SIRT1 overexpression decreases cisplatin-induced acetylation of NF-κB p65 subunit and cytotoxicity in renal proximal tubule cells
As the increased acetylation of p65 is linked to nuclear factor-κB (NF-κB) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-κB and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-κB and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-κB p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-κB during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-κB p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-κB through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.
Available from: Carmela Rita Balistreri
- "In particular, CR increases the expression of SIRT1 in multiple tissues, even if this effect does not appear to be uniform in all tissues or across different studies . It has been demonstrated that SIRT1 interacts with p65/RelA protein and specifically cleaves the acetyl group form, the lysine-310 of p65 protein, involved in enhancing the trans-activation efficiency of NF-κB system [81,82]. Thus, SIRT1 is a potent inhibitor of NF-κB system. "
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ABSTRACT: Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-kappaB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-kappaB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population.
Available from: Brian Morris
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ABSTRACT: Sirtuins are a class of NAD(+)-dependent deacetylases having beneficial health effects. This extensive review describes the numerous intracellular actions of the seven mammalian sirtuins, their protein targets, intracellular localization, the pathways they modulate, and their role in common diseases of aging. Selective pharmacological targeting of sirtuins is of current interest in helping to alleviate global disease burden. Since all sirtuins are activated by NAD(+), strategies that boost NAD(+) in cells are of interest. While most is known about SIRT1, the functions of the six other sirtuins are now emerging. Best-known is the involvement of sirtuins in helping cells adapt energy output to match energy requirements. SIRT1 and some of the other sirtuins enhance fat metabolism and modulate mitochondrial respiration to optimize energy harvesting. The AMP kinase/SIRT1-PGC-1a-PPAR axis and mitochondrial sirtuins appear pivotal to maintaining mitochondrial function. Down-regulation with aging explains much of the pathophysiology that accumulates with aging. Post-translational modifications of sirtuins and their substrates affect specificity. Although SIRT1 activation seems not to affect lifespan, activation of some of the other sirtuins might. Since sirtuins are crucial to pathways that counter the decline in health that accompanies aging, pharmacological agents that boost sirtuin activity have clinical potential in treatment of diabetes, cardiovascular disease, dementia, osteoporosis, arthritis and other conditions. In cancer, however, SIRT1 inhibitors could have therapeutic value. Nutraceuticals such as resveratrol have a multiplicity of actions besides sirtuin activation. Their net health benefit and relative safety may have originated from the ability of animals to survive environmental changes by utilizing these stress resistance chemicals in the diet during evolution. Each sirtuin forms a key hub to the intracellular pathways affected.
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To observe the expression changes of Sirt1 gene and examine the role and significance of degenerative process in human cervical endplate chondrocytes through a degeneration model of human cervical vertebral endplate chondrocyte.
Cartilage endplates of 30 patients were divided into control group (n = 16) with cervical vertebral fracture or dislocation and cervical spondylosis group (n = 14) with cervical spondylotic myelopathy. Endplate chondrocytes were isolated by enzyme digestion and cultured in vitro for 10 days. The differences of endplate chondrocytes from normal and degenerative cartilage endplates were observed by inverted phase-contrast microscope, hematoxylin and eosin staining and toluidine blue staining. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect the mRNA expressions of Sirt1, collagen II and aggrecan.
Compared with the normal group, the cellular morphology of degenerative group showed spindle-shaped changes. The mRNA expression of Sirt1 (P = 0.034) significantly decreased. Aggrecan (P = 0.0063) and collagen II (P = 0.0072) decreased also markedly.
Sirt1 gene expression is significantly down-regulated in degenerative human cervical endplate chondrocytes. Regulating the expression of Sirt1 gene may block or delay the occurrence of human cervical endplate cartilage degeneration.
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