scholarly journals Fexofenadine Protects Against Intervertebral Disc Degeneration Through TNF Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Kaiwen Liu ◽  
Jianlu Wei ◽  
Guohua Li ◽  
Ronghan Liu ◽  
Dawang Zhao ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Pathological Process ◽  
Mechanism Study ◽  
Tnf Α ◽  
Safranin O ◽  
Factor Α ◽  
Ivd Degeneration

Objective: Fexofenadine (FFD) is an antihistamine drug with an anti-inflammatory effect. The intervertebral disc (IVD) degeneration process is involved in inflammation in which tumor necrosis factor-α (TNF-α) plays an important role. This study aims to investigate the role of FFD in the pathological process of IVD degeneration.Methods: Safranin O staining was used for the measurement of cartilageous tissue in the disc. Hematoxylin-Eosin (H&E) staining was used to determine the disc construction. A rat needle puncture model was taken advantage of to examine the role of FFD in disc degeneration in vivo. Western Blotting assay, immunochemistry, and immunoflurence staining were used for the determination of inflammatory molecules. ELISA assay was performed to detect the release of inflammatory cytokines. A real-time PCR assay was analyzed to determine the transcriptional expressions of molecules.Results: Elevated TNF-α resulted in inflammatory disc degeneration, while FFD protected against TNF-α-induced IVD degeneration. Mechanism study found FFD exhibited a disc protective effect through at least two pathways. (a) FFD inhibited TNF-α-mediated extracellular matrix (ECM) degradation and (b) FFD rescued TNF-α induced inflammation in disc degeneration. Furthermore, the present study found that FFD suppressed TNF-α mediated disc degeneration via the cPLA2/NF-κB signaling pathway.Conclusions: FFD provided another alternative for treating disc degeneration through a novel mechanism. Additionally, FFD may also be a potential target for the treatment of other inflammatory-related diseases, including IVD degeneration.

TNF-α and myocardial depression in endotoxemic rats: temporal discordance of an obligatory relationship

1998 ◽  
Vol 275 (2) ◽  
pp. R502-R508 ◽  
Author(s):  
Xianzhong Meng ◽  
Lihua Ao ◽  
Daniel R. Meldrum ◽  
Brian S. Cain ◽  
Brian D. Shames ◽  
...  
Keyword(s):  
Temporal Relationship ◽  
Contractile Function ◽  
Myocardial Depression ◽  
Tnf Α ◽  
Myocardial Contractile ◽  
Factor Α ◽  
Relationship Of

Exogenous tumor necrosis factor-α (TNF-α) induces delayed myocardial depression in vivo but promotes rapid myocardial depression in vitro. The temporal relationship between endogenous TNF-α and endotoxemic myocardial depression is unclear, and the role of TNF-α in this myocardial disorder remains controversial. Using a rat model of endotoxemia not complicated by shock, we sought to determine 1) the temporal relationship of changes in circulating and myocardial TNF-α with myocardial depression, 2) the influences of protein synthesis inhibition or immunosuppression on TNF-α production and myocardial depression, and 3) the influence of neutralization of TNF-α on myocardial depression. Rats were treated with lipopolysaccharide (LPS, 0.5 mg/kg ip). Circulating and myocardial TNF-α increased at 1 and 2 h, whereas myocardial contractility was depressed at 4 and 6 h. Pretreatment with cycloheximide or dexamethasone abolished the increase in circulating and myocardial TNF-α and preserved myocardial contractile function. Similarly, treatment with TNF binding protein immediately after LPS prevented myocardial depression. We conclude that endogenous TNF-α mediates delayed myocardial depression in endotoxemic rats and that inhibition of TNF-α production or neutralization of TNF-α preserves myocardial contractile function in endotoxemia.

scholarly journals The Potential Role of Extensor Muscle Fatigue in the Onset of Intervertebral Disc Degeneration: A Novel In Vivo Model

2010 ◽  
Vol 10 (9) ◽  
pp. S74-S75
Author(s):  
Mary Beth M. Grabowsky ◽  
Nicholas A. Pallotta ◽  
Matthew W. Connelly ◽  
Brett Van Etten ◽  
Rebecca A. MacDonald ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Muscle Fatigue ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Potential Role ◽  
Extensor Muscle ◽  
In Vivo Model

scholarly journals Inhibition of aberrant Hif1α activation delays intervertebral disc degeneration in adult mice

Bone Research ◽  
2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Zuqiang Wang ◽  
Hangang Chen ◽  
Qiaoyan Tan ◽  
Junlan Huang ◽  
Siru Zhou ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Genetic Ablation ◽  
Adult Mice ◽  
Conditional Deletion ◽  
Current Therapies ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Deficient Mice

AbstractThe intervertebral disc (IVD) is the largest avascular tissue. Hypoxia-inducible factors (HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease (DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate (EP) and annulus fibrosus (AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol (2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

scholarly journals Nrf2 mediated ER-phagy protects against oxidative damage in intervertebral disc degeneration

2021 ◽  
Author(s):  
zhen lin ◽  
libin ni ◽  
cheng teng ◽  
zhao zhang ◽  
xinlei lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intervertebral Disc ◽  
Oxidative Damage ◽  
Er Stress ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Cellular Damage ◽  
Nucleus Pulposus Cells

Intervertebral disc degeneration (IDD) increases the risk of low back pain (LBP). Oxidative stress may induce cellular damage and contribute to various diseases including IDD. Endoplasmic reticulum autophagy (ER-phagy) is a specific type of autophagy, its role in oxidative stress induced damage as well as in IDD is unknown. This study explores the role of ER-phagy in oxidative damage in intervertebral disc nucleus pulposus cells (NPCs), as well as the Nrf2/FAM134B axis in ER-phagy regulation and IDD therapy. We found ER-phagy was decreased in NPCs during oxidative stress; while FAM134B may promote ER-phagy and alleviate oxidative stress induced ER-stress and apoptosis. In addition, the nuclear transcription factor Nrf2 may promote the expression of FAM134B as well as ER-phagy, and suppress ER-stress and apoptosis in NPCs. Furthermore, overexpression of FAM134B and Nrf2 could effectively attenuate the progression of IDD in rats in vivo. These results suggest Nrf2/FAM134B mediated ER-phagy may combat oxidative damage in cells; meanwhile, ER-phagy as well as Nrf2 could be potential therapeutic targets for IDD.

Exosomes derived from human placental MSCs carrying miR-4450 inhibitor alleviate intervertebral disc degeneration and ameliorate gait disturbances via up-regulation of ZNF121

2020 ◽  
Author(s):  
Qiling Yuan ◽  
Xinyi Wang ◽  
Liang Liu ◽  
Yongsong Cai ◽  
Xiaoming Zhao ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Therapeutic Effects ◽  
Nucleus Pulposus Cells ◽  
Gait Abnormality ◽  
Tnf Α ◽  
Potential Therapeutic Role

Abstract Background Exosomes derived from mesenchymal stem cells (MSCs) have emerged as novel drug and gene delivery tools. Current study aimed to elucidate the potential therapeutic role of human placental MSC (hPLMSC)-derived exosomes carrying antagomiR-4450 (EXO-antagomiR-4450) in intervertebral disc degeneration (IDD) progression. Methods Initially, the differentially expressed miRNAs related to IDD were identified by microarray analysis which provided data predicting the interaction between miR-4450 and ZNF121 in IDD. Next, miR-4450 and ZNF121 were elevated or silenced to determine their effects on the damage of NPCs treated with TNF-α. The therapeutic effects of EXO-antagomiR-4450 on nucleus pulposus cells (NPCs) were verified both in vitro and in vivo, especially gait analysis and fluorescent molecular tomopraphy were used in live IDD mice. Results Our results revealed that miR-4450 was highly expressed, while ZNF121 was poorly expressed in IDD patients and NPCs treated with TNF-α. Furthermore, miR-4450 was identified to specifically target ZNF121. Additionally, the inhibition of miR-4450 exerted an alleviatory effect on the inflammation, apoptosis and damage of the NPCs by up-regulating ZNF121. Moreover, EXO-antagomiR-4450 retarded damage of NPCs in vitro, alleviated IDD damage and ameliorated gait abnormality in vivo. Conclusion hPLMSC-derived exosomes could be a feasible nanovehicle to deliver inhibitory oligonucleotides like antagomiR-4450 in IDD.

scholarly journals Mesenchymal Stem Cell for Prevention and Management of Intervertebral Disc Degeneration

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Umile Giuseppe Longo ◽  
Nicola Papapietro ◽  
Stefano Petrillo ◽  
Edoardo Franceschetti ◽  
Nicola Maffulli ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Annulus Fibrosus ◽  
Intervertebral Disc Degeneration ◽  
Surgical Intervention ◽  
Pathological Condition ◽  
Treatment Strategies ◽  
Clinical Applications ◽  
Ivd Degeneration

Intervertebral disc degeneration (IVD) is a frequent pathological condition. Conservative management often fails, and patients with IVD degeneration may require surgical intervention. Several treatment strategies have been proposed, although only surgical discectomy and arthrodesis have been proved to be predictably effective. The aim of biological strategies is to prevent and manage IVD degeneration, improve the function, the anabolic and reparative capabilities of the nucleus pulposus and annulus fibrosus cells, and inhibit matrix degradation. At present, clinical applications are still in their infancy. Further studies are required to clarify the role of mesenchymal stem cells and gene therapy for the prevention and treatment of IVD degeneration.

Developing consistently reproducible intervertebral disc degeneration at rat caudal spine by using needle puncture

2009 ◽  
Vol 10 (6) ◽  
pp. 522-530 ◽  
Author(s):  
Huina Zhang ◽  
Frank La Marca ◽  
Scott J. Hollister ◽  
Steven A. Goldstein ◽  
Chia-Ying Lin
Keyword(s):  
Animal Model ◽  
Mr Imaging ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Collagen Type ◽  
Type Ii ◽  
Collagen Type Ii ◽  
Anulus Fibrosus ◽  
Safranin O ◽  
Ivd Degeneration

Object The goal in this study was to develop a convenient, less-invasive animal model to monitor progression of intervertebral disc (IVD) degeneration for future testing of new treatments for disc degeneration. Methods Level 5/6 and 7/8 IVDs of rat caudal spine were stabbed laterally with 18- or 21-gauge hypodermic needles to a depth of 5 mm from the subcutaneous surface with the aid of fluoroscopy. In vivo MR imaging studies were performed at 4, 8, and 12 weeks postsurgery to monitor progression of IVD degeneration. Histological analysis including H & E and safranin O staining, and immunohistochemical studies of collagen type II and bone morphogenetic protein receptor type II (BMPRII) were assessed at 12 weeks postsurgery. Results The 18- and 21-gauge needle–stabbed discs illustrated decreases in both the T2 density and MR imaging index starting at 4 weeks, with no evidence of spontaneous recovery by 12 weeks. Histological staining demonstrated a decreased nucleus pulposus (NP) area, and the NP–anulus fibrosus border became unclear during the progression of disc degeneration. Similar patterns of degenerative signs were also shown in both safranin O– and collagen type II–stained sections. The BMPRII immunohistochemical analysis of stabbed discs demonstrated an increase in BMPRII expression in the remaining NP cells and became stronger in anulus fibrosus with the severity of disc degeneration. Conclusions After introducing an 18- or 21-gauge needle into the NP area of discs in the rat tail, the stabbed disc showed signs of degeneration in terms of MR imaging and histological outcome measurements. Changes in BMPRII expression in this animal model provide an insight for the effectiveness of delivering BMPs into the region responsible for chondrogenesis for disc repair. This convenient, less-invasive, reproducible, and cost-effective model may be a useful choice for testing novel treatments for disc degeneration.

scholarly journals TonEBP regulates the hyperosmotic expression of aquaporin 1 and 5 in the intervertebral disc

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. W. Snuggs ◽  
S. Tessier ◽  
R. A. B. Bunning ◽  
I. M. Shapiro ◽  
M. V. Risbud ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Central Region ◽  
Aquaporin 1 ◽  
Enhancer Binding Protein ◽  
Ivd Degeneration ◽  
Hyperosmotic Environment

AbstractThe central region of the intervertebral disc (IVD) is rich in proteoglycans, leading to a hyperosmotic environment, which fluctuates with daily loading. The cells of the nucleus pulposus (NP cells) have adapted to this environment via the function of tonicity enhancer binding protein (TonEBP), and NP cells have been shown to express several water channels known as aquaporins (AQP). We have previously shown that AQP1 and 5 decrease during IVD degeneration. Here, the regulation of AQP1 and 5 by hyperosmotic conditions and the role of TonEBP in this regulation was investigated. AQP1 and 5 gene expression was upregulated by hyperosmotic conditions mimicking the osmolality of the healthy IVD, which was abrogated by TonEBP knockdown. Furthermore, AQP1 and 5 immunopositivity was significantly reduced in TonEBPΔ/Δ E17.5 mice when compared with wildtype controls, indicating in vivo expression of AQP1 and 5 is controlled at least in part by TonEBP. This hyperosmotic regulation of AQP1 and 5 could help to explain the decreased AQP1 and 5 expression during degeneration, when the osmolality of the NP decreases. Together this data suggests that TonEBP-regulated osmo-adaptation may be disrupted during IVD degeneration when the expression of both AQPs is reduced.

scholarly journals Longitudinal Comparison of Enzyme- and Laser-Treated Intervertebral Disc by MRI, X-Ray, and Histological Analyses Reveals Discrepancies in the Progression of Disc Degeneration: A Rabbit Study

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Marion Fusellier ◽  
Pauline Colombier ◽  
Julie Lesoeur ◽  
Samy Youl ◽  
Stéphane Madec ◽  
...  
Keyword(s):  
Animal Models ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Enzyme Treatment ◽  
In Vivo Model ◽  
Regenerative Approach ◽  
Radiation Induced ◽  
Longitudinal Comparison ◽  
Ivd Degeneration

Regenerative medicine is considered an attractive prospect for the treatment of intervertebral disc (IVD) degeneration. To assess the efficacy of the regenerative approach, animal models of IVD degeneration are needed. Among these animal models, chemonucleolysis based on the enzymatic degradation of the Nucleus Pulposus (NP) is often used, but this technique remains far from the natural physiopathological process of IVD degeneration. Recently, we developed an innovative animal model of IVD degeneration based on the use of a laser beam. In the present study, this laser model was compared with the chemonucleolysis model in a longitudinal study in rabbits. The effects of the treatments were studied by MRI (T2-weighted signal intensity (T2wsi)), radiography (IVD height index), and histology (NP area and Boos’ scoring). The results showed that both treatments induced a degeneration of the IVD with a decrease in IVD height and T2wsi as well as NP area and an increase in Boos’ scoring. The enzyme treatment leads to a rapid and acute process of IVD degeneration. Conversely, laser radiation induced more progressive and less pronounced degeneration. It can be concluded that laser treatment provides an instrumental in vivo model of slowly evolving IVD degenerative disease that can be of preclinical relevance for assessing new prophylactic biological treatments of disc degeneration.

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