ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Hongyan Li,Yiying Fu,Wangbao Gong,Guangjun Wang,Zhifei Li,Jingjing Tian,Kai Zhang,Ermeng Yu,Yun Xia,Wenping Xie,Jun Xie
The pregnane X receptor (PXR) / nuclear factor-kB (NF-kB) signaling pathway plays a critical role in regulating toxin-induced inflammation and apoptosis in mammals. Whether dietary curcumin (CUR) can prevent copper (Cu)-induced liver injury via this signaling pathway remains to be established in aquatic animals. Juvenile largemouth bass ( Micropterus salmoides ) were exposed to dietary Cu and CUR treatments for 8 weeks. The results showed that chronic Cu exposure induced oxidative stress, causing liver function damage and liver injury. Cu exposure stimulated inflammation by regulating nf-kb and pro-inflammatory genes such as tnfα and il-1β and promoted apoptotic signals in the liver by modulating bcl2 and casp3 mRNA levels. In addition, Pearson correlation analysis verified that inflammatory and apoptotic responses were important indicators of Cu-induced liver injury. CUR attenuated stress responses by enhancing the antioxidant system. Importantly, CUR significantly stimulated PXR mRNA and protein levels in the Cu + CUR group and suppressed NF-κB activation to inhibit the inflammatory and apoptotic signaling cascade. These results suggest that CUR may be an effective activator of PXR in teleost fishes, exerting cytoprotective effects on Cu-induced liver injury via a PXR-mediated NF-κB repression mechanism. In conclusion, this study is the first to demonstrate that CUR may act as a potent PXR ligand that exerts hepatoprotective effects against Cu-induced liver injury. The findings shed light on the specific regulatory role of the PXR/NF-κB signaling pathway in liver pathogenesis and its potential as a therapeutic target in teleost fishes.
研究领域:
水生毒理学
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分子生物学
·
营养学
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DOI
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2016
·
IF 3.584
Chongshan Dai,Bin Li,Yan Zhou,Daowen Li,Shen Zhang,Hui Li,Xilong Xiao,Shusheng Tang
The potential toxicity of quinocetone (QCT) has raised widely concern, but its mechanism is still unclear. This study aimed to investigate the protective effect of curcumin on QCT induced apoptosis and the underlying mechanism in human hepatocyte L02 cells. The results showed that QCT treatment significantly decreased the cell viability of L02 cell and increased the release of lactate dehydrogenase (LDH), which was attenuated by curcumin pre-treatment at 1.25, 2.5 and 5 μM. Compared to the QCT alone group, curcumin pre-treatment significantly attenuated QCT induced oxidative stress , mitochondrial dysfunction and apoptosis. In addition, curcumin pretreatment markedly attenuated QCT-induced increase of iNOS activity and NO production in a dose-dependent manner. Meanwhile, curcumin pretreatment markedly down-regulated the expression of nuclear factor –kB (NF-kB) and iNOS mRNAs, but up-regulated the expressions of Nrf2 and HO-1 mRNAs, compared to the QCT alone group. Zinc protoporphyrin IX , a HO-1 inhibitor, markedly partly abolished the cytoprotective effect of curcumin against QCT-induced caspase activation, NF-kB mRNA expression. These results indicate that curcumin could effectively inhibit QCT induced apoptosis and inflammatory response in L02 cells, which may involve the activation of Nrf2/HO-1 and inhibition of NF-kB pathway.
研究领域:
药理学
·
毒理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR ENDOCRINOLOGY
·
2022
·
IF 4.369
Dandan Wang,Yixin Zhang,Liangyi Cui,Qing Yang,Jiao Wang
Endometriosis , defined as the abnormal growth of functional endometrium outside the uterus , is characterized by the abnormal phenotype of endometrial cells. This study aimed to investigate the role of latent transforming growth factor beta binding protein 2 (LTBP2), an extracellular matrix protein , in the occurrence and development of endometriosis. Elevated LTBP2 expression levels were observed in endometrial tissues and serum of endometriosis patients and their area under the ROC curve (AUC) values for distinguishing endometriosis were 0.9044 and 0.9534, respectively. Overexpressing-LTBP2 could promote proliferation, migration, and invasion, whereas suppressing apoptosis of endometrial stromal cells (ESCs). Moreover, LTBP2 downregulation induced the opposite effect. The supernatant from ESCs overexpressing LTBP2 promoted the tube formation of human umbilical vein endothelial cells (HUVECs), thus indicating an angiogenic effect. Furthermore, overexpression of LTBP2 facilitated the inflammation and might promote endometriosis progression through the NF- k B signaling pathway . Conclusively, LTBP2 might be a potential target in the diagnosis and treatment of endometriosis.
研究领域:
妇科学
·
分子生物学
·
细胞生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INVESTIGATIVE DERMATOLOGY
·
2023
·
IF 6.5
Qinqin Meng,Mei Bai,Meiliang Guo,Zhengxiao Li,Wanwen Liu,Xiaojing Fan,Rui Sun,Xinrong Yang,Dingfen Yuan,Yuling Shi,Hui Deng
Although the anti-inflammatory effect of serum- and glucocorticoid-regulated protein kinase 1 (SGK1) has been established in other diseases, the possible regulatory role of SGK1 in psoriasis and the underlying molecular mechanisms remain largely unknown. In this study, we found that SGK1 expression was decreased in macrophages from patients with psoriasis. Moreover, a specific pharmacological SGK1 inhibitor, EMD638683, significantly enhanced imiquimod-mediated toll-like receptor 7/8 activity and proinflammatory cytokine production in RAW264.7 cells, and this result was confirmed by Sgk1 small interfering RNA . Further mechanistic data showed that SGK1 inhibition increased the phosphorylation of Bruton’s agammaglobulinemia tyrosine kinase ; moreover, Bruton’s agammaglobulinemia tyrosine kinase inhibition abrogated the proinflammatory effects of the SGK1 inhibitor on toll-like receptor 7/8 activation, thereby validating that SGK1 inhibition enhances the toll-like receptor 7/8 pathway by increasing Bruton’s agammaglobulinemia tyrosine kinase phosphorylation. In addition, our in vivo results showed that SGK1 inhibition significantly increased the secretion of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, and the infiltration of T helper 17 cells in an imiquimod-induced psoriasis mouse model. Altogether, these results show that SGK1 plays a critical role in the pathogenesis of psoriasis by modulating inflammatory responses in skin lesions , indicating that SGK1‒Bruton’s agammaglobulinemia tyrosine kinase signaling could be a novel therapeutic target for the control of psoriasis.
研究领域:
免疫学
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皮肤病学
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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
Journal of Advanced Research
·
2024
·
IF 11.4
Jun Ma,Peng Yang,Zhibin Zhou,Tengfei Song,Liang Jia,Xiaofei Ye,Wei Yan,Jiuyi Sun,Tianwen Ye,Lei Zhu
Introduction Osteoarthritis (OA) is the most common arthritis that is characterized by the progressive synovial inflammation and loss of articular cartilage. Although GYY4137 is a novel and slow-releasing hydrogen sulfide (H 2 S) donor with potent anti-inflammatory properties that may modulate the progression of OA, its underlying mechanism remains unclear. Objectives In this study, we validated the protective role of GYY4137 against OA pathological courses and elucidated its underlying regulatory mechanisms. Methods Cell transfection, immunofluorescence staining, EdU assay, transmission electron microscopy, mitochondrial membrane potential measurement, electrophoretic mobility shift assay, sulfhydration assay, qPCR and western blot assays were performed in the primary mouse chondrocytes or the mouse macrophage cell line raw 264.7 for in vitro study. DMM-induced OA mice model and Macrophage-specific p65 knockout (p65 f/f LysM-CreER T2 ) mice on the C57BL/6 background were used for in vivo study. Results We found that GYY4137 can alleviate OA progress by suppressing synovium pyroptosis in vivo. Moreover, our in vitro data revealed that GYY4137 attenuates inflammation-induced NLRP3 and caspase-1 activation and results in a decrease of IL-1β production in macrophages. Mechanistically, GYY4137 increased persulfidation of NF-kB p65 in response to inflammatory stimuli that results in a decrease of cellular reactive oxygen species (ROS) accumulation and ameliorates mitochondrial dysfunctions. Using site-directed mutagenesis, we showed that H 2 S persulfidates cysteine38 in p65 protein and hampers p65 transcriptional activity, and p65 mutant impaired macrophage responses to GYY4137. Conclusion These findings suggest a mechanism by which GYY4137 through redox modification of p65 participates in inhibiting NLRP3 activation by OA to regulate inflammatory responses. Thus, we propose that GYY4137 represents a promising novel therapeutic strategy for the treatment of OA.
研究领域:
风湿病学
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免疫学
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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
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Zhiruo Fang,Yu Yao,Liping Cao,Jiancao Gao,Quanjie Li,Zhijuan Nie,Yi Sun,Gangchun Xu,Jinliang Du
This study investigated the toxicological mechanism of deltamethrin on Chinese mitten crab Eriocheir sinensis juveniles in fresh water. We first conducted an acute toxicity test, followed by laboratory methods to detect changes in immune-related indices in terms of antioxidant enzyme markers, lipid metabolism-related genes, and autophagy-related and apoptosis genes. The acute toxicity (96-h LC50) of deltamethrin to E. sinensis was 7.195 μg/L. After 48 h of exposure, serum showed elevated immune-related indices ( P < 0.05) for alkaline phosphatase (AKP), acid phosphatase (ACP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), complement components C3 and C4, and the key pro-inflammatory cytokines interleukin-6, interleukin-1β, and tumor necrosis factor alpha (TNF-α). In hepatopancreas at 48 h, indicators related to the antioxidant system, namely superoxide dismutase (SOD) and glutathione (GSH), were significantly elevated, whereas nitric oxide and total antioxidant capacity (T-AOC) were decreased ( P < 0.05). In contrast, lipid metabolism indices for triglyceride (TG), total cholesterol (TC), and malondialdehyde (MDA) were increased ( P < 0.05). Transcriptomics and metabolomics revealed that exposure to deltamethrin disrupted the lipid metabolic process in the hepatopancreas mainly by altering fatty acid synthesis, amino acid metabolism, immune signaling, and autophagy activation, while the exposure increased the content of phospholipids and cholesterol but decreased the levels of amino acids and palmitoleic acid. Quantitative genetics revealed significantly aberrantly expressed ( P < 0.05) lipid metabolism-related genes, including acc1 , fasn , scd1 , and pnpla2 , all key genes involved in lipid accumulation. Deltamethrin exposure also significantly altered ( P < 0.05) gene expression levels for Toll-like receptor ( tlr ), myeloid differentiation factor 88 ( myd88 ), crustin1 , anti-lipopolysaccharide factor isoform 3 ( alf3 ), tumor necrosis factor alpha ( tnf-α ), and NF-κB transcription factor relish . Furthermore, deltamethrin activated the toll-like receptor/major myeloid differentiation response gene 88/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR/MyD88/NF-kB) signaling pathway, which activates a nonspecific immune response in E. sinensis . Additionally, carnitine palmitoyltransferase 1 A ( cpt1a ), cytochrome c ( cyt-c ), adenosine 5′-monophosphate (amp)-activated protein kinase ( ampk ), the autophagosomal protein microtubule-associated protein 1 light chain 3c ( lc3c ), and the autophagy-related proteins beclin1 , atg5 , atg12 were significantly induced ( P < 0.05) in the adenosine monophosphate-activated protein kinase/rapamycin (AMPK/mTOR) signaling pathway. These changes resulted in excess free radicals, causing oxidative stress in the mitochondrial membrane, promoting mitochondrial autophagy. The results confirm that deltamethrin exposure can induce hepatopancreatic injury by promoting mitochondrial autophagy, activating an immune response, and inhibiting lipid metabolism. Overall, this study provides multi-level information to reveal the toxic effects of deltamethrin on E. sinensis .
研究领域:
毒理学
·
分子生物学
·
环境科学
·
水生生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Qing Shu,Song Lai,Xiao-Mei Wang,Yun-Long Zhang,Xiao-Lei Yang,Hai-Lian Bi,Hui-Hua Li
Pathological cardiac hypertrophy is the main risk factor for heart diseases. The ubiquitin-proteasome system (UPS) is the major intracellular protein degradation system involved in the development of cardiac hypertrophic remodeling. Ubiquitin-activating enzyme E1, a key component of the UPS, catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation via proteasome . However, the functional role of E1 (UBA1) in regulation of hypertrophic remodeling in angiotensin II (Ang II)-infused mice remains unknown. In this study, male wild-type mice were treated with UBA1 inhibitor PYR-41 at two doses of 5 and 10 mg and infused with Ang II (1000 ng/kg/min) for 14 days. Systolic blood pressure was detected by using tail-cuff system. Cardiac function was assessed by echocardiography. Hypertrophic remodeling was analyzed examined by histological examinations. The expressions of genes and proteins were detected by quantitative real-time PCR and immunoblotting analysis. After 14 days, Ang II infusion significantly increased UBA1 expression at both mRNA and protein levels in the hearts. Furthermore, Ang II-infused mice showed a significant increase in systolic blood pressure compensatory cardiac function, hypertrophy, interstitial fibrosis, inflammation and oxidative stress compared with saline-treated controls, whereas these effects were dose-dependently attenuated in PYR-41-treated mice. These beneficial actions were associated mainly with inhibition of PTEN degradation and multiple downstream mediators (AKT, ERK1/2, STAT3 , TGF-β/Smad2/3 and NF-kB(p65)). In conclusion, these results indicate that inhibition of UBA1 suppresses Ang II-induced hypertrophic remodeling, and suggest that administration of low dose PYR-41 may be a new potential therapeutic approach for treating hypertensive heart diseases.
研究领域:
心脏病学
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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
PHYTOMEDICINE
·
2022
·
IF 6.656
Shuang Luo,Jinrong He,Shaowei Huang,Xiaojing Wang,Yulin Su,Yanyang Li,Yanping Chen,Guanghua Yang,Bin Huang,Shaoju Guo,Lian Zhou,Xia Luo
Background Emodin is an active ingredient of traditional Chinese medicine Rheum palmatum L. and Polygonum cuspidatum , which possesses anti-inflammatory and intestinal mucosal protection effects. Our previous study found that emodin significantly alleviated ulcerative colitis induced by sodium dextran sulfate (DSS). In this study, we found the underlying mechanism of emodin on ulcerative colitis (UC). Purpose We aimed to further explore the mechanism of emodin in the treatment of ulcerative colitis from the perspective of metabolism and intestinal flora . Methods Ulcerative colitis was induced by 3% sodium dextran sulfate (DSS) on mice, and the mice were respectively treated with mesalazine , rosiglitazone , emodin, and emodin combined with GW9662 (PPARγ inhibitor) simultaneously. Weight changes , the disease activity index (DAI), colonic length, and pathologic changes in colon were used to evaluate the efficacy of emodin. LC-MS/MS was performed for metabolomics analysis of colon. In addition, intestinal flora was assessed using 16S rDNA sequencing. A vector-based short hairpin RNA (shRNA) method was used to silence PPARγ gene expression in Caco-2 cells. Results Emodin binds to the active site of PPARγ protein and forms hydrogen bond interaction with ARG288 and CYS285 amino acids. Furthermore, Emodin significantly promotes the protein expression of PPARγ, while inhibiting iNOS and NF-kB p65 in UC mice, however, this effect is hardly shown when it is combined with GW9662 (the inhibitor of PPARγ). Meanwhile, emodin suppresses the expression of iNOS in Caco-2 cells induced with IFNγ and IL-22, but has no effect on its expression in shPPARγ-Caco-2 cells. In addition, through activating PPARγ signal pathway , emodin is capable of regulating colonic metabolism including oxidative phosphorylation and citrulline metabolism and effecting luminal availability of oxygen and nitrate. This promotes the recovery of anoxic environment of colon epithelial cells, which strains the growth and expansion of Enterobacteriaceae . Conclusion The mechanism of Emodin in the treatment of ulcerative colitis relies on its regulation of PPARγ signal pathway, which could modulate colonic metabolism and restore intestinal homeostasis .
研究领域:
药理学
·
胃肠病学
·
分子生物学
·
免疫学
·
微生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
·
IF 16.744
Zhehan Yang,Zhenjia Yang,Xiaoshu Lv,Guangming Jiang,Xiaolong Zhang,Xiaodan Li,Xiaoyu Li,Ruo Yuan,Ying Zhuo
Quantifying trace markers in clinical samples with electrochemical impedance spectroscopy (EIS) biosensors is limited mainly by ubiquitous biofouling because traditional antifouling coatings suffer from low stability and unsatisfactory antifouling capability etc. Herein, a simple and effective strategy was constructed to achieve a highly specific EIS biosensing platform for quantifying protein and DNA in serum by using single-stranded oligonucleotides (ssDNA) as antifouling coating. To achieve the optimized antifouling capability of ssDNA coating, the influence factors of ssDNA structure are investigated by combining electrochemical experiments with theoretical calculations. The results demonstrated that the chemical adsorption of adenine on the Au surface is stronger than that of the other three bases, which endows the poly adenine-ssDNA (polyAn) coating with outstanding antifouling capability. Importantly, we found that the capture ligand structure and ssDNA length remarkably affected the antifouling capability of polyAn because of steric hindrance. As a proof of concept, EIS biosensors based on polyAn antifouling coating were developed to detect target DNA and nuclear factor kappa b p65 (NF-kB p65), respectively, exhibiting outstanding capability of detecting DNA and NF-kB p65 in human serum with low interference and good accuracy. Overall, the presented work may contribute to a deeper understanding of the influence factors of ssDNA-based antifouling coating and holds great insight into the construction of highly specific biosensors for quantifying disease markers in clinical samples.
研究领域:
生物传感器
·
分析化学
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生物化学
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分子生物学
·
临床诊断
✓ 已验证
产品关联
DOI
高影响因子
CURRENT CANCER DRUG TARGETS
·
2022
·Vol. 22
·期 9
·771-783
·
IF 2.907
Cui Zhi,Sun Shiqun,Li Jia,Li Jianing,Sha Tong,He Jie,Zuo Linjing
Background: Inhibitor of growth 4 (ING4) level was reported to be decreased in head and neck squamous cell carcinoma (HNSC) tissue, however, it is unknown whether and how ING4 participates in regulating the development of oral squamous cell carcinoma (OSCC). Objective: This study
aimed to investigate the role and mechanism of ING4 in OSCC. Methods: ING4 was forced to up- or down-regulated in two OSCC cell lines, and its effects on the malignant behavior of OSCC cells were investigated in vitro. The ubiquitination level of NF-kB p65 in ING4 upregulated cells was
measured by co-immunoprecipitation. Moreover, the effects of ING4 on the methylation level of ALDH1A2 were evaluated by methylation-specific polymerase chain reaction (MSP) assay. The role of ING4 in OSCC growth in vivo was observed in nude mice. Results: Our results showed that the expression
of ING4 in OSCC cell lines was lower than that in normal oral keratinocyte cells. In vitro, ING4 overexpression inhibited the proliferation, migration, and invasion of OSCC cell lines and ING4 silencing exhibited opposite results. We also demonstrated that ING4 overexpression promoted the
ubiquitination and degradation of P65 and reduced DNA methyltransferase 1 (DNMT1) expression and Aldehyde dehydrogenase 1A2 (ALDH1A2) methylation. Moreover, overexpression of p65 rescued the suppression of malignant behavior, induced by ING4 overexpression. In addition, ING4 negatively regulated
the growth of OSCC xenograft tumors in vivo. Conclusion: Our data evidenced that ING4 played a tumor-repressing role in OSCC in vivo and in vitro via NF-ΚB/DNMT1/ALDH1A2 axis.
研究领域:
肿瘤学
·
细胞生物学
·
分子生物学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
Nature Communications
·
2022
·Vol. 13
·期 1
·1-17
·
IF 17.694
Wang Weili,Zheng Huizhen,Jiang Jun,Li Zhi,Jiang Dongpeng,Shi Xiangru,Wang Hui,Jiang Jie,Xie Qianqian,Gao Meng,Chu Jianhong,Cai Xiaoming,Xia Tian,Li Ruibin
While hypoxia promotes carcinogenesis, tumour aggressiveness, metastasis, and resistance to oncological treatments, the impacts of hyperoxia on tumours are rarely explored because providing a long-lasting oxygen supply in vivo is a major challenge. Herein, we construct micro oxygen factories, namely, photosynthesis microcapsules (PMCs), by encapsulation of acquired cyanobacteria and upconversion nanoparticles in alginate microcapsules. This system enables a long-lasting oxygen supply through the conversion of external radiation into red-wavelength emissions for photosynthesis in cyanobacteria. PMC treatment suppresses the NF-kB pathway, HIF-1α production and cancer cell proliferation. Hyperoxic microenvironment created by an in vivo PMC implant inhibits hepatocarcinoma growth and metastasis and has synergistic effects together with anti-PD-1 in breast cancer. The engineering oxygen factories offer potential for tumour biology studies in hyperoxic microenvironments and inspire the exploration of oncological treatments.
研究领域:
生物医学工程
·
肿瘤学
·
纳米技术
·
细胞生物学
·
分子生物学
✓ 已验证
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
✓ 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）