Table 7 Regulation of apoptosis by sirtuins in IVDD

Liu et al. (2018a)

An experimental study

Experimental in vitro study

To investigate how SIRT1 attenuates oxidative stress-induced apoptosis

SIRT1 overexpression decreased the rate of apoptosis in human adipose stem cells (ADSCs), whereas SIRT1 down-regulation and EX527 showed the opposite effect.SIRT1 overexpression decreased total p53 protein, whereas SIRT1 down-regulation and EX527 increased the amount of p53 protein

SIRT1 had a pivotally protective role in the regulation of ADSCs aging and apoptosis induced by H2O2

Zhang et al. (2017)

An experimental study

Experimental in vitro study

To explore the mechanism by which oxidative stress promotes FoxO1 activity

Sirtuin 1 (SIRT1), a deacetylase that suppresses FoxO1 acetylation in GCs, was downregulated by miR-181a and reversed the promoting effects of H2O2 and miR-181a on FoxO1 acetylation and GC apoptosis

miR-181a mediates oxidative stress-induced FoxO1 acetylation and GC apoptosis by targeting SIRT1 both in vitro and in vivo

Brunet et al. (2004)

An experimental study

Experimental in vitro study

Probing the molecular mechanism of Sir2 life extension

SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death

One way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance

Khan et al. (2012)

An experimental study

Experimental in vitro study

To investigate whether SIRT1 activators reduce oxidative stress and promote mitochondrial function in neuronal cells

The SIRT1 activators resveratrol (RSV) and SRTAW04 decreased ROS levels and promoted cell survival in RGC-5 cells and primary RGC cultures.The SIRT1 activators also increased succinate dehydrogenase (SDH) expression and promoted deacetylation of PGC-1α

SIRT1 activators prevent cell loss by reducing oxidative stress and promoting mitochondrial function in a neuronal cell line

Zhou et al. (2017)

An experimental study

Experimental in vivo study

To investigate the effects of SIRT1 on ICH injury and the underlying mechanisms

Activation of SIRT1 with SRT1720 (5 mg / kg) restored nuclear SIRT1, deacetylation of PGC-1α, and mitochondrial biogenesis and reduced mortality, behavioral deficits, and brain water content without significant changes in ICH-induced phosphorylated AMP-activated protein kinase (pAMPK). Activation of SIRT1 with SRT1720 also restored mitochondrial electron transport chain proteins and reduced apoptotic proteins in ICH

Activation of SIRT1 with SRT1720 (5 mg/kg) restored nuclear SIRT1, deacetylation of PGC-1α, and mitochondrial biogenesis and decreased mortality, behavioral deficits, and brain water content without significant changes in phosphorylated AMP-activated protein kinase (pAMPK) induced by ICH

Iaconelli et al. (2017)

An experimental study

Experimental in vitro study

Explore the extent to which reversible acetylation regulates AKT function

AKT is acetylated at Lys163 and Lys377 located in the kinase domain, two novel sites distinct from the acetylation sites in the PH-domain modulated by the sirtuins. Measurement of the functional effect of HDAC6 inhibition on AKT revealed decreased binding to PIP3, a correlated decrease in AKT kinase activity, decreased phosphorylation of Ser552 on β-catenin, and modulation of neuronal differentiation trajectories

Deacetylase activity of HDAC6 as a novel regulator of AKT signaling and point to novel mechanisms for regulating AKT activity with small-molecule inhibitors of HDAC6 currently under clinical development

Li et al. (2018a)

An experimental study

Experimental in vivo study

The current study was designed to investigate the role of PDE4 in EBI after SAH and explore the potential mechanism

PDE4 is predominantly located in neurons after SAH. rolipram attenuated brain edema and improved neurological function in the SAH rat model. In addition, rolipram increased the expression of Sirtuin1 (SIRT1) and upregulated Akt phosphorylation, which was accompanied by a decrease in neuronal apoptosis. Administration of sirtuinol inhibited Akt phosphorylation

PDE4 inhibition by rolipram protected rats against EBI after SAH via suppressing neuronal apoptosis through the SIRT1/Akt pathway

Zhu et al. (2021)

An experimental study

Experimental in vitro study

The aim of this study was to investigate whether m6A modification regulates TNF-α-mediated cell viability, cell cycle arrest, and cell senescence and how it works

miR-34a-5p was predicted to interact with the SIRT1 mRNA. SIRT1 overexpression counteracted the miR-34a-5p-promoted cell senescence. METTL14 participates in the TNF-α-induced m6A modification of miR-34a-5p to promote cell senescence in HNPCs and NP cells of IVDD patients. Downregulation of either METTL14 expression or miR-34a-5p leads to the inhibition of cell cycle arrest and senescence

SIRT1 mRNA is an effective binding target of miR-34a-5p, and SIRT1 overexpression mitigates the cell cycle arrest and senescence caused by miR-34a-5p

Xiang et al. (2020)

An experimental study

Experimental in vivo and in vitro study

The aimed to investigate the key role of circRNA in compression loading-induced IDD

CircRNA-CIDN was significantly downregulated in compression-treated human NP cells, and overexpressing circRNA-CIDN inhibited compression-induced apoptosis and NP ECM degradation. CircRNA-CIDN served as a sponge for miR-34a-5p, an important miRNA that enhanced compression-induced damage of NP cells via repressing the silent mating type information regulation 2 homolog 1 (SIRT1). CircRNA-CIDN was also verified to contain IDD development in an ex vivo IDD model

CircRNA-CIDN binding to miR-34a-5p played an important role in mitigating compression loading-induced nucleus pulposus cell damage via targeting SIRT1, providing a potential therapeutic strategy for IDD treatment

Xie et al. (2019)

An experimental study

Experimental in vivo and in vitro study

This study aimed to investigate the role of circular RNAs (circRNAs) in the pathogenesis of IVDD

Downregulation of circERCC2 increased the level of miR-182-5p and decreased the level of SIRT1 in degenerative NP tissues in vivo as well as in TBHP-stimulated NPCs in vitro. Treatment of SIRT1-si activated apoptosis and inhibited mitophagy. Moreover, miR-182-5p-si could regulate the mitophagy and the apoptosis of NPCs by targeting SIRT1. The effects of circERCC2 on NPCs and IVDD rat model were mediated by miR-182-5p/SIRT1 axis

First evidence that circERCC2 could ameliorate IVDD through miR-182-5p/SIRT1 axis by activating mitophagy and inhibiting apoptosis, and suggests that circERCC2 is a potentially effective therapeutic target for IVDD

Song et al. (2020b)

An experimental study

Experimental in vivo and in vitro study

Explore the mechanisms by which circular RNAs (circRNAs) regulate IDD

CircRNA_0000253 was selected as having the maximum upregulation in degenerative NPC exosomes. ceRNA analysis showed that circRNA_0000253 could adsorb miRNA-141-5p to downregulate SIRT1. circRNA_0000253 was confirmed to increase IDD by adsorbing miRNA-141-5p and downregulating SIRT1 in vivo and in vitro

Exosomal circRNA_0000253 owns the maximum upregulation in degenerative NPC exosomes and could promote IDD by adsorbing miRNA-141-5p and downregulating SIRT1

Chen et al. (2021a)

An experimental study

Experimental in vivo and in vitro study

Explore the molecular mechanisms of IDD

MiR-22-3p plays a mechanistic role in the development of IDD by targeting SIRT1, which in turn activates the JAK1/STAT3 signaling pathway. Therapeutically, the delivery of miR-22-3p inhibitors and mimics through the synthesized nanoparticles in the IDD model alleviates and aggravates IDD, respectively

The nanocarriers enhance transportation of miR-22-3p to nucleus pulposus cells, thus enabling the in vivo inhibition of miR-22-3p for therapeutic purposes and consequently promoting the development of miRNA-specific drugs for IDD

Wang et al. (2016c)

An experimental study

Experimental in vivo and in vitro study

Exploring miR-141 as an important molecular mechanism for IDD

MiR-141 is a key regulator of IDD. miR-141 drives IDD by inducing apoptosis in myeloid nucleus pulposus (NP) cells. In addition, miR-141 KO in mice attenuated spontaneous and surgically-induced IDD. Mechanistically, miR-141 promotes IDD by targeting and depleting the negative regulator of the NF-κB pathway, SIRT1. Therapeutically, up- or down-regulation of miR-141 by nanoparticle delivery in IDD models exacerbated or alleviated experimental IDD, respectively

MiR-141 promotes IDD progression in part by interacting with the SIRT1/NF-κB pathway

Chen et al. (2023a)

An experimental study

Experimental in vivo and in vitro study

To demonstrate that miR-22-3p is essential in the regulation of IDD

MiR-22-3p plays a mechanistic role in the development of IDD by targeting SIRT1, which in turn activates the JAK1/STAT3 signaling pathway. This is confirmed by a luciferase reporter assay and western blot analysis. Therapeutically, the delivery of miR-22-3p inhibitors and mimics through the synthesized nanoparticles in the IDD model alleviates and aggravates IDD, respectively

The nanocarriers enhanced the translocation of miR-22-3p to myeloid cells, which enabled the in vivo inhibition of miR-22-3p for therapeutic purposes, thus facilitating the development of miRNA-specific drugs

Ji et al. (2018)

An experimental study

Experimental in vivo and in vitro study

Understand the molecular mechanisms that regulate disc maintenance and destruction

miR-141 drives IDD by inducing apoptosis in nucleus pulposus (NP) cells. miR-141 promotes IDD by targeting and depleting SIRT1, a negative regulator of the NF-κB pathway. miR-141 also promotes IDD by targeting and depleting SIRT1, a negative regulator of the NF-κB pathway. Therapeutically, up- or down-regulation of miR-141 by nanoparticle delivery in IDD models exacerbated or alleviated experimental IDD, respectively

MiR-141 promotes IDD progression in part by interacting with the SIRT1/NF-κB pathway

Meng et al. (2023)

An experimental study

Experimental in vivo and in vitro study

The aim was to verify the potential therapeutic mechanisms of miR-106b-5p for IDD

Overexpression of miR-106b-5p in NP cells decreases cell growth, induces apoptosis, hinders extracellular matrix formation, and increases the expression of matrix-degrading enzymes through the SIRT2/MAPK/ERK signaling pathway

Targeting miR-106b-5p in intervertebral disc has therapeutic effects on IDD

Liao et al. (2019)

An experimental study

Experimental in vivo and in vitro study

To explore the mechanism by which MSC-exos inhibits excessive NP cell apoptosis during IDD

MSC-exos could attenuate ER stress-induced apoptosis by activating AKT and ERK signaling. Moreover, delivery of MSC-exos in vivo modulated ER stress-related apoptosis and retarded IDD progression in a rat tail model

MSC-exos can regulate ER stress-induced apoptosis during IVD degeneration associated with AGEs

Liu et al. (2020a)

An experimental study

Experimental in vitro study

To investigate the effects of diabetes-related hyperglycemia on NPMSC biology

High glucose concentration (HG-NPMSC) stemness gene expression as well as mRNA and protein expression of silencing information regulatory protein 1 (SIRT1), SIRT6, hypoxia-inducible factor-1α (HIF-1α), and glucose transporter protein 1 (GLUT-1) were significantly decreased, whereas apoptosis, cellular senescence, and cysteine asparagin-3 expression were increased

High glucose concentration significantly decreased cell proliferation, colony formation ability, migration and wound-healing capability of nucleus pulposus-derived mesenchymal stem cells