Urolithin A Inhibits the Catabolic Effect of TNFα on Nucleus Pulposus Cell and Alleviates Intervertebral Disc Degeneration in vivo

Abstract

Low back pain (LBP) is a common worldwide disease that causes an enormous social economic burden. Intervertebral disc degeneration (IDD) is considered as a major cause of LBP. The process of IDD is complicated and involves both inflammation and senescence. The production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)α and interleukin (IL)-1β, is increased in the degenerating intervertebral disc, inducing extracellular matrix degradation. Urolithin A (UA) is a metabolite compound resulting from the degradation of ellagitannins by gut bacteria. UA has been reported to be useful for the treatment of diseases associated with inflammation, senescence, and oxidative damage. Therefore, we hypothesized that UA may be an effective treatment for IDD. This study examined the effects of UA on IDD in vitro and in vivo and explored their underlying mechanisms. Our findings indicated that UA could attenuate cellular senescence induced by hydrogen peroxide in nucleus pulposus cells. UA treatment decreased TNFα-induced matrix metalloproteinase production and the loss of collagen II. At the molecular level, UA considerably blocked the phosphorylation of the extracellular signal-regulated kinase, c-JUN N-terminal kinase, and Akt pathways. In vivo study illustrated that UA treatment could ameliorate IDD in a needle-punctured rat tail model, which was evaluated by X-ray imaging, magnetic resonance imaging, and histological analysis. Thus, the results of our study revealed that UA may be a useful therapeutic agent for the treatment of IDD.

Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist

“…AHR knockdown by siRNA prevented the UroA repression of inflammatory mediators, suggesting that anti-inflammatory characteristic of UroA is mediated, at least in part, through AHR. However, it is important to note that multiple pathways have been reported to contribute to the anti-inflammatory activities of urolithins, including, c-Jun [41], NF-KB/AP1 [42] and MAPK [43]. The role of urolithins as potential in vivo antioxidants is controversial [10].…”

Urolithin a attenuates IL-1β-induced inflammatory responses and cartilage degradation via inhibiting the MAPK/NF-κB signaling pathways in rat articular chondrocytes

“…Interestingly, recent published studies have described the biological effects of UA, including anti-proliferation in cancer, antiinflammation, anti-oxidant activity, improved lipid metabolism [13][14][15]. UA inhibits the catabolic effect of TNF-α on nucleus pulposus cells and alleviates intervertebral disc degeneration in vivo [16]. Moreover, UA can protect skeletal muscle against acute inflammation in vitro and in vivo [17].…”

Urolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD+ and SIRT1

“…AHR transcriptionally regulates inflammatory mediators, including cytokines IL-6, IL-1β, chemokines CXCL5, CCL20, and prostaglandin-endoperoxide synthase PTGS2 [55][56][57][58] . Multiple pathways contribute to the anti-inflammatory activities of urolithins, including, c-Jun 59 , NF-κB/AP1 60 and MAPK 61 . While transcription factor NF-κB has been implicated in aging 62 , the role of AP-1 in angiogenesis is well-documented 63 .…”