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.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Jianfa Wu,Lingjie Bao,Zhenbo Zhang,Xiaofang Yi
Induction of Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) has been demonstrated to be involved in cisplatin resistance in ovarian cancer. Solute carrier family 40 member 1 (SLC40A1) is an iron exporter, which possesses many putative Nrf2 binding sites. Here we hypothesize that it may be a possible downstream gene of Nrf2. Elevated level of Nrf2 and reduced level of SLC40A1 were found in cisplatin–resistant ovarian cancer cells as compared with cisplatin-sensitive ovarian cancer cells. Exogenous knockdown of Nrf2 leaded to increased expression of SLC40A1. While overexpression of Nrf2 resulted in decreased expression of SLC40A1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay revealed that Nrf2 inhibited the transcription of SLC40A1. Overexpression of SLC40A1 was able to reverse cisplatin resistance induced by Nrf2, while knockdown of SLC40A1 restored cisplatin resistance and increased iron concentration. Desferal, an iron chelator, was found to overcome cisplatin resistance through iron deprivation. Its function was boosted when combined with brusatol, an Nrf2 inhibitor. Taken together, this study first demonstrated that Nrf2 could transcriptionally suppress the expression of SLC40A1. Iron overload induced by SLC40A1 resulted in cisplatin resistance in ovarian cancer. Targeting iron metabolism may be a new therapeutic strategy to reverse drug resistance in ovarian cancer treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
·
2021
·
IF 1.571
Fang Chen,Shi-Yun Huang,Shu-Qing Xiang,Xiao-Xu Qiao,Guo-Chao Liao,Zhong-Qiu Liu,Hua Zhou,Peng Wu
Two new phenolic glycosides (1-2), along with six existing compounds (3-8), were isolated from the ethanolic extract of Ilex pubescens roots, a traditional folk medicine. These structures were determined using HR-ESI-MS, IR, UV, and NMR (including 1 D, 2 D-NMR). The anti-inflammatory activities of three phenolic glycosides (1-3) were evaluated in the human HepG2 cell lines. The results showed that compound 3 could induce P-gp and BCRP expression through the Nrf2-mediated pathway.
研究领域:
天然产物化学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
HISTOCHEMISTRY AND CELL BIOLOGY
·
2025
·Vol. 163
·期 1
·1-15
·
IF 2.1
Zhong Wen-Jing,Xiong Jian-Bing,Zhang Chen-Yu,Jin Ling,Yang Nan-Shi-Yu,Sha Han-Xi,Liu Yu-Biao,Duan Jia-Xi,Guan Cha-Xiang,Zhou Yong,Su Feng
Pulmonary fibrosis (PF) is an insidious, progressive, and fatal age-associated disease that occurs primarily in older adults and has a poor prognosis. Alveolar epithelial cell (AEC) senescence is the critical pathological mechanism of PF. The accumulation of oxygen radicals, commonly referred to as reactive oxygen species (ROS), strongly contributes to cellular senescence. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor. Triggering via TREM-1 results in ROS, leading to the amplification of inflammation. However, whether TREM-1 is involved in PF by inducing oxidative stress to exacerbate AEC senescence remains unclear. We first observed that blockade of TREM-1 during the fibrotic phase attenuated bleomycin (BLM)-induced PF in mice, with decreased expression of senescence-related proteins, including p16, p21, p53, and γ-H2AX, in the lung tissue. Moreover, TREM-1 blockade during the fibrosis stage restored antioxidant levels by increasing the percentage of Nrf2- and HO-1-positive cells in mice with PF. Notably, TREM-1 was highly expressed in surfactant-associated protein (SPC)-positive AECs in mice with PF. In vitro, blocking TREM-1 activated Nrf2 antioxidant signaling, thereby decreasing intracellular ROS levels and diminishing BLM-induced senescence in AECs. Furthermore, inhibition of Nrf2/HO-1 partially counteracted the anti-senescence effect of blocking TREM-1 in BLM-treated AECs. In this study, we reported that TREM-1 stimulated the senescence of AECs, induced ROS and exacerbated PF. We also provide compelling evidence suggesting that the Nrf2/HO-1 signaling pathway underpins TREM-1-triggered senescence. Therefore, our findings provide new insights into the molecular mechanisms associated with TREM-1 and AEC senescence in the pathogenesis of PF.
研究领域:
医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BEHAVIOURAL BRAIN RESEARCH
·
2024
·
IF 2.6
Chenjie Ge,Shiliang Wang,Xuqi Wu,Lilei Lei
Background Depression is a common psychiatric disorder with limited effective treatments. Research suggests that depression involves apoptosis mechanisms. Quercetin (QUE) has been reported to have anti-apoptotic activities. In this study, we aimed to investigate the effects and mechanisms of QUE in chronic unpredictable mild stress (CUMS)-induced depression. Methods After establishing mouse models of CUMS-induced depression, the mice were randomly assigned into four groups: control, CUMS, CUMS+QUE, and CUMS+Fluoxetine (FLX). The body weight of the mice was measured during the study. Then, depression-associated behaviors were evaluated using the sucrose preference test (SPT), novelty suppressed feeding test (NSFT), forced swim test (FST) and tail suspension test (TST). Apoptosis in the hippocampus and prefrontal cortex was determined using flow cytometry. Bcl-2 and Nrf2 protein expressions in the hippocampus and prefrontal cortex were also detected. Furthermore, Western blot was used to measure the protein levels of p-ERK, ERK, p-CREB, CREB, and Nrf2 in brain tissues. Results QUE or FLX administration increased the body weight of the CUMS mice. Behavioral tests indicated that CUMS mice developed a state of depression, but QUE or FLX treatment improved their depression-associated behaviors. Meanwhile, QUE or FLX treatment decreased apoptosis in the hippocampus and prefrontal cortex. Furthermore, the decreased Nrf2 protein expression, ERK and CREB phosphorylation in CUMS group were enhanced by QUE or FLX administration. Conclusion QUE could attenuate brain apoptosis in mice with CUMS-induced depression, and the mechanism may be related to the ERK/Nrf2 pathway, indicating that QUE could be a potential treatment for depression.
研究领域:
神经科学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·
IF 9.6
Ren Yuanyuan,Cui Yue,Wang Zhen,Luo Yizhi,Jin Junchang,Yuan Yiyi,Li Xuan,Zhang Yaning,Cao Nan,Li Xiaofang,Yu Yi,Xiong Yuyan
Gastric cancer (GC) is a prevalent gastrointestinal malignancy in which ferroptosis, mitochondrial dysfunction, and macrophage reprogramming remarkably contribute to disease progression. However, the molecular interplay among these processes in contributing to GC remains poorly understood. In this study, we identified ferroptosis- and mitochondrial dysfunction-related genes (FMDRGs) implicated in GC through bioinformatics analyses. Among them, aldehyde dehydrogenase 3 family member A2 (ALDH3A2) was identified as a key FMDRG significantly downregulated in GC tissues and cell lines. Functional assays revealed that ALDH3A2 overexpression in GC cell lines suppressed proliferation, migration, and invasion while enhancing ferroptosis, effects that were reversed by GPX4 overexpression. ALDH3A2 also impaired the mitochondrial unfolded protein response (UPR mt ) and induced mitochondrial dysfunction. Restoration of UPR mt ameliorated ALDH3A2-induced mitochondrial dysfunction and ferroptosis. Mechanistically, ALDH3A2 impaired UPR mt by downregulating SLC47A1 through blockade of NRF2 nuclear translocation, leading to mitochondrial dysfunction, GPX4 downregulation, lipid peroxidation, and subsequent ferroptosis. Synergistically, ALDH3A2-induced ferroptosis promoted IL-6 release, which drove macrophage polarization toward the M1 phenotype with elevated IL-1β production. This macrophage reprogramming, in turn, inhibited GC cell progression by downregulating PD-L1 expression. Therapeutically, both genistein treatment and ALDH3A2 overexpression significantly attenuated GC progression in vitro and in vivo. These findings elucidate ALDH3A2 as a dual regulator of tumor-intrinsic ferroptosis and tumor-extrinsic immune remodeling in contributing to GC pathogenesis, highlighting its potential as a promising therapeutic target in GC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 5
·1103
·
IF 4.6
Bin Zhang,Xiaoyu Wei,Peiwen Du,Huangqun Luo,Lanfang Hu,Liping Guan,Guangying Chen
Polysaccharides are very promising molecules in the field of pharmacotherapy. Knowing this, the aim of this study was to extract, characterize, and evaluate the action of the polysaccharides in noni juice, using biological models of Type 2 diabetes mellitus processes. In this study, one polysaccharide named NJSPd−1 was separated from fermented noni fruit juice. The characterization assay showed that NJSPd−1 had a molecular weight ( Mw ) of 18,545 Da. NJSPd−1 consisted of galacturonic acid, galactose, rhamnose, and arabinose, with a molar ratio of 28.79:20.34:19.80:18.84 according to HPGPC analysis, and the glycosidic bond mainly included →4)- α -D-GalA p -(1→, 4)- β -D-Glc p -(1→, →2)- α -L-Rha p -(1→, and →3)- α -L-Ara f -(1→. The prevention of oxidative stress activities by NJSPd−1 was evaluated using high-glucose-induced oxidative stress in HepG2 cells. In vitro results showed that NJSPd−1 influenced the downregulation of the proteins and genes Nrf2, Keap1, HO-1, and NQO1 in HepG2 cells. These results suggest that NJSPd−1 exerted a protective effect against oxidative stress in HepG2 cells by activating the Nrf2/HO-1/NQO1 signaling pathway.
研究领域:
药理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD SCIENCE
·
2024
·Vol. 89
·期 10
·6707-6719
·
IF 3.2
Qilei Wang,Zhenzhen Feng,Chan Shi,Xingang Lyu,DaiDi Fan
Sulforaphane-loaded nanoparticles (NP-SF) were prepared in this study to improve their biological effects. Based on propylene glycol alginate and zein as wall materials and anthocyanin and CaCl 2 as crosslinking agents, the NPs were encapsulated by the crosslinking method and freeze-dried. With the increasing contents of anthocyanin and Ca 2+ , the encapsulation efficiency and loading capacity of NP-SF were both increased. In vitro simulated digestion experiments showed controlled release of SF from the NPs. The pharmacokinetics confirmed that NP-SF exerted a slower release effect in rats, with improved SF bioavailability and protective effects on liver injury induced by N -diethylnitrosamine in mice. NP-SF reduced serum indicators of liver injury, increased the activities of antioxidant enzymes and GSH levels, and reduced malondialdehyde levels in the liver. In addition, SF activated the Keap1/Nrf2 signaling pathway and upregulated the expression of the Nrf2 downstream genes NQO1 and heme oxidase 1. High doses of NP-SF, in particular, had a higher therapeutic effect. In conclusion, encapsulation enhanced the biological activity of SF and promoted physiological function.
研究领域:
药理学
·
肝脏病学
·
食品科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 5
·2148-2160
·
IF 5.396
Yaojie Liu,Ying Liu,Yatu Guo,Lin Xu,Hao Wang
Phlorizin is the main active ingredient of apple peel and has potential utilization value. Some recent studies have suggested that phlorizin may have antioxidant capacity and protect the liver. The injection of a low dose of D-galactose can cause some changes that resemble accelerated aging in mice. This study explored the protective effects of phlorizin on D-galactose-induced mice and PC12 cells. In this study, ICR mice were divided into a normal group (NOR), a D-galactose model group (D-gal) and phlorizin treatment groups (100 mg kg−1, 200 mg kg−1 and 400 mg kg−1). In addition to the NOR group, four other groups were injected with D-galactose (120 mg kg−1) for 12 weeks. The results showed that phlorizin reduced the decline of strength, coordination and spatial memory caused by aging, increased the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), increased total antioxidant capacity (T-AOC), and reduced the content of malondialdehyde (MDA). On the other hand, phlorizin increased the levels of interleukin-2 (IL-2) and acetylcholine (ACh), reduced the release of interleukin-6 (IL-6), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and decreased the activity of acetylcholinesterase (AChE) in the brain, improved the expression of antioxidant genes related to the nuclear factor E2-related factor 2 (Nrf2) pathway, and reduced the occurrence of morphological lesions in the hippocampus and liver. In addition, phlorizin improved cell viability and reduced the cytotoxicity of D-galactose-induced oxidative stress in PC12 cells. Meanwhile, the protective effect of phlorizin was abolished in Nrf2 gene knockdown PC12 cells. Furthermore, molecular docking showed that phlorizin could bind Keap1 protein, which can interact with Nrf2 protein. Therefore, these results suggest that phlorizin may delay senescence and enhance antioxidant capacity through the Nrf2 pathway.
研究领域:
老年学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Tungsten
·
2025
·
IF 11.2
Jiang Guo-Hui,Zhao Long,Liu Cheng-Hui,Tong Jing-Ming,Zhou Jing,Xu Qi-Qi,Zhang Chuan,Xu Xiao-Xue,Tang Xiao-Ping,Yang Han-Feng,Yong Yuan
Traumatic brain injury (TBI) is a key health issue that causes oxidative stress, neuroinflammation, and severe neurological dysfunction. The overexpression of reactive oxygen species (ROS) and accumulation of inflammatory cytokines following TBI exacerbate neuronal damage and impair recovery. Herein, a novel tungsten-based polyoxometalate nanocluster (W-POM NC) is presented, which is designed to alleviate TBI-related damage by targeting oxidative stress and inflammation. W-POM NCs exhibit strong ROS-scavenging properties, reducing oxidative stress through a redox mechanism, and effectively suppressing the inflammatory response. Mechanistically, W-POM activates the Nuclear factor erythroid 2-related factor 2 (Nrf2)-Musculoaponeurotic fibrosarcoma (MAF) signaling pathway, inducing upregulation of heme oxygenase-1 (HO-1) and promoting neuronal survival. Compared to the positive control drug edaravone, W-POM administration demonstrated superior efficacy in reducing proinflammatory reactions and oxidative stress biomarkers in brain tissue. In vivo studies demonstrated that W-POM notably enhanced the survival rate of TBI-afflicted rats and improved their cognitive performance, as assessed by behavioral assays. This work also offers a feasible approach for enhancing the selectivity of polyoxometalates under physiological conditions and exploring their potential applications in brain science. Graphical
研究领域:
神经科学
·
纳米医学
·
氧化还原生物学
·
炎症研究
·
分子医学
✓ 已验证
产品关联
DOI
高影响因子
AAPS Journal
·
2017
·Vol. 19
·期 6
·1703-1714
·
IF 3.423
Cao Mingnan,Wang Huixia,Guo Limei,Yang Simin,Liu Chun,Khor Tin Oo,Yu Siwang,Kong Ah-Ng
Oxidative stress is an important pathogenic factor in various hepatic diseases. Nuclear factor-erythroid 2-related factor-2 (Nrf2), which coordinates the expression of an array of antioxidant and detoxifying genes, has been proposed as a potential target for prevention and treatment of liver disease. Dibenzoylmethane (DBM) is a minor ingredient in licorice that activates Nrf2 and prevents various cancers and oxidative damage. In the present study, the mechanisms by which DBM activates Nrf2 signaling were delineated, and its protective effect against carbon tetrachloride (CCl 4 )-induced liver injury was examined. DBM potently induced the expression of HO-1 in cells and in the livers of mice, but this induction was diminished in Nrf2-deficient mice and cells. Overexpression of Nrf2 enhanced DBM-induced HO-1 expression, while overexpression of a dominant-negative fragment of Nrf2 inhibited this induction. DBM treatment resulted in dissociation from Keap1 and nuclear translocation of Nrf2. Moreover, DBM activated Akt/protein kinase B, mitogen-activated protein kinases, and AMP-activated protein kinase and increased intracellular calcium levels. Inhibition of JNK, AMPK, or intracellular calcium signaling significantly suppressed the induction of HO-1 expression by DBM. Finally, DBM treatment significantly inhibited CCl 4 -induced acute liver injury in wild-type but not in Nrf2-deficient mice. Taken together, our results revealed the mechanisms by which DBM activates Nrf2 and induces HO-1 expression, and provide molecular basis for the design and development of DBM and its derivatives for prevention or treatment of liver diseases by targeting Nrf2.
研究领域:
药理学
·
肝病学
·
分子生物学
·
毒理学
✓ 已验证
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Jue Wang,Peixian Chen,Yonghua Li,Rui Wang,Wenxin Ding,Ruizhi Yu,Qingqing Qin,Runzhu Wu,Wei Wei,Jinxin Shi,Hongbin Yuan,Chunlin Zhuang,Yi Sun
Type 2 diabetes-associated cognitive dysfunction (TDACD) is a debilitating complication characterized by neuroinflammation and oxidative stress, yet its underlying molecular mechanisms remain incompletely understood. The signal transducer and activator of transcription 3 (STAT3) pathway is increasingly implicated in neurodegeneration, but its specific role in TDACD and its interplay with the Nrf2 antioxidant defense system have not been fully elucidated. This study investigated the therapeutic potential of targeting STAT3 in TDACD using both pharmacological inhibition with niclosamide and specific genetic silencing strategies. In a high-fat diet (HFD) plus streptozotocin (STZ)-induced TDACD mouse model, STAT3 inhibition significantly ameliorated cognitive deficits and reduced neuronal pathology, including amyloid-β and phosphorylated Tau accumulation. Mechanistically, inhibition of STAT3 signaling suppressed neuroinflammation and reactive astrogliosis while simultaneously promoting the nuclear translocation of Nrf2 and the expression of downstream antioxidant enzymes. These effects were also reproduced in vitro using primary astrocytes exposed to high glucose. Specific STAT3 knockdown reversed the pro-inflammatory A1 phenotype and restored redox balance in these cells. Crucially, silencing Nrf2 eliminated the protective effects of STAT3 inhibition, suggesting a functional regulatory axis between STAT3 and Nrf2. Collectively, our findings support that STAT3 inhibition ameliorates cognitive dysfunction by disinhibiting the Nrf2 pathway to restore redox homeostasis and shift astrocytes towards a neuroprotective phenotype, highlighting the STAT3-Nrf2 axis as a promising therapeutic target for TDACD.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）