ANTIOXIDANTS & REDOX SIGNALING
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2026
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IF 6.8
Jiaxue Tian,Huimin Wang,Huimin Liu,Wenlu Xu,Mengting Xiao,Xuemei Qin,Xiaojie Liu
Aims:Depression is a prevalent mood disorder with significant suffering and heightened suicide risk. Accumulating evidence points to oxidative stress and impaired energy metabolism of the brain as key contributors to the pathogenesis of depression. Astragaloside IV (AIV) has been demonstrated to alleviate neurological damage. The capacity of AIV for antioxidation has also been gradually discovered. Yet, it still just scratches the surface of the antidepression mechanisms of AIV. Our aim was to explore a novel mechanism of action of AIV from the perspectives of redox homeostasis and energy metabolism via the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) axis.Results:AIV ameliorated anxiety and cognitive dysfunction in rats with depression-like behaviors. Furthermore, we illustrated that AIV reversed redox dyshomeostasis of rats with depression-like behaviors in terms of decreasing the level of malondialdehyde while increasing the abundances of catalase, superoxide dismutase, and glutathione peroxidase. In addition, AIV significantly increased the levels of indicators of energy metabolism that were interrupted by depression. Furthermore, in vitro, AIV significantly increased the levels of indicators related to the Nrf2/Keap1 signaling pathway in corticosterone-induced PC12 cells.Innovation:For the first time, it demonstrates that AIV alleviates depression by modulating the ROS/Nrf2/Keap1 axis and restoring hippocampal energy metabolism in a chronic unpredictable mild stress model.Conclusion:The current findings not only offer novel insights into antidepressant-like effects of AIV through the ROS/Nrf2/Keap1 axis but also provide a foundation for enhancing clinical efficiency and enriching drug selection. Antioxid. Redox Signal. 00, 000–000.
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CELLULAR SIGNALLING
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2025
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IF 3.7
YaoNan Han,XingTong Wang,DeShui Yu
Spinal cord injury (SCI) is a serious central nervous system disease. Ferroptosis is one of the major causes of spinal cord neurological loss, and targeting ferroptosis is a promising therapeutic strategy. Roflumilast has shown promising applications in the treatment of neurological diseases due to its potent anti-inflammatory and anti-oxidative stress effects. This study aimed to investigate whether roflumilast could inhibit neuronal ferroptosis to improve motor function after SCI in rats. In vitro experiments, we found that roflumilast significantly increased cell survival in an in vitro ferroptosis model, improved mitochondrial function, reduced intracellular iron, reactive oxygen species (ROS), and lipid peroxides accumulation as well as the expression of the pro-ferroptosis proteins, long-chain acyl-coenzyme A synthase 4 (ACSL4), and prostaglandin-endoperoxide synthase 2 (PTGS2), and increased the expression of ferroptosis-inhibitory protein glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) expression. Mechanistically, these protective effects were achieved by activating AMP-dependent protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and were attenuated when AMPK signaling was blocked. In vivo experiments, roflumilast attenuated spinal cord tissue damage, increased the number of motor neuron survivors, and improved motor function after SCI in rats. Overall, activation of AMPK/Nrf2/HO-1 signaling by roflumilast attenuated neuronal ferroptosis and improved motor function after SCI in rats.
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NEUROREPORT
·
2020
·Vol. 31
·期 18
·1274-1282
·
IF 1.394
Xi Zhiyu,Chen Xiao,Xu Canxin,Wang Baofeng,Zhong Zhihong,Sun Qingfang,Sun Yuhao,Bian Liuguan
The brain edema following intracerebral hemorrhage (ICH) plays a key role in the recovery process. Protocatechuic acid (PCA) has been proved possessing neuroprotection in ICH. Here we tried to explore its value in brain edema after ICH and reveal underlying mechanisms. ICH model was
created in C57 mice using collagenase IV. PCA was injected intraperitoneally at 30 mg/kg every 24 h in PCA group. On day 3 after ICH, the water content of hemorrhagic ipsilateral hemisphere in PCA group was significantly reduced compared with vehicle group. AQP4, the main water channel, was
remarkably decreased in PCA group. Additionally, ZO-1 and occludin expression were increased in PCA group. The bEnd.3 cells were cultured to understand the effect of PCA on the blood-brain barrier (BBB) integrity. Compare to hemin treated group, plus PCA enhanced the expression of HO-1 and
Nrf2 nuclear translocation. Furtherly, the overexpression of HO-1, ZO-1, occludin, in the PCA treatment group was inhibited after knockdown of Nrf2. Taken together, our results proved PCA alleviated brain edema and BBB disruption in ICH by promoting the Nrf2/HO-1 signaling pathway.
研究领域:
神经科学
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药理学
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分子生物学
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Frontiers in Bioengineering and Biotechnology
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2023
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IF 5.7
Xiong Liping,Bao Han,Li Size,Gu Deao,Li Yuyang,Yin Qianwen,Li Wen,Miao Leiying,Liu Chao
Oxidative stress is closely linked to the etiology of temporomandibular joint osteoarthritis. (TMJ-OA) and is an important therapeutic target. Cerium oxide nanoparticles (CNPs) have been broadly studied owing to their powerful antioxidant properties and potential preventive and therapeutic effects against chronic diseases. The current study was designed to explore the protective effects of CNPs on the progression of TMJ-OA and their potential mechanisms. We detected the ability of CNPs to eliminate reactive oxygen species (ROS) in chondrocytes. Moreover, their protective effects on chondrocytes were detected in the level of gene and protein. Furthermore, TUNEL assay, histology and safranin O-fast green staining were used to detect the beneficial effects of CNPs on cartilage explants. The mechanism of CNPs, protecting condylar cartilage by reducing inflammation, was further explored by knocking down the Nuclear factor-erythroid 2-related factor (Nrf2) gene. CNPs could reduce the ROS levels in chondrocytes and cartilage explants and reverse the IL-1β-induced imbalance of cartilage matrix metabolism and apoptosis. The protective effects of CNPs on cartilage were lost after key antioxidant factors including Nrf2 and heme-oxygenase 1(HO-1) were significantly reduced. In conclusion, this study demonstrated for the first time that activating the Nrf2/HO-1 signaling pathway by CNPs might have therapeutic potential for TMJ-OA.
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Food & Function
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2022
·Vol. 13
·期 5
·2782-2790
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IF 6.317
Zunli Ke,Si Tan,Haiyang Li,Shanshan Jiang,Yuping Li,Rui Chen,Mingxia Li
Nonalcoholic liver disease (NAFLD) is a pathological condition characterized by excessive fat deposition in the liver, and NAFLD usually has a close relationship with obesity or metabolic syndrome. Currently, oxidative stress is considered as an important risk factor in the progression of NAFLD, therefore, effective amelioration of oxidative stress has emerged as a promising way to improve NAFLD. Tangeretin is a natural compound having various pharmacological activities including antioxidation and hepatoprotection. However, whether tangeretin is able to improve NAFLD through reducing hepatic oxidative stress is rarely reported. In our work, the preventive effects of tangeretin on a NAFLD mouse model induced by a high fat (HF) diet were studied. The results exhibited that tangeretin supplementation observably slowed down NAFLD progression through alleviation of metabolic indexes such as glucose tolerance, serum lipid levels and inflammatory factors, hepatic oxidative stress as well as steatosis. qRT-PCR showed that tangeretin supplementation increased the nuclear factor erythroid-2-related factor 2 (Nrf2) expression and then upregulated the expression of its downstream factors including HO-1, GCLC, NQO1 and GSTA2. Furthermore, the expression of the hepatic nucleus, Nrf2, HO-1 and GCLC, was also seen to be significantly enhanced in WB analysis. Taken together, this study implies that tangeretin might alleviate NAFLD through lowering oxidative stress in the liver by partial modulation of the Nrf2 pathway. Our study provided theoretical support that tangeretin could be used as a dietary therapy for obesity related-NAFLD or related metabolic syndrome.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 23
·期 3
·1252
·
IF 6.208
Jing Yang,Xujiao Tang,Xue Ke,Yutong Dai,Jinsong Shi
Triptolide (TP), the main active ingredient ofTripterygium wilfordii Hook.f., displays potent anti-inflammatory, antioxidant, and antiproliferative activities. In the present study, the effect of TP on acute pancreatitis and the underlying mechanisms of the disease were investigated using a caerulein-induced animal model of acute pancreatitis (AP) and an in vitro cell model. In vivo, pretreatment with TP notably ameliorated pancreatic damage, shown as the improvement in serum amylase and lipase levels and pancreatic morphology. Meanwhile, TP modulated the infiltration of neutrophils and macrophages (Ly6G staining and CD68 staining) and decreased the levels of proinflammatory factors (TNF-α and IL-6) through inhibiting the transactivation of nuclear factor-κB (NF-κB) in caerulein-treated mice. Furthermore, TP reverted changes in oxidative stress markers, including pancreatic glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), in acute pancreatitis mice. Additionally, TP pretreatment inhibited intracellular reactive oxygen species (ROS) levels via upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes expression (HO-1, SOD1, GPx1 and NQO1) in vitro. Taken together, our data suggest that TP exert protection against pancreatic inflammation and tissue damage by inhibiting NF-κB transactivation, modulating immune cell responses and activating the Nrf2-mediated antioxidative system, thereby alleviating acute pancreatitis.Keywords:acute pancreatitis;triptolide;inflammatory responses;oxidative stress
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Molecular Medicine Reports
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2021
·Vol. 24
·期 6
·1-9
·
IF 2.952
Juanjuan Huang,Xianfeng Chen,Aihua Xie
Formononetin has proven to be anti‑inflammatory and able to alleviate symptoms of certain allergic diseases. The present study aimed to determine and elucidate the potential effects of formononetin in allergic rhinitis. JME/CF15 cells were pretreated with formononetin at different doses, followed by stimulation with IL‑13. Cell Counting Kit‑8 assay was performed to determine the cytotoxicity of formononetin. The expression levels of inflammation‑related proteins, histamine, IgE, TNF‑α, IL‑1β, IL‑6, granulocyte‑macrophage colony‑stimulating factor and eotaxin in IL‑13‑stimulated JME/CF15 cells were detected using ELISAs. The expression levels of phosphorylated‑NF‑κB p65, NF‑κB p65 and cyclooxygenase‑2 (Cox‑2) were analyzed using western blotting. Reverse transcription‑quantitative PCR, western blotting and immunofluorescence were performed to measure the levels of mucin 5AC oligomeric mucus/gel‑forming. Expression levels of sirtuin 1 (SIRT1) and nuclear erythroid factor 2‑related factor 2 (Nrf2) proteins were also measured using western blotting. The results of the present study revealed that formononetin exerted no cytotoxic effect on the viability of JME/CF15 cells. Following stimulation of JME/CF15 cells with IL‑13, formononetin suppressed the upregulated expression levels of proinflammatory cytokines. IL‑13‑induced formation of mucus was also attenuated by formononetin treatment. Furthermore, it was found that the SIRT1/Nrf2 signaling pathway was activated in formononetin‑treated JME/CF15 cells, whereas treatment with the SIRT1 inhibitor, EX527, reversed the effects of formononetin on IL‑13‑induced inflammation and mucus formation in JME/CF15 cells. In conclusion, the findings of the current study indicated that formononetin may activate the SIRT1/Nrf2 signaling pathway, thereby inhibiting IL‑13‑induced inflammation and mucus formation in JME/CF15 cells. These results suggested that formononetin may represent a promising agent for the treatment of allergic rhinitis.
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CHEMISTRY & BIODIVERSITY
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2021
·Vol. 18
·期 4
·e2001007
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IF 2.408
Yan Zhao,Yu Wang,Min Zhang,Yugang Gao,Zhaowei Yan
Ginsenosides (20 S )-Rg3 and (20 R )-Rg3 are famous rare ginsenosides from red ginseng, and their configurations in C-20 are different. This study aimed to investigate the protective mechanism of ginsenosides (20 S )-Rg3 and (20 R )-Rg3 on H 2 O 2 -induced H9C2 cells and compare their activity. The results showed that the ginsenosides (20 S )-Rg3 and (20 R )-Rg3 could increase the cell activity and the levels of GSH-Px, SOD and CAT, and decrease activities of LDH, MDA and ROS. Further studies showed that ginsenosides (20 S )-Rg3 and (20 R )-Rg3 could prevent oxidative stress injury of H9C2 cells by H 2 O 2 through the Keap-1/Nrf2/HO-1 pathway. But the ML385 counteracts these effects. Interestingly, among these results, ginsenoside (20 R )-Rg3 was superior to (20 S )-Rg3, indicating that ginsenoside (20 R )-Rg3 have a stronger effect of antioxidative stress. This study reflected that ginsenoside (20 R )-Rg3 could be used as a potential Nrf2 activator and a safe effective Chinese herbal monomer in the treatment of cardiovascular disease.
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Frontiers in Pharmacology
·
2020
·
IF 4.225
Yao He,Sun Jingyu,Wei Jie,Zhang Xin,Chen Bing,Lin Yajun
Over recent years, an increasing number of studies have confirmed that the occurrence and development of vascular pathological changes are closely related to oxidative stress and the inflammatory response of the vascular endothelium. Kaempferol is the most common flavonoid compound found in fruits and vegetables. Our present research identified that kaempferol had the capability to protect the vascular endothelium in a mouse model of vascular injury and explored the specific mechanisms underlying these effects by investigating oxidative stress, the extent of cardiovascular injury, and inflammatory markers such as NF-κB, TNF-α, IL-6, and the Nrf2/HO-1 signaling pathway. Analysis showed that kaempferol reduced oxidative stress and inflammation mediated by H2O2 and paraquat, respectively, both in vitro and in vivo. Furthermore, kaempferol suppressed the levels of TNF-α and IL-6, and the activation of NF-κB, in aortic tissues and human umbilical vein endothelial cells (HUVECs). Finally, we observed that kaempferol corrected the levels of antioxidants and elevated the protein levels of Nrf2 and HO-1 in aortic tissues and HUVECs. Collectively, our findings prove that kaempferol protects blood vessels from damage induced by oxidative stress and inflammation and that the Nrf2/HO-1 signaling pathway plays a key role in mediating these effects.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2023
·
IF 3.6
Zhang Yuying,Zhang Pingping,Zhang Xin,Liu Ye
Honokiol, a bioactive component found in Magnolia officinalis , has shown in protecting against ischemic stroke in animal models. However, its poor water solubility has limited its clinical applications. In this study, we introduced a hydrophilic building block on the aromatic ring of honokiol, resulting in the synthesis of four new compounds (HH-A, -B, -C and -D) with significantly improved water solubility. We then investigated the neuroprotective effects of these compounds in mouse and rat models of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) brain injury. Among the compounds tested, HH-A, also known as (S)-6-((3′,5-diallyl-2,4′-dihydroxy-[1,1′-biphenyl]-3-yl)amino)-6-oxohexane-1,5-diaminium chloride, showed the most promising results. HH-A was found to significantly reduced the infarct volume and brain edema in mice. It also outperformed the other three compounds and honokiol, even surpassing the effects of edaravone dexborneol. Additionally, HH-A demonstrated dose-dependent improvements in body weight, neurological deficits, and infarct volume. Further analysis in tMCAO/R rat model revealed that HH-A treatment led to significant upregulations of Nrf2 and HO-1 in the brain. HH-A also significantly reduced the expression of HNE, and exhibited anti-apoptotic effects by decreasing the expression of Bax and increasing the expression of Bcl-2. This was further supported by a decrease in the number of TUNEL positive cells. Taken together, the neuroprotective effects of HH-A may be attributed to its ability to target the Nrf2/HO-1 signaling pathway, leading to reduced oxidative stress and apoptosis in the brain. These findings suggest that HH-A has potential as a therapeutic agent for the treatment of ischemic stroke.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Haochun Guo,Jiajia Chen,Hanxu Yu,Lei Dong,Ran Yu,Qingju Li,Jian Song,Haoyu Chen,Haijun Zhang,Juan Pu,Wanpeng Wang
Background Radiation-induced lung injury (RILI) is a common side effect of thoracic tumor radiotherapy, including early-stage radiation-induced lung injury (RP) and late-stage radiation-induced pulmonary fibrosis (RIPF). Currently, it is urgently needed to clarify the pathogenesis of RILI and find safe and effective RILI treatment methods. Irradiation causes DNA damage and oxidative stress in tissues and cells, induces cellular senescence, and promotes the occurrence and development of RILI. In recent years, Anisodamine (654-2) has shown potential therapeutic value in acute lung injury, acute kidney injury, chlamydial pneumonia, and COVID-19. However, there is currently no research on the mechanism of 654-2-mediated cellular senescence and its preventive and therapeutic effects on RILI. Purpose This study aimed to investigate the protective effect and mechanism of 654-2 on X-ray-induced RILI. Methods In vivo experiments involved a mouse RILI model with 18 Gy X-ray irradiation. Mice were divided into control, model, medication (control + 654-2), and treatment (model + 654-2) groups. And mice in medication and treatment groups were intraperitoneal injection of 5 mg/kg 654-2 every other day until being sacrificed at week 6. In vitro experiments used MLE-12 cells irradiated with 16 Gy and divided into control, model, and model + 654-2（2 μM and 10 μM） groups. Various assays were performed to evaluate lung tissue morphology, fibrosis, apoptosis, cytokine expression, cellular senescence, protein expression, and antioxidant capacity. Results 654-2 mitigated pulmonary pathological damage, inflammation, DNA damage, cellular senescence, and apoptosis in RILI mice and MLE-12 cells. It restored epithelial cell proliferation ability and enhanced antioxidant capacity. Additionally, 654-2 activated the Nrf2/ARE pathway, increased Nrf2 phosphorylation, and upregulated antioxidant gene expression. Inhibition of Nrf2 reversed the effects of 654-2 on ROS production, antioxidant capacity, and cell senescence. Conclusion 654-2 can activate the Nrf2/ARE pathway, enhance cellular antioxidant capacity, and inhibit cellular senescence, thereby exerting a protective effect against RILI.
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PHARMACEUTICAL BIOLOGY
·
2023
·
IF 3.8
Jiayuan Li,Jiahe Yu,Jianyou Guo,Jinfeng Liu,Guohui Wan,Xiaojia Wei,Xue Yang,Jinli Shi
Context Levodopa combined with traditional Chinese medicine has a synergistic effect on Parkinson’s disease (PD). Recently, we demonstrated that Nardostachys jatamansi (D. Don) DC. [syn. Patrinia jatamansi D.Don, N. grandiflora DC.] (Valerianaceae) (NJ) can alleviate PD.Objective To explore the synergistic effect of NJ combined with levodopa against PD.Materials and methods The PD model was established by injecting rotenone. Eighty-four Sprague-Dawley rats were randomly divided into seven groups: sham, model, different doses of NJ (0.31, 0.62, or 1.24 g/kg) combined with levodopa (25 mg/kg), and levodopa alone (25 and 50 mg/kg) groups. The synergistic effect of the combination was investigated by pharmacodynamic investigation and detection of expression of nuclear factor erythro2-related factor 2 (Nrf2) and NLR family proteins containing Pyrin-related domain 3 (NLRP3) pathways.Results Compared with the model group, NJ + levodopa (1.24 g/kg + 25 mg/kg) increased the moving distance of PD rats in the open field (2395.34 ± 668.73 vs. 1501.41 ± 870.23, p < 0.01), enhanced the stay time on the rotating rod (84.86 ± 18.15 vs. 71.36 ± 17.53, p < 0.01) and the combination was superior to other treatments. The synergistic effects were related to NJ + levodopa (1.24 g/kg + 25 mg/kg) increasing the neurotransmitter levels by 38.80%-88.67% in PD rats, and inhibiting oxidative stress and NLRP3 pathway by activating Nrf2 pathway.Discussion and conclusions NJ combined with levodopa is a promising therapeutic candidate for PD, which provides a scientific basis for the subsequent clinical combination therapy of levodopa to enhance the anti-PD effect.
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