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Relationship: 2611

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decrease,SIRT1(sirtuin 1) levels leads to Increased activation, Nuclear factor kappa B (NF-kB)

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decrease,SIRT1(sirtuin 1) levels

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased activation, Nuclear factor kappa B (NF-kB)

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
DNA damage and mutations leading to Metastatic Breast Cancer	adjacent	Moderate	Moderate	Usha Adiga (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
human and other cells in culture	human and other cells in culture	High	NCBI
human	Homo sapiens	Moderate	NCBI
mice	Mus sp.	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Not Otherwise Specified	Not Specified

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Upstream event: Decreased, SIRT1

Downstream event: NF kB activity, Increased

The described Key Event Relationship (KER) delineates a sequence of events involving the regulatory impact of SIRT1 and its downstream effects. The upstream event is characterized by "Decreased SIRT1," indicating a reduction in the levels or activity of the protein SIRT1. SIRT1 is a member of the sirtuin family of proteins that plays a role in various cellular processes, including gene expression regulation and stress response.

The downstream event in this KER is an "Increased NF-κB activity," signifying an elevation in the activity of the nuclear factor kappa B (NF-κB) signaling pathway. SIRT1 has been recognized as a modulator of NF-κB activity. Decreased SIRT1 levels can lead to enhanced NF-κB activity, potentially due to the loss of SIRT1-mediated deacetylation and inhibition of NF-κB transcriptional activity.

This KER underscores the intricate interplay between proteins and signaling pathways within the cell, where changes in the levels of one protein, like SIRT1, can impact downstream signaling and cellular responses. The reduction in SIRT1 levels can contribute to heightened NF-κB activity, which in turn may influence various cellular processes, including inflammation, immune responses, and stress-related pathways.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

In alignment with OECD guidelines, an evidence collection approach was meticulously executed to validate the Key Event Relationship (KER) "Decrease in SIRT1 levels leads to Increased activation of Nuclear factor kappa B (NF-kB)." Commencing with decreased SIRT1 levels, a multitude of molecular techniques was harnessed. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to quantify SIRT1 protein and mRNA expression, respectively, corroborating the reduction in SIRT1. Complementary investigations, utilizing overexpression and knockdown experiments, further affirmed the role of SIRT1 in modulating NF-kB activity.

Mechanistic insights were gleaned through signaling pathway analyses that demonstrated the interplay between SIRT1 and NF-kB. Cellular assays investigating NF-kB translocation, DNA binding, and transcriptional activity substantiated the relationship, showing that reduced SIRT1 levels corresponded to heightened NF-kB activation. These findings were supported by studies elucidating the deacetylase activity of SIRT1 on NF-kB's regulatory proteins.

Additionally, validation through pharmacological and genetic manipulations bolstered the mechanistic plausibility. Experiments involving SIRT1 activators or inhibitors yielded corresponding changes in NF-kB activity. Cross-validation across cell lines, animal models, and human samples ensured the robustness and broad applicability of the relationship.

Real-world relevance was established by observing the consequences of SIRT1 deficiency or inhibition in scenarios involving inflammation, oxidative stress, and disease. Integrating results from varied experimental settings, mechanistic investigations, and relevant contextual studies aligned with OECD principles, a robust and substantiated evidence base for the KER "Decrease in SIRT1 levels leads to Increased activation of Nuclear factor kappa B (NF-kB)" was successfully constructed.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

SIRT1 deacetylates NFkB. In the context of NFkB, all of the evidence so far points to its signalling being inhibited after SIRT1 deacetylation (Morris, 2012). SIRT1 or SIRT1 activation by resveratrol and other polyphenols, in fact, has been found to reduce inflammatory response by deacetylating and inhibiting NFkB in both in vitro and in vivo investigations. The essential significance of NFkB in many cellular processes implicated in inflammation, ageing, cancer, and other diseases makes these findings particularly intriguing.

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

-The acetylation of many lysines on NFkB has been identified, which leads to its activation (Kiernan et al., 2003). A novel class of deacetylases known as Sirtuins has heightened interest in modulating NFkB activity. The activation of sirtuins actually inhibits NFkB.

- According to Yeung et al, SIRT1 can directly interact with and deacetylate the RelA/p65 component of the NF-B complex (Yeung et al.,2004). Deacetylation of Lys310 decreased the transactivation ability of the RelA/p65 subunit and, as a result, lowered the transcription of NF-B-dependent genes. Furthermore, deacetylation of Lys310 in the RelA/p65 protein exposed it to methylation at Lys314 and Lys315, resulting in increased ubiquitination and destruction of the protein (Yang et al.,2010). SIRT1 inhibition of NF-B signalling has been demonstrated in a number of recent studies, and activation of SIRT1 could ameliorate a variety of NF-B-driven inflammatory and metabolic illnesses (Salminen et al.,2008; Yu et al.,2010; Yao et al.,2012; Xie et al.,2013).

SIRT1 suppresses NF-B signalling either directly by deacetylating the RelA/p65 subunit or indirectly by triggering repressive transcriptional complexes, which frequently involve heterochromatin formation at NF-B promoter regions. SIRT1 expression and signalling are both inhibited by NF-B.

Zhang et al. found that overexpressing RelA/p65 protein increased SIRT1 expression at both the transcriptional and protein levels (36 h treatment), whereas knocking down RelA/p65 expression decreased TNF-induced SIRT1 expression (8 h treatment)(Zhang et al.,2010). They also discovered that the RelA/p65 protein may bind to the SIRT1 promoter's NF-B motifs. These findings suggest that NF-B may promote SIRT1 expression. Given that SIRT1 induction appeared to occur much later than NF-B activation, it appears that this action could represent a feedback response limiting inflammation and eventually generating endotoxin tolerance.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

According to Lu et al, SIRT1 inhibited the growth of gastric cancer through inhibiting the activation of STAT3 and NF-B (Lu et al.,2014). The goal was to look at SIRT1's regulatory effects on gastric cancer (GC) cells (AGS and MKN-45) as well as the links between SIRT1 and STAT3 and NF-B activation in GC cells. The SIRT1 activator (resveratrol RSV) was discovered to contribute to the repression of viability and increase of senescence, which was reversed by SIRT1 inhibitor (nicotinamide NA) and SIRT1 depletion using the CCK-8 and SA-β-gal assays, respectively. SIRT1 activation (RSV supplement) reduced not only STAT3 activation, including STAT3 mRNA level, c-myc mRNA level, phosphorylated STAT3 (pSTAT3) proteins, and acetylizad STAT3 (acSTAT3) proteins, but also pNF-B p65 and acNF-B p65 suppression. The effects of RSV were reversed by NA.

Furthermore, when STAT3 or NF-B were knocked down, neither RSV nor NA could affect cellular survival or senescence in MKN-45 cells. Overall, the outcomes of the study revealed that SIRT1 activation could cause GC in vitro to lose viability and senescence. Furthermore, our findings demonstrated that SIRT1 inhibited proliferation in GC cells and was related with deacetylation-mediated suppression of STAT3 and NF-B protein activation.

The levels of SIRT1 protein expression in non-small-cell lung cancer (NSCLC) cell lines were examined in a study by Yeung et al.,2004. In comparison to immortalised epithelial human lung NL-20 cells, NSCLC cells exhibit significant quantities of SIRT1 protein, as reported by other researchers (Luo et al, 2001; Vaziri et al, 2001).

Pharmacological modulators of Sirtuin activity were employed to see if NF-kB transcription was regulated by Sirtuins (Landry et al, 2000; Bedalov et al, 2001; Howitz et al, 2003).

Transient luciferase reporter experiments revealed that cells pretreated with resveratrol had very minimal NF-kB transcription following the presence of TNFa. TNFa-induced NF-kB activity was boosted when cells were pretreated with the Sirtuin inhibitors nicotinamide or splitomicin. NF-kB transcription was also potentiated in cells treated with trichostatin A (TSA), an HDAC class I and class II inhibitor, as expected.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

SIRT1 can inhibit NF-κB signaling directly or indirectly, in turn the NF-κB system suppresses SIRT1-mediated functions by inhibiting the downstream targets of SIRT1. Given that SIRT1 and NF-κB signaling have antagonistic characteristics, these pathways control many of the physiologically relevant metabolic and inflammatory switches required for the maintenance of cellular and organismal homeostasis.
PGC-1 is a downstream target of the SIRT/AMPK signalling cascade that promotes oxidative metabolism by promoting mitochondrial biogenesis (Fernandez et al.,2011). In cardiac cells, Alvarez-Guardia et al. found that the RelA/p65 member of the NF-B complex was constitutively linked to the PGC-1 protein. They also discovered that activating NF-B after TNF exposure boosted the association between the RelA/p65 and PGC-1 proteins, resulting in an increase in glucose oxidation (Alvarez et al., 2010). These findings show that deacetylation of PGC-1 promotes mitochondrial oxidative respiration, whereas activation of NF-B signalling inhibits SIRT1/PGC-1 communication and activates aerobic glycolysis. This shift is known as the Warburg effect, which can be seen in cancer cells but also in ageing (Salminen et al., 2010). Overexpression of PGC-1, on the other hand, decreased the transcriptional activity of NF-B by lowering the phosphorylation of the transactivating RelA/p65 component(Eisele et al.,2013)

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

^{NF-B can be activated by cytokines (TNF-, IL-1), growth factors (EGF), bacterial and viral products (lipopolysaccharide (LPS), dsRNA), UV and ionising radiation, reactive oxygen species (ROS), DNA damage, and oncogenic stress from inside the cells. Almost all stimuli eventually activate a large cytoplasmic protein complex called the inhibitor of B (IB) kinase (IKK) complex via a so-called "canonical pathway." The exact composition of this complex is unknown, however it has three fundamental components: IKK1/IKK, IKK2/IKK, and NEMO/IKK. IB is phosphorylated by the activated IKK complex, which marks it for destruction by the -transducin repeat-containing protein (-TrCP)-dependent E3 ubiquitin ligase-mediated proteasomal degradation pathway (Liu et al., 2012;Li et al., 2002). As a result, unbound NF-B dimers can go from the cytoplasm to the nucleus, bind to DNA, and control gene transcription.}
^{SIRT6 is a nuclear sirtuin that regulates the acetylation status and transcriptional activity of HIF1 and NFkB. SIRT6 deacetylates histone 3 lysine 8 (H3K9) at HIF1 target gene promoters and so acts as a corepressor of HIF1 transcriptional activity. SIRT6 modulation of glucose flow appears to be crucial, as SIRT6 deficiency results in fatal hypoglycemia (Zhong et al., 2010). SIRT6 inhibits NFkB function through a mechanism that is strikingly similar. SIRT6 also deacetylates H3K9 on the promoters of specific NFkB target genes, reducing NFkB's accessibility to these promoters (Kawahara et al., 2009). SIRT6 has a compensating impact in SIRT1 deficient animals, attenuating the enhanced NFkB activity due to an elevated acetylation state (Schug et al., 2010). Finally, although having different methods, both SIRT1 and SIRT6 are negative regulators of NFkB activity.}
^{SIRT2 has been demonstrated to deacetylate the cytoplasmic lysine 310 (K310) of NFkB subunit p65 (Rothgiesser et al., 2010). SIRT2 suppresses NFkB activation and transcription of NFkB target genes in response to TNF stimulation in this way (Rothgiesser et al., 2010). After TNF exposure, SIRT2 silenced cells show higher NFkB activity and a reduced probability of cell death (Rothgiesser et al., 2010). As a result, SIRT2 in the cytosol and SIRT1 in the nucleus can both deacetylate NFkB.}

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

	Method/ measurement reference	Reliability	Strength of evidence	Assay fit for purpose	Repeatability/ reproducibility	Direct measure
Human cell line	qRT-PCR,,Luciferase reporter assay Cell based HDAC assay(Luo et al.,2001)	Yes	Strong	Yes	Yes	Yes
Humans	qRT-PCR,immunohistochemistry (McGlynn et al.,2014)	Yes	Strong	Yes	Yes	Yes
Mouse	qRT-PCR,Southern and northern blotting, reporter gene assay(Paul et al.,2008)	Yes	Low	Yes	Yes	Yes

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

- Studies have been done on pancreatic cancer cells, Joudah et colleagues investigated the processes and correlations between SIRT1 and NF-B activation .The results showed that a 1 µM SIRT1 aptamer might limit NF-B activation by increasing SIRT1 protein activity(Joudah et al.,2021). According to the findings of SIRT1 aptamer mechanisms, it is possible that SIRT1 aptamer will be used in the treatment of pancreatic cancer in the future.

-To explore the mechanism of SIRT1 aptamer in cell lines, SIRT1 activity was measured in parallel on Aspc-1, BxPc-3, and Capan-2 cell lines under the same conditions. SIRT1 activity was measured in BxPc-3 cell lines using SIRT1 aptamer at 0.25, 0.5, and 1M. Then, using 100M resveratrol (SIRT1 activator control), 100M suramin, and nicotinamide(SIRT1 inhibitor control), assess its activity .

-The results revealed that using SIRT1 aptamer at 1M boosted SIRT1 activity in Capan-2 cells when compared to high concentrations of 100M resveratrol, 100M Suramin, and 100M Nicotinamide.

-The activation of SIRT1 in the Aspc-1 cell line when treated with SIRT1 at 1µM was higher than that of 100µM resveratrol, Suramin, and Nicotinamide.

-the effect of SIRT1 aptamer on NF-kB activation was determined in nuclear extracts of BxPC-3, Capan-2, and AsPC-1 cell lines using an ELISA-based test to measure the capacity of NF-kB p65 subunit for DNA-binding.

-At 1 µM, adding a SIRT1 aptamer caused biphasic alterations in NF-kB. At 8 hours, NF-kB binding activity in Bx-PC-3, Capan-2, and AsPC-1 cell lines was reduced by 150 percent, 130 percent, and 130 percent, respectively, compared to control 100 percent. In Bx-PC-3,Capan-2, and AsPC-1 cell lines, the decline was 180 percent, 145 percent, and 140 percent of the control 100 percent, P<0.005 at 16 hours respectively.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The events connected by this KER occur within hours.

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

SIRT1 and AMPK have a close interaction in the control of energy metabolism and inflammation as they can promote each other's activity (Ruderman et al., 2010). SIRT1 stimulates AMPK by deacetylating LKB1, which then activates AMPK (Lan et al., 2008), whereas AMPK promotes the synthesis of cellular NAD+, which is necessary for SIRT1 activity (Canto et al.,2009). SIRT1 and AMPK have many similar activities in the control of energy metabolism as a result of this positive feedback.
AMPK appears to be an efficient inhibitor of NF-B signalling and inflammatory reactions, according to new research. This topic was recent discussed in depth (Salminen et al.,2011). In a nutshell, AMPK inhibits RelA/p65 by activating SIRT1. PGC-1 is also phosphorylated by AMPK, which increases its activation (Canto et al.,2009). As a result, PGC-1 can block RelA/p65-mediated NF-B signalling.
The transcription factor FoxO3a, which is involved in metabolic and immunological homeostasis, was activated by AMPK (Eijkelenboom et al.,2013). Overexpression of FoxO3a decreased NF-B activation in cultured cells, such as after TNF treatment, by suppressing nuclear translocation of the RelA/p65 component. The inhibition of NF-B signalling by FoxO3a was corroborated in a study (Lee et al.,2008) who found that overexpression of FoxO3a caused the production of B-Ras1, an inhibitor of NF-B activation. However, FoxO3a has recently been discovered to activate the NF-B system via BCL10, which is expressed in B lymphocytes (Li et al., 2012).

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The KER has been noted in human and animal cell lines irrespevtive of gender or any specific life stage.

References

List of the literature that was cited for this KER description. More help

Alvarez-Guardia, D., Palomer, X., Coll, T., Davidson, M. M., Chan, T. O., Feldman, A. M., ... & Vázquez-Carrera, M. (2010). The p65 subunit of NF-κB binds to PGC-1α, linking inflammation and metabolic disturbances in cardiac cells. Cardiovascular research, 87(3), 449-458.

Bedalov, A., Gatbonton, T., Irvine, W. P., Gottschling, D. E., & Simon, J. A. (2001). Identification of a small molecule inhibitor of Sir2p. Proceedings of the National Academy of Sciences, 98(26), 15113-15118.

Cantó, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., ... & Auwerx, J. (2009). AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature, 458(7241), 1056-1060.

Cantó, C., & Auwerx, J. (2009). PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Current opinion in lipidology, 20(2), 98.

Eijkelenboom, A., & Burgering, B. M. (2013). FOXOs: signalling integrators for homeostasis maintenance. Nature reviews Molecular cell biology, 14(2), 83-97.

Fernandez-Marcos, P. J., & Auwerx, J. (2011). Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. The American journal of clinical nutrition, 93(4), 884S-890S.

Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425(6954), 191-196.

Kawahara, T. L., Michishita, E., Adler, A. S., Damian, M., Berber, E., Lin, M., ... & Chua, K. F. (2009). SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span. Cell, 136(1), 62-74.

Kiernan, R., Brès, V., Ng, R. W., Coudart, M. P., El Messaoudi, S., Sardet, C., ... & Benkirane, M. (2003). Post-activation turn-off of NF-κB-dependent transcription is regulated by acetylation of p65. Journal of Biological Chemistry, 278(4), 2758-2766.

Lan, F., Cacicedo, J. M., Ruderman, N., & Ido, Y. (2008). SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1: possible role in AMP-activated protein kinase activation. Journal of Biological Chemistry, 283(41), 27628-27635.

Landry, J., Slama, J. T., & Sternglanz, R. (2000). Role of NAD+ in the deacetylase activity of the SIR2-like proteins. Biochemical and biophysical research communications, 278(3), 685-690.

Lee, H. Y., Youn, S. W., Kim, J. Y., Park, K. W., Hwang, C. I., Park, W. Y., ... & Kim, H. S. (2008). FOXO3a turns the tumor necrosis factor receptor signaling towards apoptosis through reciprocal regulation of c-Jun N-terminal kinase and NF-κB. Arteriosclerosis, thrombosis, and vascular biology, 28(1), 112-120.

Li, Z., Zhang, H., Chen, Y., Fan, L., & Fang, J. (2012). Forkhead transcription factor FOXO3a protein activates nuclear factor κB through B-cell lymphoma/leukemia 10 (BCL10) protein and promotes tumor cell survival in serum deprivation. Journal of Biological Chemistry, 287(21), 17737-17745.

Liu, F., Xia, Y., Parker, A. S., & Verma, I. M. (2012). IKK biology. Immunological reviews, 246(1), 239-253.

Li, Q., & Verma, I. M. (2002). NF-κB regulation in the immune system. Nature reviews immunology, 2(10), 725-734.

Lu, J., Zhang, L., Chen, X., Lu, Q., Yang, Y., Liu, J., & Ma, X. (2014). SIRT1 counteracted the activation of STAT3 and NF-κB to repress the gastric cancer growth. International journal of clinical and experimental medicine, 7(12), 5050.

Luo, J., Nikolaev, A. Y., Imai, S. I., Chen, D., Su, F., Shiloh, A., ... & Gu, W. (2001). Negative control of p53 by Sir2α promotes cell survival under stress. Cell, 107(2), 137-148.

Joudah, M. S., Arif, I. S., & Al-Sudani, B. T. (2021). Crosstalk Between Sirt1 Activators And Nf-Κb Axis As A Therapeutic Target To Reduce Pancreatic Cancer. Systematic Reviews in Pharmacy, 12(3), 207-212.

McGlynn, L. M., Zino, S., MacDonald, A. I., Curle, J., Reilly, J. E., Mohammed, Z. M., ... & Shiels, P. G. (2014). SIRT2: tumour suppressor or tumour promoter in operable breast cancer?. European Journal of Cancer, 50(2), 290-301.

Yang, L., Wu, D., Wang, X., & Cederbaum, A. I. (2012). Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver. Free Radical Biology and Medicine, 53(5), 1170-1180.

Pfluger, P. T., Herranz, D., Velasco-Miguel, S., Serrano, M., & Tschöp, M. H. (2008). Sirt1 protects against high-fat diet-induced metabolic damage. Proceedings of the national academy of sciences, 105(28), 9793-9798.

Rothgiesser, K. M., Erener, S., Waibel, S., Lüscher, B., & Hottiger, M. O. (2010). SIRT2 regulates NF-κB-dependent gene expression through deacetylation of p65 Lys310. Journal of cell science, 123(24), 4251-4258.

Ruderman, N. B., Xu, X. J., Nelson, L., Cacicedo, J. M., Saha, A. K., Lan, F., & Ido, Y. (2010). AMPK and SIRT1: a long-standing partnership?. American Journal of Physiology-Endocrinology and Metabolism.

Salminen, A., & Kaarniranta, K. (2010). Glycolysis links p53 function with NF‐κB signaling: Impact on cancer and aging process. Journal of cellular physiology, 224(1), 1-6.

Eisele, P. S., Salatino, S., Sobek, J., Hottiger, M. O., & Handschin, C. (2013). The peroxisome proliferator-activated receptor γ coactivator 1α/β (PGC-1) coactivators repress the transcriptional activity of NF-κB in skeletal muscle cells. Journal of Biological Chemistry, 288(4), 2246-2260.

Salminen, A., Kauppinen, A., Suuronen, T., & Kaarniranta, K. (2008). SIRT1 longevity factor suppresses NF‐κB‐driven immune responses: regulation of aging via NF‐κB acetylation?. Bioessays, 30(10), 939-942.

Salminen, A., Hyttinen, J. M., & Kaarniranta, K. (2011). AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. Journal of molecular medicine, 89(7), 667-676.

Schug, T. T., Xu, Q., Gao, H., Peres-da-Silva, A., Draper, D. W., Fessler, M. B., ... & Li, X. (2010). Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Molecular and cellular biology, 30(19), 4712-4721.

Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S. I., Frye, R. A., Pandita, T. K., ... & Weinberg, R. A. (2001). hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell, 107(2), 149-159.

Xie, J., Zhang, X., & Zhang, L. (2013). Negative regulation of inflammation by SIRT1. Pharmacological Research, 67(1), 60-67.

Yao, H., & Rahman, I. (2012). Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence. Biochemical pharmacology, 84(10), 1332-1339.

Yang, X. D., Tajkhorshid, E., & Chen, L. F. (2010). Functional interplay between acetylation and methylation of the RelA subunit of NF-κB. Molecular and cellular biology, 30(9), 2170-2180.

Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Jones, D. R., Frye, R. A., & Mayo, M. W. (2004). Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase. The EMBO journal, 23(12), 2369-2380.

Yu, J., & Auwerx, J. (2010). Protein deacetylation by SIRT1: an emerging key post-translational modification in metabolic regulation. Pharmacological research, 62(1), 35-41.

Zhang, H. N., Li, L., Gao, P., Chen, H. Z., Zhang, R., Wei, Y. S., ... & Liang, C. C. (2010). Involvement of the p65/RelA subunit of NF-κB in TNF-α-induced SIRT1 expression in vascular smooth muscle cells. Biochemical and biophysical research communications, 397(3), 569-575.

Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R. E., Vadysirisack, D. D., ... & Mostoslavsky, R. (2010). The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell, 140(2), 280-293.