Table 8 Oxidative stress management by sirtuins

Li et al. (2022b)

An experimental study

Experimental in vivo and in vitro study

Explore the role of ATF3 in IDD

ATF3 positively regulates tert-butyl hydroperoxide (TBHP-)-induced nucleus pulposus cell (NPC) apoptosis, ROS production, inflammatory response, and extracellular matrix (ECM) degradation.ATF3 is a direct target of miR-874-3p, suggesting that up-regulation of ATF3 in IDD may be due, at least in part, to down-regulation of miR-874-3p in IDD, which alleviates the inhibition of ATF3 by miR-874-3p. -874-3p inhibition of ATF3

ATF3 has the potential to be used as a promising therapeutic target against IDD

Zheng et al. (2019)

An experimental study

Experimental in vivo and in vitro study

This study was performed to confirm whether TFEB was involved in IVDD development and its mechanism

The nuclear localization of TFEB declined in degenerated rat NP tissue as well as in TBHP treated NP cells.TFEB overexpression ameliorates the puncture-induced IVDD development in rats

TFEB overexpression suppressed TBHP-induced apoptosis and senescence via autophagic flux stimulation in NP cell and alleviates puncture-induced IVDD development in vivo

Chen et al. (2019)

An experimental study

Experimental in vivo and in vitro study

To study the effect of melatonin on IDD

Melatonin reduces apoptosis induced by tert-butyl hydroperoxide in nucleus pulposus (NP) cells. Melatonin was shown to preserve the extracellular matrix (ECM) content of collagen II, Aggrecan, and Sox-9, while inhibiting the expression of matrix denaturing enzymes, including MMP-13 and ADAMTS-5

Melatonin protected NP cells against apoptosis via mitophagy induction and ameliorated disc degeneration, providing the potential therapy for IDD

Li et al. (2018b)

An experimental study

Experimental in vitro study

To investigate the effect of SIRT1 on the invasiveness and inflammatory response of cultured RA-FLS

Overexpression of SIRT1 significantly inhibited RA-FLS proliferation, migration and invasion, and SIRT1 overexpression also significantly increased RA-FLS apoptosis and caspase-3 and -8 activity. Focusing on the inflammatory phenotype, we found that SIRT1 significantly reduced RA-FLS secretion of TNF-α, IL-6, IL-8 and IL-1β. Mechanistic studies further revealed that SIRT1 inhibits the NF-κB pathway by reducing p65 protein expression, phosphorylation and acetylation in RA-FLS

SIRT1 is a key regulator in RA pathogenesis by suppressing aggressive phenotypes and inflammatory response of FLS

Yao et al. (2018)

An experimental study

Experimental in vitro study

In this study, we investigated the role of SIRT1 in the FoxO1/β-catenin signaling pathway in oxidative stress and its mechanism in an osteoblast progenitor cell line (MC3T3-E1)

OB apoptosis and elevated oxidative stress in cells were simulated by H2O2, which was inhibited by moderate SIRT1 overexpression through reducing the oxidative stress. FOXO1 and β-catenin pathway activity was downregulated by SIRT1 and eventually resulted in inhibition of target genes, including the proapoptotic gene B cell lymphoma-2 interacting mediator of cell death, DNA repair gene growth arrest and DNA damage inducible protein 45 and the OB differentiation suppressor gene peroxisome proliferator activated receptor (PPAR)-γ. Furthermore, β-catenin and PPAR-γ were inhibited by SIRT1

Moderate overexpression of SIRT1 (~ threefold of normal level) may directly or indirectly inhibit apoptosis of OBs via the FOXO1 and β-catenin signaling pathway

Lin et al. (2018b)

An experimental study

Experimental in vitro study

The role of Sirt1/p53 in the protective effect of berberine (BBR) against hypoxia/reoxygenation (H/R)-mediated mitochondrial dysfunction in rat renal tubular epithelial cells (NRK-52E cells) was investigated

Pretreatment with BBR increased cell viability and inhibited mitochondrial oxidative stress and apoptosis. protein expression of Sirt1 was also enhanced with the reduction of p53. In addition, nuclear translocation of p53 and its acetylation were inhibited in NRK-52E cells pretreated with BBR. However, knockdown of Sirt1 counteracted the renoprotective effect of BBR

BBR preconditioning protects rat renal tubular epithelial cells against H/R-induced mitochondrial dysfunction via regulating the Sirt1/p53 pathway

Wang et al. (2019b)

An experimental study

Experimental in vivo study

The ability of the sirtuin-1 (SIRT1) agonist SRT1720 to reduce cognitive decline in type 2 diabetes mellitus (T2DM) was studied

SRT1720 significantly increased body weight, decreased FBG, improved cognitive function and reduced the levels of proteins associated with oxidative stress and inflammation damage in T2DM rats. Additionally, SRT1720 significantly decreased NF-κB p65 mRNA expression and increased eNOS and PPARγ expression. SRT1720 significantly reduced caspase-3 activity and HSP70 protein expression, and increased p-AMPK, SIRT1, Nrf2 and HO-1 protein expression

SRT1720 may reduce cognitive decline in T2DM rats through antioxidative and anti-inflammatory action via NF-κB and AMPK-dependent mechanisms

Shin et al. (2017)

An experimental study

Experimental in vivo study

To study the hepatoprotective mechanism of genipin in IR-induced liver injury, with a special focus on mitochondrial quality control (QC)

Hepatic IR decreased the levels of mitochondrial biogenesis related proteins (e.g., peroxisome proliferator-activated receptor gamma coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A), mitophagy related proteins (e.g., Parkin), and fusion related protein (e.g., mitofusin 2). Furthermore, hepatic IR decreased the levels of sirtuin1 protein and phosphorylation of AMP-activated protein kinase

Genipin protects against IR-induced hepatic injury via regulating mitochondrial QC

Ding et al. (2015)

An experimental study

Experimental in vivo study

To investigate the effect of upregulation of SIRT1 in the diabetic heart on susceptibility to ischemic injury

Upregulation of SIRT1 in diabetic hearts improved cardiac function and reduced infarct size to the same extent as in nondiabetic animals after MI/R, which was associated with reduced serum creatine kinase-MB, lactate dehydrogenase activity, and cardiomyocyte apoptosis.Ad-SIRT1 increased eNOS phosphorylation and decreased eNOS acetylation in diabetic hearts.The NOS inhibitor L-NAME inhibited SIRT1-enhanced eNOS phosphorylation and attenuated SIRT1-mediated antiapoptotic and antioxidant effects, as well as cardioprotective effects. The NOS inhibitor L-NAME inhibited the enhanced eNOS phosphorylation by SIRT1 and attenuated the SIRT1-mediated antiapoptotic and antioxidant effects as well as cardioprotective effects

Overexpression of SIRT1 reduces diabetes-exacerbated MI/R injury and oxidative stress via activating eNOS in diabetic rats

Jeong et al. (2007)

An experimental study

Experimental in vitro study

Probing SIRT1 attenuates apoptotic responses through deacetylation

SIRT1 enhances DNA repair and deacetylation of the repair protein Ku70. Ectopic overexpression of SIRT1 leads to increased repair of radiation-generated DNA strand breaks. In addition, SIRT1 physically complexes with the repair protein Ku70, leading to subsequent deacetylation. Dominant-negative SIRT1 is a catalytically inactivated form that does not induce deacetylation of the Ku70 protein and an increase in DNA repair capacity

SIRT1 modulates DNA repair activity, which could be regulated by the acetylation status of repair protein Ku70 following DNA damage

Xiong et al. (2011)

An experimental study

Experimental in vivo study

Explore the functional consequences of the interaction between FoxO1 and SIRT1

oxO1 directly activates SIRT1 promoter activity, and both IRS-1 and FKHD-L enable FoxO1-dependent SIRT1 transcription. FoxO1 binds to the IRS-1 and FKHD-L sites of the SIRT1 promoter. Consistently, FoxO1 overexpression increases SIRT1 expression, whereas depletion of FoxO1 by siRNA decreases SIRT1 expression at messenger RNA and protein levels in vascular smooth muscle cells and HEK293 cells

Positive feedback mechanisms regulate FoxO1-dependent SIRT1 transcription and suggest a previously unappreciated function of FoxO1

Kim et al. (2015)

An experimental study

Experimental in vivo study

Mechanisms by which CO regulates hepatic I/R injury

CO increased SIRT1 expression by inhibiting miR-34a. both CO and PFT reduced proinflammatory cytokine production in vitro. Knockdown of SIRT1 in LPS-stimulated macrophages increased NF-κB acetylation and increased proinflammatory cytokines.CO treatment decreased miR-34a expression and increased SIRT1 expression in oxidant-attacked hepatocytes; and rescued SIRT1 expression in cells transfected with either p53 or miR-34a

In response to CO, enhanced SIRT1 expression mediated by miR-34a inhibition protects against liver damage through p65/p53 deacetylation

Iacovelli et al. (2016)

An experimental study

Experimental in vitro study

This study examines the ability of PGC-1α to regulate RPE metabolic program and oxidative stress response

Maturation of ARPE-19 and hfRPE was associated with significant increase in mitochondrial mass, expression of oxidative phosphorylation (OXPHOS) genes, and PGC-1α gene expression. Overexpression of PGC-1α increased expression of OXPHOS and fatty-acid β-oxidation genes, ultimately leading to the potent induction of mitochondrial respiration and fatty-acid oxidation

This study provides important insights into the metabolic changes associated with RPE functional maturation and identifies PGC-1α as a potent driver of RPE mitochondrial function and antioxidant capacity

Liang et al. (2020)

An experimental study

Experimental in vitro study

To investigate the functional role of the SIRT1/PGC-1α pathway in the regulation of autophagy/mitochondrial autophagy and tight junction protein expression in porcine intestinal epithelial cell (IPEC-1) oxidative dysfunction

H2O2 exposure resulted in high accumulation of ROS, decreased mitochondrial membrane potential and inhibition of tight junction molecules in IPEC-1 cells. In addition, COX IV mRNA expression and the SIRT1/PGC-1α pathway were also inhibited, and SIRT1 activation significantly suppressed ROS production, leading to increased mitochondrial membrane potential and COX IV expression

Autophagy/mitophagy elevation caused by SIRT1/PGC-1α pathway activation might be a protective mechanism to increase tight junction integrity against oxidative stress-mediated ROS production in IPEC-1 cells

Zhang et al. (2013)

An experimental study

Experimental in vivo study

The study investigated the effect of nuclear factor erythroid 2-related factor 2 (Nrf2), a cellular oxidative stress sensor, on energy homeostasis and liver pathophysiology during fasting

Fasting reduced liver size in Nrf2-expressing mice but not in Nrf2 null mice. Nrf2 null mice accumulated more nonesterified free fatty acids and triglycerides in the liver after fasting compared with mice of other genotypes. It is expected that increased oxidative stress in the liver of Nrf2-null mice would lead to mitochondrial damage, which would reduce the increased oxidation and lipid accumulation in the liver of Nrf2-null mice

The Nrf2-regulated signaling pathway is critical in protecting mitochondria from oxidative stress during feed deprivation, which ensures efficient utilization of fatty acids in livers of mice

Huang et al. (2015)

An experimental study

Experimental in vitro study

To investigate the effect of RAGE (specific receptor for AGEs) on Sirt1 in terms of protein expression and deacetylase activity

Along with reduced expression of RAGE, the specific receptor for AGEs, Polydatin (PD) significantly reversed the down-regulation of Sirt1 in protein expression and deacetylase activity and attenuated FN and TGF-β1 expression in GMCs exposed to AGEs

The resistance of PD on upregulated FN and TGF-β1 induced by AGEs via oxidative stress in GMCs is closely associated with its activation of Sirt1-Nrf2-ARE pathway

Liu et al. (2018b)

An experimental study

Experimental in vitro study

The present study aimed to explore the possible molecular mechanism underlying the anti-apoptosis and protective effects of resveratrol (RES) on the co-culture of Sertoli-germ cells and rat testes

Microcystin-leucine-arginine (MC-LR) treatment inhibited proliferation and induced apoptosis in Sertoli-germ cells. In addition, SIRT1 and Bcl-2 were inhibited, whereas p53 and Ku70 acetylation, Bax expression and cleaved caspase-3 were up-regulated by MC-LR. However, RES pretreatment ameliorated MC-LR-induced apoptosis and SIRT1 inhibition and down-regulated MC-LR-induced increases in p53 and Ku70 acetylation, Bax expression and caspase-3 activation

The administration of RES could ameliorate MC-LR-induced Sertoli-germ cell apoptosis and protect against reproductive toxicity in rats by stimulating the SIRT1/p53 pathway, suppressing p53 and Ku70 acetylation and enhancing the binding of Ku70 to Bax

Jacobs et al. (2008)

An experimental study

Experimental in vitro study

Whether SIRT3 interacts with and regulates the activity of FOXO proteins

Overexpression of the wild-type SIRT3 gene increases FOXO3a DNA binding activity as well as FOXO3a-dependent gene expression. Biochemical analysis of HCT116 cells overexpressing the deacetylated mutant compared to the wild-type SIRT3 gene indicated an overall oxidized intracellular environment monitored by increased intracellular superoxide and oxidized glutathione levels

SIRT3 and FOXO3a constitute a potential mitochondrial signaling cascade response pathway

Sundaresan et al. (2009)

An experimental study

Experimental in vivo and in vitro study

Explore how Sirt3 comes to protect the mouse heart

Sirt3 blocks cardiac hypertrophy by activating the forkhead box O3a-dependent (Foxo3a-dependent), antioxidant-encoding genes manganese superoxide dismutase (MnSOD) and catalase (Cat), thereby decreasing cellular levels of ROS. Reduced ROS levels inhibit Ras activation and downstream signaling through the MAPK/ERK and PI3K/Akt pathways. This leads to inhibition of the activity of transcription factors (especially GATA4 and NFAT) and translation factors (especially eukaryotic initiation factor 4E (elf4E) and S6 ribosomal protein (S6P), which are involved in the development of cardiac hypertrophy

SIRT3 is an endogenous negative regulator of cardiac hypertrophy

Tseng et al. (2013)

An experimental study

Experimental in vitro study

Elucidate the interaction between FOXO3 is SIRT3

Hydrogen peroxide induces SIRT3 to deacetylate FOXO3 at K271 and K290, which then upregulates a set of genes critical for mitochondrial homeostasis (mitochondrial biogenesis, fission/fusion, and mitochondrial autophagy)

SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative stress provides a possible direction for aging-delaying therapies and disease intervention

Valle et al. (2005)

An experimental study

Experimental in vitro study

It is hypothesized that the transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), a major regulator of oxidative metabolism and mitochondrial biogenesis, may be involved in the transcriptional regulation of mitochondrial antioxidant defense systems in vascular endothelial cells

Endothelial cells overexpressing PGC-1alpha showed reduced accumulation of reactive oxygen species (ROS), increased mitochondrial membrane potential, and reduced apoptotic cell death. siRNA down-regulation of PGC-1alpha levels decreased the expression of mitochondrial detoxification proteins

PGC-1α may play a crucial protective role in the vascular complications of diabetes, in which mitochondrial metabolism of glucose has been shown to lead to oxidative stress and vascular endothelial cell dysfunction

Pillai et al. (2015)

An experimental study

Experimental in vivo study

Exploring HKL blockade agonist-induced and pressure overload-mediated cardiac hypertrophic responses

The presence of HKL in mitochondria nearly triples Sirt3 expression and suggests that HKL may bind to Sirt3 to further increase its activity.Increased Sirt3 activity is associated with decreased acetylation of mitochondrial Sirt3 substrates, MnSOD, and Oligomycin Sensitivity Conferring Protein (OSCP)

HKL is a pharmacological activator of Sirt3 capable of blocking, and even reversing, the cardiac hypertrophic response

Kong et al. (2010)

An experimental study

Experimental in vitro study

To investigate the molecular mechanism by which PGC-1alpha induces several key reactive oxygen species (ROS) detoxification enzymes

Knockdown of PGC-1alpha results in reduced Sirt3 gene expression.PGC-1alpha co-localizes with ERRalpha in the mSirt3 promoter. Knockdown of ERRalpha reduced induction of Sirt3 by PGC-1alpha in C(2)C(12) myotubes.Overexpression of SIRT3 or PGC-1alpha in C(2)C(12) myotubes reduced basal ROS levels

Sirt3 acts as a downstream target gene of PGC-1α and mediates the effects of PGC-1α on cellular ROS production and mitochondrial biogenesis

Zhu et al. (2023)

An experimental study

Experimental in vivo and in vitro study

Exploring the effects of crosstalk between oxidative stress and iron death in IVDD

Sirt3 is reduced and iron death occurs after IVDD. Knockdown of Sirt3 (Sirt3) promotes IVDD and poor pain-related behavioral scores by increasing oxidative stress-induced iron death. overexpression of USP11 significantly ameliorates oxidative stress-induced iron death, thereby alleviating IVDD by increasing Sirt3

USP11-mediated oxidative stress-induced iron death has been identified as a promising target for the treatment of IVDD

Song et al. (2018)

An experimental study

Experimental in vivo and in vitro study

The study examined whether the accumulation of AGEs exacerbated NP cell apoptosis and IVD degeneration and explored the mechanisms behind these effects

AGEs treatment significantly inhibited human NP cell viability and proliferation, which was mainly due to apoptosis.Impairment of Sirtuin3 (SIRT3) function and mitochondrial antioxidant network is an important mechanism of AGEs-induced oxidative stress and secondary human NP cell apoptosis

SIRT3 prevents AGEs-induced apoptosis and IVD degeneration in human NP cells

Zhou et al. (2019)

An experimental study

Experimental in vivo and in vitro study

The objective of this paper is to determine whether SIRT3 could retard intervertebral disc degeneration and study the mechanism

SIRT3 expression was reduced in the degenerating human nucleus pulposus.Nucleus pulposus cells with SIRT3 overexpression vectors expressed more collagen II.FOXO3a and superoxide dismutase 2 (SOD2), suggesting that SIRT3 may ameliorate intervertebral disc degeneration through anti-oxidative stress

SIRT3 is a protective factor for intervertebral discs and can reduce oxidative stress in the intervertebral disc

Hu et al. (2021)

An experimental study

Experimental in vivo and in vitro study

In this study, we investigated the roles of the Nrf2/Sirt3 pathway and tert-butylhydroquinone (t-BHQ) in IVDD and elucidated their potential working mechanisms

Activation of the Nrf2/Sirt3 pathway inhibited tert-butyl hydroperoxide- (TBHP-) induced apoptosis and mitochondrial dysfunction in vitro. In addition to apoptosis, upregulation of the Nrf2/Sirt3 pathway induced by t-BHQ restored TBHP-induced autophagic flux disturbances. However, its protective effect was reversed by chloroquine and Si-ATG5

The Nrf2/Sirt3 pathway and its agonist represent a potential candidate for treating IVDD

Liu et al. (2023)

An experimental study

Experimental in vitro study

The mechanism by whichDuhuo Jisheng Decoction( DHJSD) prevents IVD degeneration in IL-1β-treated human myeloid cells in vitro was investigated

DHJSD enhanced the viability of NP cells treated with IL-1β in a concentration–time-dependent manner.DHJSD treatment could effectively delay IL-1β-induced NP apoptosis by affecting the miR-494/SIRT3/mitochondrial autophagy signaling axis

MiR-494/SIRT3/mitophagy signaling pathway is responsible for the apoptosis and mitochondrial dysfunction of NP cells and that DHJSD may exert protective effects against IVD degeneration by regulating the miR-494/SIRT3/mitophagy signal axis

Wang et al. (2019c)

An experimental study

Experimental in vitro study

Investigating the inhibitory properties of metformin on mitochondrial damage

Metformin treatment upregulated SIRT3 expression and attenuated the loss of cell viability and reduced mitochondria-induced ROS production in IL-1β-stimulated chondrocytes. Metformin also attenuated the expression of IL-1β-induced catabolic genes, and the IRT3 inhibitor 3-TYP effectively inhibited the initiation of mitochondrial autophagy as a result of reduced expression of PINK1 and Parkin, decreased LC3II/LC3I, enhanced expression of MMP3 and MMP13, and decreased expression of collagen II

Metformin inhibits IL-1β-induced oxidative and osteoarthritis-like inflammatory changes through enhancement of the SIRT3/PINK1/Parkin signaling pathway