PHYTOMEDICINE
·
2023
·
IF 7.9
Yong Fang Gong,Shu Hou,Jia-Cheng Xu,Yan Chen,Le-Le Zhu,Ying-Ying Xu,Yu-Qing Chen,Miao-Miao Li,Li-Li Li,Jing-Jing Yang,Yan Yang
Background Phosphorylated Smad3 isoforms are reversible and antagonistic, and the tumour-suppressive pSmad3C can shift to an oncogenic pSmad3L signal. In addition, Nrf2 has a two-way regulatory effect on tumours, protecting normal cells from carcinogens and promoting tumour cell survival in chemotherapeutics. Accordingly, we hypothesised that the transformation of pSmad3C/3L is the basis for Nrf2 to produce both pro- and/or anti-tumourigenic effects in hepatocarcinogenesis . Astragaloside IV (AS-IV), the major component of Astragalus membranaceus , exerts anti-fibrogenic and carcinogenic actions. Lately, AS-IV administration could delay the occurrence of primary liver cancer by persistently inhibiting the fibrogenesis and regulating pSmad3C/3 L and Nrf2/HO-1 pathways synchronously. However, effect of AS-IV on hepatocarcinogenesis implicated in the bidirectional cross-talking of pSmad3C/3 L and Nrf2/HO-1 signalling, especially which one contributes palpably than the other still remains unclear. Purpose This study aims to settle the above questions by using in vivo (pSmad3C +/− and Nrf2 −/− mice) and in vitro (plasmid- or lentivirus- transfected HepG2 cells) models of HCC . Study design and methods The correlation of Nrf2 to pSmad3C/pSmad3L in HepG2 cells was analysed by Co-immunoprecipitation and dual-luciferase reporter assay. Pathological changes of Nrf2, pSmad3C, and pSmad3L in human HCC patients, pSmad3C +/- mice, and Nrf2 −/- mice were gauged by immunohistochemical, haematoxylin and eosin staining, Masson, and immunofluorescence assays. Finally, western blot and qPCR were used to verify the bidirectional cross-talking of pSmad3C/3L and Nrf2/HO-1 signalling protein and mRNA in vivo and in vitro models of HCC. Results Histopathological manifestations and biochemical indicators revealed that pSmad3C +/- could abate the ameliorative effects of AS-IV on fibrogenic/carcinogenic mice with Nrf2/HO-1 deactivation and pSmad3C/p21 transform to pSmad3L/PAI-1//c-Myc. As expected, cell experiments confirmed that upregulating pSmad3C boosts the inhibitory activity of AS-IV on phenotypes (cell proliferation, migration and invasion), followed by a shift of pSmad3L to pSmad3C and activation of Nrf2/HO-1. Synchronously, experiments in Nrf2 −/- mice and lentivirus-carried Nrf2shRNA cell echoed the results of pSmad3C knockdown. Complementarily, Nrf2 overexpression resulted in the opposite result. Furthermore, Nrf2/HO-1 contributes to AS-IV's anti-HCC effect palpably compared with pSmad3C/3L. Conclusion These studies highlight that harnessing the bidirectional crosstalk pSmad3C/3 L and Nrf2/HO-1, especially Nrf2/HO-1 signalling, acts more effectively in AS-IV's anti-hepatocarcinogenesis, which may provide an important theoretical foundation for the use of AS-IV against HCC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOLIA HISTOCHEMICA ET CYTOBIOLOGICA
·
2023
·Vol. 61
·期 2
·109-122
·
IF 1.5
Jiahui Han Di Jia Hao Yao Ting Lv Xi Xu Xin Ge
Introduction. Hemorrhagic shock (HS) is an important cause of high mortality in traumatized patients. Cryptotanshinone (CTS) is a bioactive compound extracted from Salvia miltiorrhiza Bunge (Danshen). The current study aimed to explore the effect and underlying mechanism of CTS on the liver injury induced by HS. Material and methods. Male Sprague-Dawley rats were used to establish the HS model by hemorrhaging and monitoring mean arterial pressure (MAP). CTS was intravenously administered at concentration of 3.5 mg/kg, 7 mg/kg, or 14 mg/kg 30 minutes before resuscitation. Twenty-four hours after resuscitation, the liver tissue and serum samples were collected for the following examinations. Hematoxylin and eosin (H&E) staining was used to evaluate hepatic morphology changes. The myeloperoxidase (MPO) activity in liver tissue and the serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were examined to reveal the extent of liver injury. The protein expression of Bax and Bcl-2 in liver tissue was detected by western blot. The TUNEL assay determined the apoptosis of hepatocytes. Oxidative stress of liver tissue was assessed by the examination of reactive oxygen species (ROS) generation. The content of malondialdehyde (MDA), glutathione (GSH), and adenosine triphosphate (ATP), the activity of superoxide dismutase (SOD) and oxidative chain complexes (complex I, II, III, IV), as well as cytochrome c expression in cytoplasm and mitochondria, were also used to determine the extent of oxidative injury in the liver. Immunofluorescence (IF) was employed to estimate nuclear factor E2-related factor 2 (Nrf2) expression. The mRNA and protein levels of heme oxygenase 1 (HO-1), NAD(P)H: quinone oxidoreductases 1 (NQO1), cyclooxygenase-2 (COX-2), and nitric oxide synthase (iNOS) were assessed by real-time qPCR, western blot to investigate the mechanism of CTS regulating HS-induced liver injury. Results. H&E staining and a histological score of rat liver suggested that HS induced liver injury. The activity of ALT, AST, and MPO was significantly increased by HS treatment. After CTS administration the ALT, AST, and MPO activities were suppressed, which indicates the liver injury was alleviated by CTS. The HS-induced upregulation of the TUNEL-positive cell rate was suppressed by various doses of CTS. HS-induced ROS production was decreased and the protein expression of Bax and Bcl-2 in the HS-induced rat liver was reversed by CTS administration. In the liver of HS-induced rats, the upregulation of MDA content and the downregulation of GSH content and SOD activity were suppressed by CTS. Additionally, CTS increases ATP content and mitochondrial oxidative complexes activities and suppressed the release of cytochrome c from mitochondria to the cytoplasm. Moreover, IF and western blot demonstrated that the activation of Nrf2 blocked by HS was recovered by different doses of CTS in liver tissue. The expression of downstream enzymes of the Nrf2 pathway, including HO-1, NQO1, COX-2, and iNOS, was reversed by CTS in the HS rat model. Conclusions. The current study for the first time revealed the protective effect of CTS in HS-induced liver injury. CTS effectively recovered hepatocyte apoptosis, oxidative stress, and mitochondria damage induced by HS in the rat liver partly via regulating the Nrf2 signaling pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2022
·
IF 5.895
Jiaxin Li,Hengju Ge,Yang Xu,Jiahong Xie,Fujie Yan,Wei Chen
Geniposide (GEN), a main compound extracted from Gardenia jasminoides fruit, has various biological activities including anti-inflammation, cellular damage alleviation, neuroprotection, and others. However, the effect of GEN on oxidative stress in hepatic cells is yet to be investigated. Our study uncovered that GEN eliminated excess intracellular free radicals by activating the Nrf2/ARE signaling pathway in H2O2-treated hepatocytes, while the protective effect was blocked by ML385 (an inhibitor of Nrf2). Moreover, H2O2 led to upregulation of miR-27b-3p in L02 cells, which was restrained by GEN. Overexpression of miR-27b-3p greatly weakened the antioxidant capacity of GEN in hepatocytes via directly targeting the Nrf2 gene. Our findings indicated that GEN treatment recovered H2O2-induced oxidative stress via targeting miR-27b-3p and thereby enhanced the antioxidant capacity by stimulating nuclear translocation and accumulation of Nrf2. These findings suggest that inhibition of miR-27b-3p to activate the Nrf2/ARE pathway by GEN is a potential alternative for hepatic oxidative damage alleviation.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Ya Zhang,Qifang Wu,Jian Liu,Zhongshan Zhang,Xiaojing Ma,Yaoyue Zhang,Jiawen Zhu,Ronald W. Thring,Mingjiang Wu,Yitian Gao,Haibin Tong
Insulin resistance is a characteristic feature of type 2 diabetes. Sulforaphane (SFN) is a natural antioxidant extracted from the cruciferous vegetables. Recent study reported that SFN exhibits excellent anti-diabetic effects, however, the underlying mechanism is still unclear. This study aimed to investigate the therapeutic effects of SFN on a high-fat diet (HFD)-induced insulin resistance and potential mechanism. SFN was found to effectively reduce body weight, fasting blood glucose and hyperlipidemia, and improve liver function in HFD-fed mice. Furthermore, SFN effectively increased glucose uptake and improved insulin signaling in palmitic acid (PA)-induced HepG2 cells. SFN also led to increased expression of antioxidant genes downstream of Nrf2 and decreased accumulation of lipid peroxides MDA and 4-HNE, both in vivo and in vitro. Further studies revealed that SFN significantly reduced glutathione peroxidase 4 (GPx4) inactivation-mediated oxidative stress by activating the AMPK and Nrf2 signaling pathways. In PA-induced HepG2 cells and flies , the alleviation of insulin resistance by SFN was diminished by GPx4 inhibitor. Taken together, SFN ameliorated HFD-induced insulin resistance by activating the AMPK-Nrf2-GPx4 pathway, providing new insights into SFN as a therapeutic compound for the alleviation of insulin resistance.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA HISTOCHEMICA
·
2020
·
IF 2.107
Xiaolong Sun,Xu Wang,Zhenyu Zhao,Jing Chen,Cheng Li,Gang Zhao
As one of the most frequent diabetic complications , diabetic foot ulcer (DFU) can cause limb ischemia or even amputation. Paeoniflorin (PF) has been reported to possess many kinds of biological functions, such as antioxidant and anti-inflammatory effects. However, the role of PF in DFU remains unknown. In this study, streptozotocin (STZ)-induced diabetic rat models and high glucose (HG)-treated Human immortalized keratinocytes (HaCaT) cells were established. Histological analysis, immunohistochemistry , Electrophoretic mobility shift assay , MTT assay , TUNEL assay , oxidative stress analysis, ELISA assay and western blot were used to investigate the role and underlying mechanisms of PF on healing in DFU. Our results showed that the STZ-induced diabetic rats had delayed wound healing compared with the normal rats, exhibited by intense oxidative DNA damage, low vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF-β1) expression, as well as increased apoptosis . PF treatment activated the expression of nuclear factor-E2-related factor 2 (Nrf2) and improved wound healing in DFU rats. Our in vitro experiments confirmed that PF accelerated wound healing through the Nrf2 pathway under hyperglycemic conditions, with alleviated oxidative stress, increased cell proliferation and migration, decreased apoptosis, and increased the expression of VEGF and TGF-β1. Our study demonstrates the therapeutic benefits of PF in diabetic wound healing, which provides a reference for future clinical trials using PF in DFU treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2020
·Vol. 473
·期 1
·217-228
·
IF 2.795
Wu Xinghan,Liu Chuanliang,Li Zihaoran,Gai Chengcheng,Ding Dejun,Chen Weijuan,Hao Fengyun,Li Wentong
Ferroptosis is a newly discovered form of regulated cell death and characterized by an iron-dependent accumulation of lethal lipid reactive oxygen species (ROS), ferroptosis may exhibit a novel spectrum of clinical activity for cancer therapy. However, the significance of ferroptosis in the context of carcinoma biology is still emerging. Glycogen synthase kinase-3β (GSK-3β) has been found to be a fundamental element in weaking antioxidant cell defense by adjusting the nuclear factor erythroid 2-related factor 2 (Nrf2). In our study, decreased expression of GSK-3β was observed in the cancer tissues of breast cancer patients, results of immunohistochemistry indicated that Nrf2 was highly expressed in low-GSK-3β-expressed breast cancer tissues. The contributions of aberrant expression of GSK-3β and Nrf2 to the erastin-induced ferroptosis in breast cancer were further assessed, silence of GSK-3β blocked erastin-induced ferroptosis with less production of ROS and malondialdehyde (MDA) via upregulation of GPX4 and downregulation of arachidonate 15-lipoxygenase (Alox15), overexpression of GSK-3β enhanced erastin-triggered ferroptosis with elevated ROS and MDA. Enhanced erastin-induced ferroptosis by overexpression of GSK-3β was blocked by activating Nrf2. We further confirmed that overexpression of GSK-3β strengthened erastin-induced tumor growth inhibition in breast cancer xenograft models in vivo. In summary, our findings conclude that modulation the balance between GSK-3β/Nrf2 is a promising therapeutic approach and probably will be important targets to enhance the effect of erastin-induced ferroptosis in breast cancer.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2019
·
IF 3.775
Maiquan Li,Weisu Huang,Fan Jie,Mengmeng Wang,Yongheng Zhong,Qi Chen,Baiyi Lu
Various phytochemicals have been reported to protect against oxidative stress. However, the mechanism underlying has not been systematically evaluated, which limited their application in disease treatment. Nuclear factor erythroid 2−related factor 2 (Nrf2), a central transcription factor in oxidative stress response related to numerous diseases, is activated after dissociating from the cytoskeleton−anchored Kelch−like ECH−associated protein 1 (Keap1). The Keap1–Nrf2 protein–protein interaction has become an important drug target. This study was designed to clarify whether antioxidantive phytochemicals inhibit the Keap1–Nrf2 protein–protein interaction and activate the Nrf2-ARE signaling pathway efficiently. Molecular docking and 3D−QSAR were applied to evaluate the interaction effects between 178 antioxidant phytochemicals and the Nrf2 binding site in Keap1. The Nrf2 activation effect was tested on a H 2 O 2 −induced oxidative−injured cell model. Results showed that the 178 phytochemicals could be divided into high−, medium−, and low−total−score groups depending on their binding affinity with Keap1, and the high−total−score group consisted of 24 compounds with abundant oxygen or glycosides. Meanwhile, these compounds could bind with key amino acids in the structure of the Keap1−Nrf2 interface. Compounds from high−total−score group show effective activation effects on Nrf2. In conclusion, phytochemicals showed high binding affinity with Keap1 are promising new Nrf2 activators.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2025
·
IF 9.8
Zaheer Abbas,Jing Zhang,Yucui Tong,Baseer Ahmad,Junyong Wang,Haosen Zhang,Zhenzhen Li,Xubiao Wei,Rijun Zhang,Dayong Si
The objective of this study was to isolate and characterize antioxidant peptides from mulberry leaves fermented with Bacillus subtilis H4 and Bacillus amyloliquefaciens LFB112. The results indicated that fraction F4 (<1 kDa) exhibited superior DPPH activity compared to the F1 (>10 kDa), F2 (3–10 kDa), and F3 (1–3 kDa) fractions, and cytoprotective effect against lipopolysaccharides (LPS)-induced oxidative stress in RAW264.7 cells. Three novel peptides, FRFDP, RFGG, and GPPLAFGGGP, were identified in the F4 fraction of the mulberry leaf ferment, and docking results showed that these peptides could form stable carbon (covalent) and hydrogen bonds to the active sites of Keap1, thus regulating the Keap1-Nrf2 pathway by blocking the Nrf2 binding sites on Keap1. These peptides significantly upregulated the mRNA expression of Nrf2 , HO-1 , and NQO1 , providing indirect evidence of their potential to enhance cellular antioxidant defense via the possible activation of Keap1-Nrf2 pathway. Furthermore, these peptides showed good DPPH and ABTS scavenging activities, indicating their potential as antioxidant peptides. This study offers valuable insights into the integration of these novel peptides in developing mulberry leaf ferment as a functional food and their potential use as a feed additive.
研究领域:
食品科学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Mengdi Zhang,Jindong Gao,Md. F. Kulyar,Wanhe Luo,Guodong Zhang,Xiaoqi Yang,Tianguang Zhang,Haihang Gao,Yuxuan Peng,Jiabin Zhang,Muhammad Altaf,Samah Attia Algharib,Donghai Zhou,Jianzhong He
Acute renal failure is a common clinical disease in canines, affecting antioxidant levels and decreasing the body's resistance. This study aims to explore the therapeutic mechanism of Nano-selenium in acute renal failure. The histopathological and imaging changes of kidney tissue were observed with the gene and protein expression levels of Keap1, Nrf2, HO-1, and NQO1 in the kidney. According to our findings, adding nano-selenium can effectively reduce the concentration of CRE and BUN in blood and kidney tissues. It increased the activity of GSH-PX and SOD by an effective reduction of MDA. Through pathological and imaging observations, it was found that adding nano-selenium could improve the kidney tissue structure of acute renal failure. The results of the RT-qPCR experiment showed that after the addition of nano-selenium, the mRNA expression of the Keap1 gene decreased significantly. In contrast, the mRNA expression of the Nrf2, HO-1, and NQO1 genes increased significantly. The experimental results were further verified by western blot and immunohistochemical analysis. Hence, the nano-selenium intervention improved kidney function and increased antioxidant levels in canines suffering from acute renal failure with the involvement of the Keap1-Nrf2/ARE signaling pathway.
研究领域:
兽医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Mengdi Cui,Yi An,Jingling Zhao,Miaoxin Hui,Zhili Xiong,Bing Guan,Yinfeng Shen,Yinshui Zou,Chengyin Li,Rui Wang
Background: Acute kidney injury (AKI) is a leading complication of sepsis, necessitating the exploration of novel treatment modalities. The traditional Chinese medicine Dahuang Gancao Decoction (DHGC) has potential in the treatment of sepsis-associated acute kidney injury (SA-AKI). However, its specific mechanisms require further investigation. Purpose: This study aimed to validate the antiferroptotic effects of DHGC in the treatment of SA-AKI in vivo and in vitro . Methods: C57BL/6 mice and C57BL/6-background sirtuin-3 (SIRT3) -/- mice were induced with Reagents Lipopolysaccharide (LPS), while normal and si-SIRT3 human proximal tubular epithelial (HK-2) cells were induced with erastin to establish a ferroptosis phenotype, followed by DHGC treatment. First, the DHGC components were identified via liquid chromatography-tandem mass spectrometry (LC‒MS/MS), and the potential active components were further screened through comparison with the high-performance liquid chromatography (HPLC) reference standards. Ferroptosis levels and the protective mechanisms of DHGC in vivo and in vitro were evaluated using biochemical assays, transmission electron microscopy, immunohistochemistry, immunofluorescence, and Cell Counting Kit-8 (CCK-8) assays. Key pathways were identified by RNA-seq and validated via enzyme-linked immunosorbent assay (ELISA) and western blotting. Finally, the potential active components were subjected to molecular docking with SIRT3 to select candidate monomers for subsequent in vitro functional validation. Results: LPS was used to induce SA-AKI in mice, and erastin was used to induce ferroptosis in HK-2 cells. DHGC can improve renal function, increase cell viability, and reverse abnormal changes in key ferroptosis indicators. Mechanistically, the expression levels of SIRT3/nuclear factor erythroid-2 related factor 2 (NRF2) pathway-associated proteins were downregulated, and NRF2 nuclear translocation was restricted after modeling; in contrast, DHGC upregulated the expression of SIRT3/NRF2 pathway-related proteins, promoted NRF2 nuclear translocation, and activated downstream glutathione peroxidase 4 (GPX4) expression. Importantly, DHGC failed to improve the above indicators in SIRT3-deficient models. Potential active components of DHGC were screened via HPLC reference standard comparison, and subsequent molecular docking with SIRT3 identified candidate monomers. These monomers exerted ferroptosis-inhibiting effects consistent with those of the parent compound DHGC. Conclusions: The present study offers the first demonstration that DHGC retards SA-AKI progression through stimulating SIRT3-driven deacetylation of NRF2, promoting NRF2 nuclear translocation, and inhibiting ferroptosis. These findings suggest that DHGC is a potential therapeutic candidate for SA-AKI, warranting further clinical investigation.
研究领域:
中医中药
·
肾脏病学
·
分子生物学
·
药理学
·
氧化应激
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Toxicology
·
2025
·
IF 4.6
Liu-Dan Liang,Xiao-Yue Zhao,Li Li,Sheng Liang,Jin-Min Zhang,Jian-Nan Lv,Feng-Lian Deng,Chun-Lei Lu,Qian Li,Qi-Wen Huang,Mei-Jin Huang,Hui-Xin Peng
Aluminum is toxic to both humans and animals. Exposure to AlCl 3 can lead to kidney function damage, yet the specific underlying mechanism remains elusive. This study aimed to investigate whether ferroptosis is involved in the renal toxicity induced by AlCl 3 exposure in mice and to elucidate its potential molecular mechanism. Forty-eight C57BL mice were randomly assigned to six groups, with eight mice in each group: a control group, low -, medium -, and high - dose aluminum exposure groups, a ferroptosis inhibitor group, and a ferroptosis inhibitor + high - dose aluminum exposure group. Mice in the aluminum exposure groups received intraperitoneal injections of different doses of AlCl 3 solution for 4 weeks (5 times per week), while the ferroptosis inhibitor group was intraperitoneally injected with Fer - 1 for 4 weeks (2 times per week). After the experimental period, multiple indicators were examined. The results demonstrated that AlCl 3 exposure impaired the renal function and structure of mice. It also led to an increase in lipid peroxidation products, Fe 2+ , and Al content in renal tissue. Moreover, the expression levels of genes and proteins such as GPX4 and Nrf2 were decreased, whereas the expression levels of the ACSL4 gene and protein were increased.However, after pretreatment with Fer - 1, the aforementioned indicators were ameliorated. Specifically, the expression of ACSL4 decreased, and the expression of GPX4 and other related factors increased.In conclusion, this study suggests that AlCl 3 exposure may trigger ferroptosis in renal tissue cells by inhibiting the NRF2 pathway, thereby causing kidney function damage in mice. These findings provide a novel perspective on the mechanism of AlCl 3 - induced renal toxicity.
研究领域:
毒理学
·
分子生物学
·
环境健康
✓ 已验证
产品关联
DOI
PubMed
高影响因子
REDOX REPORT
·
2021
·
IF 4.412
Nabila Jahan,Apu Chowdhury,Ting Li,Ke Xu,Fen Wei,Sicen Wang
Background Progression of Benign Prostate hyperplasia (BPH) is vulnerable to oxidative stress (OS) and prostatic enlargement among the aging males through apoptosis deregulation. Our present study aimed to investigate the effect of neferine (NF) in the regulation of oxidative stress and apoptosis in human BPH-1 cells.Methods BPH epithelial cell line BPH-1 was treated with NF for 24 and 48 h. To measure oxidative stress (OS) we investigated MDA, SOD, and GST expression along with Nrf2 and its downstream gene and protein expression. Cell proliferation and apoptosis regulation was assayed with respective methods.Results Investigation revealed NF remarkably activate Nrf2 and its downstream proteins HO-1 and NQO1 at 48 h more substantially. Nrf2/Keap1 relative gene and protein expression indicated that NF might trigger Nrf2 upregulation by decreasing Keap1 expression. Both NF concentrations (3 µM and 9 µM) were able to deplete ROS and lipid peroxidation, concurrently, up-regulated SOD and GST. NF reduced cell proliferation significantly along with the regulation of apoptotic proteins Bax, Bcl2, Cyt-C, Caspase 9, and Caspase 3 at the same time (48 h).Conclusion This study is the first to manifest that NF may potentially regulate BPH by counterbalancing between OS and apoptosis through the activation of Nrf2-ARE pathway.
研究领域:
药理学
·
泌尿学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）