Neural Regeneration Research
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2023
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IF 6.1
Jingwen Jiang,Hong Pan,Fanxia Shen,Yuyan Tan,Shengdi Chen
Alzheimer’s disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain. The ketogenic diet, a widely recognized therapeutic intervention for refractory epilepsy, has recently been proposed as a potential treatment for a variety of neurological diseases, including Alzheimer’s disease. However, the efficacy of ketogenic diet in treating Alzheimer’s disease and the underlying mechanism remains unclear. The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer’s disease. Male amyloid precursor protein/presenilin 1 (APP/PS1) mice were randomly assigned to either a ketogenic diet or control diet group, and received their respective diets for a duration of 3 months. The findings show that ketogenic diet administration enhanced cognitive function, attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice, and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway. Collectively, these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer’s disease by ameliorating the neurotoxicity associated with Aβ-induced inflammation. This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer’s disease.
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EXPERIMENTAL EYE RESEARCH
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2023
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IF 3.4
Jingfei Yang,Zhijuan Hua,Zhikun Zheng,Xuan Ma,Liang Zhu,Yan Li
Diabetes retinopathy (DR) is one of the most common microvascular complications of diabetes. Retinal pigment epithelial (RPE) cells exposed to a high glucose environment experience a series of functional damages, which is an important factor in promoting the progression of DR. Acteoside (ACT) has strong antioxidant and anti-apoptotic properties, but the mechanism of ACT in DR is not completely clear. Therefore, the purpose of the present study was to explore whether ACT inhibits the damage to RPE cells in a high glucose environment through antioxidative effects to alleviate the DR process. The DR in vitro cell model was constructed by treating RPE cells with high glucose, and the DR in vivo animal model was constructed by injecting streptozotocin (STZ) into the peritoneal cavity of mice to induce diabetes. The proliferation and apoptosis of RPE cells were detected by CCK-8 and flow cytometry assays, respectively. The expression changes in Nrf2, Keap1, NQO1 and HO-1 were evaluated by qRT‒PCR, Western blot and immunohistochemistry analyses. The MDA, SOD, GSH-Px and T-AOC contents were detected by kits. The changes in ROS and nuclear translocation of Nrf2 were observed by immunofluorescence assays. HE staining was used to measure the thickness of the outer nuclear layer (ONL) of the retina, and TUNEL staining was used to detect the number of apoptotic cells in the retinas of mice. In the present study, ACT effectively ameliorated outer retina damage in diabetic mice. In high glucose (HG)-induced RPE cells, ACT treatment had the following effects: improved proliferation, decreased apoptosis, inhibited Keap1 expression, promoted the nuclear translocation and expression of Nrf2, upregulated NQO1 and HO-1 (the target genes of Nrf2) expression, decreased ROS concentration, and increased the levels of the SOD, GSH-Px and T-AOC antioxidant indicators. However, knockdown of Nrf2 reversed the above phenomena, which indicated that the protective function of ACT in HG-induced RPE cells are closely related to Nrf2. In summary, the present study demonstrated that HG-induced oxidative stress injury is inhibited by ACT in RPE cells and the outer retina through the Keap1/Nrf2/ARE pathway.
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Advanced Healthcare Materials
·
2023
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IF 10
Xinchan Liu,Yubo Hou,Mingxi Yang,Xirui Xin,Yu Deng,Ruobing Fu,Xingchen Xiang,Niuben Cao,Xiaomeng Liu,Weixian Yu,Bai Yang,Yanmin Zhou
Periodontitis is a type of chronic inflammatory oral disease characterized by the destruction of periodontal connective tissue and progressive alveolar bone resorption. As oxidative stress is the key cause of periodontitis in the early periodontal microenvironment, antioxidative therapy has been considered a viable treatment for periodontitis. However, more stable and effective reactive oxygen species (ROS)-scavenging nanomedicines are still highly needed due to the instability of traditional antioxidants. Herein, a new type of N -acetyl- l -cysteine (NAC)-derived red fluorescent carbonized polymer dots (CPDs) has been synthesized with excellent biocompatibility, which can serve as an extracellular antioxidant to scavenge ROS effectively. Moreover, NAC-CPDs can promote osteogenic differentiation in human periodontal ligament cells (hPDLCs) under H 2 O 2 stimulation. In addition, NAC-CPDs are capable of targeted accumulation in alveolar bone in vivo, reducing the level of alveolar bone resorption in periodontitis mice, as well as performing fluorescence imaging in vitro and in vivo. In terms of mechanism, NAC-CPDs may regulate redox homeostasis and promote bone formation in the periodontitis microenvironment by modulating the kelch-like ECH-associated protein l (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. This study provides a new strategy for the application of CPDs theranostic nanoplatform for periodontitis.
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RENAL FAILURE
·
2023
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IF 3
Chenlei Lv,Tianyang Cheng,Bingbing Zhang,Ke Sun,Keda Lu
Objectives: Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte injury in DN.Methods: DN mouse models were established by feeding with a high-fat diet and injecting with streptozocin and MPC5 podocyte injury models were induced by high-glucose (HG), followed by TP treatment. Fasting blood glucose and renal function indicators, such as 24 h urine albumin (UAlb), serum creatinine (SCr), blood urea nitrogen (BUN), and kidney/body weight ratio of mice were examined. H&E and TUNEL staining were performed for evaluating pathological changes and apoptosis in renal tissue. The podocyte markers, reactive oxygen species (ROS), oxidative stress (OS), serum inflammatory cytokines, nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway-related proteins, and pyroptosis were detected by Western blotting and corresponding kits. MPC5 cell viability and pyroptosis were evaluated by MTT and Hoechst 33342/PI double-fluorescence staining. Nrf2 inhibitor ML385 was used to verify the regulation of TP on Nrf2.Results: TP improved renal function and histopathological injury of DN mice, alleviated podocytes injury, reduced OS and ROS by activating the Nrf2/heme oxygenase-1 (HO-1) pathway, and weakened pyroptosis by inhibiting the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome pathway. In vitro experiments further verified the inhibition of TP on OS and pyroptosis by mediating the Nrf2/HO-1 and NLRP3 inflammasome pathways. Inhibition of Nrf2 reversed the protective effect of TP on MPC5 cells.Conclusions: Overall, TP alleviated podocyte injury in DN by inhibiting OS and pyroptosis via Nrf2/ROS/NLRP3 axis.
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CHEMICAL RESEARCH IN TOXICOLOGY
·
2018
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IF 3.432
Zixuan Liu,Wenjing Dong,Bingwei Yang,Lu Peng,Xiaomin Xia,Lanxiang Pu,Na Zhang,Erqun Song,Yang Song
Our previous studies demonstrated that tetrachlorobenzoquinone (TCBQ) is toxic to neuron-like cells, which is related to endoplasmic reticulum (ER) stress-induced apoptosis. However, it remains unclear whether TCBQ causes the opening of cellular defense responses. Here we found that activation of nuclear factor erythroid-derived 2-like 2 (Nrf2) triggered an adaptive response against the neurotoxicity induced by TCBQ through the upregulation of intracellular glutathione (GSH) levels in rat pheochromocytoma PC12 cells. TCBQ upregulated the levels of GSH mainly by the following two ways: (i) Nrf2 activation induced the expression of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT); (ii) Nrf2 activation resulted in increased the expression of glutamylcysteine ligase. GSH is involved in cell antioxidant ability and protein thiol homeostasis, especially in the ER. Therefore, GSH has the ability to inhibit ER stress and promote cell survival. Our data showed that decreasing GSH levels exacerbated TCBQ-induced depletion of protein-SH, particularly in the ER. Conversely, increasing GSH levels attenuated TCBQ-induced protein damage, degree of ER stress, and cell death. These findings demonstrated that GSH-inhibited cells were vulnerable to TCBQ-induced ER stress and apoptosis. Overall, our results analyzed the relationships between Nrf2 and ER stress in response to TCBQ and showed that activation of Nrf2-GSH played a protective role against TCBQ-induced ER stress-associated neurotoxicity via regulating GSH synthesis and protein thiol homeostasis.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2019
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IF 3.571
Dongwen Hu,Tao Bao,Yang Lu,Hongming Su,Huihui Ke,Wei Chen
This study was aimed to investigate the protective effects of three different mulberry fruit polysaccharide fractions (MFP-I, MFP-II, and MFP-III) against palmitic acid (PA)-induced hepatocyte lipotoxicity and characterize the functional polysaccharide fraction using gel permeation chromatography, high-performance liquid chromatography, Fourier transform infrared spectroscopy, and nuclear magnetic resonance analyses. MFP-I, MFP-II, and MFP-III were isolated from mulberry fruit by stepwise precipitation with 30, 60, and 90% ethanol, respectively. MFP-II at 0.1 and 0.2 mg/mL dramatically attenuated PA-induced hepatic lipotoxicity, while MFP-I and MFP-III showed weak protection. It was demonstrated that MFP-II not only increased nuclear factor erythroid-2-related factor 2 (Nrf2) phosphorylation and its nuclear translocation, thereby activating the Nrf2/ARE signaling pathway, but also enhanced heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, and γ-glutamate cysteine ligase gene expressions and promoted catalase and glutathione peroxidase activities, which protected hepatocytes against PA-induced oxidative stress and lipotoxicity. Further investigation indicated that the molecular weight of MFP-II was 115.0 kDa, and MFP-II mainly consisted of galactose (30.5%), arabinose (26.2%), and rhamnose (23.1%). Overall, our research might provide in-depth insight into mulberry fruit polysaccharide in ameliorating lipid metabolic disorders.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Kunfeng Zhang,Hao Chen,Yunbo Hao,Wensen Li,Yong Li,Wenna Zhang,Yan Chen
We identified Armillariella tabescens polysaccharide (PAT-W), a compound isolated from a Chinese medicinal mushroom , as a potential novel oral ulcer (OU) drug. In treating OU rats with PAT-W, especially in the high-dose group, oral mucous tissue TNF- α , IL-1 β , and IL-6 levels were markedly reduced, and pathological morphology and oxidative stress were effectively improved. Western blot analysis showed that the PAT-W channel ameliorated OU mucous tissue damage, which depends on the activation of the Nrf2/HO-1 antioxidant signaling pathway . Furthermore, high-throughput sequencing results showed that PAT-W regulated the maladjustment of the oral microbiota caused by OU. Therefore, based on the new viewpoint of activating the Nrf2/HO-1 pathway and regulating oral microbiota, PAT-W is expected to become a new natural drug for treating oral ulcers and improving patients' quality of life.
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International Journal of Pharmacology
·
2026
·Vol. 22
·期 6
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IF 0.7
Yachun Guo,Jiahui Zhang,Yanchao Li
Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, and novel therapeutic strategies are urgently needed to overcome treatment resistance. Cordycepin (Cor), a bioactive nucleoside isolated from Cordyceps militaris, exhibits antitumor activity in multiple malignancies. However, whether Cor induces ferroptosis in NSCLC cells and the underlying mechanisms remain unclear. Therefore, this study aimed to investigate the modulatory effects of Cor on ferroptosis in NSCLC cells and to elucidate the underlying molecular and network pharmacology mechanisms. Methods: Human NSCLC A549 cells were treated with Cor (25, 50, and 100 μM). Cell viability was assessed using Cell Counting Kit-8 assays. Ferroptosis involvement was evaluated using ferroptosis inhibitors (ferrostatin-1, deferoxamine, and liproxstatin-1) and other programmed cell death inhibitors. Intracellular reactive oxygen species (ROS), Fe2+ accumulation, lipid peroxidation, glutathione (GSH) levels, and ferroptosis-related proteins were measured using fluorescence probes, spectrophotometric assays, and western blotting. Network pharmacology, protein-protein interaction analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and molecular docking were performed to identify potential molecular targets. Nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expression was further examined by western blotting. Results: Cor inhibited A549 cell viability in a time- and dose-dependent manner (n = 6). Among the tested death inhibitors, only ferroptosis inhibitors significantly reversed Cor-induced cytotoxicity (p < 0.05, n = 3). Cor treatment elevated intracellular ROS levels, Fe2+ accumulation, and lipid peroxidation while reducing GSH content (p < 0.05, n = 3). At the protein level, Cor downregulated glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression but upregulated transferrin and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression (p < 0.05, n = 3). Database screening identified 28 mutual targets linked to Cor, NSCLC, and ferroptosis. Molecular docking confirmed that Cor spontaneously binds to the Nrf2 and HO-1 proteins encoded by the key pathway genes nuclear factor erythroid 2 like 2 (NFE2L2) and heme oxygenase 1 (HMOX1), which correlated with a significant, dose-dependent downregulation of Nrf2 and HO-1 protein expression (p < 0.05, n = 3). Conclusions: Cordycepin induces ferroptosis in A549 NSCLC cells, characterized by oxidative stress, iron accumulation, lipid peroxidation, and suppression of antioxidant defenses. The Nrf2/HO-1 pathway may contribute to this process and represents a potential therapeutic target for NSCLC.
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FOOD CHEMISTRY
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2024
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IF 8.5
Kuiyou Wang,Kexin Huang,Xueqian Li,Hao Wu,Li Wang,Fengyu Bai,Mingqian Tan,Wentao Su
This study innovatively utilized kelp-derived nanocellulose and sodium caseinate (SC) to prepare fucoxanthin (Fx)-loaded nanoparticles, exploring their efficacy in reducing oxidative stress and inhibiting lipid accumulation. 2, 2, 6, 6-Tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation produced well-dispersed, kelp-derived nanocellulose. When these celluloses were mixed with SC at varying mass ratios, the composite nanoparticles showed excellent stability. Specifically, at a TEMPO-oxidized kelp nanocellulose (TKNC) to SC mass ratio of 1:3, the encapsulation efficiency for Fx reached 82.2 %, with a retention of 56.12 % after 14 days of storage. In vitro , the nanoparticles demonstrated good biocompatibility and were efficiently absorbed by cells, significantly enhancing Fx bioavailability . This enhanced delivery efficiency alleviates oxidative stress by activating the Nrf2/HO-1/NQO1 signaling pathways and effectively inhibits lipid droplet formation induced by excessive free fatty acids (FFAs). Moreover, distribution studies in mice revealed effective accumulation of nanoparticles in the intestines and liver, indicating their potential for targeted drug delivery. These findings provide strong experimental support for the use of TKNC and SC as biocompatible materials in nanoparticles for drug delivery and treatment applications.
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INFLAMMOPHARMACOLOGY
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2024
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IF 4.6
Li Ming-Jie,Xu Jing-Yi,Zhang Hua-Yue,Guo Min,Lan Meng-Ning,Kong Jie,Liu Shi-Wei,Zheng Hua-Jun
Alzheimer’s disease (AD) is a neurodegenerative disorder frequently accompanied by neuroinflammation and oxidative stress. The medicine and food homology (MFH) has shown potential for treating neuroinflammation and oxidative stress. This study aimed to provide a safe and efficient therapy for AD based on MFH. In this study, we develop a MFH formula consisting of egg yolk oil, perilla seed oil, raphani seed oil, cinnamon oil, and noni puree (EPRCN). To evaluate the ameliorative effects of EPRCN on AD-related symptoms, a mouse model of AD was constructed using intraperitoneal injection of scopolamine in ICR mice. Experimental results demonstrated that EPRCN supplement restored behavioral deficits and suppressed neuroinflammation and oxidative stress in the hippocampus of scopolamine-induced mice. An in vitro study was then performed using induction of Aβ (25–35) in glial (BV–2 and SW–1783) and neuron (SH–SY5Y) cell lines to examine the improvement mechanism of EPRCN on cognitive deficits. Multi-omics and in vitro studies demonstrated that these changes were driven by the anandamide (AEA)-Trpv1-Nrf2 pathway, which was inhibited by AM404 (an AEA inhibitor), AMG9810 (a Trpv1 inhibitor), and BT (an Nrf2 inhibitor). Consequently, EPRCN is an effective therapy on preventing cognitive deficits in mouse models of AD. In contrast to donepezil, EPRCN exhibits a novel modes action for ameliorating neuroinflammation. The mechanism of EPRCN on preventing cognitive deficits is mediated by improving neuroinflammation and oxidative stress via activating the AEA–Trpv1–Nrf2 pathway.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Jingjing Lin,Lu Deng,Ailin Qi,Hong Jiang,Di Xu,Yuehui Zheng,Zixuan Zhang,Xiaoman Guo,Beilei Hu,Peijun Li
Hypoxic-ischemic encephalopathy (HIE) is a brain damage caused by perinatal hypoxia and blood flow reduction. Severe HIE leads to death. Available treatments remain limited. Oxidative stress and nerve damage are major factors in brain injury caused by HIE. Catalpol, an iridoid glucoside found in the root of Rehmannia glutinosa, has antioxidant and neuroprotective effects. This study examined the neuroprotective effects of catalpol using a neonatal rat HIE model and found that catalpol might protect the brain through inhibiting neuronal ferroptosis and ameliorating oxidative stress. Behavior tests suggested that catalpol treatment improved functions of motor, learning, and memory abilities after hypoxic-ischemic injury. Catalpol treatment inhibited changes to several ferroptosis-related proteins, including p-PI3K, p-AKT, NRF2, GPX4, SLC7A11, SLC3A2, GCLC, and GSS in HIE neonatal rats. Catalpol also prevented changes to several ferroptosis-related proteins in PC12 cells after oxygen-glucose deprivation. The ferroptosis inducer erastin reversed the protective effects of catalpol both in vitro and in vivo . We concluded that catalpol protects against hypoxic-ischemic brain damage (HIBD) by inhibiting ferroptosis through the PI3K/NRF2/system Xc-/GPX4 axis.
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American Journal of Translational Research
·
2020
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IF 3.375
Xiugui Wei,Hongyuan Wang,Xuemei Sun,Xiukun Huang,Wanpeng Xu,Yingqin Liang,Lin Liu,Siyan Mo,Xing Lin,Jun Lin
The purpose of this study is to evaluate the protective effect of 4-hydroxy-2(3H)-benzoxazolone from Acanthus ilicifolius (HBAI) on acute liver injury induced by acetaminophen in mice and its mechanism. Mice were continuously treated with HBAI (200, 100, 50 mg/kg) once a day for 10 days. After that, the mice were fasted for 8 hours, followed by intraperitoneal injection of acetaminophen (300 mg/kg). The results showed that HBAI pretreatment significantly reduced acetaminophen-induced liver tissue congestion, hepatocyte apoptosis and necrosis, and inflammatory cell infiltration. HBAI could effectively reduce the levels of serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, reactive oxygen species and malondialdehyde. Interestingly, the activities of liver catalase, superoxide dismutase, glutathione and glutathione reductase were enhanced by HBAI pretreatment. Moreover, HBAI pretreatment alleviated acetaminophen-induced hepatocyte apoptosis by regulating the expression of Bcl-2 family proteins and the mitochondrial function. Further study showed that HBAI pretreatment effectively promoted the expression of Nrf2 and its signal downstream HO-1, NQO1, GCLC, GCLM, and MGST-1, suggesting the activation of the Nrf2/HO-1 signaling pathway. Meanwhile, HBAI attenuated the phosphorylation of NF-κBp65, IKKα/β, and IκBα, as well as the expression of NF-κBp50, which indicated that HBAI blocked the signal transduction of NF-κB pathway. In conclusion, HBAI protects against acetaminophen-induced acute liver injury by inhibiting the NF-κB and activating Nrf2/HO-1 signaling pathways.
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