Inhalation of Hydrogen of Different Concentrations Ameliorates Spinal Cord Injury in Mice by Protecting Spinal Cord Neurons from Apoptosis, Oxidative Injury and Mitochondrial Structure Damages

Background/Aims: Hydrogen selectively neutralizes reactive oxygen species (ROS) and ameliorates various ROS-induced injuries. Spinal cord injury (SCI) is a serious injury to the central nervous system, and secondary SCI is closely related to excessive ROS generation. We hypothesized that hydrogen inhalation ameliorates SCI, and the mechanism of action may be related to the protective effects of hydrogen against oxidative stress, apoptosis, and mitochondrial damage. Methods: Mechanically injured spinal cord neurons were incubated with different concentrations of hydrogen in vitro. Immunofluorescence staining and transmission electron microscopy were used to confirm the protective effects of hydrogen. ROS and related proteins were detected with dihydroethidium fluorescence staining, enzyme-linked immunosorbent assays, and western blotting. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays, flow cytometry, and western blotting were used to detect neuronal apoptosis. ATP concentrations, Janus Green B staining, and mitochondrial permeability transition pore (mPTP) status were assessed to investigate mitochondrial damage. RNA sequencing was performed to screen potential target genes of hydrogen application. Hydrogen was administered to mice after spinal cord contusion injury was established for 42 days. The Basso Mouse Scale (BMS) and footprint analyses were used to assess locomotor functions, and immunofluorescence staining of the injured spinal cord segments was performed to detect oxidative stress status. Results: Spinal cord neurons were preserved by hydrogen administration after mechanical injury in a dose-dependent manner. ROS generation, oxidative stress injury-related markers, and the number of apoptotic neurons were significantly reduced after hydrogen treatment. The ATP production and mPTP function in injured neurons were preserved by hydrogen incubation. The expression levels of Cox8b, Cox6a2, Cox7a1, Hspb7, and Atp2a1 were inhibited by hydrogen treatment. BMS scores and the footprint assessment of mice with SCI were improved by hydrogen inhalation. Conclusions: Hydrogen inhalation (75%) ameliorated SCI in vivo and attenuated neuronal mechanical injuries in vitro, and its protective effect on spinal cord neurons was exerted in a dose-dependent manner. The underlying mechanisms included reducing ROS generation and oxidative stress, inhibiting neuronal apoptosis, and restoring mitochondrial construction and function. Cox8b, Cox6a2, Cox7a1, Hspb7, and Atp2a1 were identified as potential target genes of hydrogen treatment.

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Knockdown of long non-coding RNA LEF1-AS1 attenuates apoptosis and inflammatory injury of microglia cells following spinal cord injury

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-020-02041-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Sheng-Yu Cui ◽

Wei Zhang ◽

Zhi-Ming Cui ◽

Hong Yi ◽

Da-Wei Xu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Viability ◽

Microglial Cells ◽

Protective Effects ◽

Loss Of Function ◽

Sprague Dawley ◽

Cord Injury ◽

Apoptosis And Inflammation

Abstract Background Spinal cord injury (SCI) is associated with health burden both at personal and societal levels. Recent assessments on the role of lncRNAs in SCI regulation have matured. Therefore, to comprehensively explore the function of lncRNA LEF1-AS1 in SCI, there is an urgent need to understand its occurrence and development. Methods Using in vitro experiments, we used lipopolysaccharide (LPS) to treat and establish the SCI model primarily on microglial cells. Gain- and loss of function assays of LEF1-AS1 and miR-222-5p were conducted. Cell viability and apoptosis of microglial cells were assessed via CCK8 assay and flow cytometry, respectively. Adult Sprague-Dawley (SD) rats were randomly divided into four groups: Control, SCI, sh-NC, and sh-LEF-AS1 groups. ELISA test was used to determine the expression of TNF-α and IL-6, whereas the protein level of apoptotic-related markers (Bcl-2, Bax, and cleaved caspase-3) was assessed using Western blot technique. Results We revealed that LncRNA LEF1-AS1 was distinctly upregulated, whereas miR-222-5p was significantly downregulated in LPS-treated SCI and microglial cells. However, LEF1-AS1 knockdown enhanced cell viability, inhibited apoptosis, as well as inflammation of LPS-mediated microglial cells. On the contrary, miR-222-5p upregulation decreased cell viability, promoted apoptosis, and inflammation of microglial cells. Mechanistically, LEF1-AS1 served as a competitive endogenous RNA (ceRNA) by sponging miR-222-5p, targeting RAMP3. RAMP3 overexpression attenuated LEF1-AS1-mediated protective effects on LPS-mediated microglial cells from apoptosis and inflammation. Conclusion In summary, these findings ascertain that knockdown of LEF1-AS1 impedes SCI progression via the miR-222-5p/RAMP3 axis.

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pH-responsive delivery of H2 through ammonia borane-loaded mesoporous silica nanoparticles improves recovery after spinal cord injury by moderating oxidative stress and regulating microglial polarization

Regenerative Biomaterials ◽

10.1093/rb/rbab058 ◽

2021 ◽

Author(s):

Yi Liu ◽

Yeying Wang ◽

Bing Xiao ◽

Guoke Tang ◽

Jiangming Yu ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Mesoporous Silica Nanoparticles ◽

Ammonia Borane ◽

Neural Regeneration ◽

Dependent Manner ◽

Cord Injury

Abstract Imbalance of oxidative and inflammatory regulation is the main contributor to neurofunctional deterioration and failure of rebuilding spared neural networks after spinal cord injury (SCI). As an emerging biosafe strategy for protecting against oxidative and inflammatory damage, hydrogen (H2) therapy is a promising approach for improving the microenvironment to allow neural regeneration. However, achieving release of H2 at sufficient concentrations specifically into the injured area is critical for the therapeutic effect of H2. Thus, we assembled SiO2@mSiO2 mesoporous silica nanoparticles and loaded them with ammonia borane (AB), which has abundant capacity and allows controllable release of H2 in an acid-dependent manner. The release of H2 from AB/SiO2@mSiO2 was satisfactory at pH 6.6, which is approximately equal to the microenvironmental acidity after SCI. After AB/SiO2@mSiO2 were intrathecally administered to rat models of SCI, continuous release of H2 from these nanoparticles synergistically enhanced neurofunctional recovery, reduced fibrotic scar formation and promoted neural regeneration by suppressing oxidative stress reaction. Furthermore, in the subacute phase of SCI, microglia were markedly polarized toward the M2 phenotype by H2 via inhibition of TLR9 expression in astrocytes. In conclusion, H2 delivery through AB/SiO2@mSiO2 has the potential to efficiently treat SCI through comprehensive modulation of the oxidative and inflammatory imbalance in the microenvironment.

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Tetrahydrocurcumin Ameliorates Diabetic Cardiomyopathy by Attenuating High Glucose-Induced Oxidative Stress and Fibrosis via Activating the SIRT1 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6746907 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 12

Author(s):

Kaifeng Li ◽

Mengen Zhai ◽

Liqing Jiang ◽

Fan Song ◽

Bin Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Diabetic Cardiomyopathy ◽

High Glucose ◽

Therapeutic Potential ◽

Ros Generation ◽

Protective Effects ◽

Collagen Iii

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.

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Development of Polymeric Nerve Guidance Conduits That Contain Anisotropic Cues Including Aligned Microfibers and Gradients of Adsorbed Laminin-1

Journal of Medical Devices ◽

10.1115/1.2934348 ◽

2008 ◽

Vol 2 (2) ◽

Author(s):

Jared M. Cregg ◽

Han Bing Wang ◽

Michael E. Mullins ◽

Ryan J. Gilbert

Keyword(s):

Spinal Cord ◽

Electrospun Fiber ◽

Axonal Growth ◽

Contact Guidance ◽

Directional Growth ◽

Spinal Cord Neurons ◽

Neurite Extension ◽

Cord Injury ◽

Laminin 1

Structures that direct neurite extension are important for regeneration following spinal cord injury and peripheral nerve injury. Within the spinal cord, neurons encounter a glial scar environment that impedes regeneration. In the peripheral nervous system, endogenous regeneration cannot occur across nerve gaps greater than 2mm. Current repair strategies use guidance conduits to channel axonal growth towards distal targets. While showing promise, conduit walls do not provide a suitable environment for neuronal attachment or extension, and axonal growth within conduits remains tortuous. Hence, there is a need for development of three-dimensional (3D) structures that use contact guidance—rather than confinement—as a means of guided regeneration. Our laboratory has developed aligned, electrospun fiber matrices that have been shown to direct neurite extension in vitro. In addition, a gradient of the glycoprotein laminin-1 has been adsorbed onto aligned microfiber matrices to stimulate directional growth. These matrices were then manipulated into 3D conduit structures. Novel polymeric conduits that utilize contact guidance and contain gradients of molecules that stimulate directional growth have the potential to foster fast, directed regeneration into and through conduit structures.

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Sodium Tanshinone IIA Silate Exerts Microcirculation Protective Effects against Spinal Cord Injury In Vitro and In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3949575 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Xing Li ◽

Dan Luo ◽

Yu Hou ◽

Yonghui Hou ◽

Shudong Chen ◽

...

Keyword(s):

Spinal Cord ◽

Endothelial Cells ◽

Notch Signaling ◽

Signaling Pathway ◽

Notch Signaling Pathway ◽

Tanshinone Iia ◽

Protective Effects ◽

Cord Injury

Spinal cord microcirculation involves functioning endothelial cells at the blood spinal cord barrier (BSCB) and maintains normal functioning of spinal cord neurons, axons, and glial cells. Protection of both the function and integrity of endothelial cells as well as the prevention of BSCB disruption may be a strong strategy for the treatment of spinal cord injury (SCI) cases. Sodium Tanshinone IIA silate (STS) is used for the treatment of coronary heart disease and improves microcirculation. Whether STS exhibits protective effects for SCI microcirculation is not yet clear. The purpose of this study is to investigate the protective effects of STS on oxygen-glucose deprivation- (OGD-) induced injury of spinal cord endothelial cells (SCMECs) in vitro and to explore effects on BSCB and neurovascular protection in vivo. SCMECs were treated with various concentrations of STS (1 μM, 3 μM, and 10 μM) for 24 h with or without OGD-induction. Cell viability, tube formation, migration, and expression of Notch signaling pathway components were evaluated. Histopathological evaluation (H&E), Nissl staining, BSCB permeability, and the expression levels of von Willebrand Factor (vWF), CD31, NeuN, and Notch signaling pathway components were analyzed. STS was found to improve SCMEC functions and reduce inflammatory mediators after OGD. STS also relieved histopathological damage, increased zonula occludens-1 (ZO-1), inhibited BSCB permeability, rescued microvessels, protected motor neuromas, and improved functional recovery in a SCI model. Moreover, we uncovered that the Notch signaling pathway plays an important role during these processes. These results indicated that STS protects microcirculation in SCI, which may be used as a therapeutic strategy for SCI in the future.

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Dehydroepiandrosterone Prevents H2O2-Induced BRL-3A Cell Oxidative Damage through Activation of PI3K/Akt Pathways rather than MAPK Pathways

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/2985956 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14

Author(s):

Longlong Li ◽

Yao Yao ◽

Zhihao Jiang ◽

Jinlong Zhao ◽

Ji Cao ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Expression ◽

Signaling Pathways ◽

Hormone Receptors ◽

Mapk Signaling ◽

Ros Generation ◽

Protective Effects ◽

Pi3k Inhibitor Ly294002 ◽

Beneficial Effects

Dehydroepiandrosterone (DHEA) is a popular dietary supplement that has well-known benefits in animals and humans, but there is not enough information about the mechanisms underlying its effects. The present study aimed at investigating these mechanisms through in vitro experiments on the effects of DHEA on rat liver BRL-3A cells exposed to oxidative stress through H2O2. The findings showed that DHEA increased the antioxidant enzyme activity, decreased ROS generation, and inhibited apoptosis in H2O2-treated cells. These effects of DHEA were not observed when the cells were pretreated with known antagonists of sex hormones (Trilostane, Flutamide, or Fulvestrant). Furthermore, treatment with estradiol and testosterone did not have the same protective effects as DHEA. Thus, the beneficial effects of DHEA were associated with mechanisms that were independent of steroid hormone pathways. With regard to the mechanism underlying the antiapoptotic effect of DHEA, pretreatment with DHEA was found to induce a significant decrease in the protein expression of Bax and caspase-3 and a significant increase in the protein expression of PI3K and p-Akt in H2O2-treated BRL-3A cells. These effects of DHEA were abolished when the cells were pretreated with the PI3K inhibitor LY294002. No changes were observed on the p-ERK1/2, p-p38, and p-JNK protein levels in H2O2-induced BRL-3A cells pretreated with DHEA. In conclusion, our data demonstrate that DHEA protects BRL-3A cells against H2O2-induced oxidative stress and apoptosis through mechanisms that do not involve its biotransformation into steroid hormones or the activation of sex hormone receptors. Importantly, the protective effect of DHEA on BRL-3A cells was mainly associated with PI3K/Akt signaling pathways, rather than MAPK signaling pathways.

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Allicin Protects PC12 Cells Against 6-OHDA-Induced Oxidative Stress and Mitochondrial Dysfunction via Regulating Mitochondrial Dynamics

Cellular Physiology and Biochemistry ◽

10.1159/000430271 ◽

2015 ◽

Vol 36 (3) ◽

pp. 966-979 ◽

Cited By ~ 44

Author(s):

Hao Liu ◽

Ping Mao ◽

Jia Wang ◽

Tuo Wang ◽

Chang-Hou Xie

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Pc12 Cells ◽

Atp Synthesis ◽

Ros Generation ◽

Antioxidant Enzyme Activities ◽

Protective Effects ◽

Cytochrome C Release ◽

Endogenous Antioxidant

Background: Parkinson disease (PD) is a common adult-onset neurodegenerative disorder, and PD related neuronal injury is associated with oxidative stress and mitochondrial dysfunction. Allicin, the main biologically active compound derived from garlic, has been shown to exert various anti-oxidative and anti-apoptotic activities in in vitro and in vivo studies. Methods: The present study aimed to investigate the potential protective role of allicin in an in vitro PD model induced by 6-hydroxydopamine (6-OHDA) in PC12 cells. The protective effects were measured by cell viability, decreased lactate dehydrogenase (LDH) release and flow cytometry, and the anti-oxidative activity was determined by reactive oxygen species (ROS) generation, lipid peroxidation and the endogenous antioxidant enzyme activities. Mitochondrial function in PC12 cells was detected by mitochondrial membrane potential (MMP) collapse, cytochrome c release, mitochondrial ATP synthesis, and the mitochondrial Ca2+ buffering capacity. To investigate the potential mechanism, we also measured the expression of mitochondrial biogenesis factors, mitochondrial morphological dynamic changes, as well as detected mitochondrial dynamic proteins by western blot. Results: We found that allicin treatment significant increased cell viability, and decreased LDH release and apoptotic cell death after 6-OHDA exposure. Allicin also inhibited ROS generation, reduced lipid peroxidation and preserved the endogenous antioxidant enzyme activities. These protective effects were associated with suppressed mitochondrial dysfunction, as evidenced by decreased MMP collapse and cytochrome c release, preserved mitochondrial ATP synthesis, and the promotion of mitochondrial Ca2+ buffering capacity. In addition, allicin significantly enhanced mitochondrial biogenesis and prevented fragmentation of mitochondrial network after 6-OHDA treatment. The results of western blot analysis showed that the 6-OHDA induced decrease in the expression of optic atrophy type 1 (Opa-1), increase in mitochondrial fission 1 (Fis-1) and dynamin-related protein 1 (Drp-1) were all partially revised by allicin. Conclusion: In summary, our data strongly suggested that allicin treatment can exert protective effects against PD related neuronal injury through inhibiting oxidative stress and mitochondrial dysfunction with dynamic changes.

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In Vitro and In Vivo Protective Effects of Lentil (Lens culinaris) Extract against Oxidative Stress-Induced Hepatotoxicity

Molecules ◽

10.3390/molecules27010059 ◽

2021 ◽

Vol 27 (1) ◽

pp. 59

Author(s):

Yeon-Seop Jung ◽

So-Hee Lee ◽

So Young Chun ◽

Dae Hwan Kim ◽

Byung Ik Jang ◽

...

Keyword(s):

Oxidative Stress ◽

Serum Levels ◽

Liver Cells ◽

Dependent Manner ◽

Protective Effects ◽

H2o2 Treatment ◽

Antioxidant Genes ◽

Hepatic Diseases

Excessive oxidative stress plays a role in hepatotoxicity and the pathogenesis of hepatic diseases. In our previous study, the phenolic extract of beluga lentil (BLE) showed the most potent in vitro antioxidant activity among extracts of four common varieties of lentils; thus, we hypothesized that BLE might protect liver cells against oxidative stress-induced cytotoxicity. BLE was evaluated for its protective effects against oxidative stress-induced hepatotoxicity in AML12 mouse hepatocytes and BALB/c mice. H2O2 treatment caused a marked decrease in cell viability; however, pretreatment with BLE (25–100 μg/mL) for 24 h significantly preserved the viability of H2O2-treated cells up to about 50% at 100 μg/mL. As expected, BLE dramatically reduced intracellular reactive oxygen species (ROS) levels in a dose-dependent manner in H2O2-treated cells. Further mechanistic studies demonstrated that BLE reduced cellular ROS levels, partly by increasing expression of antioxidant genes. Furthermore, pretreatment with BLE (400 mg/kg) for 2 weeks significantly reduced serum levels of alanine transaminase and triglyceride by about 49% and 40%, respectively, and increased the expression and activity of glutathione peroxidase in CCl4-treated BALB/c mice. These results suggest that BLE protects liver cells against oxidative stress, partly by inducing cellular antioxidant system; thus, it represents a potential source of nutraceuticals with hepatoprotective effects.

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Catalpol Protects Against Spinal Cord Injury in Mice Through Regulating MicroRNA-142-Mediated HMGB1/TLR4/NF-κB Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.630222 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hougang Xia ◽

Dandan Wang ◽

Xiaohui Guo ◽

Kaidi Wu ◽

Fuwei Huang ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Inflammatory Factors ◽

Tunel Staining ◽

Ros Generation ◽

Bv2 Cells ◽

Cord Injury ◽

Oxidative Response

Background: Spinal cord injury (SCI) is a devastating condition that leads to paralysis, disability and even death in severe cases. Inflammation, apoptosis and oxidative stress in neurons are key pathogenic processes in SCI. Catalpol (CTP), an iridoid glycoside extracted from Rehmannia glutinosa, has many pharmacological activities, such as anti-inflammatory, anti-oxidative and anti-apoptotic properties.Purpose: Here, we investigated whether CTP could exert neuroprotective effects against SCI, and explored the underlying mechanism involved.Methods: SCI was induced by a weight-drop device and treated with CTP (10 mg and 60 mg/kg). Then the locomotor function of SCI mice was evaluated by the BBB scores, spinal cord edema was measured by the wet/dry weight method, oxidative stress markers and inflammatory factors were detected by commercial kits and neuronal death was measured by TUNEL staining. Moreover, the microRNA expression profile in spinal cords from mice following SCI was analyzed using miRNA microarray. In addition, reactive oxygen species (ROS) generation, inflammatory response and cell apoptosis were detected in murine microglia BV2 cells under oxygen-glucose deprivation (OGD) and CTPtreatment.Results: Our data showed that CTP treatment could improve the functional recovery, as well as suppress the apoptosis, alleviate inflammatory and oxidative response in SCI mice. In addition, CTP was found to be up-regulated miR-142 and the protective effects of CTP on apoptosis, inflammatory and oxidative response may relate to its regulation of HMGB1/TLR4/NF-κB pathway through miR-142.Conclusion: Our findings suggest that CTP may protect the spinal cord from SCI by suppression of apoptosis, oxidative stress and inflammatory response via miR-142/HMGB1/TLR4/NF-κB pathway.

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Osthole Attenuates Bleomycin-Induced Pulmonary Fibrosis by Modulating NADPH Oxidase 4-Derived Oxidative Stress in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3309944 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Lijun Fang ◽

Wei Wang ◽

Jiazheng Chen ◽

Anju Zuo ◽

Hongmei Gao ◽

...

Keyword(s):

Oxidative Stress ◽

Pulmonary Fibrosis ◽

Lung Fibroblasts ◽

Ros Generation ◽

Dependent Manner ◽

Active Constituent ◽

Concentration Dependent Manner ◽

Nadph Oxidase 4 ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the extensive accumulation of myofibroblasts and collagens. However, the exact mechanism that underlies this condition is unclear. Growing evidence suggests that NADPH oxidases (NOXs), especially NOX4-derived oxidative stress, play an important role in the development of lung fibrosis. Bleomycin (BLM) is a tumor chemotherapeutic agent, which has been widely employed to establish IPF animal models. Osthole (OST) is an active constituent of the fruit of Cnidium ninidium. Here, we used an in vivo mouse model and found that OST suppressed BLM-induced body weight loss, lung injury, pulmonary index increase, fibroblast differentiation, and pulmonary fibrosis. OST also significantly downregulated BLM-induced NOX4 expression and oxidative stress in the lungs. In vitro, OST could inhibit TGF-β1-induced Smad3 phosphorylation, differentiation, proliferation, collagen synthesis, NOX4 expression, and ROS generation in human lung fibroblasts in a concentration-dependent manner. Moreover, NOX4 overexpression could prevent the above effects of OST. We came to the conclusion that OST could significantly attenuate BLM-induced pulmonary fibrosis in mice, via the mechanism that involved downregulating TGF-β1/NOX4-mediated oxidative stress in lung fibroblasts.

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