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Neuroinflammation is associated with the development of depression. Deacetylases SIRT1 and SIRT2 are reported to exert neuroprotective effects in aging, neurogenesis, neurodegeneration and neuroinflammation. Therefore, this study aimed to investigate the effects of SIRT1 and SIRT2 modulators on LPS-induced neuroinflammation and neurodegeneration in vitro. To achieve this, HAPI rat microglial cells were pre-treated with the SIRT1 activator resveratrol (0.1-20 µM), the selective SIRT1 inhibitor EX527 (0.1; 1 µM), the dual SIRT1/SIRT2 inhibitor sirtinol (0.1-20 µM) and the SIRT2 inhibitor AGK2 (0.1; 1 µM), prior to exposure with LPS (5 ng/mL) for 20 h. The reference antidepressant drug fluoxetine and the nonsteroidal anti-inflammatory drug ibuprofen were also evaluated in the same paradigm, both at 1 μM. Resveratrol and sirtinol inhibited TNF-α production to a greater degree than either fluoxetine or ibuprofen. Resveratrol, sirtinol, EX527 and AGK2 significantly reduced PGE 2 production by up to 100% in microglia. Then, the supernatant was transferred to treat SH-SY5Y cells for 24 h. In all cases, SIRT modulator pretreatment significantly protected undifferentiated SH-SY5Y human neuroblastoma cells from the insult of LPS-stimulated HAPI supernatant by up to 40%. Moreover, resveratrol and sirtinol also showed significantly better neuroprotection than fluoxetine or ibuprofen by up to 83 and 69%, respectively. In differentiated SH-SY5Y cells, only sirtinol (20, 10 µM) and AGK2 (0.1 µM) pretreatment protected the cells from LPS-stimulated HAPI supernatant. This study suggests that SIRT1 and SIRT2 modulators are effective in inhibiting LPS-stimulated production of TNF-α and PGE 2 in HAPI microglial cells and protecting SH-SY5Y cells from inflammation. Thus, we provide proof of concept for further investigation of the therapeutic effect of SIRT1 and SIRT2 modulators and combination with current antidepressant medication as a treatment option.

Background: Renal transplant surgical proceedings are known to elicit periods of hypoxia and consequent blood flow reestablishment triggering ischemia-reperfusion (I-R) injury. Kidney damage induced by I-R injury associates with a higher risk of graft dysfunction and rejection. Anesthetic preconditioning exerts a beneficial effect on I-R injury by reducing oxidative stress, inflammation and apoptosis. However, the degree of renoprotection stimulated by commonly used anesthetics, as well as their mechanisms of action, are largely unknown. Sirtuins are class III histone deacetylases that reduce cellular stress, promote genome stability and regulate senescence. So far, the relationship between sirtuins and anesthetic preconditioning in the context of renal I-R has not been studied. The main objective of the present work was to determine the renal expression of sirtuins after I-R damage in rats under different anesthetic preconditioning treatments., Methods: Unilateral ischemia was performed via occlusion of the left renal hilum for 45 min and followed by 24 hours of reperfusion. Anesthetic preconditioning schemes (morphine 0.5 mg/kg, fentanyl 10 µg/kg, propofol 7.5 mg/kg, or dexmedetomidine 25 µg/kg) were administered 1 hour before ischemia. Creatinine levels were determined in serum, and expression of kidney injury molecule 1 and sirtuin 1, 2, 3 and 7 in kidney tissue was quantified by RT-PCR., Results: Anesthetic preconditioning with morphine, fentanyl, propofol and dexmedetomidine reduced kidney injury markers after I-R and modulated sirtuin gene expression. Opioids or dexmedetomidine administration before ischemia increased sirtuin 2 expression and correlated with improved renal function., Conclusions: Anesthetic preconditioning is a promising strategy to prevent I-R injury associated with transplantation. Our results suggest that sirtuin 2 is involved in the protective mechanisms of some commonly used anesthetics against I-R damage.

Sirtuins have emerged as a promising novel class of anti-cancer drug targets. Inhibition of SIRT1 and SIRT2 induces apoptosis in cancer cells and they play multifaceted roles in regulating autophagy. In the present study, we found that salermide, a SIRT1/2-specific inhibitor or small interfering RNAs (siRNAs) to block SIRT1/2 expression could induce autophagy in human NSCLC cells. Moreover, SIRT1/2 inhibition increased the expression levels of ATF4 and DDIT4 and downregulated p-RPS6KB1 and p-EIF4EBP1, two downstream molecules of mTORC1. Moreover, ATF4 or DDIT4 knockdown attenuated salermide-induced autophagy, suggesting that SIRT1/2 inhibition induced autophagy through the ATF4-DDIT4-mTORC1 axis. Mechanistically, SIRT1/2 inhibition led to HSPA5 acetylation and dissociation from EIF2AK3, leading to ER stress response and followed by upregulation of ATF4 and DDIT4, triggering autophagy. Silencing of the autophagic gene ATG5 in lung cancer cells resulted in increased apoptotic cell death induced by SIRT1/2 inhibition. Our data show that inhibition of SIRT1/2 induces pro-survival autophagy via acetylation of HSPA5 and subsequent activation of ATF4 and DDIT4 to inhibit the mTOR signaling pathway in NSCLC cells. These findings suggest that combinatorial treatment with SIRT1/2 inhibitors and pharmacological autophagy inhibitors is an effective therapeutic strategy for cancer therapy.

Mycoplasma fermentans is a pathogenic bacterium that infects humans and has potential pathogenic roles in respiratory, genital and rheumatoid diseases. NAD + -dependent deacetylase is involved in a wide range of pathophysiological processes and our studies have demonstrated that expression of mycoplasmal deacetylase in mammalian cells inhibits proliferation but promotes anti-starvation stress tolerance. Furthermore, mycoplasmal deacetylase is involved in cellular anti-oxidation, which correlates with changes in the proapoptotic proteins BIK, p21 and BIM. Mycoplasmal deacetylase binds to and deacetylates the FOXO3 protein, similar with mammalian SIRT2, and affects expression of the FOXO3 target gene BIM, resulting in inhibition of cell proliferation. Mycoplasmal deacetylase also alters the performance of cells under drug stress. This study expands our understanding of the potential molecular and cellular mechanisms of interaction between mycoplasmas and mammalian cells., (Copyright © 2017 Elsevier GmbH. All rights reserved.)