Abstract:
BACKGROUND:Seven isoforms of histone deacetylase Class III have been reported - Sirtuin (SIRT) 1-7. We recently demonstrated that EX-527, an inhibitor of SIRT1, reduces mortality in a mouse model of lethal-cecal-ligationand- puncture (CLP)-induced septic shock. Our present study was aimed at determining whether selective inhibition of SIRT2, with AGK2, would decrease animal death and attenuate the inflammatory response in a septic model. METHODS:Experiment I: C57BL/6J mice were intraperitoneally given either AGK2 (82 mg/kg) in dimethyl sulfoxide (DMSO) or DMSO alone, and 2 h later subjected to CLP. Survival was monitored for 240 hours. Experiment II: mice treated the same way as Experiment I, were grouped into (i) DMSO vehicle, and (ii) AGK2, with sham mice (operating but without any treatment) serving as controls. Peritoneal fluid and peripheral blood were examined at 24 and 48 hours for cytokine production. Samples of blood at 48 h were also allocated to assess coagulability using Thrombelastography (TEG). Morphological changes of bone marrow were evaluated from long bones (femurs and tibias) with hematoxylin and eosin (H&E) staining. Bone marrow atrophy was quantified by a blinded pathologist. Experiment III: cytokines in supernatant of the cultured normal primary splenocytes were measured after the cells were stimulated by lipopolysaccharide and treated with or without AGK2 (10 µM) for 6 hours. RESULTS:AGK2 significantly reduced mortality and decreased levels of cytokines in blood (TNF-α: 298.3±24.6 vs 26.8±2.8 pg/ml, p=0.0034; IL-6: 633.4±82.8 vs 232.6±133.0 pg/ml, p=0.0344) and peritoneal fluid (IL-6: 704.8±67.7 vs 391.4±98.5 pg/ml, p=0.033) compared to vehicle control. Also, AGK2 suppressed the TNF-α and IL-6 production in the cultured splenocytes (TNF-α: 68.1±6.4 vs 23.9±2.8 pg/ml, p=0.0009; IL-6: 73.1±4.2 vs 49.6±3.0 pg/ml; p=0.0051). The TEG data showed that the mice subjected to CLP displayed prolonged fibrin formation and fibrin cross-linkage time, slower clot formation, decreased platelet function, and clot rigidity. AGK2 treatment was associated with dramatic improvements in fibrin cross-linkage and clot formation times, without a significant impact on the clot initiation parameters or platelet function. Additionally, AGK2 significantly attenuated the bone marrow atrophy (58.3±6.5 vs 30.0±8.2%, p=0.0262). CONCLUSION:Selective inhibition of SIRT2 significantly improves survival, and attenuates sepsis-associated "cytokine storm", coagulopathy, and bone marrow atrophy in a mouse model of lethal septic shock.
journal_name
Curr Mol Medjournal_title
Current molecular medicineauthors
Zhao T,Alam HB,Liu B,Bronson RT,Nikolian VC,Wu E,Chong W,Li Ydoi
10.2174/156652401507150903185852subject
Has Abstractpub_date
2015-01-01 00:00:00pages
634-41issue
7eissn
1566-5240issn
1875-5666pii
CMM-EPUB-69794journal_volume
15pub_type
杂志文章abstract::Glycogen is a branched polymer of glucose which serves as a reservoir of glucose units. The two largest deposits in mammals are in the liver and skeletal muscle but many cells are capable synthesizing glycogen. Its accumulation and utilization are under elaborate controls involving primarily covalent phosphorylation a...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/1566524024605761
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journal_title:Current molecular medicine
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abstract:PURPOSE:Protein sumoylation is a well established regulatory mechanism to control many cellular processes such as chromatin structure dynamics, transcriptional regulation of gene expression, cell proliferation and differentiation, cell transformation and carcinogenesis, autophagy and senescence. In the vertebrate visio...
journal_title:Current molecular medicine
pub_type: 杂志文章
doi:10.2174/1566524019666190112143636
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abstract::Type 2 Diabetes occurs as a result of defects in insulin secretion and its function. Although mechanisms of disease are not fully elucidated, it is recognized that a progressive decline in insulin secretory capacity is responsible for its occurrence and natural course. Metabolic syndrome, known to be a precursor of Ty...
journal_title:Current molecular medicine
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doi:10.2174/156652409787847245
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abstract::p53 tumor suppressor plays a pivotal role in maintaining genomic integrity and preventing cancer development. The importance of p53 in tumor suppression is illustrated by the observation that about 50% human tumor cells have a dysfunctional p53 pathway. Although it has been well accepted that the activity of p53 is ma...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652408786733748
更新日期:2008-12-01 00:00:00
abstract::Multiple myeloma (MM) is characterized by the clonal proliferation of malignant plasma B-lymphocytes and even as of today, it is an incurable disease. MM accounts for approximately 10% of all hematologic cancers. Its molecular pathogenesis is poorly understood, but the bone marrow microenvironment of tumor cells and g...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
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abstract::Evidence shows that artificially lowering body and brain temperature can significantly reduce the deleterious effects of brain injury in both newborns and adults. Although the benefits of therapeutic hypothermia have long been known and applied clinically, the underlying molecular mechanisms have yet to be elucidated....
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652412803833517
更新日期:2012-12-01 00:00:00
abstract::Recently, the combining of different drugs has greatly improved response and survival rates in gynecological malignancies. Results are however far from being satisfactory. Treatments used in case of advanced or recurrent disease offer limited results in terms of long-term responses. The urgent need for new and more ef...
journal_title:Current molecular medicine
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doi:10.2174/1566524011313040014
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abstract::Maintenance of ex vivo hematopoietic stem cells (HSC) pool and its differentiated progeny is regulated by complex network of transcriptional factors, cell cycle proteins, extracellular matrix, and their microenvironment through an orchestrated fashion. Strides have been made to understand the mechanisms regulating in ...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652412798376125
更新日期:2012-01-01 00:00:00
abstract::Abstract: The study of genetic alterations in tumors and their precursor lesions is often hampered by the presence of a heterogeneous background of non-neoplastic elements such as stromal cells, inflammatory cells, and angiogenic elements. Microdissection involves the extraction of specific populations of cells under ...
journal_title:Current molecular medicine
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doi:10.2174/1566524013364121
更新日期:2001-03-01 00:00:00
abstract::Plaque disruption and subsequent thrombus formation play a critical role in the clinical manifestations of atherothrombosis. Vulnerable lesions are characterized by the existence of core rich in lipid, macrophages and tissue factor (TF). Plaque disruption facilitates the interaction between flowing blood with the inne...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
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更新日期:2006-08-01 00:00:00
abstract::The testes are one of the most delicate organs in the male body and highly susceptible to the exogenous influences capable of inducing cell damage. Cancer therapies are well known to negatively affect the male reproductive tract with a severe impairment of spermatogenesis and infertility. The present work aimed to sys...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/1566524016666160802150400
更新日期:2016-01-01 00:00:00
abstract::Sickle cell disease (SCD) and beta-thalassemia (also referred to as beta-thalassemia) are common hereditary hemoglobinopathies with differing pathophysiologies and clinical courses. However, patients with both diseases exhibit increased platelet and coagulation activation, as well as decreased levels of natural antico...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652408786241366
更新日期:2008-11-01 00:00:00
abstract:BACKGROUND & OBJECTIVE:Interleukin 37 (IL-37) is an important regulator of the anti-inflammatory T-cell response. In this study, we investigated its expression and function in peripheral blood mononuclear cells (PBMCs) of patients with HLA-B27 associated acute anterior uveitis (AAU) and idiopathic AAU. METHODS:15 pati...
journal_title:Current molecular medicine
pub_type: 杂志文章
doi:10.2174/1566524018666180207152941
更新日期:2018-03-09 00:00:00
abstract:BACKGROUND:Overexpression of MDA-9/Syntenin occurs in multiple human cancer cell lines and is associated with higher grade of tumor classification, invasiveness and metastasis. In some cases, its role in cancer biology depends on relationships between MDA-9/Syntenin and NF-κB. OBJECTIVE:This study aims to analyze the ...
journal_title:Current molecular medicine
pub_type: 杂志文章
doi:10.2174/1566524019666190104105043
更新日期:2018-01-01 00:00:00
abstract::The acquisition of cellular immortality is a critical step in human tumorigenesis. While the vast majority of human tumors activate the catalytic component of telomerase (hTERT) to stabilize their telomeres and attain immortality, a significant portion (7-10%) utilize a poorly defined alternative form of telomere main...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/1566524053586653
更新日期:2005-03-01 00:00:00
abstract:BACKGROUND:Interleukins IL1ß/IL18 and Inflammasome NLRP1/NLRP3 polymorphisms can change the course of multiple human diseases, both inflammatory as infectious. SNPs these proteins were associated with the constructive activation of the Inflammasome and excessive production of IL-1β induce a serious autoinflammatory dis...
journal_title:Current molecular medicine
pub_type: 杂志文章
doi:10.2174/1566524019666190826143749
更新日期:2019-01-01 00:00:00
abstract::Focal cerebral ischemia induces neurogenesis in the subventricular zone (SVZ) of the adult human brain. Neurogenesis is controlled by proliferation, differentiation, and migration of neural progenitor cells. This article reviews emerging data that changes of cell cycle kinetics of neural progenitor cells induced by st...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652407781387136
更新日期:2007-08-01 00:00:00
abstract::Islet cell transplantation is an attractive alternative therapy to conventional insulin treatment or vascularized whole pancreas transplantation for type 1 diabetic patients. It represents a successful example of somatic cell therapy in humans based on complex procedures for islet isolation from whole pancreas. The is...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652406777435453
更新日期:2006-06-01 00:00:00
abstract::Charcot-Marie-Tooth disease (CMT) and related neuropathies are a genetically highly heterogeneous group of neurodegenerative disorders. CMT affects both the sensory and motor nerves, distal Hereditary Motor Neuropathies (dHMN) are phenotypically similar disorders involving only motor nerves, while Hereditary Sensory a...
journal_title:Current molecular medicine
pub_type: 杂志文章
doi:10.2174/1566524014666141010154205
更新日期:2014-01-01 00:00:00
abstract::Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen, which is the cause of a tick-borne illness occurring in many areas of Africa, Asia, and Europe. CCHF is characterized by a sudden onset of high fever, chills, and severe headache. Other symptoms can include gastrointestinal disorders, such a...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652405774962335
更新日期:2005-12-01 00:00:00
abstract:BACKGROUND:Four-and-a-half LIM domains protein 1 (FHL1) mutations are associated with human myopathies. However, the function of this protein in skeletal development remains unclear. METHODS:Whole-mount in situ hybridization and embryo immunostaining were performed. RESULTS:Zebrafish Fhl1A is the homologue of human F...
journal_title:Current molecular medicine
pub_type: 杂志文章
doi:10.2174/1566524018666180308113909
更新日期:2017-01-01 00:00:00
abstract::By eliminating the unneeded or mutant cells, programmed cell death actively participates in a wide range of biological processes from embryonic development to homeostasis maintenance in adult. Continuing efforts have identified multiple cell death pathways, with apoptosis, necrosis and autophage the mostly studied. Re...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/1566524015666151026100339
更新日期:2015-01-01 00:00:00
abstract::Liver cirrhosis, an end-result of a wide variety of the liver diseases, is a world wide health problem. Because of its unique organ system, i.e., portal blood supply, bile formation and enterohepatic circulation, drug metabolism system, and sinusoidal lining cells such as Kupffer, endothelial and stellate cells, the l...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/1566524033479528
更新日期:2003-09-01 00:00:00
abstract::Classical Hodgkin lymphoma (cHL) is now recognized as a B-cell-derived lymphoma which is characterized by only about 1% malignant pathognomonic Hodgkin and Reed-Sternberg (HRS) cells and an abundant infiltrate of reactive bystander cells. HRS cells are unique with respect to their lost B-cell-specific gene expression ...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652411795243423
更新日期:2011-04-01 00:00:00
abstract::Type 1 diabetes (T1D) is an organ-specific autoimmune disease resulting from the specific destruction of insulin-producing pancreatic beta-cells, culminating in a state of hypoinsulinemia and hyperglycemia. Pathogenesis of T1D comprises complex series of events from the initial sensitization of antigen-presenting cell...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652409787314471
更新日期:2009-02-01 00:00:00
abstract::HMGB1/Amphoterin is a ubiquitous, highly conserved DNA-binding protein that can be also released to the extracellular space by various cell types. Extracellular HMGB1 regulates migratory responses of several cell types through binding to RAGE that communicates with the cytoskeleton to regulate cell motility. HMGB1-ind...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652407783220750
更新日期:2007-12-01 00:00:00
abstract::The leading cause of blindness in the developed world results from several disorders that have pathologic ocular neovascularization as the common pathway leading to vision loss. These disorders include exudative age related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), retina...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652409789712783
更新日期:2009-11-01 00:00:00
abstract::As an MHC class I protein, the disease association of HLA-B27 with inflammatory arthritis has been widely assumed to imply a role for the T cell antigen receptor (TCR) in disease. However, in addition to their classical antigen-presenting role, HLA class I proteins are recognised by members of the killer immunoglobuli...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/1566524043479329
更新日期:2004-02-01 00:00:00
abstract::Autophagy is a bulk cytosolic degradative process which in the last few years has become a key pathway for the advancement of molecular medicine. Autophagy (cellular self-eating) has several implications in human disorders involving accumulation of cytosolic protein aggregates such as Alzheimer, Parkinson, Huntington ...
journal_title:Current molecular medicine
pub_type: 杂志文章,评审
doi:10.2174/156652408783769634
更新日期:2008-03-01 00:00:00