Table 5 Anti-inflammatory effects of sirtuins in IVDD
From: Sirtuins in intervertebral disc degeneration: current understanding
Authors (reference) | Type of study | Study design | Aim | Results | Conclusion |
|---|---|---|---|---|---|
Jin et al. (2019) | An experimental study | in vitro study using human IVD nucleus pulposus (NP) cells | To investigate whether baicalein has a therapeutic effect on IDD by inhibiting the inflammatory response | Baicalein inhibited the overexpression of not only inflammatory cytokines, including NO, PGE2, TNF-α and IL-6, but also COX-2 and iNOS. Baicalein reversed IL-1β-induced overexpression of MMP13 and ADAMTS5 as well as degradation of aggregated glycans and type II collagen in a dose-dependent manner. Mechanistically, baicalein inhibited IL-1β-induced activation of the NF-κB and MAPK pathways. In addition, baicalein treatment improved puncture-induced IDD in a rat model | Baicalein has a therapeutic effect on IDD by inhibiting the inflammatory response |
Han et al. (2019) | An experimental study | Rabbit annulus fibrosus stem cells (AFSCs) were treated with metformin and lipopolysaccharide (LPS) in vitro | The present study aimed to investigate the mechanism of intervertebral disc degeneration (IVDD) and identify an efficient treatment for low back pain | LPS induced HMGB1 release from the nuclei of AFSCs and caused cell senescence in a concentration-dependent manner. The production of PGE2 and HMGB1 was increased in the medium of the LPS-treated AFSCs. Certain inflammation-associated genes (IL-β1, IL-6, COX-2 and TNF-α) and proteins (IL-β1, COX-2 and TNF-α) and specific catabolic genes (MMP-3 and MMP-13) exhibited increased expression in LPS-treated AFSCs. However, the expression levels of other anabolic genes, such as collagen I and collagen II were decreased in LPS-treated AFSCs. Following addition of metformin to LPS-containing medium, HMGB1 was retained in the nuclei of AFSCs and the production of PGE2 and HMGB1 was reduced | The findings indicated that metformin exerted an anti-inflammatory effect by blocking the HMGB1 translocation and by inhibiting catabolic production and cell senescence in AFSCs |
Cai et al. (2017) | An experimental study | In vitro study | To investigate the effect of a mixture of factors secreted by degenerating disc cells on transplanted exogenous healthy NPCs | The MAPK and NF-κB pathways were implicated in dCM-mediated responses of healthy NPCs. TGF-β1 partially reversed the dCM-mediated NPC dysfunction. Increased levels of inflammatory factors and decreased TGF-β1 levels in dCM suggest an inflammatory environment in degenerated disc tissue | The catabolic effect of dCM on human healthy NPCs is mediated by MAPK and NF-κB pathways and can be reduced by TGF-β1 |
Mouser et al. (2019) | Comparative Study | Experimental in vivo and in vitro study | The aim of this study was to investigate whether decreased tonicity under restricted swelling conditions (as occurring in early disc degeneration) could initiate an inflammatory cascade that mediates further degeneration | The extracellular environment directly affects NP cells instead of inducing a classical inflammatory cascade. Furthermore, IL-8 increased in swelling restricted samples, while IL-6 and PGE2 were elevated in free swelling controls | The involvement of different mechanisms in disc degeneration with intact AF compared to herniation |
Miyamoto et al. (2000) | Comparative Study | Experimental in vivo and in vitro study | To elucidate the role of COX-2 in the pathogenesis of LDH radiculopathy | Lumbar disc herniated cells expressed mRNA for COX-2, IL-1β, and TNFα. disc-derived cells also produced large amounts of PGE2 by concomitant stimulation of inflammatory cytokines, and this PGE2 production was markedly inhibited by a selective inhibitor of COX-2,6-methoxy-2-naphthalenylacetic acid (6MNA) | COX-2 and inflammatory cytokines might play a causative role in the radiculopathy of LDH through upregulating PGE2 synthesis |
Lowe et al. (1996) | An experimental study | In vitro study | To examined the effects of PGE1, PGE2, and PGE2 alpha on second messenger generation in relation to DNA and aggrecan synthesis in the nontransformed rat RCJ 3.1C5.18 (RCJ) chondrocyte cell line | The effects of PG on aggrecan production in RCJ cells appear to be regulated at the posttranscriptional level. Forskolin and (Bu)2cAMP mimicked the suppressive effects of PGE1 on [3H]TdR incorporation, as well as the stimulatory effect of PGE1 on aggrecan synthesis. In addition, the phorbol ester 12-O-tetradecanoyl phorbol acetate mimicked PGF2 alpha stimulation of [3H]TdR incorporation and aggrecan synthesis, and the effects of PGE2 alpha on these processes were blocked by protein kinase C inhibitors | In mammalian chondrocytes, PGE1 predominantly activates the cAMP protein kinase A second messenger system, PGE2 α predominantly affects the Ca2(+)-protein kinase C system, and PGE2 activates both pathways |
Lin et al. (2018a) | An experimental study | Experimental in vivo and in vitro study | The severity of IVDD and the expression of inducible nitric oxide synthase (iNOS)/nitric oxide (NO) and cyclooxygenase (COX-2)/prostaglandin (PGE2) in Propionibacterium acnes-infected human intervertebral discs (IVDs) were quantified | The inhibition of iNOS/NO and COX-2/PGE2 activity ameliorated IVDD significantly, as evidenced by restored aggrecan and collagen II expression both in vivo and in vitro. Mechanistically, we found that P. acnes induced iNOS/NO and COX-2/PGE2 expressions via a reactive oxygen species- (ROS-) dependent NF-κB cascade | P. acnes-induced iNOS/NO and COX-2/PGE2 activation via the ROS-dependent NF-κB pathway is likely responsible for the pathology of IVDD |
Chen et al. (2017) | An experimental study | Experimentalin vitro study | This study was conducted in order to investigate the function of IL-21 in intervertebral disc degeneration | The mRNA expression of ADAMTS-7, TNF-α, and MMP-13 was enhanced by IL-21 stimulation. mRNA expression of STAT-1, STAT-3, and STAT-5b was also enhanced by IL-21 treatment, with STAT-3 being the most significantly enhanced. The mRNA expression of TNF-α was significantly reduced after treatment with AG490 compared with treatment with IL-21 only | IL-21 is involved in the pathological development of IVD degeneration and IL-21 could aggravate IVD degeneration by stimulating TNF-α through the STAT signaling pathway |
Gorth et al. (2019) | An experimental study | Experimental in vivo | To investigate the role of IL-1 in driving age-related disc degeneration | Knockout mice had significantly more degenerative changes in annular fibrosis (AF), as well as alterations in collagen type and maturation. at 20 months, there were no changes in nucleus pulposus (NP) extracellular matrix composition or cellular marker expression; however, IL-1KO NP cells accounted for a smaller proportion of NP compartments than in WT controls | Instead of protecting discs from age-related disc degeneration, global IL-1 deletion amplified the degenerative phenotype |
Li et al. (2019b) | An experimental study | Experimentalin vitro study | The present study was aimed to study the effects of resveratrol on disc nucleus pulposus (NP) cell senescence in an inflammation environment | The inflammation group significantly increased SA-β-Gal activity and ROS content, decreased cell proliferation and telomerase activity, promoted G0/1 cell cycle arrest, up-regulated gene/protein expression of senescence markers (p16 and p53) and matrix catabolic metabolizing enzymes (MMP-3, MMP-13, and ADAMTS-4), and NP matrix macromolecules (aggregated glycans and collagen II) expression was down-regulated. However, resveratrol partially reversed the effects of inflammatory cytokines on these cellular senescence-related parameters | Resveratrol was effective to suppress cell senescence in an inflammatory environment |
Guo et al. (2020) | An experimental study | Experimentalin vitro study | The aim of this study was to examine the role of circular RNA FAM169A (circ-FAM169A) in degenerative myeloid (NP) tissues and to verify its function in cultured human NP cells | Overexpression of circ-FAM169A in NP cells markedly enhanced extracellular matrix (ECM) catabolism and suppressed ECM anabolism in NP cells. Furthermore, circ-FAM169A sequestered miR-583, which could potentially upregulate BTRC, an inducer of the NF-κB signaling pathway | Circ-FAM169A promotes IDD development via miR-583/BTRC signaling |
Yeung et al. (2004) | An experimental study | Experimentalin vitro study | The purpose of this study is that SIRT1 is a nicotinamide adenosine dinucleotide-dependent histone deacetylase that regulates the transcriptional activity of NF-kappaB | SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310 | SIRT1 activity augments apoptosis in response to TNFalpha by the ability of the deacetylase to inhibit the transactivation potential of the RelA/p65 protein |
Lee et al. (2011) | An experimental study | Experimentalin vitro study | This study examined the role of SIRT1 in mediating heat stress and lipopolysaccharide (LPS)-induced immune and defense gene expression in HDPCs | LPS and heat stress synergistically increased the expression of SIRT1 and immune and defense genes. Resveratrol enhanced LPS- and heat stress-induced HO-1 and hBD-2 expression but decreased IL-8 messenger RNA levels. LPS stimulated HO-1 and hBD-2 messenger RNA expression, and heat stress inhibited sirtinol; SIRT1 small interfering RNA; and inhibitors of p38, ERK, JNK, and nuclear factor κB | SIRT1 mediates the induction of immune and defense gene expression in HDPCs by LPS and heat stress. SIRT1 may play a pivotal role in host immune defense system in HDPCS |
Yoshizaki et al. (2010) | An experimental study | Experimental in vivo and in vitro study | Explore the role of SIRT1 in regulating pro-inflammatory pathways within macrophages | SIRT1 knockdown leads to increased expression of inflammatory genes. Treatment of Zucker adipose rats with SIRT1 activators greatly improves glucose tolerance, reduces hyperinsulinemia, and enhances systemic insulin sensitivity | SIRT1 as an important regulator of macrophage inflammatory responses in the context of insulin resistance |
Yoshizaki et al. (2009) | An experimental study | Experimentalin vitro study | Exploring the potential effects of SIRT1 on insulin signaling pathways | SIRT1 expression was negatively correlated with inflammatory gene expression. In conclusion, we found that treatment of 3T3-L1 adipocytes with SIRT1 activators attenuated tumor necrosis factor α-induced insulin resistance | SIRT1 is a positive regulator of insulin signaling through, at least in part, its anti-inflammatory effects in 3T3-L1 adipocytes |
Schug et al. (2010) | An experimental study | Experimental in vivo and in vitro study | Explore the important role played by SIRT1 in the immune response | Ablation of SIRT1 in macrophages hyperacetylates NF-κB, leading to increased transcriptional activation of pro-inflammatory target genes. Consistent with the increased expression of pro-inflammatory genes, Mac-SIRT1 KO mice attacked with a high-fat diet showed high levels of activated macrophages in the liver and adipose tissue, predisposing the animals to systemic insulin resistance and metabolic disorders | SIRT1 in macrophages functions to inhibit NF-κB-mediated transcription |
Gillum et al. (2011) | An experimental study and clinical trial | Experimental in vivo study | To explore whether a reduction in SirT1 links overnutrition and adipose tissue inflammation | In vivo induced or genetic reduction of SirT1 leads to macrophage recruitment to adipose tissue, whereas overexpression of SirT1 prevents adipose tissue macrophage accumulation induced by prolonged high-fat feeding.SirT1 expression in human subcutaneous fat negatively correlates with adipose tissue macrophage infiltration | SirT1 regulates adipose tissue inflammation by controlling the gain of proinflammatory transcription in response to inducers such as fatty acids, hypoxia, and endoplasmic reticulum stress |
Rajendrasozhan et al. (2008) | An experimental study and clinical trial | Experimentalin vitro study | To determine the expression of SIRT1 in lungs of smokers and patients with COPD, and to elucidate the regulation of SIRT1 in response to cigarette smoke in macrophages, and its impact on nuclear factor (NF)-kappaB regulation | Treatment of MonoMac6 cells with CSE showed decreased levels of SIRT1 associated with increased acetylation of RelA/p65 NF-kappaB. Mutation or knockdown of SIRT1 resulted in increased acetylation of nuclear RelA/p65 and IL-8 release, whereas overexpression of SIRT1 decreased IL-8 release in response to CSE treatment in MonoMac6 cells | SIRT1 plays a pivotal role in regulation of NF-kappaB-dependent proinflammatory mediators in lungs of smokers and patients with COPD |
Lim et al. (2013) | An experimental study | Experimental in vivo and in vitro study | The purpose of this study was to determine (1) the effect of human preterm labor on SIRT6 expression in human gestational tissues and (2) the effect of SIRT6 inhibition using small interfering RNA (siRNA) on the pro-labor media | IL1B induced NFKB transcriptional activity. However, NFKB transcriptional activity was reduced when cells were also cotransfected with a vector expressing SIRT6 | SIRT6 plays a role in regulating the terminal effector pathways of human labor and delivery via the NFKB pathway |
Wu et al. (2019) | An experimental study | Experimental in vivo and in vitro study | This study focused on investigating SIRT6 expression in ACC and how it generates cancer phenotypes | Knockdown of SIRT6 promoted cell invasion, proliferation and migration, and inhibited cell death. In addition, SIRT6 knockdown was found to upregulate TLR4 and enhance phosphorylation of nuclear transcription factor-kappa B (NF-κB) subunit p65 as well as nuclear factor kappa-B kinase inhibitor. In addition, knockdown of SIRT6 significantly enhanced the expression of calcitonin gene-related peptide and transient receptor potential vanilloid isoform 1 | SIRT6 serves as a tumor suppressor via regulation of the NF-κB pathway, which could offer an innovative strategy to treat ACC |
Liu et al. (2017) | An experimental study | Experimental in vivo and in vitro study | To investigate whether Sirt6 prevents podocyte injury by epigenetically regulating Notch signaling | Sirt6 has pleiotropic protective effects in podocytes, including anti-inflammatory and anti-apoptotic effects, involvement in actin cytoskeleton maintenance and promotion of autophagy.Sirt6 also reduces expression of the urokinase fibrinogen activator receptor, a key factor in podocyte podocyte protrusion loss and proteinuria | Sirt6 represses Notch1 and Notch4 transcription by deacetylating histone H3K9 |
Ashburner et al. (2001) | An experimental study | Experimentalin vitro study | To investigate whether the trans-activation function of NF-kappaB is regulated through the interaction of the p65 (RelA) subunit with histone deacetylase (HDAC) co-repressor proteins | Inhibition of HDAC activity by tricostatin A (TSA) leads to an increase in basal and inducible expression of integrated NF-κB-dependent reporter genes. HDAC1 and HDAC2 target NF-kappaB through direct binding of HDAC1 to the Rel homology domain of p65. HDAC2 does not interact directly with NF-κB but can regulate NF-κB activity through binding to HDAC1. HDAC2 does not directly interact with NF-κB, but can regulate NF-κB activity by binding to HDAC1 | The association of NF-kappaB with the HDAC1 and HDAC2 corepressor proteins functions to repress expression of NF-kappaB-regulated genes as well as to control the induced level of expression of these genes |
Ma et al. (2014) | An experimental study | Experimentalin vitro study | To investigate the effect of jolkinolide B (JB), isolated from the roots of Morinda citrifolia, on NF-κB ligand receptor activator (RANKL)-induced osteoclast formation | JB inhibited RANKL-induced osteoclast differentiation from bone marrow macrophages (BMMs) without cytotoxicity. Furthermore, the expression of osteoclastic marker genes, such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CtsK), and calcitonin receptor (CTR), was significantly inhibited. JB inhibited RANKL-induced activation of NF-κB by suppressing RANKL-mediated IκBα degradation. Moreover, JB inhibited RANKL-induced phosphorylation of mitogen-activated protein kinases (p38, JNK, and ERK) | JB is an inhibitor of osteoclast formation |
Li et al. (2014a) | An experimental study | Experimentalin vitro study | This study characterizes the potential to inhibit inflammatory cytokine production in degenerative disc (NP) cells by IL-10 and TGF-β treatment in a canine model of IDD | IL-10 and TGF-β treatment inhibited the expression of IL-1β and TNF-α and suppressed the development of inflammatory responses | IL-10 and TGF-β should be evaluated as therapeutic approaches for the treatment of lower back pain mediated by IDD |
Wuertz et al. (1976) | An experimental study | Experimental in vivo and in vitro study | To determine whether resveratrol may be useful in treating nucleus pulposus (NP)-mediated pain | In vitro, resveratrol exhibited an anti-inflammatory and anticatabolic effect on the messenger RNA and protein level for IL-6, IL-8, MMP1, MMP3 and MMP13. This effect does not seem to be mediated via the MAP kinase pathways (p38, ERK, JNK) or via the NF-κB/SIRT1 pathway, although toll-like receptor 2 was regulated to a minor extent. In vivo, resveratrol significantly reduced pain behavior triggered by application of NP tissue on the dorsal root ganglion for up to 14 days | Resveratrol was able to reduce pro-inflammatory cytokine levels in vitro and showed analgesic potential in vivo |
Song et al. (2020a) | An experimental study | Experimentalin vitro study | The aim of this study is to investigate the effect of DHP on nucleus pulposus (NP) cells in vitro | DHP inhibited IL-1β-induced up-regulation of ROS, TNF-α, IL-6, MMP-3, and ADAMTS-5. dHP significantly increased sirt1 and antioxidant protein SOD-1 levels. Furthermore, DHP significantly protected against IL-1β-induced degradation of collagen-II and aggregated glycans | DHP inhibited the ROS, inflammatory response and ECM degradation through activating Sirt1 in human NP cells |
Cai et al. (2020) | An experimental study | Experimental in vivo and in vitro study | To explore whether Sirt1 inhibits MCP-1 in the intervertebral disc | MCP-1 was upregulated in the degenerated condition, which was opposite to Sirt1 expression. Res suppressed AP-1, the phosphorylation of c-Fos/c-Jun, and the MCP-1 expression. On the contrary, Sirt1 downregulation by Nico aggravated the phosphorylation of c-Fos/c-Jun and MCP-1 expression. However, the MCP-1 suppression did not affect the Sirt1 and AP-1 levels. The destruction of AP-1 activation also inhibited MCP-1 expression but not Sirt1. The upregulation of Sirt1 and suppression of MCP-1 improved the type II collagen expression and cell viability, which was injured by IL-1β | Sirt1 suppresses the MCP-1 production in the degenerated NP cells by suppressing the phosphorylation of the AP-1 subunits c-Fos and c-Jun |
Li et al. (2022a) | An experimental study | Experimentalin vitro study | To investigate the effect of PPARβ/δ on COX-2 expression in the kidney | PPARβ/δ was functionally expressed in human mesangial cells (hMCs), where its expression was increased by interleukin-1β (IL-1β) treatment concomitant with enhanced COX-2 expression and prostaglandin E2 (PGE2) biosynthesis. PPARβ/δ could further augment the IL-1β-induced COX-2 expression and PGE2 production in hMCs. Moreover, both PPARβ/δ activation and overexpression markedly increased sirtuin 1 (SIRT1) expression | PPARβ/δ could augment the IL-1β-induced COX-2 expression and PGE2 production in hMCs via the SIRT1 pathway |
Lim et al. (2015) | An experimental study | Experimentalin vitro study | The mechanism underlying Korean red ginseng water extract (KRG-WE) inhibition of hypoxia-induced COX-2 in human distal lung epithelial A549 cells | Hypoxia-induced COX-2 protein and mRNA levels and promoter activity were inhibited by KRG-WE. Hypoxia-induced cell migration was significantly reduced by KRG-WE. Inhibition of Sirt1 eliminated the effects of KRG-WE on hypoxia-induced COX-2 inhibition and cell invasion, suggesting that the inhibition was mediated by Sirt1 | KRG-WE inhibits the hypoxic induction of COX-2 expression and cell invasion through Sirt1 activation |
Kumar et al. (2021) | An experimental study | Experimental in vivo study | This study investigated the protective effects of melatonin on LPS-induced testicular nitro-oxidative stress, inflammation, and associated damages in the testes of male golden hamsters, Mesocricetus auratus | LPS upregulates NF-kB, COX-2, and iNOS expression to increase testicular inflammatory load, leading to decreased germ cell proliferation and survival, which ultimately leads to germ cell apoptosis, as shown by AO-EB staining and caspase-3 expression. Melatonin treatment upregulates testicular SIRT-1 expression to inhibit LPS-induced inflammatory proteins, i.e. NF-kB/COX-2/iNOS expression | Melatonin rescued testes from LPS-induced testicular nitro-oxidative stress, inflammation, and associated damages by upregulation of SIRT-1 |
Zhang et al. (2010) | An experimental study | Experimentalin vitro study | Whether SIRT1 deacetylates activator protein-1 (AP-1) to affect its transcriptional activity and target gene expression | SIRT1 directly interacts with the basic leucine zipper structural domains of c-Fos and c-Jun, the major components of AP-1, through which SIRT1 represses the transcriptional activity of AP-1. This process requires the deacetylase activity of SIRT1 | SIRT1 may be a mediator of CR-induced macrophage regulation, and its deacetylase activity contributes to the inhibition of AP-1 transcriptional activity and COX-2 expression leading to amelioration of macrophage function |
Kang et al. (2017) | An experimental study | Experimentalin vitro study | This study aimed to determine whether sirtuin 6 (SIRT6), a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylases, protects the NP from ECM degradation in IDD | During the progression of IDD, SIRT6 expression was significantly reduced. overexpression of SIRT6 prevented IL-1β-induced degradation of the NP ECM, and RNA interference in NP cells resulted in SIRT6 depletion leading to ECM degradation. In addition, SIRT6 physically interacted with nuclear factor-κB (NF-κB) catalytic subunit p65, whose transcriptional activity was significantly inhibited by SIRT6 overexpression | SIRT6 prevented NP ECM degradation in vitro via inhibiting NF-κB-dependent transcriptional activity and that this effect depended on its deacetylase activity |
Xie et al. (2022a) | An experimental study | Experimentalin vitro study | The purpose of the present study was to explore the effects of luteolin on Tumor necrosis factor (TNF)-α-induced inflammatory injury and senescence of human nucleus pulposus cells (HNPCs), as well as the underlying mechanisms of action of this compound | TNF-α induced a significant decrease in HNPC viability and an increase in the levels of inflammatory factors, whereas the application of lignans effectively increased cell viability and decreased intracellular interleukin (IL)-1β and IL-6 expression levels. In addition, lignocaine reduced apoptosis in a dose-dependent manner compared with the TNF-α group | Lignans inhibit TNF-α-induced inflammatory injury and senescence in HNPCs via the Sirt6/NF-κB pathway |