SIRT1 Modulating Compounds from High-Throughput Screening as Anti-Inflammatory and Insulin-Sensitizing Agents

Nayagam, Vasantha M.; Wang, Xukun; Tan, Yong; Poulsen, Anders; Goh, Kunli; Ng, Tony; Wang, Haishan; Song, Hong; Ni, Binhui; Entzeroth, Michael; Stünkel, Walter

doi:10.1177/1087057106294710

Cited by 133 publications

(90 citation statements)

References 36 publications

(39 reference statements)

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“…SIRT1 has an antiinflammatory effect by interfering with the nuclear factor-B signaling pathway, 37,38 a vasodilatory effect via endothelial nitric oxide synthase-derived nitric oxide, 39 and an antioxidant effect resulting from its properties of scavenging reac- COX-2KO mice were injected intraperitoneally with DMSO (C) or with resveratrol;. 24 hours later (B), carotid artery thrombosis was induced with FeCl 3 , and time to form an occlusive thrombus was measured, and (C) TF activity was assayed in (i) carotid artery, (ii) plasma microparticles, and (iii) total leukocytes.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner

et al. 2012

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Background-Selective inhibitors of cyclooxygenase (COX)-2 increase the risk of myocardial infarction and thrombotic events, but the responsible mechanisms are not fully understood. Methods and Results-We found that ferric chloride-induced arterial thrombus formation was significantly greater in COX-2 knockout compared with wild-type mice. Cross-transfusion experiments excluded the likelihood that COX-2 knockout platelets, despite enhanced aggregation responses to collagen and thrombin, are responsible for increased arterial thrombus formation in COX-2 knockout mice. Importantly, we observed that COX-2 deletion decreased prostacyclin synthase and production and peroxisome proliferator-activated receptor-and sirtuin-1 (SIRT1) expression, with consequent increased upregulation of tissue factor (TF), the primary initiator of blood coagulation. Treatment of wild-type mice with a prostacyclin receptor antagonist or a peroxisome proliferator-activated receptor-␦ antagonist, which predisposes to arterial thrombosis, decreased SIRT1 expression and increased TF activity. Conversely, exogenous prostacyclin or peroxisome proliferator-activated receptor-␦ agonist completely reversed the thrombotic phenotype in COX-2 knockout mice, restoring normal SIRT1 levels and reducing TF activity. Furthermore, inhibition of SIRT1 increased TF expression and activity and promoted generation of occlusive thrombi in wild-type mice, whereas SIRT1 activation was sufficient to decrease abnormal TF activity and prothrombotic status in COX-2 knockout mice. Conclusions-Modulation of SIRT1 and hence TF by prostacyclin/peroxisome proliferator-activated receptor-␦ pathways not only represents a new mechanism in controlling arterial thrombus formation but also might be a useful target for therapeutic intervention in the atherothrombotic complications associated with COX-2 inhibitors. (Circulation. 2012; 126:1373-1384.)Key Words: blood coagulation Ⅲ carotid arteries Ⅲ prostacyclin Ⅲ signal transduction Ⅲ thrombosis P rostanoids are a family of bioactive lipid mediators formed from arachidonic acid by cyclooxygenases (COXs; COX-1 and COX-2). 1 Prostanoids are involved in a variety of physiological activities, including platelet aggregation, vasorelaxation and vasoconstriction, local inflammatory response, and leukocyte-endothelial cell adhesion. 2,3 In this context, prostanoids modulate the pathogenesis of vascular diseases such as arterial thrombosis and atherosclerosis. 4 The role of COX-2 in atherothrombosis is complex. This enzyme generates not only proinflammatory, but also anti-inflammatory prostanoids, such as prostacyclin (PGI 2 ), which, under certain conditions, may counteract platelet-derived thromboxane (TXA 2 ). 5 PGI 2 is a potent vasodilator and an inhibitor of platelet aggregation, leukocyte adhesion, and vascular smooth muscle cell proliferation. 6 These actions of PGI 2 are mediated through specific cell surface receptors known as PGI 2 receptors (IPs). Each IP is a 7-membrane-spanning G-protein-coupled receptor that elicits cAMP p...

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Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner

et al. 2012

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“…Similar to PARP-2 gene inactivation, SIRT1 activation has been shown to inhibit the production of inflammatory mediators and suppress certain forms of inflammation [92][93][94]. It is therefore plausible that the induction of SIRT1 may be responsible for the antiinflammatory effect of PARP-2 depletion in colitis [59] and in astrocyte activation [58] .…”

Section: Interaction With Sirt1mentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

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Abstract:Poly(ADP-ribose) polymerase (PARP)-2 is a nuclear enzyme that belongs to the PARP family and PARP-2 is responsible for 5-15% of total cellular PARP activity. PARP-2 was originally described in connection to DNA repair and in physiological and pathophysiological processes associated with genome maintenance (e.g. centromere and telomere protection, spermiogenesis, thymopoesis, azoospermia and tumorigenesis). Recent reports identified important rearrangements in gene expression upon the knockout of PARP-2. Such rearrangements heavily impact on inflammation and metabolism. Metabolic effects are mediated through modifying PPARg and SIRT1 function. Altered gene expression gives rise to a complex phenotype characterized primarily by enhanced mitochondrial activity that results both in beneficial (loss of fat, enhanced insulin sensitivity) and in disadvantageous (pancreatic beta cell hypofunction upon high fat feeding) consequences. Enhanced mitochondrial biogenesis provides protection in oxidative stress related diseases. Hereby, we review the recent developments in PARP-2 research with special attention to the involvement of PARP-2 in transcriptional and metabolic regulation. We would like to thank the referee for his/her efforts to further improve our manuscript.1. Page 2 -the modifications here are fairly minimalistic and the abbreviations ARTD2 and ARTD1 are not even defined. Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporationand ARTD1 are not even defined.In the corresponding section we incorporated the basic information on the newly proposed nomenclature in our previous version upon the suggestion of the Reviewer. We agree with the Reviewer that the appearance of the new nomenclature in our manuscript is important. Moreover, in the current version we added ARTD-2 as a keyword to help those future readers that follow the new nomenclature. The fact that ARTD1 is the equivalent of PARP-1 is defined in the chapter "PARP superfamily" second paragraph, first row. We added the abbreviation of ARDT-2 in the last sentence in the first paragraph of the chapter "The PARP superfamily". We think that these are sufficient for the understanding of the position of PARP-2 in the PARP/ARTD superfamily.We would like to note here, that the proposed new nomenclature did not gain ground in the scientific community yet. There are only 3 relevant papers on Medline for the keyword ARTD1, ARTD2 or ARTD (since 2010, the publication of the paper by In summary, we are confident that our review sufficiently takes the new nomenclature into consideration despite of the fact that it is not yet accepted by the scientific community. Sequence homology modeling was carried out by Ame and co-workers (Ame et al. Bioessays. 26:882-893. 2004). They classified sequences as PARPs on the basis of sequence homology, therefore sequence homology does exist. However, mutation(s) in a sequence does not necessarily mean that sequence homology is lost. In the incriminated text, mutations mean rather point mutations that aff...

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“…However, it remains unclear whether SIRT1 serves as a tumor suppressor or a tumor promoter (13-16). SIRT1 expression is relatively higher in many malignancies, including colon, breast, prostate, and skin cancers and leukemia, as compared with their corresponding normal tissues (17)(18)(19)(20)(21)(22). But the specific correlation is not clear-cut.…”

mentioning

confidence: 99%

Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C

Ming

Shea

Guo

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

125

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Disruption of the nucleotide excision repair (NER) pathway by mutations can cause xeroderma pigmentosum, a syndrome predisposing affected individuals to development of skin cancer. The xeroderma pigmentosum C (XPC) protein is essential for initiating global genome NER by recognizing the DNA lesion and recruiting downstream factors. Here we show that inhibition of the deacetylase and longevity factor SIRT1 impairs global genome NER through suppressing the transcription of XPC in a SIRT1 deacetylase-dependent manner. SIRT1 enhances XPC expression by reducing AKTdependent nuclear localization of the transcription repressor of XPC. Finally, we show that SIRT1 levels are significantly reduced in human skin tumors from Caucasian patients, a population at highest risk. These findings suggest that SIRT1 acts as a tumor suppressor through its role in DNA repair.ucleotide excision repair (NER) is a versatile DNA repair pathway that eliminates a wide variety of helix-distorting base lesions, including UV radiation-induced cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts (6-4PPs) (1, 2), as well as bulky adducts induced by numerous chemical compounds. Defects in NER by mutations cause the autosomal recessive xeroderma pigmentosum (XP) and Cockayne syndromes (3-5). XP patients are clinically characterized by cutaneous sensitivity to sunlight exposure and a predisposition to skin cancer. Seven NER-deficient genetic complementation groups of XP (XP-A to -G) have been identified, and all of the corresponding genes have now been cloned (3-5).Mammalian NER consists of two distinct subpathways: global genome NER (GG-NER), which operates throughout the genome, and transcription-coupled NER (TC-NER), which specifically removes lesions on the transcribed DNA strand of active genes. A major difference between these two pathways appears to lie in the strategies for detecting damaged bases. Accumulating evidence indicates that the XP group C (XPC) protein plays an essential role in GG-NER-specific damage recognition (6-8). Although biochemical and genetic analyses have characterized the function of XPC in considerable detail, much remains to be elucidated with regard to its regulation and interaction with other critical cellular pathways.Sirtuin 1 (SIRT1), a mammalian counterpart of the yeast silent information regulator 2 (Sir2) and a proto member of the sirtuin family, is an NAD-dependent longevity-promoting deacetylase. SIRT1 is crucial for cell survival, metabolism, senescence, and stress response in several cell types and tissues (9-13). Both histone and nonhistone targets of SIRT1 have been identified, including FOXO, p53, and PPARγ (10,12,14). SIRT1 has been implicated as an important player in cancer. However, it remains unclear whether SIRT1 serves as a tumor suppressor or a tumor promoter (13-16). SIRT1 expression is relatively higher in many malignancies, including colon, breast, prostate, and skin cancers and leukemia, as compared with their corresponding normal tissues (17)(18)(19)(20)(21)(22). But the specific c...

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SIRT1 Modulating Compounds from High-Throughput Screening as Anti-Inflammatory and Insulin-Sensitizing Agents

Cited by 133 publications

References 36 publications

Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner

Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C

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