7 replies to this topic

[Hedgehog]

Pallàs M, Verdaguer E, Tajes M, Gutierrez-Cuesta J, Camins A.Unitat de Farmacologia i Farmacognòsia i Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain. pallas@ub.edu.

Aging is characterized by a progressive deterioration of physiological functions and metabolic processes. Healthy aging remains one of the ideals of modern society. In aging and in diseases associated with the elderly, such as Alzheimer's or Parkinson's, the loss of cells in vital structures or organs may be related to several factors, among which the production of reactive oxygen species (ROS) by mitochondria is a common denominator, one that leads to DNA damage, apoptosis and death. Although a diet rich in antioxidants seems to offer hope in delaying the onset of unhealthy disorders that accompany aging, no clinical treatment as such has yet been developed and anti-aging drugs are still unavailable. It is well established that reducing food intake (caloric restriction) extends the life-span in a wide range of species. The protein implicated in this protective process is the silent information regulator 2 (SIR2, SIRT1 in mammals), an enzyme that belongs to a nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylases. SIRs regulate gene silencing, DNA repair, rDNA recombination, and ageing, apart from regulating programmed cell death. In this context, increasing SIRT1 has been found to protect cells against amyloid-beta-induced ROS production and DNA damage, thereby reducing apoptotic death in vitro. Moreover, it has been demonstrated that Alzheimer's and Huntington's disease neurons are rescued by the over-expression of SIRT1, induced by either caloric restriction or administration of resveratrol, a potential activator of this enzyme. The therapeutic use of resveratrol (a polyphenol present in red wines) and other related compounds, which utilize SIRT1 pathway modulators, in treating aging-related brain disorders will be discussed in this review. Provided herein are novel new compound related with resveratrol or sirtinol that are able to modulate sirtuin activity that will be tested to treat and/or prevent a wide variety of diseases including, disorders related to aging or neurodegenerative diseases.

PMID: 18221243 [PubMed - in process]

[sUper GeNius]

When was the article published Hedge?

[Hedgehog]

When was the article published Hedge?

Recent Patents CNS Drug Discov. 2008 Jan;3(1):61-9.

Pubmed just got a hold of it.

[inawe]

I guess "Modulation of sirtuins" would be interpreted as up-regulation. Many of us are enthusiastically up-regulating, gobbling up RSV (irrational exuberance?).
But, modulation can mean down as well as up. The Sirtrinol mentioned in the abstract is an inhibitor of Sirt1, and it's being proposed as an anticancer agent:

Oncogene. 2006 Jan 12;25(2):176-85.
Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells.Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M, Kozaki K, Akishita M, Ouchi Y, Kaneki M.
Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.

PMID: 16170353 [PubMed - indexed for MEDLINE]

I know, this is very confusing. Some people want to fight cancer by feeding Sirtuins while others try to do it by starving them.

[maxwatt]

When was the article published Hedge?

Recent Patents CNS Drug Discov. 2008 Jan;3(1):61-9.

Pubmed just got a hold of it.

This looks like a hell of an interesting journal: Recent Patents on CNS Drug Discovery

Curiously it seems to be published in the United Arab Emirates; Aubrey de Grey is a contributor. Lots on small molecule activators of sirtuins, function of different sirtuins, NAD and other deacetylase and aging.

[sUper GeNius]

I guess "Modulation of sirtuins" would be interpreted as up-regulation. Many of us are enthusiastically up-regulating, gobbling up RSV (irrational exuberance?).
But, modulation can mean down as well as up. The Sirtrinol mentioned in the abstract is an inhibitor of Sirt1, and it's being proposed as an anticancer agent:

Oncogene. 2006 Jan 12;25(2):176-85.
Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells.Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M, Kozaki K, Akishita M, Ouchi Y, Kaneki M.
Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.

PMID: 16170353 [PubMed - indexed for MEDLINE]

I know, this is very confusing. Some people want to fight cancer by feeding Sirtuins while others try to do it by starving them.

Hmmm. Makes one wonder. It would be nice if someone listed the pros and cons of resveratrol in one place, so we could reference it easily.

[Hedgehog]

I guess "Modulation of sirtuins" would be interpreted as up-regulation. Many of us are enthusiastically up-regulating, gobbling up RSV (irrational exuberance?).
But, modulation can mean down as well as up. The Sirtrinol mentioned in the abstract is an inhibitor of Sirt1, and it's being proposed as an anticancer agent:

Oncogene. 2006 Jan 12;25(2):176-85.
Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells.Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M, Kozaki K, Akishita M, Ouchi Y, Kaneki M.
Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.

PMID: 16170353 [PubMed - indexed for MEDLINE]

I know, this is very confusing. Some people want to fight cancer by feeding Sirtuins while others try to do it by starving them.

If you change the homoeostasis of cancer cell either by turning on or off pathways (even the same pathway) that the cancer needs you can achieve stoppage of growth.

For example if you put the mitochondria in a different state the cell can use this and go under its normal apoptosis because either a pathway is being upregulated or downregulated. Lets assume that SIRT inhbitors turn off cancer pathways. This would give you stoppage of growth. Maybe SIRT activators activate a potent apoptotic gene that out weighs other pathways...

I haven't looked at any papers regarding how SIRT modulators activate or deactivate certain pathways...

[krillin]

Krillin is totally confused. I get the impression from this paper and this slide show that butyrate, diallyl disulfide (DADS), and sulforaphane (SFN) are class I and II histone deacetlyase inhibitors, but do not inhibit sirtuins, which are class III.

But this abstract says that some sirtuins are upregulated while others are downregulated by class I and II inhibitors. Are broccoli and garlic compatible with resveratrol?

Cell Mol Life Sci. 2003 Sep;60(9):1990-7.
Differential regulation of the Sir2 histone deacetylase gene family by inhibitors of class I and II histone deacetylases.
Kyrylenko S, Kyrylenko O, Suuronen T, Salminen A.
Department of Neuroscience and Neurology, University of Kuopio, 70211 Kuopio, Finland.

The Sir2 histone deacetylase gene family consists of seven mammalian sirtuins (SIRTs) which are NAD-dependent histone/protein deacetylases. Sir2 proteins regulate, for instance, genome stability by chromatin silencing in yeast. In mammals, their function is still largely unknown. Due to the NAD+ dependency, Sir2 might be the link between metabolic activity and histone/protein acetylation. Regulation of gene expression also seems to play an important role in Sir2 functions, since increasing the dosage of Sir2 genes increases genome stability in yeast and Caenorhabditis elegans. We observed that the modification of histone/protein acetylation status by several class I and II histone deacetylase (HDAC) inhibitors induces differential changes in gene expression profiles of seven SIRT mRNAs in cultured neuronal cells. SIRT2, SIRT4 and SIRT7 were upregulated, whereas SIRT1, SIRT5 and SIRT6 were downregulated by trichostatin A (TSA) and n-butyrate. The upregulation of SIRT mRNAs was inhibited by actinomycin D. Interestingly, the regulation of SIRT mRNAs was highly similar both in mouse Neuro-2a neuroblastoma cells and post-mitotic rat primary hippocampal and cerebellar granule neurons. Using a chromatin immunoprecipitation technique, we showed that the upregulation of SIRT2 expression with TSA is related to the hyperacetylation of DNA-bound histone H4 within the first 500 bp upstream of the transcription start site of the SIRT2 gene. Chemically different types of HDAC inhibitors, such as TSA, apicidin, SAHA, M344 and n-butyrate induced remarkably similar responses in SIRT1-7 mRNA expression patterns. Differential responses in SIRT mRNA expression profiles indicate that the expression of the Sir2 family of genes is selectively regulated and dependent on histone/protein acetylation status.

PMID: 14523559