SCIENCE OF THE TOTAL ENVIRONMENT
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2020
·
IF 6.551
Haiyang Zhang,Mian Wei,Xiangyu Lu,Qinghong Sun,Chuqiao Wang,Jiuyan Zhang,Honggang Fan
Aluminum (Al) is an inorganic pollutant that induces nerve cells apoptosis and necroptosis, thereby causing depression and neurodegenerative diseases. IL-1β/JNK signaling pathway can regulate apoptosis and necroptosis. However, it remains unclear whether IL-1β/JNK signaling pathway is involving in the regulation of Al-induced hippocampal neural cells apoptosis and necroptosis. To investigate the mechanism of Al on neural cells apoptosis and necroptosis, rats were orally exposed to different doses of AlCl 3 for 90 days. The open-field test results showed that AlCl 3 caused depressive behavior in rats. Histopathological evidence showed that AlCl 3 induced hippocampal neural cells apoptosis and necrosis. Moreover, Bax/Bcl-2 mRNA expression ratio, caspase-3 activity and mRNA expression and TUNEL positive rates were upregulated, meanwhile, TNF-α mRNA and protein expression levels, TNFR1, RIP1, RIP3 and MLKL proteins levels were increased, while caspase-8 protein level was decreased in the hippocampus of Al-exposed groups. These results proved that AlCl 3 induced hippocampal neural cells apoptosis and necroptosis. Combined with histopathology and correlation analysis, we deduced that hippocampal neural cells were more likely to undergo necroptosis at high doses (450 mg/kg) of AlCl 3 , while <150 mg/kg AlCl 3 tended to induce apoptosis. Finally, AlCl 3 increased the proteins level of IL-1β, IL-1RI, IL-1RAcP, JNK and p-JNK, indicating that AlCl 3 activated IL-1β/JNK signaling pathway. However, the application of IL-1 receptor antagonist (IL-1Ra) inhibited the phosphorylation of JNK and the related genes expression of apoptosis and necroptosis caused by AlCl 3 . Thus, we concluded that AlCl 3 induced hippocampal neural cells death and depression-like behavior in rats by activating IL-1β/JNK signaling pathway.
研究领域:
神经科学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
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2022
·
IF 1.798
Qiushi LI,Xuying LIU,Ruixian XING,Rubo SUI
Stroke, a type of acute cerebrovascular disease, is a global disease with high mortality. Neuronal ischemia and hypoxia are closely related to occurrence and development of cognitive impairment. Transmembrane p24 trafficking protein 10 (TMED10) as a transmembrane protein involves in vesicle protein transport in the secretory pathways. However, the function and mechanism of TMED10 on ischemic stroke and cognitive impairments remain unclear. In current study, TMED10 was highly expressed in cerebral ischemic penumbra of middle cerebral artery occlusion (MCAO) mouse model. Downregulation of TMED10 suppressed cell survival and facilitated apoptosis in primary cortical neurons, which were grown under oxygen glucose deprivation/reoxygenation (OGD/R) condition. Upregulation of TMED10 protected neurons form apoptosis induced by OGD/R. Further research indicated that the decrease of TMED10 resulted in neuronal mitochondrial injury through increasing reactive oxygen species (ROS) production. Meanwhile, TMED10 reduction induced neuronal apoptosis and mitochondrial damage through activating the c-Jun N-terminal kinase (JNK) pathway. Moreover, the knockdown of TMED10 increased cerebral infarction area, aggravated neuronal injury and promoted neuronal apoptosis through activating the JNK pathway in the cerebral ischemic penumbra of MCAO mouse model. Additionally, Morris water maze test verified that the severity of cognitive impairment increased with the decline of TMED10. Collectively, this study reveals that TMED10 inhibits mitochondrial damage, and protects neurons from apoptosis in MCAO-induced ischemic stroke and cognitive impairment via blocking the JNK pathway.
研究领域:
神经科学
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分子生物学
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细胞生物学
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医学研究
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Lifeng Ding,Lili Jiang,Ze Xing,Huixu Dai,Jingzan Wei
The regulatory mechanism on granulosa cells (GCs) oxidative injury is becoming increasingly important in polycystic ovary syndrome (PCOS) studies. Serine/threonine kinase mitogen-activated protein 4 kinase 4 (Map4k4) is linked with oxidative injury and possibly associated with premature ovarian failure and ovarian dysgenesis. Herein, we investigated the function and mechanism of Map4k4 in a PCOS rat model. A microarray from GEO database identified Map4k4 was up-regulated in the ovarian of PCOS rats, and functional enrichments suggested that oxidative stress-associated changes are involved. We verified the raised Map4k4 expression in an established PCOS rat model and also in the isolated PCOS-GCs, which were consistent with the microarray data. Map4k4 knockdown in vivo contributed to regular estrous cycle, restrained steroid concentrations and ovarian injury in PCOS rats. Both Map4k4 silencing in vivo and in vitro attenuated the PCOS-related GC oxidative stress and apoptosis. Mechanically, Map4k4 activated the JNK/c-JUN signaling pathway. Importantly, a JNK agonist restored the suppressive effects of Map4k4 silencing on PCOS-induced granulosa cell injury and oxidative stress. Besides, Map4k4 may be a target gene of miR-185-5p. In conclusion, Map4k4, a potential target of miR-185-5p, is up-regulated and induces ovarian GC oxidative injury by activating JNK/c-JUN pathway in PCOS. The Map4k4/JNK/c-JUN mechanism may provide a new idea on the treatment of PCOS.
研究领域:
生殖生物学
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分子生物学
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内分泌学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
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IF 5.6
Sisi Ruan,Jiqing Xie,Linhai Wang,Lulu Guo,Yan Li,Wu Fan,Rongzhan Ji,Zhenlin Gong,Yan Xu,Jian Mao,Jianping Xie
Introduction: Nicotine (Nic) has previously been proven to reduce neurodegeneration in the models of Parkinson’s disease (PD). The present study is intended to investigate the detailed mechanisms related to the potential neuroprotective effects of Nic in vivo . Methods: We established a PD model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced C57BL6 mice (25 mg/kg/d, 5 d, i.p.) to investigate the neuropharmacological modulation of Nic pretreatment (2.5 mg/kg/d, 5 d, i.p., 30 min before MPTP injection) from the perspectives of neurobehavioral assessment, the pathological alterations, microglial cell inflammation and MAPK signaling pathways in specific brain regions. Results: The open field test, elevated plus maze, rotarod and traction test suggested that Nic pretreatment could significantly improve MPTP-induced motor impairment and had an anxiolytic effect. Nic was found to improve neuroapoptosis, enhance tyrosine hydroxylase activity, and reduce the accumulation of the phosphorylated α-synuclein in the substantia nigra and striatal regions of PD mice by TUNEL and immunohistochemical assays. Immuno-fluorescent method for labeling Iba1 and CD68 indicated that Nic remarkably alleviates the activation of microglia which represents the M1 polarization state in the mice brain under MPTP stimulation. No significant difference in the expression of p38/MAPK pathway was found in the nigrostriatal regions, while Nic could significantly inhibit the elevated p-JNK/JNK ratio and increase the declined p-ERK/ERK ratio in the substantia nigra of MPTP-exposed brains, which was further confirmed by the pretreatment of CYP2A5 inhibitor to decline the metabolic activity of Nic. Discussion: The molecular signaling mechanism by which Nic exerts its neuroprotective effects against PD may be achieved by regulating the JNK and ERK signaling pathways in the nigra-striatum related brain regions.
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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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
·
IF 5.988
Xu Hao,Xu Guangyu,Xu Qianhui,Xu Chang,Zhou Xiaohu,Bai Yang,Yin Lu,Ding Yuan,Wang Weilin
Background: Intrahepatic Cholangiocarcinoma (iCCA) is a highly malignant tumor with limited treatment options that contributes largely to cancer-related deaths worldwide. Compared with traditional transcriptomic analysis, single-cell RNA sequencing (scRNA-seq) is emerging as a more advanced and popular tool for the in-depth exploration of cellular diversity and molecular complexity. As a next-generation proteasome inhibitor, MLN2238 presents better pharmacodynamics, pharmacokinetics, and therapeutic responses in various cancers. However, its effects and mechanisms of action in iCCA remain unknown.Methods: iCCA tumor heterogeneity was determined based on 4,239 qualified scRNA-seq data from 10 iCCA samples. The potential biological roles of proteasome-related genes in iCCA were investigated using a pseudo-trajectory reconstruction. The effect of MLN2238 on iCCA cell proliferation was estimated using the CCK-8, EdU, and clone formation assays. Flow cytometry was used to examine the effect of added MLN2238 on cell cycle and apoptosis levels. Autophagic flux was detected using AdPlus-mCherry-GFP-LC3B cells. ROS levels and mitochondrial membrane potential were determined using DCFH-DA probing and JC-1 staining. JNK activation and mitochondrial apoptosis were observed using western blotting and immunofluorescence microscopy, respectively. Finally, we used a tumor-bearing mouse model to validate its efficacy in vivo for iCCA treatment.Results: Proteasome-related genes were dysregulated in iCCA progression and expressed at higher levels in tumor tissues. MLN2238 suppressed cell proliferation, blocked the cell cycle in the G2/M phase, promoted apoptosis, and induced cytoprotective autophagy in iCCA cells. Furthermore, MLN2238 increased ROS levels and activated the JNK signaling pathway. Inhibition of ROS and JNK activation by NAC and SP600125 significantly reversed MLN2238-induced apoptosis. MLN2238 also suppressed the growth of iCCA tumors in vivo.Conclusion: Proteasome-related genes play pivotal roles in iCCA development. MLN2238, as a proteasome inhibitor, induces apoptosis in iCCA cells through ROS/JNK/mitochondrial signaling pathways, and hence, making MLN2238 a potential therapeutic choice for iCCA.
研究领域:
肿瘤学
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分子生物学
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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
ENVIRONMENTAL POLLUTION
·
2020
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IF 6.793
Xuying Lv,Zixuan Liu,Lei Xu,Erqun Song,Yang Song
Tetrachlorobenzoquinone (TCBQ) is a common metabolite of persistent organic pollutants pentachlorophenol (PCP) and hexachlorobenzene (HCB). Current reports on the toxicity of TCBQmainly focused on its reproductive toxicity, neurotoxicity, carcinogenicity and cardiovascular toxicity. However, the possible immunotoxicity of TCBQ remains unclear. The release of neutrophil extracellular traps (NETs) is a recently discovered immune response mechanism, however, excess NETs play a pathogenic role in various immune diseases. In an attempt to address concerns regarding the immunotoxicity of TCBQ, we adopted primary mouse neutrophils as the research object, explored the influence of TCBQ on the formation of NETs. The results showed that TCBQ could induce NETs rapidly in a reactive oxygen species (ROS)-dependent manner. Moreover, TCBQ promoted the phosphorylation of c-Jun N-terminal kinase (JNK) mitogen activated protein kinase (MAPK), but not p38 or extracellular signal related kinase (ERK) in neutrophils. Mechanistically, JNK activation enhanced the expression of NADPH oxidase enzyme 2 (NOX2), which further accelerated the generation of ROS and thus amplified the formation of NETs. The pharmacologic blockage of JNK or NOX2 effectively ameliorated TCBQ-induced ROS and NETs, implying that ROS-JNK-NOX2 positive feedback loop was involved in TCBQ-induced NETs. In conclusion, we speculated that targeting NETs formation would be a promising therapeutic strategy in modulating the immunotoxicity of TCBQ.
研究领域:
毒理学
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免疫学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2019
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IF 5.808
Yayun Liu,Wei Xu,Ting Zhai,Jiaojiao You,Yong Chen
Non-alcoholic steatohepatitis (NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro . The in vivo study was performed using male C57BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h, then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibinin significantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp , reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2E1 and CYP4A in vivo . These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β -oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity (CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity (CYP2E1 and CYP4A) to relieve oxidative stress.
研究领域:
药理学
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肝病学
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代谢性疾病
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
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2019
·Vol. 19
·期 3
·1781-1790
·
IF 1.851
Yan Luo,Daogong Zhang,Yueling Chen,Zhongsheng Cao,Zhaomin Fan
The brain‑derived neurotrophic factor (BDNF) and c‑Jun NH 2‑terminal kinase (JNK) signaling pathways are therapeutic targets to prevent degeneration in the central nervous system. Dexamethasone (DXMS), a glucocorticoid, protects against vestibular brain injury, however, the molecular mechanisms have yet to be fully elucidated. To investigate whether the BDNF and JNK signaling pathways are involved in the protective effects of DXMS in rats with vestibular dysfunction, a rat model of severe vestibular deficits was established by middle ear injection of arsanilic acid (AA; 100 mg/ml; 0.05 ml). After 3 days, rat symptoms and behavior scores with vestibular disorders were detected. In brain tissues, histopathological alterations, cell apoptosis, expression levels and patterns of BDNF signaling pathway‑associated BDNF, tyrosine receptor kinase B (TrKB) and K+/Cl‑ cotransporter isoform 2 (KCC2), and the expression of apoptosis‑related cleaved‑caspase 3 and the JNK signaling pathway were detected. It was identified that DXMS relieved AA‑induced vestibular dysfunction, leading to improvement in rat behavior scores to normal levels, minimizing brain damage at the histopatholojnnkngical level, reducing cell apoptosis, enhancing the expression of BDNF, TrKB and KCC2, and downregulating cleaved‑caspase 3 and phosphorylated‑JNK1/2 in brain tissues. Together, these findings indicated the protective effect of DXMS on AA‑induced rat vestibular dysfunction, and that activating BDNF and inhibiting JNK singling pathways were the underlying mechanisms. In addition, with additional treatment of mifepristone (RU486), a specific glucocorticoid agonist, all the events elicited by DXMS mentioned above in the AA‑treated rat rats were reversed. In conclusion, DXMS was identified as a therapeutic agent targeting the BDNF and JNK singling pathways for AA‑induced rat vestibular dysfunction.
研究领域:
神经科学
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药理学
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前庭障碍
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DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2020
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IF 5.186
Hong Lin,Chen Jundixia,Wu Fang,Wu Fengjiao,Shen Xin,Zheng Peisen,Shao Rongrong,Lu Kongqin,Liu Zhiguo,Chen Daoxing,Liang Guang,Cai Yuepiao,Zou Peng,Xia Yiqun
Colon cancer is one of the leading causes of cancer-related death in the world. The development of new drugs and therapeutic strategies for patients with colon cancer are urgently needed. Isodeoxyelephantopin (ESI), a sesquiterpene lactone isolated from the medicinal plant Elephantopus scaber L., has been reported to exert antitumor effects on several cancer cells. However, the molecular mechanisms underlying the action of ESI is still elusive. In the present study, we found that ESI potently suppressed cell proliferation in human colon cancer cells. Furthermore, our results showed that ESI treatment markedly increased cellular reactive oxygen species (ROS) levels by inhibiting thioredoxin reductase 1 (TrxR1) activity, which leads to activation of the JNK signaling pathway and eventually cell death in HCT116 and RKO cells. Importantly, we found that ESI markedly enhanced cisplatin-induced cytotoxicity in HCT116 and RKO cells. Combination of ESI and cisplatin significantly increased the production of ROS, resulting in activation of the JNK signaling pathway in HCT116 and RKO cells. In vivo, we found that ESI combined with cisplatin significantly suppressed tumor growth in HCT116 xenograft models. Together, our study provide a preclinical proof-of-concept for ESI as a potential strategy for colon cancer treatment.
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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产品关联
DOI
PubMed
高影响因子
POULTRY SCIENCE
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2022
·
IF 4.014
Yusong Miao,Dong Niu,Ze Wang,Jian Wang,Zhiyong Wu,Jiaxin Bao,Xiaodi Jin,Rui Li,Muhammad Ishfaq,Jichang Li
ABSTRACT Mycoplasma gallisepticum ( MG ) is an avian pathogen that commonly causes respiratory diseases in poultry. Methylsulfonylmethane ( MSM ) is a sulfur-containing natural compound that could alleviate inflammatory injury through its excellent anti-inflammatory and antioxidant properties. However, it is still unclear whether MSM prevents MG infection. The purpose of this study is to determine whether MSM has mitigative effects on MG-induced inflammatory injury in chicken and chicken like macrophages ( HD11 cells ). In this research, White Leghorn chickens and HD11 cells were used to build the MG-infection model. Besides, the protective effects of MSM against MG infection were evaluated by detecting MG colonization, histopathological changes, oxidative stress and inflammatory injury of trachea, and HD11 cells. The results revealed that MG infection induced inflammatory injury and oxidative stress in trachea and HD11 cells. However, MSM treatment significantly ameliorated oxidative stress, partially alleviated the abnormal morphological changes and reduced MG colonization under MG infection. Moreover, MSM reduced the mRNA expression of proinflammatory cytokines-related genes and decreased the number of death cells under MG infection. Importantly, the protective effects of MSM were associated with suppression of nuclear factor-kappa B ( NF-κB ) and extracellular signal-related kinases (ERK) /Jun amino terminal kinases (JNK) -mitogen-activated protein kinases ( MAPK ) pathway in trachea and HD11 cells. These results proved that MSM has protective effects on MG-induced inflammation in chicken, and supplied a better strategy for the protective intervention of this disease.
研究领域:
兽医学
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免疫学
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微生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Natural Products and Bioprospecting
·
2024
·Vol. 14
·期 1
·1-17
·
IF 4.8
Su Qiyuan,Hu Qian,Wu Songtao,Yang Suqin,Su Hanwen,Zhang Zhengjun,Ling Chengxiu
This study aimed to evaluate the therapeutic properties of the traditional Chinese medicine Xuesanqi (XSQ, from the rhizome of Polygonum amplexicaule D. Don) in treating ulcerative colitis. We hypothesized that its many active components can alleviate symptoms of colitis by regulating the gut microbiota, its metabolites, and various signaling pathways. To test our hypotheses, we designed a DSS- induced colitis model in C57BL/6 male mice. Apparent metrics were evaluated in each group of mice and performed histological analysis of relevant tissues. The gut microbial composition was analyzed by 16S rRNA sequencing of bacteria. Simultaneously, the SCFAs content was detected by gas chromatography, inflammatory factor secretion was evaluated by ELISA or western-blot, the expression of tight junction protein and key proteins of the MAPK signaling pathway were analyzed by western-blot. Our result showed that the treatment with XSQ alleviated significant various symptoms such as weight loss, blood in stool, and shortening of colon. In addition, XSQ treatment restored the dysregulated gut microbiota in colitis mice, increased short chain fatty acids (SCFAs) and normalized the MAPK/ERK/JNK signaling pathways, promoted expression of tight junction protein Occludin, Claudin-1, and E-cadherin proteins. Furthermore, we also observed a dose-dependent pattern in these treatment responses. These findings demonstrated the active components of XSQ is a promising new treatment platform for ulcerative colitis. Graphical
研究领域:
药理学
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胃肠病学
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微生物学
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免疫学
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传统中药
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产品关联
DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
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2022
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IF 5.202
Long Zhu,Yongjing Guan,Xuening Li,Xiaofan Xiong,Jialin Liu,Zaizhao Wang
Bisphenol-A (BPA) has been reported to disrupt blood-testis barrier (BTB) integrity in mammals. However, its effects on fish testis sertoli cell (SC) barrier and the underlying mechanisms have been largely unknown to date. To study the SC barrier toxicity induced by BPA, male rare minnows ( Gobiocypris rarus ) were exposed to 15 μg L − 1 BPA for 7, 14 and 21 d. Meanwhile, a 25 ng L −1 17α-ethynyl estradiol (EE2) group was set up as the positive control. Results showed that BPA induced immune response in the testes and decreased offspring hatching rate. The biotin tracer assay showed that BPA exposure destroyed the integrity of the testis SC barrier. In addition, BPA exposure decreased the expressions of occludin, ZO-1, CX43 and N-cadherin proteins. The transcripts of CX43 and occludin were significantly decreased and SP1 recruitment in each gene promoter was repressed after BPA exposure. Moreover, the cytokines (TNFα and IL-1β) were significantly increased while the JNK signal pathway was activated after BPA exposure. BPA also increased the matrix metalloproteinases 1 (MMP1) and MMP2 levels in the testes. In addition, estrogenic effect did not entirely explain the mechanism by which BPA disrupted the SC barrier in G. rarus testes. These results suggested that BPA disrupted the SC barrier integrity by inhibiting SP1 enrichments within CX43 and occludin 5′ flanking regions through activated cytokines/JNK signaling pathway. MMPs were also involved in the disruption of SC barrier caused by BPA exposure.
研究领域:
环境毒理学
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生殖生物学
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水生毒理学
✓ 已验证
DOI
PubMed
高影响因子
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