Experimental and Therapeutic Medicine
·
2015
·Vol. 9
·期 6
·2072-2080
·
IF 1.269
Yang Li,Jiefang Wang,Guangming Chen,Shuiwang Feng,Panpan Wang,Xiaofeng Zhu,Ronghua Zhang
The aim of the present study was to investigate the effects of quercetin on the mitogen-activated protein kinase (MAPK) signaling pathway in the osteogenic differentiation of rat mesenchymal stem cells (MSCs). A 3-(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay and an alkaline phosphatase (ALP) assay were used to determine the effects of quercetin (concentrations of 0.1, 1 and 10 µmol/l) on the proliferation and differentiation of MSCs and the expression of ALP, respectively. In addition, through the introduction of inhibitors of p38 MAPK, extracellular signal‑regulated kinase (ERK)1/2 and c‑Jun NH2‑terminal kinase (JNK), the effects of quercetin on the proteins, ALP, collagen type I (COL I) and bone γ‑carboxyglutamate protein (BGP), which are indicators of osteogenic differentiation, were investigated. Immunoblotting was performed to determine the phosphorylation levels of p38 MAPK, ERK1/2 and JNK, while fluorescent quantitative polymerase chain reaction was used to determine the mRNA expression levels of transforming growth factor (TGF)‑β1, bone morphogenetic protein (BMP)‑2 and core binding factor (CBF)α1. At all the concentrations tested, the concentrations of 10, 1 and 0.1 µmol/l quercetin were shown to promote the differentiation of MSCs and the expression of ALP, in which the concentration of 10 µmol/l was optimal. When compared with the control group, the phosphorylation levels of p38 MAPK, ERK1/2 and JNK, the protein expression levels of ALP, COL I and BGP, and the mNRA expression levels of TGF‑β1, BMP‑2 and Cbfα1 were increased in the quercetin‑treated group. However, with the introduction of inhibitors, the levels of phosphorylated p38 MAPK, ERK1/2 and JNK, and the protein expression levels of ALP, COL I and BGP decreased. Furthermore, the mRNA expression levels of TGF‑β1, BMP‑2 and CBFα1 decreased in the quercetin + SP600125 (inhibitor of JNK) and quercetin + PD98059 (inhibitor of ERK1/2) groups. Therefore, quercetin was demonstrated to promote the osteogenic differentiation of MSCs by activating the MAPK signaling pathway. The ERK1/2 and JNK signaling pathways regulate the expression of TGF‑β1, BMP‑2 and CBFα1. Thus, activation of the ERK1/2 and JNK signaling pathways may play a leading role in the quercetin‑promoted osteogenic proliferation and differentiation of MSCs.
研究领域:
药理学
·
干细胞生物学
·
细胞信号转导
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DOI
PubMed
高影响因子
MICROBIAL PATHOGENESIS
·
2023
·
IF 3.8
Yuxiao Qian,Yuqian Jiang,Hongrong Hong,Xinxin Gao,Wei Liu,Meiyi Chen,Qinqin Jin,Zha Jin,Xin Li,Xiaocen Wang,Jianhua Li,Quan Liu,Xichen Zhang,Nan Zhang,Zhengkai Wei
Pigeons are natural intermediate host of Neospora caninum ( N. caninum ). In comparison to ruminants, N. caninum causes milder clinical symptoms and less financial loss to pigeons. Natural infectious rates and high prevalence of N. caninum in pigeons, and death cases of N. caninum- infected pigeons under experimental conditions have been reported, but the detailed pathological characteristics and congenital immunological responses of pigeons-infected with N. caninum remain not well described. In this study, pigeons were infected intraperitoneally with 10 7 N. caninum tachyzoites . N. caninum in tissues was detected by qPCR. Pathological changes of tissues were examined by hematoxylin-eosin staining. Blood smears were prepared for counting eosinophils changes in blood. Heterophil extracellular traps (HETs) in vivo and in vitro were quantified by Pico Green. N. caninum- induced HETs structures were observed by immunofluorescence staining. The model of pigeons-infected with N. caninum was successfully established. Lung and duodenum were the main target organs of pigeons-infected with N. caninum . N. caninum caused hemorrhage, edema and inflammatory cell infiltration in liver, pulmonary congestion and hemorrhage, organizational destruction in lung, and shorter villi or even disappear in duodenum. N. caninum also increased the number of eosinophils in blood of pigeons. Moreover, N. caninum -induced HETs release in the congenital immunological system of pigeons were first demonstrated, and the HETs structures were consisted of DNA as the skeleton and modified with citH3 and elastase . N. caninum -induced HETs release was related with NADPH oxidase , TLR 2 and 4, ERK 1/2 and p38 MAPK signaling pathways , and glycolysis. In summary, it is the first report on the detailed pathological characteristics and congenital immunological responses of pigeons-infected with N. caninum , which may provide theoretical basis for the prevention and control of Neosporosis in pigeons.
研究领域:
兽医学
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免疫学
·
病理学
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产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2023
·
IF 8.8
Chen Hong,Yifan Zhang,Lili Yang,Haoyang Xu,Kang Cheng,Zhi Lv,Kaixian Chen,Yiming Li,Huali Wu
Epimedin B (EB) is one of the main flavonoid ingredients present in Epimedium brevicornum Maxim., a traditional herb widely used in China. Our previous study showed that EB was a stronger inducer of melanogenesis and an activator of tyrosinase (TYR). However, the role of EB in melanogenesis and the mechanism underlying the regulation remain unclear. Herein, as an extension to our previous investigation, we provide comprehensive evidence of EB-induced pigmentation in vivo and in vitro and elucidate the melanogenesis mechanism by assessing its effects on the TYR family of proteins (TYRs) in terms of expression, activity, and stability. The results showed that EB increased TYRs expression through microphthalmia-associated transcription factor-mediated p-Akt (referred to as protein kinase B [PKB])/glycogen synthase kinase 3β (GSK3β)/β-catenin, p-p70 S6 kinase cascades, and protein 38 (p38)/MAP kinase (MAPK) and extracellular regulated protein kinases (ERK)/MAPK pathways, after which EB increased the number of melanosomes and promoted their maturation for melanogenesis in melanoma cells and human primary melanocytes/skin tissues. Furthermore, EB exerted repigmentation by stimulating TYR activity in hydroquinone- and N -phenylthiourea-induced TYR inhibitive models, including melanoma cells, zebrafish, and mice. Finally, EB ameliorated monobenzone-induced depigmentation in vitro and in vivo through the enhancement of TYRs stability by inhibiting TYR misfolding, TYR-related protein 1 formation, and retention in the endoplasmic reticulum and then by downregulating the ubiquitination and proteolysis processes. These data conclude that EB can target TYRs and alter their expression, activity, and stability, thus stimulating their pigmentation function, which might provide a novel rational strategy for hypopigmentation treatment in the pharmaceutical and cosmetic industries.
研究领域:
药理学
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化妆品学
·
细胞生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Xu Zhang,Zhang Yuan,Jianshuang Wu,Ye He,Guifang Lu,Dan Zhang,Yan Zhao,Rongqian Wu,Yi Lv,Kaiyong Cai,Shuixiang He
Traditional drug-based treatments for inflammatory bowel disease (IBD) have significant limitations due to their potential off-target systemic side-effects. Currently, there is a lack of understanding on how to effectively address excessive oxidative stress, dysregulated immune homeostasis, and microbiota dysbiosis within the IBD microenvironment. Herein, we introduce a nanotherapeutic approach, named LBL-CO@MPDA, for IBD treatment. LBL-CO@MPDA is an orally administered formulation that supplies carbon monoxide (CO) for therapeutic purposes. To create the LBL-CO@MPDA nanocomposite, we developed a layer by layer (LBL) self-assembly strategy where we coated chitosan/alginate polyelectrolytes onto the surface of CO prodrug-loaded mesoporous polydopamine nanoparticles (CO@MPDA). Benefiting from the negatively charged surface of the LBL coating, it allows for targeted accumulation of LBL-CO@MPDA specifically onto the positively charged inflamed colon lesions through electrostatic interactions. Furthermore, in the oxidative microenvironment of the inflamed colon, the nanotherapeutic system releases CO in a responsive manner. Interestingly, CO@MPDA ameliorates inflammatory conditions by MPDA-mediated ROS-scavenging and CO-mediated immunomodulation. CO-supplying activates heme oxygenase-1, leading to macrophage M2 polarization via the Notch/Hes1/Stat3 signaling pathway, while suppressing the inflammatory response by down-regulating the p38 MAPK and NF-κB (p50/p65) signaling pathways. In the mice model of dextran sulfate sodium (DSS)-induced IBD, LBL-CO@MPDA effectively reverses the pro-inflammatory microenvironment and restores gut barrier functions through multiple mechanisms, including scavenging oxidative stress, restoring immune homeostasis, and modulating the gut microbiota. Collectively, our findings highlight the promising potential of this innovative nanotherapeutic strategy for the targeted treatment of IBD.
研究领域:
药学
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纳米技术
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免疫学
·
胃肠病学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2019
·
IF 4.527
Yang Wu,Yan Li,Liangqing Zheng,Pengcheng Wang,Yan liu,Yongning Wu,ZhiYong Gong
Nε-(carboxymethyl)lysine (CML) is a potentially noxious compound that is causing widespread concern due to its use in various food products. In this study, we investigated CML neurotoxicity via an in vivo experiment with mice, and an in vitro experiment using a 3D microvascular network model (with human brain vascular endothelial cell and human astrocyte) that simulated the blood-brain barrier. We found that CML could induce cell survival status variations, and histopathological changes to the brain. In addition, CML increased levels of oxidative stress , prompted the protein expression of the receptor for advanced glycation end-products (RAGE). CML up-regulated both the gene expression of RAGE, the activating protein-1 (AP-1), the inflammatory cytokines Interleukin-6 (IL-6), vascular cell adhesion molecule1 (VCAM-1), monocyte chemotactic protein1 (MCP-1). We, therefore, postulated that CML has the potential to deleteriously affect the nervous system through oxidative stress and that activation of the p38 MAPK-AP-1 signaling pathway might be implicated in this pathological process.
研究领域:
神经科学
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毒理学
·
细胞生物学
·
食品科学
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DOI
PubMed
高影响因子
ACS Omega
·
2023
·
IF 4.1
Wei Wang,Han Li,Jiamin Lv,Ghulam Jilany Khan,Hong Duan,Juan Zhu,Nina Bao,Kefeng Zhai,Zhenglian Xue
Isodon suzhouensis from Suzhou, China, is a traditional Chinese herb with wide applications in medicine and food. The antioxidant activity against oxidative stress of the leaves of Isodon suzhouensis is a myth since long and is not explored earlier thoroughly. The present study is focused to explore the active components in Isodon suzhouensis leaf extracts responsible for antioxidant effects against oxidative stress and the potential mechanism of this activity. We obtained the chromatograms of Isodon suzhouensis leaf extracts by the high-performance liquid phase (HPLC) for possible detection of antioxidant constituents. Some compounds in Isodon suzhouensis leaf extracts were then further assessed through the luminol luminescence mechanism combined with HPLC analysis as well as with SwissTargetPrediction database that helped to screen out the other constituents. The targets for effects against oxidative stress were then further screened through the GeneCards database, and the PPI network was constructed. The targets were analyzed by GO and KEGG using the David database. The obtained results were then further studied by employing in vitro experimentation and protein expression analyses by Western blotting. It is found that Isodon suzhouensis leaf extracts contain rutin, isoquercetin, glaucocalyxin A, glaucocalyxin B, and other compounds with antioxidant activity. The activity map of the free radical scavenging signals from Isodon suzhouensis showed a strong ability to scavenge free radicals with the highest capacity of glaucocalyxin B followed by isoquercetin succeeding the glaucocalyxin A supervening the rutin. Further network pharmacological analyses and in vitro experimentation showed that Isodon suzhouensis leaf extracts interfere with TNF and the p38 MAPK signaling pathway for antioxidant effects against oxidative stress. Conclusively, it is found that Isodon suzhouensis leaf extracts possess strong antioxidant potential via targeting TNF and p38 MAPK signaling pathways against oxidative stress, providing scientific foundation for further studies on Isodon suzhouensis for the further therapeutic approach.
研究领域:
药理学
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生物信息学
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植物科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 13
·期 16
·8593-8604
·
IF 6.317
Yanfang Yu,Yuhuan Chen,Xuping Shi,Chuan Ye,Junwen Wang,Jinzhi Huang,Bing Zhang,Zeyuan Deng
This study investigated the hepatoprotective effects of various mulberry (Morus alba L.) leaf extracts (MLEs), including mulberry ethanol extract (MEE), aqueous extract (MAE) and a combination extract (MCE) against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury in rats. It aimed to explore the possible molecular mechanism of the liver-protecting function of mulberry leaves and provide a reference for choosing the appropriate extraction method. The results showed that the three extracts contained different amounts of phenolic compounds, 1-deoxynojirimycin (DNJ) and polysaccharides. MLEs markedly improved the pathological status of rat liver tissue, decreased the levels of AST, ALT, TNF-α, IL-1β, IL-6 and MDA, while increased the levels of GSH, SOD and CAT in the D-GalN/LPS-treated rats at the same time. MEE, with the highest amount of total phenolics, exhibited the highest antioxidant activity corresponding to the protein expression level of Nrf2 and HO-1. MCE significantly suppressed the expression of apoptosis-related dot-like protein (ASC) and Caspase-1 and inhibited the phosphorylation of p38 MAPK and ERK1/2, thereby showing high anti-inflammatory activity. These results indicated that the active components from mulberry leaves protected rats against acute liver injury, attributed to a reduction in both oxidative stress and inflammatory response. The protective effect may be implicated in regulating the Nrf2, NLRP3 and MAPK signaling pathways.
研究领域:
药理学
·
肝病学
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生物化学
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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 CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 23
·e70271
·
IF 4.3
Zongrui Yang,Yuanyuan Feng,Mingcai Zhang,Yongming Liu,Yizhe Xiong,Xiang Wang,Ying Shi,Bo Chen,Zhengming Wang,Haiya Ge,Hongsheng Zhan,Zhibi Shen,Guoqing Du
HBP-A is the main active component of a traditional Chinese medicine Huaizhen Yanggan Capsule, for the remarkable treatment of knee osteoarthritis (KOA). This study aimed to elucidate the ameliorative effect of HBP-A on meniscus hypertrophy and mineralisation in KOA and the molecular mechanism of its action. An Hartley guinea pig model of KOA that underwent anterior cruciate ligament transection (ACLT) and a model of rat primary meniscus fibrochondrocytes (PMFs) were used to investigate the ameliorative effect of HBP-A on meniscal hypertrophy and calcification and its signal transduction mechanism of action. The results show that Guinea pig's meniscus width, as well as the area of meniscus calcification and meniscus and articular cartilage injury score, were significantly reduced in the HBP-A intervention group compared to the ACLT group. The expression levels of mtrix metalloproteinase 13 (MMP13), runt-related transcription factor 2 (Runx2), Indian hedgehog (Ihh), alkaline phosphatase (ALP), and ankylosis homologue (ANKH) at the protein and gene level significantly decreased in the HBP-A intervention group compared to the ACLT group. In vitro study, apoptosis, hypertrophy, and calcification of rat PMFs after 10% stretch force were significantly improved with HBP-A intervention. Western blot and RT-qPCR showed that hypertrophy, calcification, and p38 MAPK signalling pathway-related markers of PMFs were incredibly depressed in the HBP-A intervention group compared to the 10% stretch force group. In conclusion, HBP-A can slow down meniscus hypertrophy and mineralisation induced by abnormal mechanical loading, and its mechanism of action may be through the p38-MAPK signalling pathway.
研究领域:
药理学
·
骨科
·
分子生物学
·
传统中药
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Guangzhen Yang,Mengni Fan,Jingwu Zhu,Chen Ling,Lihuang Wu,Xin Zhang,Ming Zhang,Jiayi Li,Qingqiang Yao,Zhongwei Gu,Xiaojun Cai
Specifically inhibiting the proliferation of activated macrophages and clearing the high levels of reactive oxygen species (ROS) secreted by macrophages is crucial for osteoarthritis (OA) treatment. Moreover, if the clearance of these high levels of ROS can be simultaneously used to induce oxidation-responsive release of anti-inflammatory drugs, the therapeutic effect of OA may be further improved. Here, a multifunctional anti-inflammatory drug (CPHs) based on a peptide dendrimer nanogel was constructed by physically encapsulating CORM-401 and wrapping its surface with folic acid (FA)-modified hyaluronic acid (HA). CPHs is capable of efficiently entering activated macrophages via FA- and HA-mediated specific targeting effects and then rapidly release large amounts of CO by massive consumption of H 2 O 2 . The generated CO effectively suppresses the secretion of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α by inhibiting cell proliferation ; inducing the activation of heme oxygenase (HO-1), and downregulating the expression of p38 MAPK , NF-kB (p50/p65) and TLR-2. In vivo experiments further confirmed that CPHs can massively deplete ROS in OA joints and effectively suppress the degradation of articular cartilage and their extracellular matrix. More importantly, CPHs is non-toxic to normal macrophages, and the high levels of CO generated in the joints do not result in notable changes in the HbCO levels in blood. Together, these results show that CPHs is an effective and safe anti-inflammatory drug and has essential application prospects in OA treatment.
研究领域:
药理学
·
炎症
·
纳米技术
·
骨科
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Xu Zhang,Huan Yang,Ye He,Dan Zhang,Guifang Lu,Mudan Ren,Yi Lyu,Zhang Yuan,Shuixiang He
Excessive oxidative stress, dysregulated immune homeostasis, and disruption of the intestinal epithelial barrier are crucial features of inflammatory bowel disease (IBD). Traditional treatments focusing solely on inflammation resolution remain unsatisfactory. Herein, a yeast-inspired orally administered nanocomposite was developed. First, the MD@MPDA core was fabricated by integrating manganese dioxide (MnO2) nanozymes onto diallyl trisulfide (H2S prodrug)-loaded mesoporous polydopamine nanoparticles (MPDA). Then, yeast cell wall (YCW) was chosen to encapsulate MD@MPDA, namely, YMD@MPDA. The β-glucan embedded in the YCW shell not only protected the nanocomposite from the harsh gastrointestinal environment but also allowed the targeting enrichment in the inflamed colon. Furthermore, M1 macrophages triggered the intracellular GSH-responsive H2S release in the pathological microenvironment. MD@MPDA effectively alleviated inflammatory responses by MnO2-mediated ROS-scavenging and H2S-participated immunomodulation. The synergistic action contributed to macrophage mitochondrial function restoration and M2 polarization by suppressing NOX4 signaling and p38 MAPK pro-inflammatory signaling. In the mice model of dextran sulfate sodium (DSS)-induced IBD, the multipronged manner of scavenging oxidative stress, remodeling innate and adaptive immune homeostasis, and reshaping gut microbiota caused by YMD@MPDA effectively ameliorated inflammation and restored intestinal barrier functions. Overall, the YMD@MPDA nanocomposite provides a promising codelivery strategy of antioxidative nanozymes and gas prodrugs for the comprehensive management of IBD.
研究领域:
纳米医学
·
胃肠病学
·
免疫学
·
药学
✓ 已验证
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）