Frontiers in Pharmacology
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2023
·
IF 5.6
Sheng Mingyue,Chen Xun,Yu Yan,Wu Qi,Kou Junping,Chen Gangling
Backgrounds: The circadian clock protein Rev-erbα is a crucial regulator of circadian rhythms that affects multiple molecular, cellular, and physiology pathways that control susceptibility, injury, and recovery in the neurological disorders. Emerging evidence suggest that Rev-erbα plays a key role in the inflammation and oxidative stress, two pivotal mechanisms in the pathogenesis, progression, and recovery process of ischemic stroke. However, it remains inconclusive whether Rev-erbα activation is protective against ischemic brain damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a master regulator of inflammatory and oxidative responses. Our study aimed to determine whether pharmacological activation of Rev-erbα by SR9009 protects against acute ischemic brain damage partly via Nrf2 pathway.Methods: Adult mice were pretreated with SR9009 or Nrf2 inhibitor all-trans-retinoic acid (ATRA) for 3 days prior to Sham or middle cerebral artery occlusion (MCAO) operation. After ischemia for 1 h and reperfusion for 24 h, the neurological function and cerebral infarction volume were determined, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and glutathione peroxidase (GSH-PX) activity in serum were detected by kit. The mRNA and/or protein level of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), Period (Per)1, Brain and muscle arnt-like1 (Bmal1), Circadian locomotor output cycles kaput (Clock), Rev-erbα, Nrf2, heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1) in cerebral cortex were detected by q-PCR and Western blot.Results: We confirmed that SR9009 activated Rev-erbα gene in the cerebral cortex under basal condition. At 24 h after reperfusion, SR9009 ameliorated acute neurological deficits, reduced infarct volume. Meanwhile, the inflammatory TNF-α, IL-1β, iNOS and MDA content levels were significant decreased, SOD and GSH-PX activity were obviously increased, which were markedly blunted (or abolished) by ATRA. SR9009 enhanced the induction of Nrf2 and its downstream target genes HO-1 and NQO1 after ischemic insult. In addition, we found that SR9009 restored Rev-erbα, Bmal1, Clock, Per1 genes expression in the cerebral cortex under ischemic condition.Conclusion: Taken together, Rev-erbα activation by SR9009 protects against ischemic stroke damage, at least, partly through Nrf2 pathway.
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Food & Function
·
2023
·Vol. 14
·期 4
·1884-1896
·
IF 6.1
Huiyi Li,Qiqing Weng,Shuai Gong,Weixian Zhang,Jiaqi Wang,Yuqiao Huang,Yuanjun Li,Jiao Guo,Tian Lan
Acetaminophen (APAP)-induced liver injury (AILI) has become a growing public health problem. Ferroptosis, an iron-dependent form of cell death associated with lipid peroxide accumulation, has been recently implicated in AILI. The activation of the Nrf2 signaling pathway is a potential therapy for AILI. Kaempferol (KA), a flavonoid widely existing in edible plants, has been reported to exert profound anti-inflammatory and antioxidant activities. This study aimed to investigate whether KA exerts anti-AILI effects via the Nrf2 signaling pathway. Mice were fasted for 22 h and injected intraperitoneally with APAP (250 mg kg−1) to induce AILI. Mice were pre-injected intragastrically with KA for 2 h followed by APAP injection. The hepatic injury was observed by H&E staining. Biochemical parameters of the serum and liver were measured using kits. KA alleviated hepatic injury and inflammatory response in AILI mice and ameliorated APAP-induced hepatic iron overload and oxidative stress in mice. In addition, the protective effects of KA against APAP-induced hepatotoxicity were examined in L02 cells in vitro. Cell viability was assayed by the CCK8 assay. Mitochondrial reactive oxygen species (ROS) in L02 cells were detected by MitoSox fluorescence. KA reversed the APAP-induced decrease in cell viability and GSH levels and inhibited the accumulation of intracellular ROS. Furthermore, KA activated the Nrf2 pathway and upregulated Gpx4 in mouse livers and L02 cells to inhibit ferroptosis induced by APAP. Finally, molecular docking indicated the potential interaction of KA with Keap1. Taken together, KA ameliorated oxidative stress and ferroptosis-mediated AILI by activating Nrf2 signaling.
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Food & Function
·
2023
·Vol. 14
·期 2
·1087-1098
·
IF 6.1
Chengzhu Song,Dongning Li,Jie Zhang,Xiaoyan Zhao
Imatinib mesylate (IMA) belonging to the selective tyrosine kinase inhibitor family has been proven to induce cardiotoxic effects along with therapeutic strategies. Nrf2-dependent ferroptosis has been implicated in the cardiotoxicity induced by IMA. The present study was designed to investigate the protective effects of berberine hydrochloride (Ber) on cardiac injuries induced by IMA and to explore its potential mechanisms. In H9c2 cells, cell viability, the generation of reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and labile iron pool (LIP) levels were measured. In a mouse model of IMA-induced cardiomyopathy, serum biomarkers and cardiac tissues were examined. A western blot assay was performed to evaluate the expression of ferroptosis-related proteins in vitro and in vivo. Our results indicated that Ber increased cell viability and MMP and decreased cellular ROS and iron levels in comparison to the IMA group of H9c2 cells. In mice, Ber significantly improved cardiac status and attenuated the level of ferroptosis biomarkers including malonaldehyde (MDA) and iron content. Additionally, Ber downregulated the expression of transferrin receptor (TfR) and P53 and upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO1), ferritin heavy chain-1 (FTH1), and glutathione peroxidase 4 (GPX4) in H9c2 cells and mice. The present data indicated that Ber has the potential to protect against IMA-induced cardiotoxicity, partly via inhibiting Nrf2-dependent ferroptosis.
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Antioxidants
·
2021
·Vol. 11
·期 1
·38
·
IF 6.313
Zhiwei Qiu,Jinzhao He,Guangying Shao,Jiaqi Hu,Xiaowei Li,Hong Zhou,Min Li,Baoxue Yang
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The purpose of this study was to discover an effective therapeutic drug for ADPKD. With virtual screening, Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney-specificPkd1knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library.In vitroexperiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner.In vivo, obacunone treatment significantly reduced the renal cyst development in PKD mice. Western blot and morphological analysis revealed that obacunone served as a NRF2 activator in ADPKD, which suppressed lipid peroxidation by up-regulating GPX4 and finally restrained excessive cell proliferation by down-regulating mTOR and MAPK signaling pathways. Experimental data demonstrated obacunone as an effective renal cyst inhibitor for ADPKD, indicating that obacunone might be developed into a therapeutic drug for ADPKD treatment.Keywords:obacunone;autosomal dominant polycystic kidney disease;NRF2;glutathione peroxidase;lipid peroxidation;MAPK;mTOR
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ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Yishi Lu,Ziyue Zu,Nan Zhong,Yang Li,Xuan Sha,Shangyu Lu,Jie Zhang,Hanyao Sun,Xi Luo,Ziqing Xu,Feiyun Wu,Yuxia Tang,Shouju Wang
Autophagy blockade has emerged as a promising strategy to enhance the antitumor efficacy of pancreatic ductal adenocarcinoma (PDAC). However, autophagy inhibition in PDAC may induce compensatory macropinocytosis to maintain cellular homeostasis by upregulating nuclear factor erythroid 2-related factor 2 (NRF2). In this study, lysosomal-activated nanoreactors loaded with the NRF2 inhibitor ML385 (CPZI-Ms) are developed to spatiotemporally block autophagy and inhibit macropinocytosis. The nanoreactors, which preferentially accumulate in lysosomes, undergo degradation in the acidic lysosomal environment, triggering a Fenton-like reaction between the released Cu 2 ⁺ ions and H₂O₂ to generate hydroxyl radicals. This results in lysosomal membrane permeabilization, which further leads to not only lysosomal autophagy blockade, but also the leakage of Cu 2 ⁺ and ML385 into the cytoplasm. Cu 2 ⁺ induces extensive oxidative stress throughout the whole cell, while ML385 suppresses compensatory macropinocytosis response activated by autophagy blocking. As a result, the Panc02 cells become a “besieged fortress”, with impaired autophagic clearance and restricted nutrient uptake. In vivo, CPZI-Ms effectively suppress tumor growth in Panc02-bearing mice, offering a promising nanoplatform for enhancing cancer cell killing. Taken together, the present work provides an innovative anti-tumor insight by spatiotemporally blocking autophagic flux and inhibiting compensatory macropinocytosis.
研究领域:
肿瘤学
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药理学
·
纳米医学
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TOXICOLOGY
·
2017
·
IF 3.582
Chuanyang Su,Zixuan Liu,Yawen Wang,Yuxin Wang,Erqun Song,Yang Song
The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is the most important cellular defense mechanisms against oxidative attack. BTB and CNC homology-1 (Bach1), like Kelch-like ECH-associated protein 1 (Keap1), is one of a negative regulator of Nrf2 that control antioxidant response elements (ARE)-dependent gene expressions. In the current study, we found that quinones show greater capacity than hydroquinones in nuclear Bach1 export, as well as ubiquitin-dependent Bach1 degradation in our experimental time frame. Consistently, quinones are easier than hydroquinones in Nrf2 activation and ARE-driven antioxidant protein expressions. Considering the redox cycling potential of quinone-hydroquinone couple, we investigated the effect of transit metal oxidation on the regulation of Nrf2 activity. As shown, Fe 3+ enhanced hydroquinone-induced Nrf2 activation and ARE-driven gene expressions, suggesting quinones rather than hydroquinone activate Nrf2 through Bach1 arylation. Taking together, our investigation illustrated that the electrophilic character of quinones ensure their conjugation with Bach1, which is important for the downregulation of Bach1 and the upregulation of Nrf2 signaling.
研究领域:
生物化学
·
分子生物学
·
细胞信号传导
·
氧化应激
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npj Science of Food
·
2025
·Vol. 9
·期 1
·234
·
IF 7.8
Cao Lixue,Lei Qi,Dong Yujia,Meng Chuyang,Qi Qianqian,Li Lisi,Liu Hongwei,Liu Xifu,Wang Meng
Alcohol abuse results in alcoholic liver disease which are associated with high morbidity and mortality worldwide. Whereas luteolin has shown potential hepatoprotective effects on ethanol-induced liver damage and the underlying mechanism remains unclear. In this study, a chronic plus a single binge ethanol feeding mouse model was employed to mimic acute-on-chronic alcoholic liver injury in humans, and the primary hepatocytes were isolated for the mechanism investigation. Our study demonstrated that luteolin protects against ethanol-induced liver injury by restoring NRF2 stability, thereby blocking the nuclear accumulation of ACSS2 and histone H3 acetylation. This subsequently led to reduced hepatic lipogenesis, and ultimately ameliorated alcoholic liver damage. Our findings elucidate the protective mechanism of luteolin in alcoholic liver injury and provide a new therapeutic strategy for the treatment of alcoholic liver disease.
研究领域:
肝脏病学
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分子生物学
·
药理学
·
营养生物化学
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RENAL FAILURE
·
2025
·
IF 3
Shu Zhang,Xin Dong,Gangyi Chen,Chao Wang
Background Oxidative stress is a critical pathological mechanism in septic acute kidney injury (AKI). Tanshinone IIA (Tan IIA), a bioactive compound derived from Salvia miltiorrhiza, exhibits antioxidative properties. This study aimed to explore the protective mechanisms of Tan IIA in septic AKI.Methods A mouse model of lipopolysaccharide (LPS)-induced AKI was established, with Tan IIA administered prior to LPS injection. Renal function was assessed by serum creatinine and urea nitrogen levels, while histopathological damage and apoptosis were evaluated using PAS and TUNEL staining. Oxidative stress was assessed by SOD activity, ROS levels, and 8-OHdG staining. In vitro, LPS-stimulated HK-2 cells were treated with Tan IIA or RIP3 siRNA. The expression of RIP3, p-RIP3, Nrf2, HO-1, KEAP1, and downstream antioxidant genes (NQO1, GCLC) was analyzed by qRT-PCR, immunohistochemistry, and Western blot. Apoptosis was further evaluated by Annexin V-FITC/PI flow cytometry and detection of apoptosis-related proteins (Bax, cleaved caspase-3, Bcl-2). Co-immunoprecipitation was performed to examine RIP3–Nrf2 interaction.Results In vivo, Tan IIA significantly improved renal function and alleviated tubular damage. It decreased ROS production and 8-OHdG positivity while restoring SOD activity. In vitro, Tan IIA or RIP3 silencing decreased ROS levels, enhanced SOD activity, promoted Nrf2 nuclear translocation, and upregulated antioxidant genes. Flow cytometry confirmed reduced apoptotic cell populations, and Western blot showed reversal of LPS-induced pro-apoptotic protein changes. The co-immunoprecipitation confirmed an interaction between RIP3 and Nrf2 under LPS stimulation.Conclusion These findings suggest that Tan IIA protects against LPS-induced AKI by inhibiting RIP3 expression and restoring Nrf2-mediated antioxidant defenses, thereby attenuating oxidative stress and apoptosis.
研究领域:
药理学
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肾脏病学
·
分子生物学
·
氧化应激研究
·
炎症
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AMERICAN JOURNAL OF CHINESE MEDICINE
·
2019
·Vol. 47
·期 05
·1113-1131
·
IF 3.51
Li-Ying Peng,Lin An,Ning-Yuan Sun,Yi Ma,Xiao-Wei Zhang,Wen-Hua Liu,Bao-Lin Liu,Ping Li,Jun Chen
Pulmonary fibrosis (PF) is characterized by myofibroblast activation, which can be triggered by oxidative stress. In this study, we investigated the antifibrotic effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on PF and examined the underlying molecular mechanism. EASM suppressed myofibroblast activation with reduced extracellular matrix deposition in the lungs of mice subjected to bleomycin (BLM) challenge, demonstrating the inhibitory effects on PF. EASM positively alleviated oxidative stress by upregulating nuclear factor-erythroid 2-related factor 2 (Nrf2) and concomitantly downregulating NADPH oxidase 4 (Nox4) in the lungs of BLM-treated mice. This effect was also observed in an in vitro model of transforming growth factor beta 1 (TGF- β 1)-stimulated fibroblast activation. EASM reduced reactive oxygen species (ROS) generation in fibroblasts by stabilizing Nrf2 protein with promoting kelch-like ECH-associated protein 1 (Keap1) degradation. Nrf2 knockdown in the lungs of BLM-treated mice diminished the inhibitory effects of EASM on fibrosis, providing evidence in vivo to address the unique role of Nrf2. Additionally, EASM inhibited TGF- β 1/Smad3 signaling by downregulating protein kinase C delta (PKC- δ ) and Smad3 phosphorylation (p-Smad3), which led to suppression of the TGF- β 1-induced fibrogenic response. These results indicate that EASM exhibits potent antifibrotic activity in vitro and in vivo , which might be associated with activation of Nrf2 pathway and inhibition of TGF- β 1/Smad3 pathway. Our findings support that EASM may act as an effective antifibrotic remedy for PF.
研究领域:
药理学
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肺科学
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分子生物学
·
氧化应激研究
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BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Wen-yuan Zhang,Qian-qian Wei,Tao Zhang,Chunmei Geng,Hai-yan Wu,Chang-shui Wang,Jing Chen,Lei Feng,Pei Jiang
Background and Purpose Despite breakthroughs in immunotherapy and targeted therapies, chemotherapy remains indispensable in oncology. Experimental Approach This study seeks to pinpoint key pathways in doxorubicin (DOX)-treated mouse hippocampus, utilising comprehensive transcriptomic and metabolomic analyses, and validating the mechanisms in vitro and in vivo. Key Results Our multi-omics investigation revealed that sustained DOX exposure induced significant down-regulation of 5-aminolevulinate synthase 2 (ALAS2) and its catalytic product 5-aminolevulinic acid (5-ALA) in the hippocampal region. ALAS2 deficiency was specific to hippocampal neurons, which were more sensitive to oxidative damage than astrocytes or microglia. In vivo and in vitro studies demonstrated that 5-ALA administration or ALAS2 overexpression protected the brain from DOX-induced neurotoxicity. ALAS2 catalyses the condensation of glycine and succinyl-CoA to form 5-ALA, the key precursor of haem. Beyond its role in erythropoiesis, haem is a metabolite that modulates cellular redox homeostasis through interactions with the BACH1 (BTB and CNC homology 1)/NRF2 (nuclear factor erythroid 2 like 2) pathway. We found that DOX suppressed the ALAS2/5-ALA axis, thereby enhancing BACH1 stability. This stabilised BACH1 competes with NRF2 for binding to antioxidant response elements (AREs) in target gene promoters. Conversely, reinforcing the ALAS2/5-ALA axis elevated intracellular haem levels, promoting BACH1 degradation and enhancing NRF2 activity. Using a zebrafish model, we further highlighted the antioxidant and neuroprotective role of 5-ALA against DOX-induced neurotoxicity. Conclusions and Implications In conclusion, this study elucidates a novel endogenous neuroprotective mechanism wherein the ALAS2/5-ALA axis modulates the BACH1/NRF2 pathway. 5-ALA shows promise for repurposing to mitigate chemotherapy-associated neurotoxicity. Graphical
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Theranostics
·
2026
·Vol. 16
·期 7
·3363
·
IF 13.3
Qiujie Luo,Wei Meng,Jiahui Wang,Xiang Zhang,Qingbo Meng,Mengjie Hu,Shunbo Wei,Xiaobo Yu,Dawei Deng,Yuqin Zhang,Zixuan Ma,Shentao Li,Shuang Wang,Binhao Zhang,Jingli Ding,Jinping Liu,Jianliang Zhou
Rationale: Abdominal aortic aneurysm (AAA) is a significant cause of death worldwide, with both mortality and incidence rates gradually increasing. Its complex pathological mechanisms hinder drug development. This work aims to develop a biomimetic multifunctional nanoparticle for targeted AAA therapy. Methods: Leveraging the multi-pore property of mesoporous Prussian blue nanoparticles (MPB NPs), we encapsulated the rosiglitazone (RLZ) into MPB NPs to synthesize MPB-RLZ NPs. Then, macrophage-biomimetic nanoparticles (MPB-RLZ@MM NPs) were prepared by coating MPB-RLZ NPs with macrophage membranes (MM). The characterization and reactive oxygen species (ROS)-scavenging ability of MPB-RLZ@MM NPs were evaluated. Next, the biocompatibility and biological functions of MPB-RLZ@MM NPs were evaluated. Finally, we assessed the targeting efficacy and therapeutic efficacy of MPB-RLZ@MM NPs in vivo . Results: MPB-RLZ@MM NPs reduced ROS levels in human umbilical vein endothelial cells (HUVECs) and apoptosis in vascular smooth muscle cells (VSMCs). MPB-RLZ@MM NPs inhibited M1-like macrophage polarization via the Nrf2/NF-κB pathway. In addition, MPB-RLZ@MM NPs accumulated in dilated aneurysms. After 4 weeks of treatment, MPB-RLZ@MM NPs effectively delayed aneurysm dilation. Conclusions : MPB-RLZ@MM NPs exhibited excellent biosafety and therapeutic efficacy against AAA. This macrophage-biomimetic strategy presents a promising therapeutic approach for AAA treatment.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Keshu Liu,Aina Zhou,Zhihui Liu,Baoai Han,Cuiping Qi,Xiaoping Ming,Weisong Cai,Yiwei Feng,Zehua Lin,Wu Hu,Xiong Chen
Several clinical studies have shown that sleep deprivation is strongly associated with intestinal barrier dysfunction. Nootkatone (NKT), a principal bioactive sesquiterpenoid from grapefruit, has shown therapeutic potential for sleep and gastrointestinal disorders, although its mechanisms remain unclear. This study investigated the protective effects of NKT on SD-induced colonic injury. NKT significantly ameliorated SD-induced intestinal barrier dysfunction by upregulating key epithelial proteins and inducing mucin production. NKT also suppressed the expression of proinflammatory cytokines. Transcriptomic analysis revealed that NKT modulated pathways associated with mitochondrial function, oxidative stress, and intestinal inflammation. Importantly, NKT treatment also restored the gut microbial composition, increased the abundance of beneficial bacteria, and improved microbiota–metabolite interactions. Mechanistically, NKT activated the nuclear factor erythroid 2-related factor 2(Nrf2) pathway, leading to reduced reactive oxygen species accumulation and improved mitochondrial function in colonic tissues. These results highlight the potential of NKT as a plant-derived therapeutic agent for sleep-related gastrointestinal disorders.
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