American Journal of Translational Research
·
2017
·
IF 2.829
Yuanfeng Zhu,Shijun Fan,Ning Wang,Xiaoli Chen,Yongjun Yang,Yongling Lu,Qian Chen,Jiang Zheng,Xin Liu
Activation of NADPH oxidase 2 (NOX2) triggers reactive oxygen species (ROS) generation, both of which are essential for robust microbial clearance by phagocytes. However, it is unknown whether inhibition of NOX2 activation or ROS generation affects cellular phagocytosis. Here, we found that the classic NOX2 inhibitor diphenyleneiodonium (DPI) induced uptake of E. coli by murine peritoneal macrophages through enhancing phagocytosis, and this effect was temperature-sensitive and attenuated by cytochalasin D as well as chemical inhibition of Syk and PLCγ, two downstream kinases involved in actin polymerization during phagocytosis. DPI also decreased the production of TNF-α and IL-6 resulting from E. coli stimulation. The DPI-induced enhancement of phagocytosis was independent of NOX2 inhibition or ROS generation but depended on increased intracellular calcium and activation of the p38 MAPK signaling pathway. Furthermore, DPI enhanced bacterial elimination and ameliorated inflammation in E. coli -infected mice, leading to improved survival. Our results demonstrate that DPI facilitates ROS-independent bacterial phagocytosis by macrophages through activation of calcium and p38 MAPK signaling pathways.
研究领域:
免疫学
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分子生物学
·
医学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Lei Wang,Wan-Yang Xu,Yi-Wen Tang,Feng Hu
Pulmonary fibrosis is common in the development of inflammatory lung diseases with no effective clinical drug treatment currently. As an essential redox enzyme, thioredoxin (Trx) has been reported to be involved in pulmonary fibrosis, but the mechanism is to be revealed. Therefore, in bleomycin-indued pulmonary fibrosis model in C57 mice, Trx activity and nitrated Trx were examined.,p38-MAPK apoptosis pathway was determined in lung tissues. Additionally, before BLM administration, C57/BL6 mice were treated with aminoguanidine (AG, a peroxynitrite scavenger), recombinant human Trx-1 (rhTrx-1), or SIN-1 (a peroxynitrite donor) nitrated Trx-1 ( N -Trx-1). In bleomycin (BLM)-induced pulmonary fibrosis model in C57/BL6 mice, we observed that nitrated Trx increased, while its activity decreased, with the increase of alveolar epithelial cells (AECs)apoptosis by p38-MAPK pathway. We demonstrated that AG or rhTrx-1, but not N -Trx-1 significantly reduced pulmonary fibrosis. Taken together, the results above revealed that blockade of Trx-1 nitration, or supplementation of exogenous rhTrx-1, might represent novel therapies to attenuate pulmonary fibrosis in idiopathic pulmonary fibrosis patients.
研究领域:
医学
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药理学
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病理学
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DOI
PubMed
高影响因子
CTS-Clinical and Translational Science
·
2020
·Vol. 14
·期 5
·2075-2084
·
IF 3.373
Hongtao He,Kuangyuan Qiao,Chao Wang,Wuhan Yang,Zhuo Xu,Zhilei Zhang,Yuming Jia,Chong Zhang,Li Peng
Hydrazinocurcumin (HZC), a synthetic derivative of curcumin (CUR), has been documented to show anticancer potential in impeding tumor growth in several cancers, including hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms remain unclear. This study aimed to explore the function and underlying mechanisms of HZC on HCC cells, which may involve the p38 mitogen activated protein kinase (MAPK) pathway. HZC was first purified and identified. HepG2 cells were then subjected to treatment with HZC or CUR of different concentrations and p38 MAPK signaling inhibitor (SB203580) to verify their effects on HCC cell apoptosis and proliferation. Furthermore, the functional relevance between HZC and the p38 MAPK pathway in HCC was examined. It was observed that 40 μM HZC exhibited the best pro-apoptosis effect in HCC cells. HZC was found to inhibit HCC cell proliferation and promote apoptosis, the effect of which was stronger than 5-fluorouracil (5-FU). More importantly, the anti-oncogenic effect of HZC and 5-FU was implicated with activation of the p38 MAPK pathway. In vivo experimental results showed that HZC inhibited tumor growth more effectively than 5-FU through the p38 MAPK pathway. These results provide evidence that HZC exerted anti-oncogenic and pro-apoptosis effects in HCC cells through activation of the p38 MAPK pathway.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
CURRENT MOLECULAR MEDICINE
·
2020
·Vol. 20
·期 4
·307-317
·
IF 1.6
Yang Yuan,Huang Jin,Li Jianzhong,Yang Huansheng,Yin Yulong
Background: Butyric acid (BT), a short-chain fatty acid, is the preferred colonocyte energy source. The effects of BT on the differentiation, proliferation, and apoptosis of small intestinal epithelial cells of piglets and its underlying mechanisms have not been fully elucidated.
Methods: In this study, it was found that 0.2-0.4 mM BT promoted the differentiation of procine jejunal epithelial (IPEC-J2) cells. BT at 0.5 mM or higher concentrations significantly impaired cell viability in a dose- and time-dependent manner. In addition, BT at high concentrations inhibited
the IPEC-J2 cell proliferation and induced cell cycle arrest in the G2/M phase. Results: Our results demonstrated that BT triggered IPEC-J2 cell apoptosis via the caspase8-caspase3 pathway accompanied by excess reactive oxygen species (ROS) and TNF-α production. BT at high concentrations
inhibited cell autophagy associated with increased lysosome formation. It was found that BT-reduced IPEC-J2 cell viability could be attenuated by p38 MAPK inhibitor SB202190. Moreover, SB202190 attenuated BT-increased p38 MAPK target DDIT3 mRNA level and V-ATPase mRNA level that were responsible
for normal acidic lysosomes. Conclusion: In conclusion, 1) at 0.2-0.4 mM, BT promotes the differentiation of IPEC-J2 cells; 2) BT at 0.5 mM or higher concentrations induces cell apoptosis via the p38 MAPK pathway; 3) BT inhibits cells autophagy and promotes lysosome formation at high
concentrations.
研究领域:
细胞生物学
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分子生物学
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动物生理学
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DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2023
·Vol. 43
·期 6
·913-928
·
IF 3.3
Hongmei Chang,Li Li,Yaxin Deng,Guanling Song,Yan Wang
Titanium dioxide nanoparticles (nano-TiO 2 ) is one of the most widely used and produced nanomaterials. Studies have demonstrated that nano-TiO 2 could induce hepatotoxicity through oxidative stress, and lycopene has strong antioxidant capacity. The present study aimed to explore if lycopene protects the liver of mice from nano-TiO 2 damage. Ninety-six ICR mice were randomly divided into eight groups. They were control group, nano-TiO 2 -treated group (50 mg/kg BW), lycopene-treated groups (5, 20, and 40 mg/kg BW), and 50 mg/kg BW nano-TiO 2 - and lycopene-co-treated groups (nano-TiO 2 + 5 mg/kg BW of lycopene, nano-TiO 2 + 20 mg/kg BW of lycopene, nano-TiO 2 + 40 mg/kg BW of lycopene). After treated by gavage for 30 days, the histopathology of the liver was observed. Liver function was evaluated using changes in serum biochemical indicators of the liver (AST, ALT, ALP); and the level of ROS was indirectly reflected by the level of SOD, GSH-Px, MDA, GSH, and T-AOC. TUNEL assay was performed to examine the apoptosis of hepatocytes. Proteins of p53, cleaved-caspase 9, cleaved-caspase 3, Bcl-2, and Bax as well as p38 were detected. Results showed that lycopene alleviated the liver pathological damage and reduced the injury to liver function induced by nano-TiO 2 , as well as decreased nano-TiO 2 -induced ROS. Meanwhile, lycopene mitigated apoptosis resulting from nano-TiO 2 , accompanied by the reversed expression of apoptosis-related proteins. Furthermore, lycopene significantly reversed the upregulation of p-p38 induced by nano-TiO 2 . In conclusion, this study demonstrated that nano-TiO 2 resulted in hepatocyte apoptosis through ROS/ROS-p38 MAPK pathway and led to liver function injury. Lycopene protected mice liver against the hepatotoxicity of nano-TiO 2 through antioxidant property.
研究领域:
毒理学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2025
·
IF 4.3
Wan Yu-hui,Cheng Zeng-jing,Fan Ling-xiang,Yang De-hong,Chen Bing-lin,Chen Xiang-xin,Zhu Qing
Subarachnoid hemorrhage (SAH) is associated with high mortality and morbidity rates. In its early stages, a substantial influx of blood into the subarachnoid space triggers excessive activation of microglia, which markedly contributes to early brain injury (EBI), a pivotal determinant of poor prognosis. Tremella fuciformis polysaccharides (TFPSs), as acidic heteropolysaccharides from the fruiting bodies of Tremella, exhibit robust anti-inflammatory characteristics and many biological properties. Nonetheless, the impact of TFPSs on EBI after SAH has yet to be reported, and the molecular mechanisms underlying these effects remain elusive. We used in vivo and in vitro models to study the effects of TFPSs on microglia post-SAH. Network pharmacology analysis was used to predict the targets of TFPSs and the pathways through which it exerts its therapeutic effects. These predictions were subsequently corroborated through flow cytometry, Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), and quantitative real‑time polymerase chain reaction, both in vivo and in vitro. After 24 h post-SAH, TFPS-treated mice presented improved neurological function and reduced cerebral edema. TFPSs reversed microglial activation, enhanced phagocytic ability, and reduced neuronal apoptosis. Network pharmacology identified KDR as a potential target of TFPSs, with the P38 MAPK pathway as the downstream pathway. TFPSs attenuated KDR expression, inhibited the P38 MAPK/NF-κB pathway, reduced inflammatory cytokine expression, and increased microglial phagocytic capacity post-SAH. This investigation revealed that TFPSs may ameliorate EBI after SAH, potentially via the regulation of the KDR-mediated P38 MAPK/NF-κB pathway and phagocytic function.
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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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2019
·
IF 3.775
Tongtong Shen,Yufan Miao,Chenchen Ding,Wentao Fan,Shuhui Liu,Yanan Lv,Xiaona Gao,Marthe De Boevre,Liping Yan,Sheila Okoth,Sarah De Saeger,Suquan Song
Zearalenone (ZEA) can widely contaminate crops and agricultural products. The ingestion of ZEA-contaminated food or feed affects the integrity and functions of the intestines. In this study, we aimed to find the potential protective mechanism against ZEA ingestion. We found that ZEA induced cell death in IPEC-J2 cells. Meanwhile, the cytoprotective autophagy was activated in ZEA-treated cells. Further studies demonstrated that a p38/MAPK inhibitor down-regulated autophagy and increased cell death compared to those of the controls. Furthermore, ZEA could induce the accumulation of ROS , and eliminating ROS with NAC resulted in a decline in cell death, p38/MAPK phosphorylation, and the expression of LC3-II compared to those of ZEA-group. In addition, cytochrome P450 reductase (CYPOR) was significantly increased in ZEA-treated cells compared to that in the controls, and an inhibitor of CYPOR decreased ROS levels and mitigated cell death compared to those of the ZEA-group. More importantly, we found that blocking both p38/MAPK signalling and autophagy could enhance CYPOR expression and elevate ROS levels. Overall, our study indicated that the p38/MAPK pathway could activate protective autophagy in response to the CYPOR-dependent oxidative stress that was induced by ZEA in IPEC-J2 cells.
研究领域:
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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DOI
PubMed
高影响因子
BMC Medicine
·
2025
·Vol. 23
·期 1
·1-16
·
IF 8.3
Li Yinyan,Yang Sizu,Jiang Feng,Luo Siqi,Liang Jinlong,Jiang Linrui,Chen Zhixuan,Chen Xin,Yang Jie
Background Influenza A virus (IAV) is a major cause of seasonal and global pandemics, posing serious health risks. Repositioning approved drugs offers an efficient antiviral strategy, particularly as calcium (Ca 2 ⁺) is crucial for IAV infection, making Ca 2 ⁺ channel blockers (CCBs) promising candidates for antiviral agents. Methods The in vitro antiviral activity of cilnidipine was evaluated using MTT assays, qRT-PCR, plaque assays, and western blotting. Mechanistic studies involved time-of-addition, viral internalization, pseudovirus neutralization, and HA (hemagglutinin) syncytium assays. For in vivo analysis, BALB/c mice were intranasally infected to evaluate the effects of cilnidipine on viral titer, lung index, pulmonary inflammatory mediators, and survival rate. Results In vitro, cilnidipine exhibits antiviral activity against IAV during the early stages of infection. It disrupts clathrin- and caveolin-mediated endocytosis to inhibit the internalization of IAV and interacts with the viral HA2 subunit to impede virus membrane fusion. Additionally, cilnidipine suppresses the PI3K-AKT and p38 MAPK pathways activated by IAV infections. In vivo, cilnidipine reduces virus titers and lung index, ameliorates lung pathology, and inhibits pulmonary inflammatory mediator expression, improving survival rates. Conclusions These findings highlight the promising anti-IAV properties of cilnidipine both in vitro and in vivo, suggesting its potential as a clinical agent for emergencies against influenza outbreaks.
研究领域:
病毒学
·
药理学
·
分子生物学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2022
·
IF 5.168
Yi Peng,Jie Pan,Fengting Ou,Wenchao Wang,Haihong Hu,Lu Chen,Su Zeng,Kui Zeng,Lushan Yu
Fenbendazole, a broad-spectrum anti-parasitic drug, can be a potential anti-tumor agent. In this study, we synthesized and purified its derivative, analog 6, intending to achieve improved efficacy in cancer cells and decreased toxicity in normal cells. To evaluate in vitro anti-tumor activities of fenbendazole and analog 6 in different cancer cell lines, a CCK-8 assay was performed, and we found that human cervical cancer HeLa cells were more sensitive to analog 6 than to fenbendazole. Furthermore, we explored the associated mechanism, and our results showed that analog 6 and fenbendazole could induce oxidative stress by accumulating ROS . It not only activated the p38-MAPK signaling pathway, thereby inhibiting the proliferation of HeLa cells and enhancing the apoptosis of HeLa cells, but also significantly induced impaired energy metabolism and restrained their migration and invasion. In addition, the modified analog 6 showed reduced toxicity to normal cells without decreased anti-cancer effect. In conclusion, fenbendazole and analog 6 have multiple targets and strong anti-tumor effects on HeLa cells in vitro and in vivo . The optimized analog 6 could inhibit the viability of HeLa cells with lower toxicity than normal human cells, promising to be developed as an antitumor active compound.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Weicheng Qin,Qi Shang,Gengyang Shen,Bing Li,Peng Zhang,Yuzhuo Zhang,Wenhua Zhao,Honglin Chen,Huiwen Liu,Bin Xie,Zhida Zhang,Hui Ren,Xiaobing Jiang
Diabetes can lead to a disorder of bone-fat balance, a significant cause of osteoporosis due to changes in environmental factors. Baicalin (Bai), an active ingredient of Scutellaria baicalensis , has been confirmed to possess antioxidant, hypoglycemic, and anti-osteoporotic effects. However, a comprehensive understanding of Bai's influence on diabetic osteoporosis (DOP), including its effects and underlying mechanisms, remains elusive. This study investigated Bai's impact on the bone-fat equilibrium in rats with DOP. The results indicated that Bai alleviated bone damage in DOP by promoting osteogenesis and inhibiting adipogenesis. Concurrently, through bioinformatics analysis, it was suggested that Bai's mechanism of action might involve the P38-MAPK pathway. In vitro , Bai was found to enhance the development of bone marrow mesenchymal stem cells (BMSCs) towards osteogenic lineages while suppressing their differentiation towards adipogenic lineages. It was discovered that Bai's promotion of BMSC osteogenic differentiation depends on the P38-MAPK pathway. Additionally, the synergistic effect mediated by Bai and P38-MAPK inhibitor suppressed BMSC adipogenic differentiation. Our research indicates that the P38-MAPK pathway play a role in Bai's effects on the osteogenic-adipogenic differentiation of BMSCs, showcasing the potential for DOP treatment. This study highlights Bai's ability to regulate the equilibrium between bone and fat, presenting a novel approach to adressing DOP.
研究领域:
药理学
·
内分泌学
·
骨科学
·
分子生物学
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DOI
PubMed
高影响因子
Nutrients
·
2022
·Vol. 14
·期 9
·1940
·
IF 6.706
Kuaitian Wang,Xiao Kong,Mengdi Du,Wei Yu,Zhenhua Wang,Bo Xu,Jianrong Yang,Jingru Xu,Zhili Liu,Yongqiang Cheng,Jing Gan
DEDEQIPSHPPR, the calcium-binding peptide (CBP) identified in soy yogurt, was proven to be a potential cofactor in osteoporosis prevention in our previous study, but the mechanism was unknown. In this study, the activity of alkaline phosphatase (ALP) and osteocalcin (OCN), the regulation of RUNX2, and the expression of TβRI were investigated to elucidate the underlying mechanism. The results show that CBP upregulated ALP activity and OCN concentration and increased the expression of RUNX2 and the activation of the MAPK signaling pathway. Similarly, the expression of osteogenesis-related genes in osteoblasts also increased upon CBP treatment. Moreover, the CBP-induced enhancement of ALP activity and phosphorylation levels in the p38 pathway was inhibited by treatment with a p38 inhibitor (SB203538) and TβRI inhibitor (SB431542), respectively, suggesting that p38 and TβRI were involved in the osteogenic action. Based on the signaling pathways, the intracellular calcium concentration was significantly elevated by CBP, which was correlated with the increased behavioral functions and the relative fluorescence intensity of the bone mass. These findings suggest that CBP stimulates osteoblast differentiation and bone mineralization through the activation of RUNX2 via mechanisms related to the TβRI-p38-MAPK signaling pathways, further highlighting CBP’s important potential for treating osteoporosis.Keywords:bone remodeling;soy peptide CBP;osteoblast;differentiation;p38-MAPK;RUNX2
研究领域:
生物学
·
生物化学
·
药理学
·
骨骼生物学
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产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2020
·
IF 4.486
Ruiqi Huang,Yanjing Zhu,Lijuan Lin,Simin Song,Liming Cheng,Rongrong Zhu
Oxidative stress of neurons caused by a series of complex neuropathological processes will induce certain neurodegenerative disorders including epilepsy. Curcumin (Cur) is an effective natural antioxidant compound; however, the poor bioavailability obstructs its neural protective applications. In this study, Cur is encapsulated in solid lipid nanoparticles (SLNs) for better neuroprotective efficacy. In vitro study certified that Cur-SLNs functioned obviously better against neuronal apoptosis than Cur, by significantly decreasing the level of free radical and reversing mitochondrial function through the activation of the Bcl-2 family. In vivo experiments showed that SLNs transported Cur through the blood–brain barrier (BBB). The behavioral performance of epileptic mice was improved by Cur-SLNs, with more NeuN but less TUNEL positive cells observed in hippocampus. The in vivo mechanism was also explored. Cur-SLNs reduced neuronal apoptosis through Bcl2 family and P38 MAPK pathways. Overall, Cur-SLNs have better protective effects toward oxidative stress in neurons than free Cur both in vitro and in vivo, which suggests they may be a promising agent against neurodegenerative disorders including epilepsy.
研究领域:
药理学
·
神经科学
·
纳米技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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