scholarly journals ROS: Crucial Intermediators in the Pathogenesis of Intervertebral Disc Degeneration

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Chencheng Feng ◽  
Minghui Yang ◽  
Minghong Lan ◽  
Chang Liu ◽  
Yang Zhang ◽  
...  

Excessive reactive oxygen species (ROS) generation in degenerative intervertebral disc (IVD) indicates the contribution of oxidative stress to IVD degeneration (IDD), giving a novel insight into the pathogenesis of IDD. ROS are crucial intermediators in the signaling network of disc cells. They regulate the matrix metabolism, proinflammatory phenotype, apoptosis, autophagy, and senescence of disc cells. Oxidative stress not only reinforces matrix degradation and inflammation, but also promotes the decrease in the number of viable and functional cells in the microenvironment of IVDs. Moreover, ROS modify matrix proteins in IVDs to cause oxidative damage of disc extracellular matrix, impairing the mechanical function of IVDs. Consequently, the progression of IDD is accelerated. Therefore, a therapeutic strategy targeting oxidative stress would provide a novel perspective for IDD treatment. Various antioxidants have been proposed as effective drugs for IDD treatment. Antioxidant supplementation suppresses ROS production in disc cells to promote the matrix synthesis of disc cells and to prevent disc cells from death and senescence in vitro. However, there is not enough in vivo evidence to support the efficiency of antioxidant supplementation to retard the process of IDD. Further investigations based on in vivo and clinical studies will be required to develop effective antioxidative therapies for IDD.

2021 ◽  

Myocardial infarction is a serious representation of cardiovescular disease, MicroRNAs play a role in modifying I/R injury and myocardial infarct remodeling. The present study therefore examined the potential role of miR-187 in cardiac I/R injury and its underlying mechanisms. miR-187 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with miR-187 mimic or inhibitor to confirm the function of miR-187 in H/R. DYRK2 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with DYRK2 inhibitor. A myocardium I/R mouse model was established. Circulating levels of miR-187 or DYRK2 was detected by quantitative realtime PCR and protein expression was detected by western blotting. The cell viability in all groups was determined by MTT assay and the apoptosis ratio was detected by flow cytometry after staining with Annexin V-FITC. The effect of miR-187 on cellular ROS generation was examined by DCFH-DA. The level of lipid peroxidation and SOD expression were determined by MDA and SOD assay. The findings indicated that miR-187 may be a possible regulator in the protective effect of H/R-induced cardiomyocyte apoptosis, cellular oxidative stress and leaded to DYRK2 suppression at a posttranscriptional level. Moreover, the improvement of miR-187 on H/R-induced cardiomyocyte injury contributed to the obstruction of DYRK2 expression. In addition, these results identified DYRK2 as the functional downstream target of miR-187 regulated myocardial infarction and oxidative stress.These present work provided the first insight into the function of miR-187 in successfully protect cardiomyocyte both in vivo and in vitro, and such a protective effect were mediated through the regulation of DYRK2 expression.


2020 ◽  
Author(s):  
Fang-da Fu ◽  
Sai Yao ◽  
Zhi-tao Sun ◽  
Cheng-cong Zhou ◽  
Huan Yu ◽  
...  

Abstract Background Whole body vibration (WBV) is a non-pharmaceutical therapy that has been widely incorporated into clinical practice for musculoskeletal disorders, including low back pain (LBP). Intervertebral disc (IVD) degeneration (IVDD) is clinically associated with LBP and is known as the main cause for LBP. However, cumulative evidence also suggested WBV might have an adverse impact on IVDs. Moreover, previous studies have been focusing on the effects of WBV on healthy mice, rather than those suffering from IVDD. Thus, uncertainties still exist concerning the effects of WBV on IVDs undergoing IVDD. This study was aiming to evaluate the effects of WBV intervention on the development and progression of IVDD mouse model induced by lumbar spine instability (LSI) surgery. Methods LSI surgery, by resecting the lumbar 3 rd -5 th spinous processes along with the supraspinous and interspinous ligaments, was conducted in 10-week-old male mice which then received WBV treatment (1 h per day, 5 days per week, at 3 Hz with peak acceleration at 0.4 g) or sham treatment. The progression of IVDD was evaluated by MRI, μCT and histological analyses after WBV treatment. The matrix metabolism, distribution of sensory nerves, pyroptosis in IVDs tissues were determined by immunohistological analysis or real-time PCR. The apoptosis of IVD cells was detected by TUNEL assay. Results LSI surgery was successful in producing IVDD modeling. WBV caused decreases in IVD height and annulus fibrosus (AF) score, as well as increased numbers of apoptotic cells in IVD tissues. WBV contributed to sensory innervation into AF and upregulation of Adamts5 and MMP3 expression in IVDD mice received LSI surgery. In addition, WBV treatment triggered earlier activation of Wnt/β-catenin signaling in IVDD mice with WBV treatment compared with those without WBV treatment. Unexpectedly, WBV significantly attenuated Caspase-1 and IL-1β expression in AF. Conclusions Collectively, our findings demonstrate that WBV treatment may worsen the development of ongoing IVDD. Decrease of IL-1β expression after WBV intervention may partially account for patient self-reported pain relief after WBV treatment in some previous trials. This study may help us better understand the effects of WBV intervention on patients experiencing LBP resulting from the degeneration of lumbar IVDs.


2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Kaifeng Li ◽  
Mengen Zhai ◽  
Liqing Jiang ◽  
Fan Song ◽  
Bin Zhang ◽  
...  

Hyperglycemia-induced oxidative stress and fibrosis play a crucial role in the development of diabetic cardiomyopathy (DCM). Tetrahydrocurcumin (THC), a major bioactive metabolite of natural antioxidant curcumin, is reported to exert even more effective antioxidative and superior antifibrotic properties as well as anti-inflammatory and antidiabetic abilities. This study was designed to investigate the potential protective effects of THC on experimental DCM and its underlying mechanisms, pointing to the role of high glucose-induced oxidative stress and interrelated fibrosis. In STZ-induced diabetic mice, oral administration of THC (120 mg/kg/d) for 12 weeks significantly improved the cardiac function and ameliorated myocardial fibrosis and cardiac hypertrophy, accompanied by reduced reactive oxygen species (ROS) generation. Mechanically, THC administration remarkably increased the expression of the SIRT1 signaling pathway both in vitro and in vivo, further evidenced by decreased downstream molecule Ac-SOD2 and enhanced deacetylated production SOD2, which finally strengthened antioxidative stress capacity proven by repaired activities of SOD and GSH-Px and reduced MDA production. Additionally, THC treatment accomplished its antifibrotic effect by depressing the ROS-induced TGFβ1/Smad3 signaling pathway followed by reduced expression of cardiac fibrotic markers α-SMA, collagen I, and collagen III. Collectively, these finds demonstrated the therapeutic potential of THC treatment to alleviate DCM mainly by attenuating hyperglycemia-induced oxidative stress and fibrosis via activating the SIRT1 pathway.


2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Feng Wang ◽  
Li-ping Nan ◽  
Shi-feng Zhou ◽  
Yang Liu ◽  
Ze-yu Wang ◽  
...  

Stem cell-based tissue engineering in treating intervertebral disc (IVD) degeneration is promising. An appropriate cell scaffold can maintain the viability and function of transplanted cells. Injectable hydrogel has the potential to be an appropriate cell scaffold as it can mimic the condition of the natural extracellular matrix (ECM) of nucleus pulposus (NP) and provide binding sites for cells. This study was aimed at investigating the effect of injectable hydrogel-loaded NP-derived mesenchymal stem cells (NPMSC) for the treatment of IVD degeneration (IDD) in rats. In this study, we selected injectable 3D-RGD peptide-modified polysaccharide hydrogel as a cell transplantation scaffold. In vitro, the biocompatibility, microstructure, and induced differentiation effect on NPMSC of the hydrogel were studied. In vivo, the regenerative effect of hydrogel-loaded NPMSC on degenerated NP in a rat model was evaluated. The results showed that NPMSC was biocompatible and able to induce differentiation in hydrogel in vivo. The disc height index (almost 87%) and MRI index (3313.83±227.79) of the hydrogel-loaded NPMSC group were significantly higher than those of other groups at 8 weeks after injection. Histological staining and immunofluorescence showed that the hydrogel-loaded NPMSC also partly restored the structure and ECM content of degenerated NP after 8 weeks. Moreover, the hydrogel could support long-term NPMSC survival and decrease cell apoptosis rate of the rat IVD. In conclusion, injectable hydrogel-loaded NPMSC transplantation can delay the level of IDD and promote the regeneration of the degenerative IVD in the rat model.


2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Youngmun Lee ◽  
Sunyoung Kim ◽  
Yeonsoo Oh ◽  
Young-Mi Kim ◽  
Young-Won Chin ◽  
...  

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer’s disease.


2015 ◽  
Vol 12 (104) ◽  
pp. 20141191 ◽  
Author(s):  
Maria Molinos ◽  
Catarina R. Almeida ◽  
Joana Caldeira ◽  
Carla Cunha ◽  
Raquel M. Gonçalves ◽  
...  

Intervertebral disc (IVD) degeneration is one of the major causes of low back pain, a problem with a heavy economic burden, which has been increasing in prevalence as populations age. Deeper knowledge of the complex spatial and temporal orchestration of cellular interactions and extracellular matrix remodelling is critical to improve current IVD therapies, which have so far proved unsatisfactory. Inflammation has been correlated with degenerative disc disease but its role in discogenic pain and hernia regression remains controversial. The inflammatory response may be involved in the onset of disease, but it is also crucial in maintaining tissue homeostasis. Furthermore, if properly balanced it may contribute to tissue repair/regeneration as has already been demonstrated in other tissues. In this review, we focus on how inflammation has been associated with IVD degeneration by describing observational and in vitro studies as well as in vivo animal models. Finally, we provide an overview of IVD regenerative therapies that target key inflammatory players.


2021 ◽  
Vol 30 ◽  
pp. 096368972110453
Author(s):  
Wen-Cheng Lo ◽  
Chi-Sheng Chiou ◽  
Feng-Chou Tsai ◽  
Chun-Hao Chan ◽  
Samantha Mao ◽  
...  

Apart from aging process, adult intervertebral disc (IVD) undergoes various degenerative processes. However, the nicotine has not been well identified as a contributing etiology. According to a few studies, nicotine ingestion through smoking, air or clothing may significantly accumulate in active as well as passive smokers. Since nicotine has been demonstrated to adversely impact various physiological processes, such as sympathetic nervous system, leading to impaired vasculature and cellular apoptosis, we aimed to investigate whether nicotine could induce IVD degeneration. In particular, we evaluated dose-dependent impact of nicotine in vitro to simulate its chronic accumulation, which was later treated by platelet-derived biomaterials (PDB). Further, during in vivo studies, mice were subcutaneously administered with nicotine to examine IVD-associated pathologic changes. The results revealed that nicotine could significantly reduce chondrocytes and chondrogenic indicators (Sox, Col II and aggrecan). Mice with nicotine treatment also exhibited malformed IVD structure with decreased Col II as well as proteoglycans, which was significantly increased after PDB administration for 4 weeks. Mechanistically, PDB significantly restored the levels of IGF-1 signaling proteins, particularly pIGF-1 R, pAKT, and IRS-1, modulating ECM synthesis by chondrocytes. Conclusively, the PDB impart reparative and tissue regenerative processes by inhibiting nicotine-initiated IVD degeneration, through regulating IGF-1/AKT/IRS-1 signaling axis.


2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Ershun Liang ◽  
Xue Liu ◽  
Zhanhui Du ◽  
Ruixue Yang ◽  
Yuxia Zhao

Andrographolide (Andro), a major bioactive component obtained from Andrographis paniculata Nees, has exerted wide antioxidant as well as cytoprotective properties. However, whether Andro treatment could retard the progress of diabetic cardiomyopathy (DCM) remains unknown. In this study, we evaluated the effects of Andro against diabetes-induced myocardial dysfunction and explored the underlying mechanism in STZ-induced diabetic mice. As a result, treatment with Andro dose dependently suppressed cardiac inflammation and oxidative stress, accompanied by decreasing cardiac apoptosis, which subsequently ameliorated cardiac fibrosis and cardiac hypertrophy. Further, Andro blocked hyperglycemia-triggered reactive oxygen species (ROS) generation by suppressing NADPH oxidase (NOX) activation and augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression both in vitro and in vivo. Our results suggest that the cardioprotective effects afforded by Andro treatment involve the modulation of NOX/Nrf2-mediated oxidative stress and NF-κB-mediated inflammation. The present study unravels the therapeutic potential of Andro in the treatment of DCM by attenuating oxidative stress, inflammation, and apoptosis.


2021 ◽  
Vol 22 (4) ◽  
pp. 1579 ◽  
Author(s):  
Eun Roh ◽  
Anjani Darai ◽  
Jae Kyung ◽  
Hyemin Choi ◽  
Su Kwon ◽  
...  

Intervertebral disc (IVD) degeneration can cause chronic lower back pain (LBP), leading to disability. Despite significant advances in the treatment of discogenic LBP, the limitations of current treatments have sparked interest in biological approaches, including growth factor and stem cell injection, as new treatment options for patients with chronic LBP due to IVD degeneration (IVDD). Gene therapy represents exciting new possibilities for IVDD treatment, but treatment is still in its infancy. Literature searches were conducted using PubMed and Google Scholar to provide an overview of the principles and current state of gene therapy for IVDD. Gene transfer to degenerated disc cells in vitro and in animal models is reviewed. In addition, this review describes the use of gene silencing by RNA interference (RNAi) and gene editing by the clustered regularly interspaced short palindromic repeats (CRISPR) system, as well as the mammalian target of rapamycin (mTOR) signaling in vitro and in animal models. Significant technological advances in recent years have opened the door to a new generation of intradiscal gene therapy for the treatment of chronic discogenic LBP.


Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1814
Author(s):  
Tulendy Nurkenov ◽  
Andrey Tsoy ◽  
Farkhad Olzhayev ◽  
Elvira Abzhanova ◽  
Anel Turgambayeva ◽  
...  

There are numerous publications demonstrating that plant polyphenols can reduce oxidative stress and inflammatory processes in the brain. In the present study we have investigated the neuroprotective effect of plant extract isolated from the roots of L. gmelinii since it contains a rich source of polyphenols and other biologically active compounds. We have applied an oxidative and inflammatory model induced by NMDA, H2O2, and TNF-α in human primary neurons and astrocytes, and mouse cerebral endothelial cell (CECs) line in vitro. The levels of ROS generation, NADPH oxidase activation, P-selectin expression, and activity of ERK1/2 were evaluated by quantitative immunofluorescence analysis, confocal microscopy, and MAPK assay. In vivo, sensorimotor functions in rats with middle cerebral artery occlusion (MCAO) were assessed. In neurons NMDA induced overproduction of ROS, in astrocytes TNF-α initiated ROS generation, NADPH oxidase activation, and phosphorylation of ERK1/2. In CECs, the exposure by TNF-α induced oxidative stress and triggered the accumulation of P-selectin on the surface of the cells. In turn, pre-treatment of the cells with the extract of L. gmelinii suppressed oxidative stress in all cell types and pro-inflammatory responses in astrocytes and CECs. In vivo, the treatment with L. gmelinii extract improved motor activity in rats with MCAO.


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