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
研究领域:
药理学
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肾病学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 2
·e70358
·
IF 4.2
Jiangfang Lian,Hui Lin,Zuoquan Zhong,Yongfei Song,Xian Shao,Jiedong Zhou,Lili Xu,Zhenzhu Sun,Yongyi Yang,Jufang Chi,Ping Wang,Liping Meng
The clinical application of doxorubicin (DOX) is limited due to its cardiotoxicity, which is primarily attributed to its interaction with iron in mitochondria, leading to lipid peroxidation and myocardial ferroptosis. This study aimed to investigate the role of the gut microbiota‐derived metabolite, indole‐3‐lactic acid (ILA), in mitigating DOX‐induced cardiotoxicity (DIC). Cardiac function, pathological changes, and myocardial ferroptosis were assessed in vivo. The cardioprotective effects and mechanisms of ILA were explored using multi‐omics approaches, including single‐nucleus RNA sequencing (snRNA‐seq) and bulk RNA‐seq, and were further validated in Nrf2 knockout mice. The findings revealed that DOX treatment disrupted gut microbiota, significantly reducing the levels of the tryptophan metabolite ILA. In DIC models, ILA supplementation markedly improved cardiac function, reduced collagen deposition, and mitigated cardiac atrophy. The bulk and snRNA‐seq analyses indicated that myocardial ferroptosis played a crucial role in the cardioprotective effects of ILA. Experimental data demonstrated that ILA decreased DOX‐induced ferroptosis in both DIC mice and DOX‐treated H9C2 cells, evidenced by restoration of GPX4 and SLC7A11 levels and reduction of ACSL4. Mechanistically, ILA functions as a ligand for the aryl hydrocarbon receptor (AhR), leading to the upregulation of Nrf2 expression. The protective effects of ILA against ferroptosis were abolished by silencing AhR. Moreover, the beneficial effects of ILA on DIC were eliminated in Nrf2‐deficient mice. In conclusion, ILA exerts therapeutic effects against DIC by inhibiting ferroptosis through activation of the AhR/Nrf2 signalling pathway. Identifying the cardioprotective role of the microbial metabolite ILA could offer viable therapeutic strategies for DIC.
研究领域:
药理学
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分子生物学
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心脏病学
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微生物组研究
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DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL HYPERTENSION
·
2025
·
IF 3.5
Hao Wang,Ke Zhou,Xiaoling Chen,Yao Tong,Qiuyan Jiang,Qiang She,Jun Xiao
Myocardial infarction (MI) is a leading cause of morbidity and mortality globally, primarily due to oxidative stress-induced cardiomyocyte apoptosis and adverse cardiac remodeling. OL-FS13, a neuroprotective peptide derived from Odorrana livida, has previously shown anti-apoptotic effects in cerebral ischemia models. However, its role in myocardial protection remains unclear. In this study, we investigated the cardioprotective effects of OL-FS13 in both in vitro and in vivo models of MI. Hydrogen peroxide (H₂O₂) was used to induce oxidative stress in primary neonatal rat cardiomyocytes, while permanent ligation of the left anterior descending (LAD) coronary artery was employed to establish a murine MI model. OL-FS13 treatment significantly attenuated cardiomyocyte apoptosis, reduced ROS accumulation, improved left ventricular function, and decreased infarct size. Mechanistically, OL-FS13 activated the Nrf2/HO-1 signaling pathway, restoring antioxidant protein levels and suppressing oxidative stress-induced apoptosis. Pharmacological inhibition of Nrf2 with ML385 abrogated the antioxidant and anti-apoptotic effects of OL-FS13 both in vitro and in vivo, confirming the central role of this pathway. These findings demonstrate that OL-FS13 exerts potent cardioprotective effects via Nrf2/HO-1 pathway activation and ROS suppression, suggesting its potential as a novel therapeutic agent for the treatment of myocardial infarction.
研究领域:
心血管病学
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分子药理学
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氧化应激生物学
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心肌缺血再灌注损伤
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信号转导
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DOI
PubMed
高影响因子
LIPIDS
·
2022
·Vol. 57
·期 3
·153-162
·
IF 1.646
Danping Wang,Jinglong Chen,Huangbing Sun,Wenjing Chen,Xiaojing Yang
Oxidative stress is an important factor in the occurrence and development of liver disease. Medium-chain fatty acids (MCFAs) have potential antioxidant function, whereas the exact underlying mechanism of MCFA in oxidative injury of hepatocytes remains unclear. In our present study, three different MCFAs, 8-carbon octanoic acid (OA), 10-carbon capric acid (CA), and 12-carbon lauric acid (LA), have been performed to observe their protective action for hepatocyte under the H 2 O 2 challenge. The result showed that MCFA treatment significantly increased the cell viability, T-AOC, and expression of antioxidant-related genes in AML12 cells under oxidative stress condition, and reduced reactive oxygen species (ROS) production. Moreover, MCFA treatment significantly increased the protein expression of Nrf2 and the phosphorylation level of ERK1/2; LA treatment significantly promoted the Nrf2 nuclear translocation. With a further test, the rescue ability of MCFA was blocked by treating with the ERK inhibitor U0126. Overall, our data suggested that MCFA treatment has positive impact on protecting AML12 cells against oxidative stress through ERK1/2/Nrf2 pathway.
研究领域:
细胞生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Foods
·
2021
·Vol. 10
·期 11
·2765
·
IF 4.35
Fanghua Guo,Rong Tsao,Chuyao Li,Xiaoya Wang,Hua Zhang,Li Jiang,Yong Sun,Hua Xiong
As a processing by-product, green pea hull (GPH) was found to be rich in phenolic components in our previous studies. In this study, UHPLC-LTQ-OrbiTrap-MS (Ultra performance liquid chromatography-linear ion trap orbitrap tandem mass spectrometry) technique was used to quantify polyphenols, and DSS (sodium dextran sulfate)-induced colitis mouse model was established to explore the effect of GPH extracts on colitis. The results showed that quercetin and its derivatives, kaempferol trihexanside and catechin and its derivatives were the main phenolic substances in the extract, reaching 2836.57, 1482.00 and 1339.91 µg quercetin/g GPH extract, respectively; GPH extracts can improved inflammatory status, repaired colonic function, regulated inflammatory factors, and restored oxidative balance in mice. Further, GPH extracts can activate Keap1-Nrf2-ARE signaling pathway, regulate downstream antioxidant protease and gut microbiota by increasing F/B value and promoting the growth ofLactobacillaceaeandLachnospiraceae, and improve the level of SCFAs (short-chain fatty acids) to relieve DSS-induced colitis in mice. Therefore, GPH may be a promising dietary resource for the treatment of ulcerative colitis.Keywords:polyphenols;colitis;UHPLC-LTQ-OrbiTrap-MS;GPH extracts;Keap1-Nrf2;gut microbiota
研究领域:
药理学
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营养学
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免疫学
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微生物学
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DOI
PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·44909
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IF 3.9
Xia Xiuyuan,Zhang Zhenghan,Wang Yizhen,Chen Chen,Wang Yaqi,Luo Yanting,Gao Ying,Hong Weiyong,Ren Chuanpeng
Quercetin and carnosine, natural antioxidants with anti-aging and photoprotective potential, face therapeutic limitations due to poor skin permeability. We engineered EV-QuerCar, a liposomal-based nanoparticles (LPNs) system co-encapsulating both compounds, to enhance transdermal delivery and evaluate its structural and functional efficacy. EV-QuerCar was prepared biomimetically using thermophilic bacterial lipids via ultracentrifugation, thin-film hydration, and high-pressure homogenization. Physicochemical properties, transdermal penetration, cellular uptake, and cytotoxicity were tested in vitro. Molecular docking and qPCR assessed pathway targeting. EV-QuerCar exhibited uniform size (94.70 ± 0.71 nm), high encapsulation efficiency (90.07%), sustained release, and 3.21-fold enhanced transdermal absorption compared to free compounds. Cellular uptake in fibroblasts increased time-dependently (up to 5.48-fold at 4 h). Molecular docking and qPCR confirmed interactions with NRF2 and HES1 targets, significantly upregulating their mRNA levels (2.29- and 3.35-fold, respectively) in UV-exposed human fibroblasts. EV-QuerCar improves skin permeability and antioxidant efficacy, highlighting its cosmeceutical promise.
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DOI
PubMed
高影响因子
Frontiers of Chemical Science and Engineering
·
2023
·Vol. 17
·期 7
·976-989
·
IF 4.5
Yan Bowen,Lu Geng,Wang Rong,Kang Shixiong,Huang Caoxing,Wu Hao,Yong Qiang
Lignin exhibits antioxidative and various other biological properties. However, its neuroprotection capability has rarely been studied. In this study, three types of lignin with different structures were prepared from grape seeds by using different isolation techniques. The antioxidative and neuroprotective effects of the lignin fractions were evaluated with the apoptosis model of murine neuroectodermal (NE-4C) neural stem cells stimulated with bisphenol AF. The results demonstrated that the half maximal inhibitory concentration for scavenging 2,2-diphenyl-1-picrylhydrazyl with water-soluble lignin (L-W, 58.19 µg·mL −1 ) was lower than those of lignin in the autohydrolyzed residue of grape seeds (84.27 µg·mL −1 ) and original lignin in grape seeds (99.44 µg·mL −1 ). BPAF exposure had negative effects on the reactive oxygen species, malondialdehyde content, and superoxide dismutase and glutathione peroxidase activities in NE-4C cells, which can be reversed by using the prepared lignin to reduce oxidative stress. An immunofluorescence assay demonstrated that grape seed lignin induced protective effects on BPAF-injured NE-4C cells via the nuclear factor erythroid 2-related Factor 2 pathway. In addition, correlational analyses showed that lignin (L-W) with lower molecular weights and noncondensed phenolic hydroxyl group content and higher contents of COOH groups effectively prevented cell apoptosis, scavenged reactive oxygen species, and ensured protection from nerve injury. This study demonstrated that grape seed lignin can be used as a neuroprotective agent and serves as a demonstration of active lignin production from grape seed waste.
研究领域:
神经科学
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植物化学
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毒理学
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DOI
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Hongli Zhang,Ziyu Lan,Hui Wang,Haojie Yao,Ruiyan Zheng,Zijing Chen,Xiang Luo,Peng Wu,Yuanyuan Cheng,Zhongqiu Liu
Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, characterized by a complex clinical syndrome. Pubescenoside A (PBA), a phenylpropanoid derived from Ilex pubescens , exhibits significant anti-inflammatory effects; however, the impact and underlying mechanism of PBA on UC remain unclear. Therefore, the aim of this study is to investigate the potential mechanism of PBA against UC using in vivo and in vitro experiments. Pubescenoside A effectively enhances weight loss in UC mice, decreases the disease activity index (DAI). Regarding colonic morphology, PBA ameliorates colorectal stenosis and shortening, reduces intestinal mucosal ulceration, diminishes inflammatory cell infiltration, and tends to normalize glandular arrangement. Furthermore, PBA effectively suppresses pro-inflammatory factors. Mechanism studies have shown that PBA can directly target Kelch Like ECH Associated Protein 1 (Keap1), subsequently promoting the interaction between Keap1 and DEAD-box RNA helicase 5 (DDX5) to enhance ubiquitination and degradation of DDX5, leading to a down-regulation of C-C motif chemokine ligand 3 (CCL3) expression. Additionally, PBA disrupts the Keap1/Nrf2 complex, facilitating Nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear entry to inhibit the Nuclear factor-κB (NF-κB) pathway. Importantly, in Gpt-lgr5-creERT2 Keap1 flox/flox mice, the anti-UC effect of PBA was attenuated. Our results indicated that PBA mitigated UC by targeting Keap1, thereby promoting the ubiquitination degradation of DDX5 and facilitating the nuclear entry of Nrf2.
研究领域:
药理学
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分子生物学
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免疫学
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胃肠病学
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生物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Mengling Zhong,Mingmei Feng,Xinlin Chen,Yuxin Zhang,Yupeng Wang,Peizhi Yuan,Tianyao Zhang,Zhipeng Han,Chenglun Tang,Qi Zhang,Yang Sun
Immunosuppression causing the host more vulnerable to pathogen invasion, increases the risk of malignant tumors and inflammatory diseases. Cordycepin possesses diverse pharmacological activities, including anti-inflammatory, antioxidant, and antitumor effects. However, the immunomodulatory mechanisms of cordycepin remain poorly understood. This study aimed to explore the immunoregulatory effect of cordycepin and elucidate its underlying mechanisms. In our study, cordycepin restored body weight, organ indices and ameliorated splenic damage in cyclophosphamide (CTX)-induced immunosuppressed mice. Cordycepin enhanced the proliferation of T and B lymphocytes stimulated by ConA and LPS. Cordycepin normalized the counts of white blood cells (WBC), lymphocytes (LYM), neutrophils (NEU) and eosinophils (EOS), and increased the levels of immunoglobulins (immunoglobulin A (IgA), IgM, IgG). Cordycepin also increased the production of pro-inflammatory cytokines IL-2 and IFN-γ, but decreased the level of inhibitory cytokines IL-10. Additionally, cordycepin reduced serum level of malondialdehyde (MDA), enhanced content of glutathione (GSH) and the enzymatic activities of superoxide dismutase (SOD) and catalase (CAT). Moreover, metabolomic analysis of spleen and serum revealed that cordycepin counteracted the metabolic disturbance induced by CTX, particularly regulating pyruvate metabolism pathway. Network pharmacology approaches suggested that cordycepin modulated metabolic and immune pathways by targeting EGFR. Furthermore, cordycepin reduced the protein level of phosphorylated EGFR and upregulated the protein expression of Nrf2, NQO1 and HO-1 in the spleens of immunosuppression mice. In conclusion, this study demonstrated that cordycepin ameliorated CTX-induced immunosuppression of mice by reversing metabolic dysfunction and activating Nrf2 pathway through regulating EGFR, indicating its potential as a therapeutic agent for immunosuppression.
研究领域:
药理学
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免疫学
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生物化学
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代谢生物学
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肿瘤学
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天然产物化学
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 2
·268
·
IF 5.5
Yunhua Teng,Jiaojiao Ma,Junxia Zhang,Bohan Liang,Aijie Zhang,Yanjie Li,Shiqi Dong,Huirong Fan
Background:It has been documented that radiation can influence the pharmacokinetics of chemotherapy drugs, yet the underlying mechanisms remain poorly understood. In clinical practice, a considerable number of cancer patients undergo radiotherapy, and those with comorbid hypertension required antihypertensive drugs, including valsartan, an angiotensin II receptor blocker. However, there is no research investigating whether radiotherapy poses a risk of altering the pharmacokinetics.Objective:The objective of this study is to investigate the impact of X-ray abdominal irradiation on the pharmacokinetics of valsartan and to preliminarily elucidate the underlying mechanism.Methods:The pharmacokinetics of valsartan after X-ray irradiation was investigated in rats and in vitro by detecting the concentration of valsartan in biological samples by LC-MS/MS. The oxidative stress in the intestine and the mRNA expression of partial transporters and Nrf2 in the liver and small intestine were detected by biochemical reagent kit or RT-qPCR.Results: In vivo studies showed that X-ray irradiation resulted in a significant decrease in the AUC and Cmaxof valsartan, and the cumulative fractional excretion of valsartan in bile and urine, although there was no significant change in fecal excretion. In vitro studies showed that the uptake of valsartan by both intestine and Caco-2 cells decreased after irradiation, and the cellular uptake could be restored by Mrp2 inhibitor MK571. The levels of GSH, SOD, and CAT in the intestine decreased after irradiation. The mRNA expressions of Mrp2 and P-gp in the intestine or Caco-2 cells were significantly upregulated after irradiation while there was a downregulation of Mrp2 and oatp1b2 in liver. Nrf2 and HO-1 in the intestine were also significantly upregulated, which clarified the involvement of Mrp2 and the possible molecular mechanism.Conclusions:Abdominal X-ray irradiation can cause oxidative stress and upregulate intestinal Mrp2, which may be related to oxidative stress and upregulation of Nrf2, reducing intestinal absorption of valsartan and leading to a significant decrease in the blood concentration of valsartan.
研究领域:
药理学
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分子生物学
·
放射医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF DAIRY SCIENCE
·
2025
·
IF 4.4
Shuang Guan,Yuanmeng Wang,Ranran Zhang,Xinyu Yao,Shujing Lu,Xuming Deng,Jing Lu
Alcohol, one of the most widely popular and consumed beverages worldwide, often leads to acute alcoholic liver injury (AALI) when excessively consumed within a short timeframe. It can further induce alcoholic hepatitis, posing a serious risk to human health and public health safety. Pyroptosis, a typical mode of programmed cell death, is closely associated with the body's inflammatory response and plays a central role in AALI. However, the role of yogurt in acute alcohol-induced pyroptosis and inflammation is unclear. In this study, we found that yogurt and its metabolite d -lactate effectively mitigate alcohol-induced liver damage in mice, reducing hepatocyte pyroptosis and attenuating the inflammatory response. For the specific mechanism, further studies have shown that yogurt may inhibit autophagy through its substance d -lactate, leading to the accumulation of P62 protein in cells. This accumulation subsequently triggers the activation of Nrf2 through nonclassical pathways. Nrf2 translocates to the nucleus to play its antioxidant role, thereby reducing intracellular reactive oxygen species levels, inhibiting the activation of the alcohol-induced NLRP3 inflammasome, and ultimately alleviating pyroptosis and inflammation. Overall, this study reveals the potential protective effect of yogurt and its metabolite d -lactate in alleviating AALI, offering new insights and scientific basis for yogurt as a dietary strategy to improve AALI.
研究领域:
肝病学
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营养学
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分子生物学
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免疫学
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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
BIOFACTORS
·
2021
·Vol. 48
·期 1
·190-203
·
IF 6.113
Huijie Chen,Jianqing Chen,Xu Shi,Lu Li,Shiwen Xu
Bisphenol A (BPA) has caused serious pathologies in varying organs of humans and animals, especially reproductive organs. Naringenin (NRG) is a flavanone compound that has shown protective effects against several environmental chemicals through suppression of oxidative stress and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Herein, we described the discovery path of NRG inhibition on apoptosis in BPA exposed swine testis (ST) cells through targeting Kelch-like ech-associated protein (Keap1). We found that NRG could specifically bound to the active residues of DGR domain in Keap1, thereby activating Nrf2 signaling pathway, and then increasing the levels of SOD, GPx and CAT, and finally inhibiting oxidative stress and mitochondrial apoptosis induced by BPA in ST cells. Altogether, our results showed that NRG inhibits oxidative stress and mitochondrial apoptosis induced by BPA in ST cells by targeting Keap1/Nrf2 signaling pathway, indicating that NRG could serve as an antagonistic therapy against BPA.
研究领域:
毒理学
·
生殖生物学
·
药理学
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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）