MOLECULAR NEUROBIOLOGY
·
2022
·Vol. 59
·期 11
·6903-6917
·
IF 5.682
Zhao Maofang,Cheng Yuan,Wang Xiaoxuan,Cui Xiaoying,Cheng Xiaojing,Fu Qian,Song Yilin,Yu Peiquan,Liu Yi,Yu Yinghua
Obesity has become a public health epidemic worldwide and is associated with many diseases with high mortality including hypertension, diabetes, and heart disease. High-fat diet (HFD)-induced energy imbalance is one of the primary causes of obesity, but the underlying mechanisms are not fully elucidated. Our study showed that HFD reduced the level of hydrogen sulfide (H 2 S) and its catalytic enzyme cystathionine β-synthase (CBS) in mouse hypothalamus and plasma. We found that HFD activated mTOR, IKK/NF-κB, the main pathway regulating inflammation. Activation of inflammatory pathway promoted the production of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α, which caused cell damage and loss in the hypothalamus. The disturbance of the hypothalamic neuron circuits resulted in body weight gain in HFD-induced mice. Importantly, we also showed that restoration of H 2 S level with NaHS or activation of CBS with SAMe attenuated HFD-induced activation of mTOR, IKK/NF-κB signaling, which reduced the inflammation and the neuronal cell loss in the hypothalamus, and also inhibited body weight gain in mice. The same effects were obtained by inhibiting mTOR or NF-κB, which suggested that mTOR and NF-κB were the critical molecular factors involved in hypothalamic inflammation. Taken together, this study identified that HFD-induced hypothalamus inflammation plays a critical role in the development of obesity. Moreover, the inhibition of hypothalamic inflammation by regaining H 2 S level could be a potential therapeutic to prevent the development of obesity. Graphical abstract
研究领域:
营养学
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内分泌学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2023
·
IF 3.6
Zhu Xiaona,Bai Bin,Ge Xiangting,Zheng Bin,Xiao Zhongxiang,Tang Yue,Fang Letong,Tang Yelin,Dai Yuanrong,Zhang Bing,Zhang Yali
Inflammation is an important pathological process of many acute and chronic diseases, such as sepsis, arthritis, and cancer. Many factors can lead to an inflammatory state of the body, among which bacterial infection plays an important role. Bacterial infection often leads to sepsis, acute lung injury (ALI), or its more serious form of acute respiratory distress syndrome, which are the main fatal diseases in intensive care units. Costunolide has been reported to possess excellent anti-inflammatory activity; however, whether it can affect inflammation induced by gram-negative bacterial is still unclear. Lipopolysaccharide (LPS) stimulated mouse peritoneal macrophages (MPMs) to release proinflammatory cytokines was used as the cell model. The mouse model of sepsis and ALI was built through injecting intravenously and intratracheally of LPS. In the present study, costunolide inhibited LPS-induced inflammatory response through IKK/NF-κB signaling pathway in macrophages. In vivo, costunolide attenuated LPS-induced septic death in mice. Meanwhile, costunolide treatment alleviated LPS-induced lung injury and inflammation via inhibiting the infiltration of inflammatory cells and the expression of inflammatory cytokines. Taken together, these results demonstrated that costunolide could attenuate gram-negative bacterial induced inflammation and diseases and might be a potential candidate for the treatment of inflammatory diseases.
研究领域:
免疫学
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药理学
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炎症研究
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Anti-Cancer Agents in Medicinal Chemistry
·
2018
·Vol. 18
·期 3
·422-427
·
IF 2.556
Kuang Shan,Sima Zhenhua,Liu Jiawei,Li Wuguo,Song Qiaoling,Zhang Qing,Yu Qiang
Background: 2-Methoxystypandrone (2-MS), isolated from the roots of Polygonum cuspidatum, is a potent dual inhibitor of the STAT3 and NF-ΚB pathways. Objective: To investigate the molecular targets and mechanisms of 2-MS. Method: A biotin-conjugated 2-MS analog, named
2-MS-Biotin, was designed and synthesized. The effects of 2-MS-Biotin on the STAT3 and NF-ΚB pathways were examined by Western blotting. The cytotoxicity of 2- MS-Biotin was evaluated using real-time cell analysis system. Proteins directly bound to 2-MS-Biotin were pulled down through
streptavidin agarose beads and were detected using Western blotting. Results: 2-MS-Biotin retained the inhibition activities of the parent compound 2-MS on the STAT3 and NF-ΚB pathways as well as on cancer cell growth. Also, JAK2 and IKK proteins can be effectively pulled down by
2- MS-Biotin. Conclusion: Using 2-MS-Biotin as a tool, both JAK2 and IKK were identified as the targets of 2-MS.
研究领域:
药理学
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分子生物学
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癌症研究
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生物化学
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2015
·
IF 2.084
Juanli Fu,Qiong Shi,Xiufang Song,Xiaomin Xia,Chuanyang Su,Zixuan Liu,Erqun Song,Yang Song
Tetrachlorobenzoquinone (TCBQ) is a joint metabolite of persistent organic pollutants (POPs), hexachlorobenzene (HCB) and pentachlorophenol (PCP). Previous studies have been reported that TCBQ contributes to acute hepatic damage due to its pro-oxidative nature. In the current study, TCBQ showed the highest capacity on the cytotoxicity, ROS formation and inflammatory cytokines release among four compounds, i.e., HCB, PCP, tetrachlorohydroquinone (TCHQ, reduced form of TCBQ) and TCBQ, in PC 12 cells. Further mechanistic study illustrated TCBQ activates nuclear factor-kappa B (NF-κB) signaling. The activation of NF-κB was identified by measuring the protein expressions of inhibitor of nuclear factor kappa-B kinase (IKK) α/β, p-IKKα/β, an inhibitor of NF-κB (IκB) α, p-IκBα, NF-κB (p65) and p-p65. The translocation of NF-κB was assessed by Western blotting of p65 in nuclear/cytosolic fractions, electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. In addition, TCBQ significantly induced protein and mRNA expressions of inflammatory cytokines and mediators, such as interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor inhibited these effects efficiently, further suggested TCBQ-induced inflammatory responses involve NF-κB signaling. Moreover, antioxidants, i.e., N-acetyl- l -cysteine (NAC), Vitamin E and curcumin, ameliorated TCBQ-induced ROS generation as well as the activation of NF-κB, which implied that ROS serve as the upstream molecule of NF-κB signaling. In summary, TCBQ exhibits a neurotoxic effect by inducing oxidative stress-mediated inflammatory responses via the activation of IKK/IκB/NF-κB pathway in PC12 cells.
研究领域:
毒理学
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神经科学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2020
·Vol. 40
·期 11
·1526-1533
·
IF 2.997
Yalei Yu,Youyou Zhang,Jie Zhang,Chuhuai Guan,Liang Liu,Liang Ren
Cantharidin is of high medicinal value but has strong toxicity. Nowadays, multiple research has focused on the mechanism of its antitumor activity while research on toxicological profiles associated with cantharidin poisoning is still limited. Its hepatotoxicity has attracted attention recently for the crucial role of the liver in detoxification. Here, we aim to find a potential mechanism for cantharidin-induced acute hepatotoxicity with a view to assisting subsequent research or clinical use or detoxification. Twenty-one male Sprague-Dawley rats were randomly divided into control, low-dose (1.34 mg/kg) and high-dose (2.67 mg/kg) cantharidin exposure groups. We used hematoxylin-eosin to observe pathological changes and used immunofluorescent staining, western blotting and real-time quantitative polymerase chain reaction to detect the expression of the markers. The main pathological changes in livers of cantharidin-treated rats were necrosis, inflammatory infiltration and hemorrhage. We found coexpression of tumor necrosis factor alpha (TNF-α), IkappaB kinase-alpha (IKK-α) and caspase3 by immunofluorescent staining in livers of cantharidin-treated rats. Compared with the control, the levels of TNF-α, IKK-α and caspase3 increased significantly in the experimental groups ( P < .05). The ratio of B-cell lymphoma-2 (Bcl-2)/Bax increased in the low-dose group but decreased in the high-dose group ( P < .05). Cantharidin exposure raised IKK-α mRNA and caspase3 mRNA levels ( P < .05). In conclusion, the participation of TNF-α, IKK-α, Bcl-2, Bax and caspase3 uncovered a novel mechanism underlying cantharidin-induced acute hepatotoxicity, and the mechanism needs to be studied further.
研究领域:
药理学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2022
·
IF 2.65
Yingying Cai,Jiali Hu,Mingjie He
Materials and Methods LOAD rats and A β microglia were constructed by using A β 1-40 and IBO mixture. The effect of KL-FGF23-VD axis on LOAD was investigated by transfecting overexpressing and interfering with KL gene adenovirus, and IKK-16 was added to A β microglia to explore the effect of KL-FGF23-VD axis on regulation of IKK/NF- κ B signaling pathway. Results The results showed that, in KL-OE group, FGF23 was decreased in the hippocampus of LOAD rats compared with control and KL-si, and the trend was opposite in the KL-si group. The KL-FGF23-VD axis can alleviate inflammatory response, reduce the deposition of A β , and inhibit activation of the NF- κ B pathway and neuron apoptosis in brain tissue of LOAD rats. In A β microglia, the expression of KL-FGF23-VD axis was consistent with animal experiments. The KL-FGF23-VD axis can inhibit the expression of A β microglia inflammatory factors and the activation of microglia and NF- κ B pathway. Meanwhile, IKK expression was decreased in KL-OE group compared with KL-si and Control. In the IKK-16 addition group, the ability of KL-FGF23-VD axis to inhibit the activation of microglia and NF- κ B pathway was enhanced. Conclusions These findings suggest a potential role of the KL-FGF23-VD axis in AD treatment by regulating the IKK/NF- κ B pathway.
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
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
·
IF 6.8
Yan Wang,Yue Zhang,Jinglong Xue,Leqiang Gao,Xiangyang Li,Moxuan Zhao,Dong Zhao,Xianqing Zhou
Decabromodiphenyl ether (BDE-209) is an environmental toxin. Increasing evidence showed that BDE-209 exposure induced liver injury, but the mechanism still remains unknown. The present study explored the effect and mechanism of ferroptosis on hepatotoxicity triggered by BDE-209 in vivo and in vitro . In vivo experiment, ICR mice were exposed to BDE-209 for 50 days, and then recovered for 50 days; HepG2 and L02 cells were treated with BDE-209 or/and ferrostatin-1 (Fer-1) for establishing in vitro model. In vivo , the results showed that BDE-209 accumulated in liver and induced liver damage, increased Fe 2+ and MDA contents, and blocked the activation of SLC7A11/GSH/GPX4 pathway in liver; BDE-209 also activated IKK/IκB/NF-κB pathway and elevated inflammatory cytokines levels in liver after exposure for 50 days. After BDE-209 stopping exposure 50 days, the severity of liver damage, ferroptosis and inflammatory response were still higher than the corresponding control group. In vitro , ferroptosis inhibitor Fer-1 rescued ferroptotic damage and attenuated cell death in BDE-209-treated HepG2 and L02 cells. In addition, Fer-1 reversed the activation of IKK/IκB/NF-κB pathway and the increase of pro-inflammatory cytokines levels in BDE-209-treated HepG2 and L02 cells. Together, the above results suggested that BDE-209 induced tissue damage and inflammatory response by activating ferroptosis through increasing iron-dependent lipid peroxidation and blocking the activation of SLC7A11/GSH/GPX4 pathway in liver, indicating that ferroptosis is a potential mechanism for BDE-209-induced hepatotoxicity.
研究领域:
毒理学
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肝病学
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细胞生物学
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环境科学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Haiying Liu,Yuqi Liu,Xiaoxi Lin,Jianhui Fan,Zhao Huang,Ao Li
Background Lipopolysaccharide (LPS) triggers the activation of nuclear factor kappa B (NF-κB) by interacting with Toll-like receptor 4 (TLR4), leading to the production of various proinflammatory enzymes and cytokines that are crucial in the development of acute lung injury (ALI). Mitoxantrone (MTX) has been demonstrated to mitigate the inflammatory response caused by LPS; however, its precise function in the context of ALI is not fully comprehended. Purpose This study aimed to investigate the inhibitory effects and underlying mechanisms of MTX against LPS-induced ALI. Methods ALI was induced in C57BL/6 mice via a single intratracheal administration of LPS (5 mg/kg), followed by an intraperitoneal injection of MTX to evaluate its therapeutic potential. The effects of MTX on lung injury and the progression of inflammation in ALI mice were assessed using a comprehensive range of techniques, including hematoxylin-eosin (H&E) staining, immunohistochemistry (IHC), myeloperoxidase activity measurement, cell enumeration in bronchoalveolar lavage fluid (BALF), Western blotting, and enzyme-linked immunosorbent assay (ELISA). Additionally, IHC, Western blotting, and co-immunoprecipitation were used to elucidate the specific signaling pathways and molecular mechanisms by which MTX exerted its anti-inflammatory effects in ALI mice. Surface plasmon resonance (SPR) and molecular docking were used to examine the target to which MTX binds directly to reduce inflammation. We also established a lung epithelial cell injury model using LPS-treated A549 cells. The polyubiquitination of IκBα and TRAF6 in LPS-induced A549 cells was detected through Western blotting following immunoprecipitation. Results In mice with LPS-induced ALI, MTX exhibits anti-inflammatory effects by ameliorating histopathological abnormalities caused by LPS, reducing inflammatory cell infiltration, and decreasing the production of proinflammatory enzymes and cytokines. It has been observed that MTX directly binds to the NEDD8 activating enzyme (NAE), thereby inhibiting the transfer of NEDD8 to the substrates UBC12, Cul1, and Cul5. Consequently, the polyubiquitination of IκBα and TRAF6 is disrupted, leading to the suppression of TAK1 activation by TRAF6. This suppression of TAK1 activity hindered the phosphorylation of IKK and MAPK. By stabilizing IκBα through dephosphorylation via IKK inhibition and preventing polyubiquitination, NF-κB activation is reduced. This cascade of events ultimately leads to a reduction in the production of proinflammatory enzymes and cytokines, effectively mitigating the inflammatory response in ALI. In A549 cells, MTX reduces the LPS-induced K48-linked polyubiquitination of IκBα and K63-linked polyubiquitination of TRAF6. This process can be reversed by the overexpression of NEDD8. Additionally, treatment with MG-132, a proteasome inhibitor, can restore the polyubiquitination of IκBα that was inhibited by MTX. Conclusions These findings confirm the essential role of Cul1/5 neddylation in ALI and suggest that MTX could be a promising therapeutic agent for ALI.
研究领域:
药理学
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免疫学
·
肺医学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Yihang Wu,Zixiu Liu,Zhenxiu He,Jumei Yi,Xingfang Qiao,Chunbin Tan,Yajing Xing,Yaobo Zeng,Dajian Yang,Junlin Yin,Baomin Fan,Guangzhi Zeng
Ulcerative colitis is a chronic inflammatory disease with a remitting-relapsing clinical course, it has evolved into a global burden given its high incidence worldwide. Cantharidin (CTD) derivatives are a class of compounds whose structures characterized with a 7-oxabicyclo [2.2.1]heptane core. Though potent cytotoxicity CTD and its derivatives showed, their clinical usage as anti-cancer drugs was limited by the toxicity in organs. In order to find new CTD analogues with good activity and lower toxicity, 21 CTD analogues with or without alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core were synthesized, some compounds showed better in vitro anti-inflammatory activity compared to CTD and norcantharidin (NCTD). Based on the structure-activity relationship results of in vitro experiment, analogue 3i was chosen for further study. Results from the acute toxicity in mice showed that 3i was hypotoxic with the single-dose MTD (maximum tolerated dose) for oral administration is over 1852 mg/kg, at least 35-fold lower than that of NCTD. Mechanism study indicated that 3i could potently inhibit TNF-α induced activation of NF-κB signaling by down-regulation the expression levels of phosphor- IKK, IκBα , and NF-κB p65 , and alleviated dextran sulfate sodium-induced colitis in mice. This study indicated that CTD analogues with alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core is a kind of new compounds with good anti-inflammatory activity and lower toxicity in vivo, and might be used as therapeutic agents for inflammatory diseases.
研究领域:
药理学
·
炎症
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药物发现
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
International Journal of Oral Science
·
2023
·Vol. 15
·期 1
·1-14
·
IF 14.9
Wang Yushang,Wang Lihua,Sun Tianyong,Shen Song,Li Zixuan,Ma Xiaomei,Gu Xiufeng,Zhang Xiumei,Peng Ai,Xu Xin,Feng Qiang
Fusobacterium nucleatum ( F. nucleatum ) is an early pathogenic colonizer in periodontitis, but the host response to infection with this pathogen remains unclear. In this study, we built an F. nucleatum infectious model with human periodontal ligament stem cells (PDLSCs) and showed that F. nucleatum could inhibit proliferation, and facilitate apoptosis, ferroptosis, and inflammatory cytokine production in a dose-dependent manner. The F. nucleatum adhesin FadA acted as a proinflammatory virulence factor and increased the expression of interleukin(IL)-1β, IL-6 and IL-8. Further study showed that FadA could bind with PEBP1 to activate the Raf1-MAPK and IKK-NF-κB signaling pathways. Time-course RNA-sequencing analyses showed the cascade of gene activation process in PDLSCs with increasing durations of F. nucleatum infection. NFκB1 and NFκB2 upregulated after 3 h of F. nucleatum -infection, and the inflammatory-related genes in the NF-κB signaling pathway were serially elevated with time. Using computational drug repositioning analysis, we predicted and validated that two potential drugs (piperlongumine and fisetin) could attenuate the negative effects of F. nucleatum -infection. Collectively, this study unveils the potential pathogenic mechanisms of F. nucleatum and the host inflammatory response at the early stage of F. nucleatum infection.
研究领域:
微生物学
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免疫学
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分子生物学
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干细胞研究
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2021
·
IF 4.581
Min Gu,Shihui Pan,Wanzhen Deng,Qing Li,Zezheng Qi,Chuwen Chen,Nan Bai
Soya-saponins represent key anti-nutritional factors that contribute to soybean meal-induced enteritis , and glutamine is an effective fish intestine protectant that combats the negative effects of soya-saponins. Nuclear transcription factor-kappa B (NF-кB) systems are involved in the interactions between soya-saponins and glutamine, and the goal of the present work was to clarify the related molecular mechanisms used by the NF-кB kinase (IKK)/inhibitor of NF-κB (IκB)/NF-кB system. Primary cultured turbot ( Scophthalmus maximus L.) intestinal epithelial cells were concurrently administrated with 1 mg/mL of soya-saponins and several levels of glutamine (0, 0.5, 1.0 and 2.0 mM) for 12 h and then subjected to real-time PCR and Western blot assays. Compared with cells treated with soya-saponins alone, glutamine significantly decreased the expression of interleukin-1 beta, interleukin 8 and tumor necrosis factor α genes, significantly reduced nuclear and cytosolic NF-κB p65 abundance levels in a dose-dependent manner, increased the IκBα protein level but decreased its phosphorylation, and down-regulated the IKKα/β and phosphorylated IKKα/β levels. In conclusion, this in vitro work confirmed that glutamine attenuated soya-saponin-induced inflammatory responses in turbot intestines. Moreover, it identified molecular pathways in which glutamine first decreased the p65 level and then prevented its nuclear translocation. In addition, glutamine reduced IκBα phosphorylation and maintained its level. Finally, glutamine decreased IKK expression and phosphorylation.
研究领域:
水产养殖
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2017
·
IF 2.956
Zhixin Peng,Xiaobao Gong,You Yang,Ligua Huang,Qingyan Zhang,Peng Zhang,Rongzhen Wan,Baoshun Zhang
Quercetin is regarded as a potential hepatoprotective agent in the treatment of acute liver injury. However, the underlying mechanism of how quercetin to protect against lipopolysaccharides/ d -galactosamine (LPS/ d -GalN) induced acute liver injury remains unclear. To investigate the mechanism, the antioxidative, anti-inflammatory and antiapoptotic responses were performed. The results showed that quercetin pretreatment improved the survival rate and substantially reduced the liver histopathological changes in mice. It also alleviated the hepatic damage and reduced the productions of oxidative markers induced by LPS/ d -GalN. In addition, quercetin pretreatment significantly diminished the production of inflammatory cytokines, including TNF-α, IL-6 and IL-1β, and inhibited the activation of the NF-κB and MAPK signaling pathways as well as the expression of apoptotic-related proteins induced by LPS/ d -GalN. We found that the potential mechanism of this quercetin-induced protection is mainly mediated through its powerful antioxidative capacity, inhibition of hepatocyte apoptosis and suppression of inflammatory cytokines through the IKK/NF-κB and MAPK signaling pathways. Thus, quercetin shows a promising therapeutic effect on acute liver injury in mice.
研究领域:
药理学
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免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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