ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2024
·
IF 3.8
Haiyan Zhu,Yijing Yang,Yenan Duan,Xin Zheng,Zixiong Lin,Jie Zhou
Sodium aescinate (SA), an active compound found in horse chestnut seeds, is widely used in clinical practice. Recently, the incidence of SA-induced adverse events , particularly renal impairment, has increased. Our previous work demonstrated that SA causes severe nephrotoxicity via nephrocyte ferroptosis ; however, the underlying mechanism remains to be fully elucidated. In the current study, we investigated additional molecular pathways involved in SA-induced nephrotoxicity. Our results showed that SA inhibited cell viability , disrupted cellular membrane integrity, and enhanced reactive oxygen species (ROS), ferrous iron (Fe 2+ ), and malondialdehyde (MDA) levels, as well as lipid peroxidation in rat proximal renal tubular epithelial cell line (NRK-52E) cells. SA also depleted coenzyme Q10 (CoQ10, ubiquinone) and nicotinamide adenine dinucleotide (NADH) and reduced ferroptosis suppressor protein 1 (FSP1) and polyprenyltransferase (coenzyme Q2, COQ2) activity, triggering lipid peroxidation and ROS accumulation in mouse kidneys and NRK-52E cells. The overexpression of COQ2, FSP1, or CoQ10 (ubiquinone) supplementation effectively attenuated SA-induced ferroptosis, whereas iFSP1 or 4-formylbenzoic acid (4-CBA) pretreatment exacerbated SA-induced nephrotoxicity. Additionally, SA decreased nuclear factor-erythroid-2-related factor 2 (Nrf2) levels and inhibited Nrf2 binding to the −1170/-1180 bp ARE site in FSP1 promoter, resulting in FSP1 suppression. Overexpression of Nrf2 or its agonist dimethyl fumarate (DMF) promoted FSP1 expression, thereby improving cellular antioxidant capacity and alleviating SA-induced ferroptosis. These results suggest that SA-triggers renal injury through oxidative stress and ferroptosis, driven by the suppression of the Nrf2/FSP1/CoQ10 axis.
研究领域:
药理学
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毒理学
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细胞生物学
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分子生物学
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肾脏生理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Yan Zhou,Tian Wen,Shan Yang,Binru Meng,Jing Wei,Jing Zhang,Lun Wang,Xiaofei Shen
Ethnopharmacological relevance Cichorium intybus is a traditional medicinal herb for hepatitis treatment in China and Europe. Sesquiterpene lactones are the main active ingredients in C. intybus . However, their structure-activity relationship (SAR) and molecular mechanisms of anti-inflammatory and hepatoprotective effects require further elucidation. Aim of the study To identify new sesquiterpene lactones from C. intybus , and further evaluate their anti-inflammatory effects, SAR, and mechanisms of anti-inflammatory and hepatoprotective properties. Methods Identification of sesquiterpene lactones from C. intybus using chromatographic fractionation, NMR, and mass spectrometry. The repression of inflammation was evaluated in RAW264.7 macrophages incubated with LPS. Western blotting was employed to investigate the anti-inflammatory mechanisms. The hepatoprotective effect was measured in LPS/D-galactosamine (D-GalN)-induced acute hepatitis in mice. Results We identified 3 new sesquiterpene lactones and 15 known analogues from C. intybus . SAR analysis showed that the α-methylene-γ-lactone moiety was essential for their anti-inflammatory properties. Furthermore, 8-deoxylactucin was identified as the most potent anti-inflammatory component in LPS-induced RAW264.7 macrophages by reduction of nitric oxide production via inhibiting iNOS expression, and suppression of IL-1β, IL-6, and TNF-α expression. Mechanistically, 8-deoxylactucin not only blocked LPS-induced IKKα/β phosphorylation, IκBα phosphorylation and degradation, and NF-κB nuclear accumulation, but also enhanced NRF2 expression and nuclear translocation, HO-1 and NQO1 expression, and reduced ROS generation in vitro . In vivo , 8-deoxylactucin mitigated LPS/D-GalN-induced acute hepatitis, which manifested as reduction in inflammatory infiltration, live injury, serum levels of AST and ALT, and production of pro-inflammatory cytokines and 4-hydroxynonenal. Conclusion 8-Deoxylactucin, the sesquiterpene lactone isolated from C. intybus , exerted anti-inflammatory and hepatoprotective effects by blocking NF-κB activation and enhancing NRF2 activation.
研究领域:
药理学
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植物化学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Tongwang Luo,Shengzhe Song,Shujie Wang,Sheng Jiang,Bin Zhou,Quanjiang Song,Lingjun Shen,Xiaodu Wang,Houhui Song,Chunyan Shao
Cadmium (Cd), a pervasive environmental toxicant, poses significant threats to human and animal health through multi-organ toxicity. While ferroptosis has been implicated in Cd-induced pathologies, the molecular mechanisms underlying Cd-mediated nephrotoxicity remain poorly understood. This study elucidates the ferroptosis pathway in CdCl 2 -exposed PK-15 cells and murine kidney, characterized by iron overload, lipid peroxidation, and mitochondrial dysfunction, which were ameliorated by ferroptosis inhibitor ferrostatin-1. Transcriptomic analysis revealed substantial upregulation of heme oxygenase-1 (HO-1) following CdCl 2 exposure. Mechanistically, CdCl 2 triggered nuclear translocation of nuclear factor erythroid 2-related factor-2 (NRF2), subsequently activating HO-1 transcription. Over-activated HO-1 catalyzes the decomposition of heme and releases free iron, accompanied with the degradation of ferritin heavy chain 1 (FTH1) induced by CdCl 2 exposure, which leads to intracellular iron overload and excessive lipid peroxides production through Fenton reaction, resulting in ferroptosis ultimately. In vivo validation confirmed NRF2/HO-1-mediated ferroptosis in CdCl 2 -induced murine nephrotoxicity. Both pre-treatment with HO-1 competitive inhibitor Zinc protoporphyrin IX (ZnPP) and knockout of HO-1 gene remarkably alleviated PK-15 cells against ferroptosis induced by CdCl 2 treatment. Our findings demonstrate that Cd exposure initiates NRF2-mediated HO-1 overexpression, driving iron-dependent lipid peroxidation and subsequent ferroptosis. This mechanistic insight provides potential therapeutic targets for mitigating Cd-induced renal damage, advancing our understanding of heavy metal toxicity and its cellular consequences.
研究领域:
毒理学
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细胞生物学
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环境健康科学
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产品关联
DOI
PubMed
高影响因子
Current Nanoscience
·
2024
·Vol. 21
·期 4
·757-765
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IF 1.4
Zirui Liu,Dan Li,Baofeng Zhao,Xifan Mei
BackgroundGouty arthritis, characterized by excruciating pain and discomfort, poses a significant burden on patients. While nanomedicines have shown promise in addressing this ailment, their complicated synthesis processes often involve potentially toxic procedures, contributing to adverse side effects in disease management.MethodsIn this study, we introduce a straightforward and elegant solution by utilizing easily prepared gold platinum (AuPt) nanoparticles for the treatment of gouty arthritis. The synthesis of these nanoparticles involves the use of gold and platinum precursors in conjunction with NaBH4, simplifying the manufacturing process. Experimental models of gout were established in both in vivo and in vitro settings through lipopolysaccharide and monosodium urate crystal induction.ResultsOur findings revealed that AuPt nanoparticles exhibited potent anti-inflammatory effects against gout. This effect was attributed to their ability to activate the Nrf2/HO-1 pathway, resulting in pain alleviation and the inhibition of inflammation, ultimately leading to the reduction of joint edema. With their uncomplicated synthesis and promising therapeutic potential, these simply prepared AuPt nanoparticles emerge as a compelling candidate for pharmaceutical intervention in the treatment of gouty arthritis.ConclusionThis approach not only holds the promise of delivering effective relief to patients but also minimizes the risk of unwanted side effects associated with complex nanomedicine synthesis processes.
研究领域:
药理学
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纳米医学
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炎症研究
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DOI
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2019
·Vol. 393
·期 1
·57-65
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IF 2.058
Zhai Jiajia,Li Zeping,Zhang Huifeng,Ma Louyan,Ma Zhengquan,Zhang Yi,Zou Jian,Li Mo,Ma Li,Li Xiaomiao
The present study has been designed and carried out to evaluate the potential of coptisine on diabetic nephropathy. Diabetes was induced in SD rats through one single intraperitoneal injection of streptozotocin (65 mg/kg) method, and then diabetic rats were orally administered with 25 mg/kg/day coptisine or 50 mg/kg/day coptisine for 8 weeks. Severe impairment of renal function in rats with diabetes was observed as indicated by increased urine protein excretion, kidney hypertrophy index, serum creatinine level, and blood urea nitrogen level. Oxidative stress damage was observed as indicated by increased levels of reactive oxygen species, malondialdehyde, and decreased levels of glutathione, superoxide dismutase, and catalase. However, these alterations in kidneys of rats with diabetes were alleviated by administration of coptisine. Furthermore, the expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and its targeted antioxidative genes heme oxygenase 1 and NADPH quinone oxidoreductase 1 in the diabetic kidneys were significantly increased after coptisine treatment. These results suggested that coptisine ameliorated oxidative renal injury in diabetic rats, and the possible mechanisms for the renoprotective effects of coptisine may be related to activation of the Nrf2 signaling pathway.
研究领域:
药理学
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糖尿病
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肾脏生理学
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氧化应激
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产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL CHEMISTRY JOURNAL
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2018
·Vol. 52
·期 2
·95-102
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IF 0.679
Xu Xiaoya,Chen Yajun,Zhang Min,Wang Dianlei,Wu Jie,Yao Zhaomin,Wu Qingqing,Fang Wei
The therapy of Huatanjiangqi capsule (HTJQ) has been used in the treatment of chronic obstructive pulmonary disease (COPD) clinically, with remarkable benefits. A lower functional activity of MRP1 is related to COPD development. However, the mechanism that contributes to MRP1 up-regulation by HTJQ was unclear. This study aimed to investigate the effects of HTJQ on the expression of Nrf2 and MRP1 in COPD rats. Rats were exposed to cigarette smoke plus lipopolysaccharide tracheal instillation to induce a COPD model. Then, Nrf2, HO-1, and MRP1 mRNA expression and their protein production in lung tissues were examined. The model group showed significant changes in the above assessments as compared to those of the control group ( p < 0.05). The lung function of model group treated with low/high dose of HTJQ was significantly strengthened (both p < 0.05), and the inflammatory cells and goblet cells were decreased in lung tissues. Treatment with low/high dose of HTJQ resulted in obvious increase in Nrf2, HO-1, and MRP1 mRNA and protein expression levels ( p < 0.05). HTJQ could up-regulate Nrf2 and MRP1 expression in lung tissues of COPD model rats. The mechanism by which HTJQ up-regulates MRP1 expression may be associated with Nrf2.
研究领域:
药理学
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呼吸病学
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分子生物学
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产品关联
DOI
高影响因子
Toxicology Research
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2024
·Vol. 13
·期 1
·
IF 2.2
Zhang Chu,Liao Yupei,Li Tangjia,Zhong Haijing,Shan Luchen,Yu Pei,Xia Chenglai,Xu Lipeng
The 2022 US Cancer Statistics show that breast cancer is one of the most common cancers in women. Epidemiology has shown that adding flavonoids to the diet inhibits cancers that arise in particular women, such as cervical cancer, ovarian cancer, and breast cancer. Although there have been research reports on apigenin (API) and breast cancer, its anti-tumor effect and potential mechanism on breast cancer have not yet been clarified. Therefore, in this study, we used 4T1 cells and a 4T1 xenograft tumor mouse model to investigate the antitumor effect of API on breast cancer and its underlying mechanism. In vitro, we used MTT, transwell, staining, and western blotting to investigate the inhibitory effect of apigenin on 4T1 and the underlying molecular mechanism. In vivo by establishing a xenograft tumor model, using immunohistochemistry, and flow cytometry to study the inhibitory effect of apigenin on solid breast tumors and its effect on the tumor immune microenvironment. The results showed that API can induce breast cancer cell apoptosis through the PI3K/AKT/Nrf2 pathway and can improve the tumor immune microenvironment in mice with breast tumors, thereby inhibiting the growth of breast cancer. Thus, API may be a promising agent for breast cancer treatment.
研究领域:
肿瘤学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
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IF 4.7
Ji-Ping Wei,Bo Zhao,Zi-Jian Jiang,Peng-Yu Wang,Yan Xu,Ning Ding,Yuan-Yuan Hu,Wei Wang,Bo-Tao Jiang
Renal ischemia/reperfusion (I/R) injury is the most common cause of acute kidney injury (AKI). It can progress to chronic injury and subsequently to chronic kidney disease (CKD) via the renal fibrosis pathway. Luteolin is one of the most commonly occurring flavonoids and exhibits potential therapeutic activity against various pathophysiological processes. In this study, we investigated the protective role of luteolin in counteracting renal I/R injury and its potential mechanisms through systematic network pharmacology, molecular docking, and in vivo experimental studies. Using network pharmacology, we constructed and analyzed a luteolin-renal I/R injury target network. We assessed the relationship between luteolin and renal I/R injury targets using molecular docking analysis. Subsequently, we established a rat model of AKI to CKD transition using unilateral ischemia/reperfusion injury (UIRI), and detected changes in the expression of related proteins using biochemical indices. Network pharmacological analysis and molecular docking showed that luteolin affected renal I/R injury through multiple targets and pathways. As demonstrated by in vivo experiments, luteolin significantly attenuated renal I/R-induced oxidative injury by inhibiting renal lipid peroxidation in rats through the modulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Luteolin attenuated the levels of relevant inflammatory markers, significantly upregulated the synthesis of apoptosis-related proteins, and downregulated the expression of anti-apoptotic proteins. Our results suggest that luteolin effectively inhibited oxidative damage, inflammation, apoptosis, and fibrosis caused by renal I/R injury, thus exerting a nephroprotective effect. The antioxidant effects of luteolin may be related to the regulation of Nrf2/HO-1 signaling.
研究领域:
药理学
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分子生物学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Xin Guo,Pingping Cao,Xiongfeng Lian,Meng Hu,Jingyi Zhao,Wenjing Shen,Haili Wang,Hailong Yu,Yingzhu Chen
Phillyrin, a natural plant extract, has significant antioxidant and anti-apoptotic effects. However, its effect on intracerebral hemorrhage (ICH) remains unclear. In this study, we investigated a potential role for phillyrin in the regulation of the oxidative stress and apoptosis induced by ICH. A model of ICH was induced by collagenase IV (0.2 U in 1 μl sterile normal saline) in male C57BL/6J (B6) mice and different doses of phillyrin (5, 15, or 30 mg/kg) were intraperitoneally (i.p.) injected at 30 min, 6 h, and 22 h after modeling. We found that phillyrin significantly reduced neural function and lesion volume, improved injury of white and grey matter around the lesion, decreased apoptosis and oxidative stress, increased the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase 1(HO-1), NADPH quinone oxidoreductase 1 (NQO1) and Superoxide Dismutase-1(SOD-1) in vitro and in vivo , and protected neurons from the stimulation of hemin by promoting Nrf2 nuclear translocation. Treatment with ML385 (Nrf2 inhibitor) completely reversed the protective effects of phillyrin in vivo after ICH injury. Based on our findings, we conclude that phillyrin treatment alleviates ICH injury-induced apoptosis and oxidative stress via activation of the Nrf2 signaling pathway, highlighting a potential role for phillyrin as an ICH therapeutic.
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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF SURGICAL RESEARCH
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2022
·
IF 2.417
Ming Deng,Ping Xie,Junqi Liu,Yan Zhou,Zhonghui Chen,Yonggang Ma,Jianwei Yang
Introduction α-Cyperone has anti-inflammatory activities, but its effects on spinal cord injury (SCI) remain obscure. Thus, this study attempts to investigate the effects and modulatory mechanisms of α-Cyperone on SCI. Materials and methods An SCI model was established in rats which were further treated with α-Cyperone. Basso-Beattie-Bresnahan (BBB) scoring was used to assess motor rehabilitation of rats modeled with SCI. The spinal cord tissues were collected, and the effect of α-Cyperone on the histopathology of rats modeled with SCI was detected by hematoxylin-eosin staining. Rat primary cortical neuron was stimulated with H 2 O 2 and further treated with α-Cyperone and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385. The levels of Nrf2, interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), Akt, toll-like receptor 4 (TLR4), and tumor necrosis factor-alpha (TNF-α) were detected by immunofluorescence staining and western blotting . Results α-Cyperone elevated the BBB score and ameliorated the damage of spinal cord tissue in rats modeled with SCI. The levels of IL-6, Nrf2, NF-κB, TLR4, and TNF-α were upregulated, whereas that of Akt was downregulated in rats and cells modeled with SCI. Furthermore, α-Cyperone diminished the levels of IL-6, NF-κB, TLR4, and TNF-α, while augmenting those of Nrf2 and Akt in rats and cells modeled with SCI. ML385 inhibited the Nrf2 level that had been promoted by α-Cyperone in the nucleus and elevated the Nrf2 level that had been suppressed by α-Cyperone in the cytosol of cells modeled with SCI. ML385 increased the levels of IL-6, NF-κB, TLR4, and TNF-α that had been inhibited by α-Cyperone and decreased the Akt level that had been enhanced by α-Cyperone in cells modeled with SCI. Conclusions α-Cyperone suppressed SCI-induced inflammation and spinal cord tissue damage via activating Akt/Nrf2 and suppressing NF-κB pathways.
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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病理学
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DOI
PubMed
高影响因子
Animal Diseases
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2024
·Vol. 4
·期 1
·1-16
·
IF 0
Liu Jinglei,Zhang Yuhan,Song Mengzhen,Guo Xuming,Fan Jinping,Tao Shiyu
Oxidative stress is an important contributor to gastrointestinal diseases in multiple ways. Taurodeoxycholic acid (TDCA) is a metabolite of bile acids and has anti-inflammatory and protective effects on the intestinal tract. However, whether TDCA can alleviate oxidative stress in the intestine is still unclear. Here, we investigated the effects of TDCA on diquat-induced oxidative stress in the jejunum and its mechanism. The results revealed that TDCA increased the concentrations of antioxidant enzymes in the serum, jejunal tissue and intestinal epithelial cells of the mice, as did the expression of tight junction-associated proteins and the Nrf2 protein in the jejunal epithelial tissue and intestinal epithelial cells. We then explored the mechanism of Nrf2 with ML385 (a specific Nrf2 inhibitor). The results showed that after ML385 treatment, the levels of antioxidant enzymes were significantly decreased in the serum, jejunum, and intestinal epithelial tissues of the mice. The expression of tight junction proteins in jejunum epithelial tissues and intestinal epithelial cells was also decreased. In conclusion, our study suggests that TDCA alleviates oxidative stress to improve intestinal barrier function through the Nrf2-mediated signaling pathway. These findings help elucidate the role of TDCA in protecting the intestinal barrier and its mechanism of action, providing insights for the prevention and treatment of intestinal diseases caused by oxidative stress.
研究领域:
生物化学
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分子生物学
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药理学
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DOI
Food & Function
·
2020
·Vol. 11
·期 6
·5156-5165
·
IF 4.171
Yu-Sheng Shi,Xiao-Xing Li,Hao-Tian Li,Yan Zhang
Liver fibrosis is a histological change that often occurs due to hepatic stellate cell (HSC) activation and excessive formation of an extracellular matrix in the liver. Pelargonidin (PEL) is a natural anthocyanidin existing in blueberries, berries, strawberries, and red radishes and has been demonstrated to possess health beneficial effects. Herein, we investigated the effect of PEL on liver fibrosis induced by CCl4 and hepatic stellate cells induced by transforming growth factor-β (TGF-β). We found that PEL administration prevented liver injury and liver fibrosis induced by CCl4 in a dose-dependent manner. Further data revealed that PEL increased liver nuclear factor E2-related factor 2 (Nrf2) and reduced liver oxidative stress and the expression levels of NLRP3, caspase-1 and IL-1β. In TGF-β-challenged HSCs (LX-2 cells), PEL effectively inhibited the LX-2 cell activation. In addition, the anti-fibrosis effects of PEL in LX-2 cells were abolished by Nrf2 knockdown. In summary, our study demonstrated that PEL ameliorated CCl4-induced liver fibrosis and HSC activation induced by TGF-β. The possible molecular mechanisms of PEL in liver fibrosis may be attributed to its suppression of ROS-NLRP3-IL-1β signaling by Nrf2 activation.
研究领域:
药理学
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肝病学
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分子生物学
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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）