Experimental and Therapeutic Medicine
·
2024
·Vol. 27
·期 5
·1-10
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IF 2.4
Jiaqi Shi,Li Chen,Xu Wang,Xin Ma
Steroid‑induced osteonecrosis of the femoral head (ONFH) is a serious complication caused by long‑term or excessive use of glucocorticoids. The present study aimed to ascertain the effects of tripartite motif‑containing protein 21 (TRIM21) on the process of steroid‑induced ONFH and its hidden action mechanism. TRIM21 expression in dexamethasone (Dex)‑treated mouse MC3T3‑E1 preosteoblast cells was examined using reverse transcription‑quantitative PCR and western blotting. The Cell Counting Kit‑8 (CCK‑8) method and lactate dehydrogenase release assay were used to respectively measure cell viability and injury. Flow cytometry analysis was used to assay cell apoptosis. Caspase 3 activity was evaluated using a specific assay, while alkaline phosphatase and Alizarin red S staining were used to evaluate osteogenesis. 2,7‑dichloro‑dihydrofluorescein diacetate fluorescence probe was used to estimate reactive oxygen species generation. Specific assay kits were used to appraise oxidative stress levels. In addition, the expression of apoptosis‑, osteogenic differentiation‑ and Kelch‑like ECH‑associated protein 1 (Keap1)/nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling‑associated proteins was assessed using western blotting. In Nrf2 inhibitor (ML385)‑pretreated MC3T3‑E1 cells exposed to Dex, cell apoptosis, osteogenesis and oxidative stress were detected again as aforementioned. Results revealed that TRIM21 expression was raised in Dex‑induced MC3T3‑E1 cells and TRIM21 deletion improved the viability and osteogenic differentiation, whereas it hampered the oxidative stress and apoptosis in MC3T3‑E1 cells with Dex induction. In addition, silencing of TRIM21 activated Keap1/Nrf2 signaling. Moreover, ML385 partially abrogated the effects of TRIM21 depletion on the oxidative stress, apoptosis and osteogenic differentiation in MC3T3‑E1 cells exposed to Dex. In conclusion, TRIM21 silencing might activate Keap1/Nrf2 signaling to protect against steroid‑induced ONFH.
研究领域:
骨科
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Cell Death Discovery
·
2023
·Vol. 9
·期 1
·1-15
·
IF 7
Lu Yang-yang,Zhu Chun-yang,Ding Yi-xin,Wang Bing,Zhao Shu-fen,Lv Jing,Chen Shu-ming,Wang Sha-sha,Wang Yan,Wang Rui,Qiu Wen-sheng,Qi Wei-wei
Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata , is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.
研究领域:
肿瘤学
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药理学
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细胞生物学
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生物化学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Yunjia Wang,Zhongjing Jiang,Linhua Deng,Gengming Zhang,Xia Xu,Emmanuel Alonge,Hongqi Zhang,Chaofeng Guo
Glucocorticoid-induced osteoporosis (GIOP) represents the foremost cause of secondary osteoporosis and fragility fractures. Novel therapeutic strategies for GIOP are needed, with improved safety profiles and reduced costs compared to current options. Dendrobium officinale ( D. officinale ) is a traditional Chinese medicine that has been reported to have beneficial effects on bone metabolism. Here, we sought to investigate the impacts of D. officinale polysaccharides (DOP), the main active constituents of D. officinale , on GIOP in vivo models and dexamethasone (DEX)-treated osteoblast lineage cells. We found that low concentrations of DOP are relatively safe in vitro and in vivo , respectively. Importantly, we found that DOP treatment significantly inhibited DEX-induced osteoporosis in two in vivo models, zebrafish and mice, while boosting osteogenic differentiation of hBMSCs exposed to DEX. Futhermore, our data reveal that DOP elevates nuclear Nrf2 levels under DEX treatment, by suppressing of Nrf2 ubiquitination. Leveraging Keap1b knockout zebrafish and RNAi approach, we demonstrated that DOP disrupts the association of Nrf2/Keap1, resulting in the inhibition of Nrf2 ubiquitination. Taken together, these results illuminate that DOP stimulates osteogenesis in the presence of DEX by destabilizing the Nrf2/Keap1 interaction. These findings suggest that DOP may serve as a novel drug against osteoporosis caused by glucocorticoids.
研究领域:
药理学
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骨骼生物学
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传统中药
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分子生物学
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DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2021
·
IF 3.503
Jiaqi Lu,Lili Gu,Qin Li,Ningzi Wu,Hongxing Li,Xinyue Zhang
Context Andrographolide (Andro) has a neuroprotective effect and a potential for treating Alzheimer’s disease (AD), but the mechanism has not been elucidated.Objective The efficacy of Andro on p62-mediated Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathways in the aluminium maltolate (Al(mal)3)-induced neurotoxicity in PC12 cell was explored.Materials and methods PC12 cells were induced by Al(mal)3 (700 μM) to establish a neurotoxicity model. Following Andro (1.25, 2.5, 5, 10, 20, 40 μM) co-treatment with Al(Mal)3, cell viability was detected with MTT, protein expression levels of β-amyloid precursor protein (APP), β-site APP cleaving enzyme 1 (BACE1), Tau, Nrf2, Keap1, p62 and LC3 were measured via western blotting or immunofluorescence analyses. Nrf2, Keap1, p62 and LC3 mRNA, were detected by reverse transcription-quantitative PCR.Results Compared with the 700 μM Al(mal)3 group, Andro (5, 10 μM) significantly increased Al(mal)3-induced cell viability from 67.4% to 91.9% and 91.2%, respectively, and decreased the expression of APP, BACE1 and Keap1 proteins and the ratio of P-Tau to Tau (from 2.75- fold to 1.94- and 1.70-fold, 2.12-fold to 1.77- and 1.56-fold, 0.68-fold to 0.51- and 0.55-fold, 1.45-fold to 0.82- and 0.91-fold, respectively), increased the protein expression of Nrf2, p62 and the ratio of LC3-II/LC3-I (from 0.67-fold to 0.93- and 0.94-fold, 0.64-fold to 0.88- and 0.87-fold, 0.51-fold to 0.63- and 0.79-fold, respectively), as well as the mRNA expression of Nrf2, p62 and LC3 (from 0.48-fold to 0.92-fold, 0.49-fold to 0.92-fold, 0.25-fold to 0.38-fold). Furthermore, Nrf2 and p62 nuclear translocation were increased and keap1 in the cytoplasm was decreased in the presence of Andro. Silencing p62 or Nrf2 can significantly reduce the protein and mRNA expression of Nrf2 and p62 under co-treatment with Andro and Al(mal)3.Discussion and conclusions Our results suggested that Andro could be a promising therapeutic lead against Al-induced neurotoxicity by regulating p62-mediated keap1-Nrf2 pathways.
研究领域:
神经科学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BMC Complementary Medicine and Therapies
·
2023
·Vol. 23
·期 1
·1-16
·
IF 3.9
Ma Jianping,Zheng Miao,Zhang Xinyue,Lu Jiaqi,Gu Lili
Background Alzheimer’s disease (AD) is the most prevalent neurodegenerative and remains incurable. Aluminum is a potent neurotoxin associated with AD. The main pathological features of AD are extracellular amyloid-β protein deposition and intracellular hyperphosphorylated Tau protein. A body of evidence suggest that oxidative stress and autophagy are involved in the pathogenesis of AD. Andrographis paniculata (AP) is a native plant with anti-inflammatory, anti-oxidative stress, and regulation of autophagy properties. AP significantly alleviated cognitive impairments, reduced Aβ deposition and has neuroprotective effect. However, its effects on aluminum-induced AD model have not been studied much. In this study, we investigated whether AP protect against aluminum-induced neurotoxicity through regulation of p62-Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathway and activation autophagy in vivo and in vitro.Methods UPLC-ESI-qTOF-MS/MS was used to identify the chemical constituents of AP ethanol extract. The mice with cognitive deficit were established by injecting aluminum chloride and D-galactose, and treated with either AP extract (200, 400, or 600 mg/kg/d) or andrographolide (2 mg/kg/2d).The spatial memory ability was detected by Morris water maze, HE staining were used to detect in brain tissue,Oxidative stress indexs and SOD activity in both serum and brain tissue were detected by kit.The expression of p62-Nrf2 pathway proteins were measured via western blotting. Furthermore, the neurotoxicity model was induced by aluminum maltolate (700 µM) in PC12 cells. Following AP and andrographolide treatment, the cell viability was detected. The relevant mRNA and protein expressions were detected in cells transfected with the p62 siRNA.Results The main active components of AP included andrographolide, neoandrographolide and deoxyandrographolide as identified. AP and andrographolide significantly improved the spatial memory ability of mice, attenuated pathological changes of hippocampal cells, reduced the level of malondialdehyde, and increased superoxide dismutase activity in serum or brain tissue as compared to model control. In addition, the Nrf2, p62 and LC3B-II proteins expression were increased, and p-Tau and Keap1 proteins were decreased in the hippocampus after AP and andrographolide treatment.Furthermore, AP increased aluminum maltolate-induced cell viability in PC12 cells. Silencing p62 could reverse the upregulation expression of Nrf2 and downregulation of Keap1 and Tau proteins induced by AP in aluminum maltolate-treated cells.Conclusion sAP had neuroprotective effects against aluminum -induced cognitive dysfunction or cytotoxicity, which was involved in the activation of the p62-keap1-Nrf2 pathway and may develop as therapeutic drugs for the treatment of AD. However, this study has certain limitations, further optimize the protocol or model and study the molecular mechanism of AP improving AD.
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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毒理学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
·
IF 6.8
Bo Xu,Tiantian He,Hong Yang,Wenjie Dai,Ling Liu,Xiaoqian Ma,Jiaxue Ma,Guoqin Yang,Rui Si,Xing Du,Xufeng Fu,Xiuying Pei
Di-(2-ethylhexyl) phthalate (DEHP) is widely used in various plastics but has been demonstrated to cause female reproductive toxicity. However, the exact mechanism underlying the ovarian damage induced by DEHP remains unclear. In this study, DEHP was administered orally to 5-week-old female mice for 30 days at doses of 0, 250, 500, and 1000 mg/kg/day. The findings demonstrated that DEHP exposure disrupted ovarian function and follicular development as well as induced oxidative stress and autophagy in ovarian granulosa cells (GCs). Further, 200 µM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP in vivo , induced autophagy in both human ovarian granulosa cells line (KGN) and mouse primary GCs within 24 h in vitro . However, it did not affect the p62-dependent autophagy flux. Furthermore, MEHP-induced autophagy was inhibited by the autophagy inhibitor 3-MA and exacerbated by the autophagy activator rapamycin, indicating that MEHP induces excessive autophagy in GCs. Subsequently, we found that MEHP-induced autophagic cell death was primarily attributed to oxidative damage from elevated intracellular ROS levels. Meanwhile, MEHP exposure induced nuclear translocation of erythroid-derived factor 2-related factor (Nrf2), a key regulator of antioxidant activity resulting in activating antioxidant effects. Interestingly, we also found that MEHP-induced increase in p62 competitively binds Keap1, thereby facilitating nuclear translocation of Nrf2 and establishing a positive feedback loop in antioxidant regulation. Therefore, this study demonstrated that inhibition of Nrf2 could aggravate oxidative damage and enhance excessive autophagy caused by MEHP, while activation of Nrf2 could reverse the trend. These findings have also been reinforced in studies of cultured ovaries in vitro . Our study suggests that the p62-Keap1-Nrf2 pathway may serve as a potential protective mechanism against DEHP-induced oxidative stress and excessive autophagy in mouse GCs.
研究领域:
生殖毒理学
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分子生物学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2021
·
IF 6.291
Qianhua Ke,Jiao Yang,Huan Liu,Zhuoquan Huang,Lingling Bu,Dengpeng Jin,Chunhong Liu
Nonylphenol (NP) is a representative environmental endocrine-disrupting compound that can induce oxidative stress in organisms. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway acts an important role in preventing oxidative stress. The aim of this study was to investigate the influence of oxidative stress caused by NP on Keap1-Nrf2 pathway in rats. Rats were treated with NP (30, 90, 270 mg/kg) for different exposure time (7, 14 and 28 days). The levels of reactive oxygen species (ROS) in serum and glutathione S-transferase (GST), UDP-Glucuronosyl Transferase (UGT) in liver were detected by ELISA kits. Western blot was used to detect Keap1, Nrf2 protein expression in liver and cerebral cortex. The results showed that 28 days of NP exposure significantly increased ROS levels in NPH group. And 14 days exposure to NP significantly enhanced the levels of GST and UGT, while 28 days of exposure showed a suppressive effect. In liver, Keap1 levels was upregulated at 7, 14 and 28 days of NP exposure, while nuclear Nrf2 levels decreased at 7 and 28 days but increased at 14 days. In cerebral cortex, Keap1 and Nrf2 expression increased at 14 days but decreased at 28 days. Besides, with the prolongation of NP exposure time, the GST and UGT levels in NPM and NPH groups were increased firstly and then decreased, while Keap1 and Nrf2 protein levels were constantly decreased in liver and cerebral cortex. In conclusion, the lower dose and shorter exposure time of NP activated the Keap1-Nrf2 pathway that may reduce the damage of oxidative stress, but when further exposed to NP at higher dose and time, the pathway could be inhibited.
研究领域:
毒理学
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环境健康
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Man Zheng,Fenglei Zhang,Xiang Gong,Haitao Yuan
The oxidative damage to vascular endothelial cells induced by smoking represents a significant pathogenic factor in the development of atherosclerosis. In the present study, we isolated ginseng oligopeptide extract (GOE), which emerges as a promising candidate for protecting human aortic endothelial cells (HAECs) from nicotine-induced oxidative stress. The underlying mechanisms were also explored. The GOE effectively reversed the decline in cell viability and protected HAECs from nicotine-induced oxidative damage by inhibiting the overproduction of intracellular reactive oxygen species (ROS) while preserving superoxide dismutase (SOD) activity. We identified five ginseng oligopeptides (GOPs) as the primary components of GOE. Furthermore, we demonstrated that GOE significantly alleviated nicotine-induced mitochondrial dysfunction in HAECs while promoting the nitric oxide (NO) release and the expression of GTP cyclohydrolase 1 (GTPCH1). Although the precise mechanism through which GOE mitigates nicotine-induced oxidative stress in HAECs remains to be fully elucidated, our findings indicate that GOP-1–5 serve as bioactive constituents of GOE and play a significant synergistic role in reducing nicotine-induced apoptosis and oxidative damages in HAECs. This is achieved through modulation of cellular antioxidant systems via maintaining balance within the Keap1/Nrf2/HO-1 signaling pathway. These findings suggest that GOE may function as a potential therapeutic agent against cigarette smoking-induced atherosclerosis.
研究领域:
心血管生物学
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药理学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
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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.
研究领域:
牙科学
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纳米医学
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分子生物学
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药学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL EYE RESEARCH
·
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.
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
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糖尿病研究
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眼科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Xiaoliang Dong,Lu Qu,Bingxin Wang,Xiaowei Sha,Bo Wu,Yudong Sun,Xiaohua Pan,Juan Xiong,Jia Sun,Li-Long Pan
ABSTRACT Background Cardiovascular disease is one of the main causes of global mortality, and there is an urgent need for effective treatment strategies. Gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) promotes the development of cardiovascular diseases, and shizukaol C, a natural sesquiterpene isolated from Chloranthus multistachys with various biological activities, might exhibit beneficial role in preventing TMAO-induced vascular inflammation. Purpose The purpose of this study was to investigate the anti-inflammatory effects and the underlying mechanisms of shizukaol C on TMAO-induced vascular inflammation. Methods The effect and underlying mechanism of shizukaol C on TMAO-induced adhesion molecules expression, bone marrow-derived macrophages (BMDM) adhesion to VSMC were evaluated by western blot, cell adhesion assay, co-immunoprecipitation, immunofluorescence assay, and quantitative Real-Time PCR, respectively. To verify the role of shizukaol C in vivo , TMAO-induced vascular inflammation model were established using guidewire-induced injury on mice carotid artery. Changes in the intima area and the expression of GSTpi, VCAM-1, CD68 were examined using haematoxylin-eosin staining, and immunofluorescence assay. Results Our data demonstrated that shizukaol C significantly suppressed TMAO-induced adhesion molecule expression and the bone marrow-derived macrophages (BMDM) adhesion in vascular smooth muscle cells (VSMC). Mechanically, shizukaol C inhibited TMAO-induced c-Jun N-terminal kinase (JNK)-nuclear factor-kappa B (NF-κB)/p65 activation, and the JNK inhibition was dependent on the shizukaol C-mediated glutathione-S-transferase pi (GSTpi) expression. By further molecular docking and protein-binding analysis, we demonstrated that shizukaol C directly binds to Keap1 to induce Nrf2 nuclear translocation and upregulated GSTpi expression. Consistently, our in vivo experiment showed that shizukaol C elevated the expression level of GSTpi in carotid arteries and alleviates TMAO-induced vascular inflammation. Conclusion : Shizukaol C exerts anti-inflammatory effects in TMAO-treated VSMC by targeting Keap1 and activating Nrf2-GSTpi signaling and resultantly inhibits the downstream JNK-NF-κB p65 activation and VSMC adhesion, and alleviates TMAO-induced vascular inflammation in vivo , suggesting that shizukaol C may be a potential drug for treating TMAO-induced vascular diseases.
研究领域:
药理学
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心血管疾病
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炎症
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aging-US
·
2019
·
IF 5.515
Jin-Lan Huang,Chao Yu,Min Su,Si-Man Yang,Fan Zhang,Yuan-Yuan Chen,Jin-Yuan Liu,Yi-Fan Jiang,Zhen-Guo Zhong,Deng-Pan Wu
Oxidative stress plays a vital role in the initiation and progression of age-related neurodegenerative diseases. Ameliorating oxidative damage is therefore considered as a beneficial strategy for the treatment of age-related neurodegenerative disorders. Probucol (Prob), a lipid-lowering prototype agent, was reported to treat cardiovascular diseases, chronic kidney disease and diabetes mellitus. However, whether Prob has an effect on age-related neurodegenerative diseases remains unknown. In the study, it was found that Prob ameliorated D-galactose (D-gal) induced cognitive deficits and neuronal loss in the hippocampal CA1 region. Moreover, Prob alleviated ROS and MDA levels by elevating SOD, GSH-PX and HO-1 mRNA and protein expressions, and improving plasmic and cerebral SOD and GSH-PX activities in D-gal treated mice. Furthermore, Prob promoted the dissociation of Keap1/Nrf2 complex leading to the accumulation of Nrf2 in nucleus, implying that the improved anti-oxidant property of Prob is mediated by Keap1/Nrf2 pathway. The study firstly demonstrates the favorable effects of Prob against cognitive impairments in a senescent mouse model, rendering this compound a promising agent for the treatment or prevention of age-related neurodegenerative disease.
研究领域:
神经科学
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药理学
·
衰老研究
✓ 已验证
DOI
PubMed
高影响因子
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