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Cell Death Dis ; 11(2): 103, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029706


N6 methyladenosine (m6A) is one of the most prevalent epitranscriptomic modifications of mRNAs, and plays a critical role in various bioprocesses. Bone-derived mesenchymal stem cells (BMSCs) can attenuate apoptosis of nucleus pulposus cells (NPCs) under compression; however, the underlying mechanisms are poorly understood. This study showed that the level of m6A mRNA modifications was decreased, and the autophagic flux was increased in NPCs under compression when they were cocultured with BMSCs. We report that under coculture conditions, RNA demethylase ALKBH5-mediated FIP200 mRNA demethylation enhanced autophagic flux and attenuated the apoptosis of NPCs under compression. Specific silencing of ALKBH5 results in impaired autophagic flux and a higher proportion of apoptotic NPCs under compression, even when cocultured with BMSCs. Mechanistically, we further identify that the m6A "reader" YTHDF2 is likely to be involved in the regulation of autophagy, and lower m6A levels in the coding region of FIP200 lead to a reduction in YTHDF2-mediated mRNA degradation of FIP200, a core molecular component of the ULK1 complex that participates in the initiating process of autophagy. Taken together, our study reveals the roles of ALKBH5-mediated FIP200 mRNA demethylation in enhancing autophagy and reducing apoptosis in NPCs when cocultured with BMSCs.

World Neurosurg ; 133: e84-e88, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31470152


BACKGROUND: Spinopelvic sagittal parameters have a significant influence on adjacent segment degeneration (ASD) after fusion surgery. The association between ASD and sagittal balance is not well understood. The purpose of this study was to investigate the biomechanical influence of various sacral slope (SS) degrees on adjacent segments after transforaminal lumbar interbody fusion (TLIF) at the L4-L5 level. METHODS: We conducted a finite element model of the L1-S1 based on computed tomography scan images. The L1-S1 model with L4-L5 TLIF was modified with various SS degrees (33°, 38°, 43°, and 48°) to investigate the biomechanical influence of SS on adjacent segments. The range of motion (ROM) and intradiscal pressure (IDP) of the adjacent segments (L3-L4 and L5-S1) were compared among models using various SS angles. RESULTS: When the SS angle increased, the ROM and IDP in L5-S1 decreased gradually after TLIF at the L4-L5 level in all motion patterns. Nevertheless, the ROM and IDP in L3-L4 were not significantly different among various SS angles. CONCLUSIONS: Decreased SS after lumbar fusion surgery may pose a higher risk of ASD. Therefore, restoring appropriate SS should be considered during decision-making prior to fusion surgery to reduce the risk of degenerative changes.

Vértebras Lombares/cirurgia , Sacro/diagnóstico por imagem , Fusão Vertebral/métodos , Antropometria , Fenômenos Biomecânicos , Análise de Elementos Finitos , Humanos , Disco Intervertebral/fisiopatologia , Vértebras Lombares/diagnóstico por imagem , Pressão , Amplitude de Movimento Articular , Sacro/patologia , Tomografia Computadorizada por Raios X
FEBS J ; 286(21): 4356-4373, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31230413


Previous studies identified advanced glycation end products (AGEs) accumulation in the intervertebral disc (IVD) as an essential risk factor associated with IVD degeneration via accelerated cell apoptosis and impeded extracellular-matrix metabolism; however, the underlying mechanisms have not been fully elucidated. Here, we investigated the effects and mechanisms of AGEs-mediated apoptosis in vitro and in vivo. We evaluated the effects of AGEs on endoplasmic reticulum (ER) stress, apoptosis, and subcellular calcium (Ca2+ ) redistribution. Our data indicated time- and concentration-dependent upregulation of ER-stress responses in AGEs-treated nucleus pulposus (NP) cells. Additionally, we observed marked suppression of AGEs-mediated apoptosis following the inhibition of ER stress using 4-phenylbutyric acid. Moreover, AGEs-induced sustained cytosolic Ca2+ ([Ca2+ ]c) elevation and ER luminal Ca2+ ([Ca2+ ]er) depletion in a concentration- and time-dependent manner in NP cells. Furthermore, we observed significant increases and decreases in levels of the ER-resident Ca2+ -release channels inositol 1,4,5-triphosphate receptor and ryanodine receptor and ER Ca2+ -reuptake pumps sarco/endoplasmic reticulum Ca2+ -ATPase, respectively. Pharmacologically blocking ER Ca2+ release using Ca2+ antagonists significantly ameliorated Ca2+ dyshomeostasis, ER stress, and subsequent apoptosis in NP cells and partially attenuated the progression of IVD degeneration in vivo. These results demonstrated that impaired Ca2+ homeostasis plays an essential role in AGEs-mediated ER stress and subsequent apoptosis in NP cells, with blockage of ER Ca2+ release partially ameliorating subcellular Ca2+ redistribution, ER stress, and apoptosis. Our findings provide novel mechanistic insight into the role of AGEs in the pathogenesis of IVD degeneration and a potential therapeutic strategy.

Life Sci ; 228: 85-97, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31047897


AIM: Nucleus pulposus (NP) cell apoptosis induced by oxidative stress is known to be closely involved in the pathogenesis of intervertebral disc (IVD) degeneration. Berberine, a small molecule derived from Rhizoma coptidis, has been found to exert antioxidative activity and preserve cell viability. The present study aims to investigate whether berberine can prevent NP cell apoptosis under oxidative damage and the potential underlying mechanisms. METHODS AND MATERIALS: The effects of berberine on IVD degeneration were investigated both in vitro and in vivo. KEY FINDINGS: Our results showed that berberine significantly mitigated oxidative stress-decreased cell viability as well as apoptosis in human NP cells. Berberine treatment could attenuate oxidative stress-induced ER stress and autophagy in a concentration-dependent manner. With 4-PBA (ER stress specific inhibitor) and 3-MA (autophagy specific inhibitor) administration, we demonstrated that berberine inhibited oxidative stress-induced apoptosis by modulating the ER stress and autophagy pathway. We also found that the IRE1/JNK pathway was involved in the induction of ER stress-dependent autophagy. With Ca2+ chelator BAPTA-AM utilization, we revealed that oxidative stress-mediated ER stress and autophagy repressed by berberine could be restored by inducing intracellular Ca2+ dysregulation. Furthermore, in vivo study provided evidence that berberine treatment could retard the process of puncture-induced IVD degeneration in a rat model. SIGNIFICANCE: Our results indicate that berberine could prevent oxidative stress-induced apoptosis by modulating ER stress and autophagy, thus offering a novel potential pharmacological treatment strategy for IVD degeneration.

Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Berberina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Degeneração do Disco Intervertebral/tratamento farmacológico , Núcleo Pulposo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/uso terapêutico , Autofagia/efeitos dos fármacos , Berberina/uso terapêutico , Células Cultivadas , Feminino , Humanos , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Núcleo Pulposo/citologia , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Ratos Sprague-Dawley
World Neurosurg ; 126: e819-e824, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30862579


OBJECTIVE: To analyze the biomechanical changes of lumbar adjacent segment by comparing the biomechanics after the surgery of transforaminal lumbar interbody fusion (TLIF) and oblique lumbar interbody fusion (OLIF). METHODS: The finite element model of the L1-S1 was reconstructed via computed tomography scan images. The models of TLIF and OLIF were constructed and analyzed. A 400-N vertical axial pre-load was imposed on the superior surface of L1 and a 10-N·m moment was applied on the L1 superior surface along the radial direction to simulate 4 different physiological motions: flexion, extension, bending, and torsion. The range of motion (ROM) and the intradiscal pressure (IDP) were evaluated and compared with investigate the biomechanical influences of TLIF and OLIF on the adjacent segments (L3-L4 and L5-S1). RESULTS: Compared with the normal model, TLIF and OLIF in all motion patterns increased the ROM and the IDP of adjacent segments. However, the ROM and the IDP between TLIF and OLIF had no significant difference. CONCLUSIONS: The biomechanical analysis showed that both TLIF and OLIF can increase ROM and IDP. It indicates that TLIF and OLIF probably increase the potential risk of adjacent segment degeneration similarly.

Vértebras Lombares/cirurgia , Fusão Vertebral/métodos , Adulto , Fenômenos Biomecânicos/fisiologia , Parafusos Ósseos , Análise de Elementos Finitos , Humanos , Vértebras Lombares/diagnóstico por imagem , Masculino , Modelos Anatômicos , Amplitude de Movimento Articular/fisiologia , Tomografia Computadorizada por Raios X