible for building a tumor-suppressive microenvironment. In addition to tumor cells, it is now well-recognized that metabolic rewiring occurs in all cellular components of the tumor microenvironment, affecting epigenetic regulation of gene expression and influencing differentiation/proliferation decisions of these cells. Nicotinamide adenine dinucleotide (NAD) is an essential co-factor for energy transduction in metabolic processes. It is also a key component of signaling pathways, through the regulation of NAD-consuming enzymes, including sirtuins and PARPs, which can affect DNA plasticity and accessibility. In addition, both NAD-biosynthetic and NAD-consuming enzymes can be present in the extracellular environment, adding a new layer of complexity to the system. In this review we will discuss the role of the “NADome” in the metabolic cross-talk between cancer and infiltrating immune cells, contributing to cancer growth and immune evasion, with an eye to therapeutic implications.
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Affiliation(s)
- Valentina Audrito
- Department of Medical Sciences, University of Turin, Turin, Italy.,Italian Institute for Genomic Medicine, Turin, Italy
| | - Antonella Managò
- Department of Medical Sciences, University of Turin, Turin, Italy.,Italian Institute for Genomic Medicine, Turin, Italy
| | - Federica Gaudino
- Department of Medical Sciences, University of Turin, Turin, Italy.,Italian Institute for Genomic Medicine, Turin, Italy
| | - Leonardo Sorci
- Division of Bioinformatics and Biochemistry, Department of Materials, Environmental Sciences and Urban Planning, Polytechnic University of Marche, Ancona, Italy
| | - Vincenzo Gianluca Messana
- Department of Medical Sciences, University of Turin, Turin, Italy.,Italian Institute for Genomic Medicine, Turin, Italy
| | - Nadia Raffaelli
- Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Silvia Deaglio
- Department of Medical Sciences, University of Turin, Turin, Italy.,Italian Institute for Genomic Medicine, Turin, Italy
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Melatonin Modulates the Microenvironment of Glioblastoma Multiforme by Targeting Sirtuin 1. Nutrients 2019; 11:nu11061343. [PMID: 31207928 PMCID: PMC6627125 DOI: 10.3390/nu11061343] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 06/06/2019] [Accepted: 06/10/2019] [Indexed: 01/21/2023] Open
Abstract
Natural products have historically been regarded as an important resource of therapeutic agents. Resveratrol and melatonin have been shown to increase SIRT1 activity and stimulate deacetylation. Glioblastoma multiforme (GBM) is the deadliest of malignant types of tumor in the central nervous system (CNS) and their biological features make treatment difficult. In the glioma microenvironment, infiltrating immune cells has been shown to possess beneficial effects for tumor progression. We analyzed SIRT1, CCL2, VCAM-1 and ICAM-1 in human glioma cell lines by immunoblotting. The correlation between those markers and clinico-pathological grade of glioma patients were assessed by the Gene Expression Omnibus (GEO) datasets analysis. We also used monocyte-binding assay to study the effects of melatonin on monocyte adhesion to GBM. Importantly, overexpression of SIRT1 by genetic modification or treatment of melatonin significantly downregulated the adhesion molecular VCAM-1 and ICAM-1 expression in GBM. CCL2-mediated monocyte adhesion and expression of VCAM-1 and ICAM-1 were regulated through SIRT1 signaling. SIRT1 is an important modulator of monocytes interaction with GBM that gives the possibility of improved therapies for GBM. Hence, this study provides a novel treatment strategy for the understanding of microenvironment changes in tumor progression.
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