Full
Outline
To explore the effect of Sirtuin 1 (Sirt1) on nucleus pulposus cells (NPCs) by regulating histone H3K18 lactylation and its implications for intervertebral disc degeneration (IVDD).
Puncture-induced intervertebral disc degeneration (PIDD) was modeled in the rat caudal vertebrae. The severity of disc degeneration was evaluated, and the expression levels of lactic acid (La), malondialdehyde (MDA), reactive oxygen species (ROS), H3K18la, and Sirt1 were detected in both the normal control (NC) group and the PIDD group using histopathological staining, biochemical assay, flow cytometry, and Western blot analysis. Gradient concentrations of La were used to treat NPCs, and Sirt1 was knocked down or overexpressed via lentiviral transduction. Changes in H3K18la, ROS, and MDA levels were analyzed by immunofluorescence and biochemical assays. The genes regulated by H3K18la and their associated pathways were identified using Cleavage Under Targets and Tagmentation (CUT&Tag) and bioinformatic analyses. Then 24 rats were assigned into normal control (NC), PIDD, PIDD with Sirt1 overexpression (PIDD+oe-Sirt1), and PIDD with viral control (PIDD+Vector) groups, in order to assess the therapeutic effect of Sirt1 overexpression on intervertebral disc degeneration.
The PIDD group had significantly higher histological scores and elevated levels of La, ROS, and MDA, and enhanced expression of H3K18la but decreased Sirt1 expression when compared with the NC group (P<0.01). In cellular experiments, H3K18la, ROS, and MDA levels were in a concentration-dependent increase with the increments of La concentration. Sirt1 overexpression significantly reduced H3K18la expression (P<0.01), whereas its knockdown conversely increased it (P<0.01). CUT&Tag analysis indicated that H3K18la plays a regulatory role in oxidative stress in NPCs. In animal experiments, the PIDD+oe-Sirt1 group exhibited significantly lower histological scores, along with reduced levels of ROS, H3K18la, and MDA in comparison to the PIDD and PIDD+Vector groups (P<0.01).
The expression of Sirt1 is significantly decreased in degenerative intervertebral discs. As a delactylase for histone H3K18la, Sirt1 may play a critical role in intervertebral disc degeneration by modulating oxidative stress in nucleus pulposus cells through H3K18la lactylation.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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