Frontiers in Cell and Developmental Biology
·
2020
·
IF 5.186
Chen Xiao,Liang Huaibin,Xi Zhiyu,Yang Yong,Shan Huimin,Wang Baofeng,Zhong Zhihong,Xu Canxin,Yang Guo-Yuan,Sun Qingfang,Sun Yuhao,Bian Liuguan
Intracerebral hemorrhage (ICH) is a particularly severe form of stroke, and reactive astrogliosis is a common response following injury to the central nervous system (CNS). Mesenchymal stem cells (MSCs) are reported to promote neurogenesis and alleviate the late side effects in injured brain regions. Gap junctions (Gjs) are abundant in the brain, where the richest connexin (Cx) is Cx43, most prominently expressed in astrocytes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor regulating antioxidant reactions. Here, we aimed to explore whether bone marrow MSCs (BM-MSCs) could alleviate brain injury and protect astrocytes from apoptosis, by regulating Cx43 and Nrf2. We validated the effect of BM-MSC transplantation in an ICH model in vivo and in vitro and detected changes using immunofluorescence, as well as protein and mRNA expression of glial fibrillary acidic protein (GFAP), vimentin (VIM), Cx43, Nrf2, and heme oxygenase-1 (HO-1). Our results showed that BM-MSC transplantation attenuated brain injury after ICH and upregulated VIM expression in vivo and in vitro. Additionally, Cx43 upregulation and Nrf2 nuclear translocation were observed in astrocytes cocultured with BM-MSC. Knockdown of Cx43 by siRNA restrained Nrf2 nuclear translocation. Cx43 and Nrf2 had a connection as determined by immunofluorescence and coimmunoprecipitation. We demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and have anti-apoptotic abilities after BM-MSC transplantation, where Cx43 upregulation triggers Nrf2 nuclear translocation and promotes its phase II enzyme expression. The Cx43/Nrf2 interaction of astrocytes after BM-MSC transplantation may provide an important therapeutic target in the management of ICH.
研究领域:
神经科学
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干细胞研究
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神经病学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Rao Jian,Xie Haishu,Liang Zeyan,Yang Zhelun,Chen Pingping,Zhou Maochao,Xu Xiongjie,Lin Yike,Lin Fabin,Wang Rui,Wang Chunhua,Chen Chunmei
Background: Oxidative stress and apoptosis of neurons significantly contribute to the pathophysiological cascade of spinal cord injury (SCI). However, the role of hypoxic-preconditioned mesenchymal stem cell-derived small extracellular vesicles (H-sEVs) in promoting SCI repair remains unclear. Hence, the present study aims to investigate the regulatory effects of H-sEVs on neuronal oxidative stress and apoptotic responses following SCI.Methods: The administration of H-sEVs of SCI rats was assessed using behavioral evaluations such as Basso-Beattie-Bresnahan (BBB) scores, neuroelectrophysiological monitoring, and Catwalk gait analysis. Indices of oxidative stress (including superoxide dismutase [SOD], total antioxidant capacity [T-AOC], and malondialdehyde [MDA]) were measured. Neuronal survival was evaluated through Nissl staining, while the expression level of sirtuin 1 (SIRT1) was examined using immunohistochemical staining. Additionally, histological evaluation of lesion size was performed using hematoxylin-eosin (HE) staining. Tunel cell apoptosis staining and analysis of apoptosis-associated proteins (B-cell lymphoma-2 [Bcl2] and BCL2-Associated X [Bax]) were conducted through immunofluorescence staining and western blot, respectively. Furthermore, the model of oxidative stress was established using PC12 cells, and apoptosis levels were assessed via flow cytometry and western blot analysis. Importantly, to ascertain the critical role of SIRT1, we performed SIRT1 knockout experiments in PC12 cells using lentivirus transfection, followed by western blot.Results: Using those behavioral evaluations, we observed significant functional improvement after H-sEVs treatment. Nissl staining revealed that H-sEVs treatment promoted neuronal survival. Moreover, we found that H-sEVs effectively reduced oxidative stress levels after SCI. HE staining demonstrated that H-sEVs could reduce lesion area. Immunohistochemical analysis revealed that H-sEVs enhanced SIRT1 expression. Furthermore, Tunel cell apoptosis staining and western blot analysis of apoptosis-related proteins confirmed the anti-apoptotic effects of H-sEVs. The PC12 cells were used to further substantiate the neuroprotective properties of H-sEVs by significantly inhibiting neuronal death and attenuating oxidative stress. Remarkably, SIRT1 knockout in PC12 cells reversed the antioxidant stress effects induced by H-sEVs treatment. Additionally, we elucidated the involvement of the downstream Nrf2/HO-1 signaling pathway.Conclusion: Our study provides valuable insights into the effects of H-sEVs on neuronal oxidative stress and apoptosis after SCI. These findings underscore the potential clinical significance of H-sEVs-based therapies for SCI.
研究领域:
神经科学
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干细胞生物学
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分子生物学
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细胞生物学
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再生医学
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DOI
PubMed
高影响因子
Iranian Journal of Basic Medical Sciences
·
2023
·
IF 2.2
Junyuan Li,Gang Wang,Yehao Zhang,Xiaodi Fan,Mingjiang Yao
Objective(s): To explore the ability and underlying molecular mechanisms involved in the protective effects of Baicalin (BA) against L-Glutamate-induced mouse hippocampal neuron cell line HT-22. Materials and Methods: The cell injury model of HT-22 cells was induced by L-glutamate, and cell viability and damage were detected by CCK-8 and LDH assays. Generation of intracellular reactive oxygen species (ROS) was measured by DCFH-DA in situ fluorescence method. The SOD activity and MDA concentration in the supernatants were determined by WST-8 and colorimetric method, respectively. Furthermore, Western blot and real-time qPCR analysis were utilized to detect the expression levels of the Nrf2/HO-1 signaling pathway and NLRP3 inflammasome proteins and genes. Results: L-Glutamate exposure induced cell injuries in HT-22 cells, and the concentration of 5 mM L-Glutamate was chosen to be the modeling condition. Co-treatment with BA significantly promoted cell viability and reduced LDH release in a dose-dependent manner. In addition, BA attenuated the L-Glutamate-induced injuries by decreasing the ROS production and MDA concentration, while increasing the SOD activity. Moreover, we also found that BA treatment up-regulated the gene and protein expression of Nrf2 and HO-1, and then inhibited the expression of NLRP3. Conclusion: Our study found that BA could relieve oxidative stress damage of HT-22 cells induced by L-Glutamate, and the mechanism might be related to the activation of Nrf2/HO-1 and inhibition of NLRP3 inflammasome.
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Runhong Zhou,Jianan Hu,Jingnan Qiu,Shengsheng Lu,Haixing Lin,Ruifeng Huang,Shaofen Zhou,Guoqing Huang,Jian He
Influenza A virus (IAV) is one of the leading causes of respiratory illness and continues to cause pandemics around the world. Against this backdrop, drug resistance poses a challenge to existing antiviral drugs, and hence, there is an urgent need for developing new antiviral drugs. In this study, we obtained a phenolic compound SG -7, a derivative of natural compound 2-hydroxymethyl-1,4-hydroquinone, which exhibits inhibitory activity toward a panel of influenza viruses and has low cellular toxicity. Mechanistic studies have shown that SG -7 exerts its anti-IAV properties by acting on the virus itself and modulating host signaling pathways. Namely, SG -7 targets the HA2 subunit of hemagglutinin (HA) to block the fusion of viral-cellular membranes and inhibits IAV-induced oxidative stress and overexpression of pro-inflammatory factors by activating the Nrf2/HO-1 pathway and reducing NF-κB activation. In addition, SG -7 can enhance type I IFN antiviral response by inducing Nrf2 expression. Importantly, SG-7 showed the ability to inhibit viral replication in the lungs of IAV-infected mice and reduce their mortality. Therefore, SG-7 may be a promising lead compound for anti-influenza drug development .
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2018
·
IF 3.118
Zheng Li,Haihua Feng,Yue Wang,Bingyu Shen,Ye Tian,Lin Wu,Qiaoling Zhang,Meiyu Jin,Guowen Liu
Rosmarinic acid (RA) has antioxidation, anticancer, antibacterial, anti-inflammatory and various biological functions. In our study, we aim to evaluate effects of RA on acute liver injury caused by LPS and d -galactosamine ( d -GalN) and its underlying molecular mechanism in mice. Our findings showed that RA could protect C57BL/6 mice from LPS/ d -GalN-induced acute liver injury, which not only reflected on declining aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of the serum, but also restrained the phosphorylation of nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase (ERK1/2) and p38 protein expression and the content of tissue myeloperoxidase (MPO) elevation. Moreover, RA could enhance the level of glutathione-dependent peroxidase (GSH-PX). Furthermore, RA promoted that nuclear factor erythroid-2-related factor 2 (Nrf2) transported into nucleus, and then up-regulated heme oxygenase 1 (HO-1), glutamate-cysteine ligase catalytic (GCLC), glutamate cysteine ligase modifier (GCLM) and quinone oxidoreductase (NQO1). These results indicated that RA could protect the mice from acute liver injury induced by LPS/ d -GalN.
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Wenqian Wang,Qingfu Zhang,Tong Zhang,Fuping Lu,Fufeng Liu
Current therapeutic options for Parkinson's disease (PD) are limited in efficacy and burdened with severe side-effects. Inflammation, intertwined with oxidative stress and influenced by gut microbiota-related changes making the gut-brain axis the main target of innovative therapies. This study reveals the multiple protective effects of polysaccharides extracted from Ulva lactuca (UPE) on PD models. In vitro, UPE was shown to have direct cytoprotective effects, including mitigating 1-methyl-4-phenylpyridinium-induced cell apoptosis, reducing reactive oxygen species levels, and maintaining mitochondrial membrane potential. In vivo, oral UPE significantly restored motor deficits and dopaminergic neuron loss caused by MPTP. These in vivo benefits were associated with the inhibition of oxidative stress and inflammation. Moreover, oral UPE inhibits the excessive activation of glial cells and the excessive production of pro-inflammatory factors and oxidative stress markers in serum. Furthermore, 16S rRNA analysis of gut microbiota revealed that UPE reshaped the gut microbiota of PD mice by increasing the abundance of norank_f_Murbaculaceae and decreasing the abundance of Desulfovibrio . Mechanically, the Nrf2/HO-1 and TLR4/NF-κB signaling pathways are involved in the anti-PD effect of UPE. In general, UPE offers new perspectives on PD treatment and demonstrates the potential of natural polysaccharides in treating neurodegenerative diseases.
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PubMed
高影响因子
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
·
2025
·Vol. 51
·期 5
·2152-2169
·
IF 1.7
Luo Zeping,Pan Liwei
Objective: With the molecular formula C 16 H 12 O 4 , formononetin (FMN) is an appealing synthon exhibiting a wide range of biological activities, including antioxidant, anti-infective, and anti-apoptotic effects. Due to increasing interest in the mechanisms of action of antioxidants, our group aimed to identify the cellular target sites of these compounds. Methods: Cell Counting Kit-8 (CCK-8), enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy (TEM), TdT-mediated dUTP nick end labeling (TUNEL) staining, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blot were used to analyze the effects of oxidative stress on PC12 cell survival, antioxidant enzyme activity, mitochondrial morphology, apoptosis, key intracellular proteins, and signaling pathways. The potential roles of candidate targets were further investigated using proteomics, molecular docking, kinetic simulation, and cellular thermal shift assay (CETSA). Results and Discussion: One of the compounds, ( VI ) (5-(8-(((1-(benzyloxy)-3-hydroxy-1-oxopropan-2-yl)amino)methyl)-7-hydroxy-4-oxo-4 H -chromen-3-yl)-2-methoxybenzenesulfonic acid), was highly active. It enhanced PC12 cell proliferation, reduced lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, and increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, effectively inhibiting apoptosis and ameliorating mitochondrial damage. Meanwhile, ( VI ) upregulated the expression of PI3K/Akt and Nrf2/HO-1 proteins. The study also demonstrated that ( VI ) binds significantly to the oxidative stress-related protein HO-1. Conclusions: Compound ( VI ) effectively protects PC12 cells against H 2 O 2 -induced oxidative damage. Its protective mechanism may involve activation of the PI3K/Akt and Nrf2/HO-1 signaling pathways, with HO-1 serving as a potential key target of its action.
研究领域:
药理学
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分子生物学
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神经科学
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药物化学
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细胞生物学
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抗氧化研究
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信号转导
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DOI
高影响因子
MOLECULAR NEUROBIOLOGY
·
2016
·Vol. 54
·期 3
·2209-2222
·
IF 5.397
Chen Zi-wei,Liu Anmin,Liu Qingyu,Chen Jingkao,Li Wen-ming,Chao Xiao-juan,Yang Qian,Liu Pei-qing,Mao Zi-xu,Pi Rong-biao
Methylene blue (MB) can ameliorate behavioral, neurochemical, and neuropathological impairments in animal models of acute and chronic neurodegenerative disorders, but the underlying mechanism remains unclear. Myocyte enhancer factor 2 (MEF2D) is known to promote neuronal survival in several models, and several survival and death signals converge on MEF2D and regulate its activity. Here, we investigated the role of MEF2D in the neuroprotective effect of MB against glutamate-induced toxicity in HT22 neuronal cells. Our results showed that MB, event at less than 100 nM, improved the viability of HT22 cells exposed to 2 mM glutamate. MB attenuated the mitochondrial impairment and quenches the reactive oxygen species (ROS) induced by glutamate. Surprisingly, MB at 50–200 nM did not affect the Nrf2/HO-1 pathway, an important endogenous anti-oxidative system. Further study showed that MB increased the transcription and translation of MEF2D. In addition, MB upregulated the expression of mitochondrial NADH dehydrogenase 6 (ND6) in a MEF2D-dependent manner. Knockdown of MEF2D abolished both MB-medicated increase of ND6 and MB-induced neuroprotection against glutamate-induced toxicity. Moreover, we showed that MB promoted Akt function activity, suppressed GSK-3β activity, and increased MEF2D level in hippocampus of mice and HT22 cells. These findings for the first time demonstrate that MB protects HT22 neuronal cells against glutamate-induced cell death partially via the regulation of MEF2D-associated survival pathway.
研究领域:
神经科学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2021
·Vol. 22
·期 6
·1-10
·
IF 2.447
Qian Li,Zhaoyan Qiu,Yan Wang,Chunyan Guo,Xu Cai,Yandong Zhang,Li Liu,Hongkun Xue,Jintian Tang
Tea polyphenols (TPs) are the major bioactive extract from green tea that have been extensively reported to prevent and treat oxidative stress damage. In previous studies, TPs have been demonstrated to protect cells against oxidative injury induced by hydrogen peroxide (H2O2). However, the underlying mechanism remains unclear. The aim of the current study was to investigate whether the protective and regulatory effects of TPs on oxidative stress damage were dependent on the mammalian STE20‑like protein kinase (Mst)/nuclear factor (erythroid‑derived 2)‑like 2 (Nrf2) axis and the Kelch‑like ECH‑associated protein 1 (Keap1)/Nrf2/heme oxygenase 1 (HO‑1) pathway in RAW264.7 cells, a murine macrophage cell line. Maintaining a certain range of intracellular reactive oxygen species (ROS) levels is critical to basic cellular activities, while excessive ROS generation can override the antioxidant capacity of the cell and result in oxidative stress damage. The inhibition of ROS generation offers an effective target for preventing oxidative damage. The results of the present study revealed that pretreatment with TPs inhibited the production of intracellular ROS and protected RAW264.7 cells from H2O2‑induced oxidative damage. TPs was also demonstrated to attenuate the production of nitric oxide and malondialdehyde and increase the levels of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase). In addition, following TPs treatment, alterations in Mst1/2 at the mRNA and protein level inhibited the production of ROS and promoted the self‑regulation of antioxidation. TPs‑induced Keap1 gene downregulation also increased the expression of Nrf2 and HO‑1. Collectively, the results of the present study demonstrated that TPs provided protection against H2O2‑induced oxidative injury in RAW264.7 cells.
研究领域:
药理学
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细胞生物学
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分子生物学
·
生物化学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
WenBin Liu,ZhengWei Tan,YueChao Zhao,YanNa Zhao,XiaoLing Yu,BoLin Wang,FengLin Shen,Ai Mi,JinJian Lan,RuiLan Gao
Panaxadiol saponin (PND) is a latent targeted drug for the treatment of aplastic anemia (AA). In this study, we examined the effects of PND on ferroptosis in iron-overload AA and Meg-01 cells. We utilized RNA-seq to analyze differentially expressed genes in iron-induced Meg-01 cells treated with PND. The effects of PND or combined with deferasirox (DFS) on iron deposition, labile iron pool (LIP), several ferroptosis events, apoptosis, mitochondrial structure, as well as ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR pathway-related markers in iron-induced Meg-01 cells were examined by Prussian-blue staining, flow cytometer, ELISA, Hoechst 33342 staining, transmission electron microscope, and Western blot assays, respectively. Additionally, an AA mice model with iron overload was established. Then, the blood routine was assessed, and the number of bone marrow-derived mononuclear cells (BMMNCs) in mice was counted. Also, serum iron, ferroptosis events, apoptosis, histology, T lymphocyte percentage, ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related targets in primary megakaryocytes of AA mice with iron overload were assessed by commercial kits, TUNEL staining, hematoxylin and eosin (H&E) staining, Prussian blue staining, flow cytometer, and qRT-PCR analysis, respectively. PND suppressed iron-triggered iron overload, and apoptosis, and ameliorated mitochondrial morphology in Meg-01 cells. Importantly, PND ameliorated ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related marker expressions in iron-induced Meg-01 cells or primary megakaryocytes of AA mice with iron overload. Moreover, PND ameliorated body weight, peripheral blood cell counts, the number of BMMNCs, and histological injury in the iron-overload AA mice. Also, PND improved the percentage of T lymphocytes in the iron-overload AA mice. PND attenuates ferroptosis against iron-overload AA mice and Meg-01 cells via activating Nrf2/HO-1 and PI3K/AKT/mTOR pathway and is a promising novel therapeutic candidate for AA.
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PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2024
·
IF 5.4
Xinyu Zhao,Huirong Huang,Xinyu Jiang,Shimin Zheng,Chenyu Qiu,Yingfeng Cheng,Yinhao Lin,Yunzhi Wang,Yuqi Yan,Xinyu Di,Miyun Hu,Wanling Zhu,Fugen Wu,Xianbao Shi,Ruijie Chen,Longfa Kou
Osteoarthritis (OA) is a chronic inflammation that gradually leads to cartilage degradation. Prolonged chondrocyte oxidative stress contributes to the development of diseases, including chondrocyte apoptosis, cartilage matrix degradation, and aggravation of articular cartilage damage. Bilirubin (BR) possesses strong antioxidant properties by scavenging reactive oxygen species (ROS) and potent protection effects against inflammation. However, its insolubility and short half-life limit its clinical use. Therefore, we developed a supramolecular system of ε-polylysine (EPL) conjugated by β-cyclodextrin (β-CD) on the side chain, and bilirubin was loaded via host-guest interactions, which resulted in the self-assemble of this system into bilirubin-loaded polylysine-β-cyclodextrin nanoparticle (PB) with improving solubility while reducing toxicity and prolonging medication action time. To explore PB's potential pharmacological mechanisms on OA, we established in vitro and in vivo OA models. PB exerted ROS-scavenging proficiency and anti-apoptotic effects on rat chondrocytes by activating the Nrf2-HO-1/GPX4 signaling pathway. Additionally, PB reprogrammed the cartilage microenvironment by regulating the NF-κB signaling pathway to maintain chondrocyte function. Animal experiments further confirmed that PB had excellent scavenging ability for ROS and inflammatory factors related to charge adsorption with cartilage as well as long retention ability. Together, this work suggests that PB has superior protective abilities with beneficial effects on OA, indicating its great potential for intervention therapy targeting chondrocytes.
研究领域:
药理学
·
纳米技术
·
骨科
·
炎症
·
氧化应激
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Yulu Wang,Minghao Yuan,Sihui Li,Jiamei Tang,Yan Wan,Xue Liang,Yiping Guo,Li Guo
Alcohol liver disease (ALD) is a chronic liver disorder resulting from long-term heavy alcohol consumption. The pathogenesis of ALD is multifactorial, and existing therapeutic agents primarily target specific aspects of the disease while presenting significant side effects, including drug-induced liver injury and hepatobiliary disease. Silibinin (SLB) has attracted widespread attention for its hepatoprotective effects and favorable safety profile. However, inherent limitations associated with SLB, such as poor solubility and bioavailability, have significantly limited its clinical application. Drug delivery systems, including liposomes, offer promising potential for the delivery of hydrophobic drugs. However, the selection of an appropriate delivery vehicle requires optimization. Ursodeoxycholic acid sodium (UAS) serves as a promising alternative to cholesterol in liposomal formulations, offering a potential strategy to mitigate the health risks associated with cholesterol. In this study, UAS was employed as the liposomal membrane material to prepare a UAS liposome loaded with SLB (SUL), and its efficacy and mechanism of action in alcoholic-induced liver injury were subsequently evaluated. The experimental results demonstrated that SUL exhibited a uniform particle size distribution, good stability, and an effective release profile in vitro. Following oral administration, SUL effectively inhibited alcohol-induced liver damage, oxidative stress, and fat accumulation. In addition, SUL regulated the expression of the kelch-1ike ECH- associated protein l (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) proteins, thereby exerting antioxidative stress effects. Furthermore, it also modulated apoptosis-related factors, including B-cell lymphoma-2 (Bcl-2), BCL-2-associated X (Bax), cysteinyl aspartate specific proteinase-3 (Caspase-3), and cleaved caspase-3, to mitigate hepatocyte apoptosis. In summary, SUL demonstrates enhanced therapeutic efficacy against ALD, offering a novel approach for the clinical application of SLB in the prevention and treatment of ALD.
研究领域:
药理学
·
肝病学
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药物递送系统
·
分子生物学
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DOI
PubMed
高影响因子
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