CHEMICAL & PHARMACEUTICAL BULLETIN
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2022
·Vol. 70
·期 1
·66-73
·
IF 1.903
Li Han,Aimei Chen,Ling Liu,Fang Wang
Despite the precise mechanisms for renal ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) are poorly understood, nuclear factor erythroid 2 related factor 2 (Nrf2) and Toll-like receptor 4 (TLR4) pathways were considered as the important targets. Leonurine (LEO) is a special alkaloid extracted from Chinese motherwort (Leonurus japonicus Houtt), which has an anti-inflammatory effect and reduces oxidative stress. We conducted the study to explore the efficacy of LEO against I/R-induced AKI in rats and further investigated the underlying mechanisms. Ischemic renal injury was induced by temporary vascular clamping for 45 min. We have measured the levels of inflammation-related biomarkers and antioxidative stress markers. Next, Western blot analysis and Real-time PCR were performed to analyze whether the Nrf2 and TLR4/nuclear factor-kappaB (NF-κB) pathways were involved in this process. We found that LEO pretreatment remarkably decreased serum creatinine and blood urea nitrogen (BUN) in I/R rats and attenuated acute tubular damage. In addition, LEO markedly increased the expression of antioxidant proteins and decreased the levels of inflammatory factors. Further study revealed that LEO promoted Nrf2 into the nucleus, promoted the expression of heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO-1), and suppressed the TLR4/NF-κB signal pathway in kidney tissues of ischemic AKI rats. The study reveals that LEO has a protective effect to prevent ischemic AKI through activation of Nrf2 nuclear translocation resisting oxidative stress injury and inhibition of the TLR4/NF-κB pathway mediated inflammatory gene expression.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 9
·8265
·
IF 5.6
Jing Li,Jianchao Zhang,Yan Zhu,Lukman O. Afolabi,Liang Chen,Xuesong Feng
Triple-negative breast cancer (TNBC) has been clearly recognized as a heterogeneous tumor with the worst prognosis among the subtypes of breast cancer (BC). The advent and application of current small-molecule drugs for treating TNBC, as well as other novel inhibitors, among others, have made treatment options for TNBC more selective. However, there are still problems, such as poor patient tolerance, large administration doses, high dosing frequency, and toxic side effects, necessitating the development of more efficient and less toxic treatment strategies. High expression of Nrf2, a vital antioxidant transcription factor, often promotes tumor progression, and it is also one of the most effective targets in BC therapy. We found that in MDA-MB-231 cells and SUM159 cells, brusatol (BRU) combined with polydatin (PD) could significantly inhibit cell proliferation in vitro, significantly downregulate the expression of Nrf2 protein as well as the expression of downstream related target genesHeme Oxygenase-1 (HO-1)andNAD(P)H dehydrogenase, quinone 1 (NQO1), and promote reactive oxygen species (ROS) levels to further strengthen the anti-tumor effect. Furthermore, we discovered in our in vivo experiments that by reducing the drug dosage three times, we could significantly reduce tumor cell growth while avoiding toxic side effects, providing a treatment method with greater clinical application value for TNBC treatment.Keywords:breast cancer;brusatol;polydatin;Nrf2;HO-1;NQO1;ROS
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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
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Antioxidants
·
2021
·Vol. 10
·期 11
·1697
·
IF 6.313
Shiling Feng,Chunyan Zhang,Tao Chen,Lijun Zhou,Yan Huang,Ming Yuan,Tian Li,Chunbang Ding
Oleuropein (OLE) is a secoiridoid glycoside that mainly exists in olives with multifaceted health benefits. The present study aimed to investigate the stress resistance and lifespan extension effects of OLE inCaenorhabditis elegans. The results showed that OLE could significantly prolong the lifespan ofC. elegansby 22.29%. Treatment with OLE also significantly increased the survival rates of worms against lethal heat shock and oxidative stress. Meanwhile, OLE supplementation increased the expression and activity of antioxidant enzymes and suppressed the generation of malondialdehyde in nematodes. In addition, the results from mutants implied that OLE might mediate longevity and stress resistance via DAF-16/FoxO, which played a vital role in the insulin/IGF-1 signaling (IIS) pathway. To further identify the molecular targets of OLE, mRNA level and loss-of-function mutants of IIS-associated genes were investigated. The data revealed that OLE activated IIS by down-regulating the upstream components,daf-2andage-1. Furthermore, another stress response and longevity pathway in parallel to DAF-16, SKN-1/Nrf2, was also shown to involve in OLE-induced beneficial effects. Collectively, these results provide the theoretical basis that OLE could enhance the stress resistance and increase the lifespan ofC. elegansthrough the IIS and SKN-1/Nrf2 signaling pathways.Keywords:oleuropein;Caenorhabditis elegans;longevity;stress resistance
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JOURNAL OF PERIODONTAL RESEARCH
·
2023
·
IF 3.5
Yifan Ma,Yi Qian,Yuteng Chen,Xiaoxu Ruan,Xiaoya Peng,Yi Sun,Jue Zhang,Jingjing Luo,Songlin Zhou,Chao Deng
Objective The purpose of this study was to investigate resveratrol's specific role as an anti-inflammatory and osteogenic differentiation of hPDLSCs in periodontitis and to reveal the mechanisms involved. Background Numerous studies have shown that inhibiting the inflammatory response of periodontal tissues and promoting the regeneration of alveolar bone are crucial treatments for periodontitis. Resveratrol has been found to have certain anti-inflammatory property. However, the anti-inflammatory mechanism and osteogenic effect of resveratrol in periodontitis are poorly understood. Materials and Methods We constructed an in vitro periodontitis model by LPS stimulation of hPDLSCs and performed WB, RT-qPCR, and immunofluorescence to analyze inflammatory factors and related pathways. In addition, we explored the osteogenic ability of resveratrol in in vitro models. Results In vitro, resveratrol ameliorated the inflammatory response associated with activation of the NF-κB pathway through activation of the NRF2/HO-1 pathway, characterized by inhibition of p65/p50 nuclear translocation and the proinflammatory cytokines interleukin-1β levels. Resveratrol also has a positive effect on osteogenic differentiation. Conclusions Observations suggest that resveratrol modulates the inflammatory response in hPDLSCs via the NRF2/HO-1 and NF-κB pathways and promotes osteogenic differentiation.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2021
·
IF 5.279
Jinwen Yuan,Siyan Che,Li Zhang,Zheng Ruan
Luteolin, a dietary flavonoid, has gained increasing interest as an intestinal protectant. This study aimed to evaluate the reparative effect of luteolin against ethanol-induced intestinal barrier damage in a Caco-2 cell monolayer model and the potential mechanisms. Luteolin attenuated ethanol-induced intestinal barrier injury, by increasing transepithelial monolayer resistance (TEER, 27.75 ± 14.75% of the ethanol group, p < 0.01), reducing Lucifer yellow flux (13.21 ± 1.23% of ethanol group, p < 0.01), and upregulating the expression of tight junction (TJ) proteins zonulin occludin-1 (ZO-1), occludin, and claudin-1 (37.963 ± 8.62%, 17.69 ± 7.35%, and 29.40 ± 8.08% of the ethanol group, respectively, p < 0.01). Further mechanistic studies showed that luteolin suppressed myosin light chain 2 (MLC) phosphorylation, myosin light chain kinase (MLCK) activation, nuclear factor kappa-B (NF-κB) nuclear translocation, and mitogen-activated-protein-kinase (MAPK) phosphorylation. Moreover, luteolin also acted as antioxidants indirectly by upregulating antioxidant-responsive-element (ARE) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation to relieve ethanol-induced oxidative damage and TJ dysfunction. The results of the study indicate that luteolin may play an effective role in relieving intestinal barrier damage, and this effect is at least partially due to its indirect antioxidant capacity.
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CELLULAR SIGNALLING
·
2021
·
IF 4.315
Hao Huang,Xielan Kuang,Xiaobo Zhu,Hao Cheng,Yuxiu Zou,Han Du,Han Tang,Linbin Zhou,Jingshu Zeng,Huijun Liu,Jianhua Yan,Chongde Long,Huangxuan Shen
Retinal ischemia-reperfusion (I/R) often results in intractable visual impairments, where blood retinal barrier (BRB) homeostasis mediated by retinal pigment epithelium (RPE) and retinal microvascular endothelium (RME) is crucial. However, strategies targeting the BRB are limited. Thus, we investigated the inconclusive effect of lycopene (LYC) in retinal protection under I/R. LYC elevated cellular viability and reversed oxidative stress in aRPE-19 cells/hRME cells under I/R conditions based on oxygen-glucose deprivation (OGD) in vitro . Molecular analysis showed that LYC promoted NRF2 expression and enhanced the downstream factors of the KEAP1/NRF2/ARE pathway: LYC increased the activities of antioxidants, including SOD and CAT , whereas it enhanced the mRNA expression of HO-1 ( ho-1 ) and NQO-1 ( nqo-1 ). The activation resulted in restrained ROS and MDA. On the other hand, LYC ameliorated the damage to retinal function and morphology in a mouse I/R model, which was established by unilateral ligation of the left pterygopalatine artery/external carotid artery and reperfusion . LYC promoted the expression of NRF2 in both the neural retina and the RPE choroid in vivo . This evidence revealed the potential of LYC in retinal protection under I/R, uncovering the pharmacological effect of the KEAP1/NRF2/ARE pathway in BRB targeting. The study generates new insights into scientific practices in retinal research.
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FEBS Open Bio
·
2021
·Vol. 11
·期 8
·2118-2126
·
IF 2.693
Na Wei,Tan Lu,Libin Yang,Yonghan Dong,Xiaotan Liu
Ferroptosis is an iron-dependent programmed cell death, which participates in the pathogenesis of spinal cord injury (SCI). Our previous study has revealed that Lipoxin A4 (LXA4) exerts a protective role in SCI. Here, we investigated whether LXA4 can protect SCI through inhibiting neuronal ferroptosis. We treated primary spinal cord neurons with Erastin (ferroptosis activator) to induce ferroptosis. Erastin treatment reduced cell viability and enhanced cell death of primary spinal cord neurons, which was rescued by ferrostatin-1 (ferroptosis inhibitor). Moreover, Erastin repressed glutathione peroxidase 4 (GPX4) expression and the levels of glutathione and cysteine in primary spinal cord neurons. Erastin also enhanced the expression of ferroptosis biomarkers (PTGS2 and ACSL4) and the levels of reactive oxygen species (ROS) in primary spinal cord neurons. The influence conferred by Erastin was effectively abolished by LXA4 treatment. Furthermore, LXA4 enhanced the protein expression of p-AKT, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and haem-oxygenase-1 (HO-1) in primary spinal cord neurons. LXA4-mediated inhibition of ferroptosis of primary spinal cord neurons was prohibited by LY294002 (AKT inhibitor), brusatol (Nrf2 inhibitor) or zinc protoporphyrin (HO-1 inhibitor). In conclusion, this work demonstrated that LXA4 exerted a neuroprotective effect in Erastin-induced ferroptosis of primary spinal cord neurons by activating the Akt / Nrf2 / HO-1 signaling pathway. Thus, this work provides novel insights into the mechanisms of action of LXA4 in ferroptosis of primary spinal cord neurons and indicates that LXA4 may be a potential therapeutic agent for SCI.
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Food & Function
·
2020
·Vol. 11
·期 12
·10852-10863
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IF 4.171
Mingbao Gu,Jie Jin,Chenghao Ren,Ximiao Chen,Weiyang Gao,Xiangyang Wang,Yaosen Wu,Naifeng Tian,Zongyou Pan,Aimin Wu,Yifei Zhou,Xiaolei Zhang
As an ordinary joint vestigial disease, osteoarthritis (OA) contributes to a considerable proportion of disability cases worldwide. Inflammation, as the main pathological factor, mediates the occurrence and development of OA. Akebia Saponin D (ASD), also known as Asperosaponin VI, is one of the active components extracted from Dipsaci Radix and is rich in Dipsacus loose tea. It has shown sound therapeutic effects on various diseases; nevertheless, its role in OA therapy is not completely understood. This study demonstrated the anti-inflammatory activity of ASD in OA through a series of in vivo and in vitro experiments. In vitro experiments revealed that ASD might prohibit the production of inflammatory mediators in IL-1β treated chondrocytes such as COX-2, iNOS, NO, PGE2, IL-6, and TNF-α. Meanwhile, it may also inhibit the production of ADAMTS-5 and MMP13 and promote the production of Aggrecan and Collagen II. The mechanism study demonstrated that ASD exerted an anti-inflammatory effect by activating the NRF2 target, upregulating the expression of HO-1, and preventing P65 from binding to DNA. In vivo experiments demonstrated that ASD might improve the progression of OA in a DMM mouse model. These research results provide evidence for the potential application of ASD in OA therapy.
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Frontiers in Chemistry
·
2020
·
IF 3.693
Mei Qixiang,Deng Guoying,Huang Zehua,Yin Yue,Li Chunlin,Hu Junhui,Fu Yang,Wang Xingpeng,Zeng Yue
Severe acute pancreatitis (SAP) is associated with high rates of mortality and morbidity. Chitosan oligosaccharides (COSs) are agents with antioxidant properties. We developed porous COS@SiO2 nanocomposites to study the protective effects and mechanisms of COS nanomedicine for the treatment of acute pancreatitis. Porous COS@SiO2 nanocomposites released COSs slowly under pH control, enabling sustained release and maintaining the drug at a higher concentration. This study aimed to determine whether porous COS@SiO2 nanocomposites ameliorate SAP and associated lung injury. The SAP model was established in male C57BL/6 mice by intraperitoneal injection of caerulein. The expression levels of myeloperoxidase, malondialdehyde, superoxide dismutase, nuclear factor-kappa B (NF-κB), the NOD-like receptor protein 3 (NLRP3) inflammasome, nuclear factor E2-related factor 2 (Nrf2), and inflammatory cytokines were detected, and a histological analysis of mouse pancreatic and lung tissues was performed. In the SAP groups, systemic inflammation and oxidative stress occurred, and pathological damage to the pancreas and lung was obvious. Combined with porous COS@SiO2 nanocomposites before treatment, the systemic inflammatory response was obviously reduced, as were oxidative stress indicators in targeted tissues. It was found that Nrf2 was significantly activated in the COS@SiO2 treatment group, and the expressions of NF-κB and the NLRP3 inflammasome were notably decreased. In addition, this protective effect was significantly weakened when Nrf2 signaling was inhibited by ML385. This demonstrated that porous COS@SiO2 nanocomposites activate the Nrf2 signaling pathway to inhibit oxidative stress and reduce the expression of NF-κB and the NLRP3 inflammasome and the release of inflammatory factors, thus blocking the systemic inflammatory response and ultimately ameliorating SAP and associated lung injury.
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FOOD AND CHEMICAL TOXICOLOGY
·
2020
·
IF 4.679
Hang Qu,Shuang Liu,Cuilin Cheng,Haitian Zhao,Xin Gao,Zhenyu Wang,Juanjuan Yi
Previously, we obtained a purified polysaccharide (PNP40c-1) from Pinus koraiensis pine nut and reported its protective effect on carbon tetrachloride (CCl 4 )-induced liver injury in vitro . The object of this study is to investigate its hepatoprotective activity in vivo and elucidate the mechanism underlying the hepatoprotection . PNP40c-1 effectively prevented the accumulation of serum liver injury biomarkers including alanine aminotransferase , aspartate aminotransferase, alkaline phpsphatase and total bilirubin stimulated by CCl 4 . The pathological changes in PNP40c-1-treated mice livers were also markedly ameliorated. Results showed that PNP40c-1 suppressed the production of reactive oxygen species (ROS) and lipid peroxidation, upregulated Nrf2/ARE pathway and enhanced the antioxidant capacity of hepatocytes. Furthermore, the reaction between Nrf2 and ARE promoted the generation of Mkp1 , which inhibited the activation of JNK induced by CCl 4 , and suppressed hepatocytes apoptosis by regulating the protein expression of Bax, cleaved-Caspase-3 and Bcl2, exerting hepatoprotective activity. Taken together, upregulation of Nrf2/ARE pathway and suppression of JNK activation via Nrf2/ARE/Mkp1/JNK signaling pathways are the main mechanisms underlying the hepatoprotective effect of PNP40c-1 against CCl 4 -induced mice liver injury. These results indicated that PNP40c-1 has potential to serve as a hepatoprotective agent against chemical induced hepatotoxicity.
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Journal of Neuroinflammation
·
2020
·Vol. 17
·期 1
·1-13
·
IF 5.793
Bian Hetao,Wang Gaohua,Huang Junjie,Liang Liang,Zheng Yage,Wei Yanyan,Wang Hui,Xiao Ling,Wang Huiling
Background Recently, depression has been identified as a prevalent and severe mental disorder. However, the mechanisms underlying the depression risk remain elusive. The neuroinflammation and NLRP3 inflammasome activation are known to be involved in the pathology of depression. Dihydrolipoic acid (DHLA) has been reported as a strong antioxidant and exhibits anti-inflammatory properties in various diseases, albeit the direct relevance between DHLA and depression is yet unknown. The present study aimed to investigate the preventive effect and potential mechanism of DHLA in the lipopolysaccharide (LPS)-induced sickness behavior in rats. Methods Adult male Sprague–Dawley rats were utilized. LPS and DHLA were injected intraperitoneally every 2 days and daily, respectively. Fluoxetine (Flu) was injected intraperitoneally daily. PD98059, an inhibitor of ERK, was injected intraperitoneally 1 h before DHLA injection daily. Small interfering ribonucleic acid (siRNA) for nuclear factor erythroid 2-like (Nrf2) was injected into the bilateral hippocampus 14 days before the DHLA injection. Depression-like behavior tests were performed. Western blot and immunofluorescence staining detected the ERK/Nrf2/HO-1/ROS/NLRP3 pathway-related proteins. Results The DHLA and fluoxetine treatment exerted preventive effects in LPS-induced sickness behavior rats. The DHLA treatment increased the expression of ERK, Nrf2, and HO-1 but decreased the ROS generation levels and reduced the expression of NLRP3, caspase-1, and IL-1β in LPS-induced sickness behavior rats. PD98059 abolished the effects of DHLA on preventive effect as well as the levels of Nrf2 and HO-1 proteins. Similarly, Nrf2 siRNA reversed the preventive effect of DHLA administration via the decreased expression of HO-1. Conclusions These findings suggested that DHLA exerted a preventive effect via ERK/Nrf2/HO-1/ROS/NLRP3 pathway in LPS-induced sickness behavior rats. Thus, DHLA may serve as a potential therapeutic strategy for depression.
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