CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2021
·Vol. 26
·期 1
·1-16
·
IF 5.787
Xing Ying,Liu Yang,Qi Zhong,Liu Zhengrong,Wang Xin,Zhang Hongyi
Background Hepatocellular carcinoma (HCC) is now the second leading cause of cancer death worldwide and lacks effectual therapy due to its high rate of tumor recurrence and metastasis. The aim of this study was to investigate the effects of L antigen family member 3 (LAGE3, a member of the LAGE gene family involved in positive transcription) on the progression of HCC. Methods The expression of LAGE3 was detected by quantitative real-time polymerase chain reaction. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation assay, EdU, and cell cycle analysis assay were employed to evaluate the proliferation of HCC cells. Annexin V-FITC/PI and TUNEL assay were used to assess the apoptosis rate of HCC cells. Wound healing and transwell assay were used to investigate the migration and invasion of HCC cells. A xenograft model of HCC was established with 2 × 10 6 Hep3B or SK-HEP1 cells to investigate the in vivo effects of LAGE3. Then, the protein levels of LAGE3, p-p38, p-38, c-Jun N-terminal kinase (JNK),p-JNK, extracellular signal-regulated kinase (ERK), and p-ERK were detected by western blot. Results We found that LAGE3 was upregulated in HCC tissues compared to adjacent tissues, and its high expression was correlated with poor overall survival by bioinformatics analysis. Next, we manually regulated the expression of LAGE3 in HCC cells. The knockdown of LAGE3 inhibited the proliferation of HCC cells by arresting the cell cycle in G1 phase. Also the downregulation of LAGE3 inhibited cell migration and invasion and induced apoptosis of HCC cells, while overexpression of LAGE3 promoted the malignant phenotypes of HCC. These results were further confirmed by the in vivo growth of HCC xenografts and the inhibition of apoptosis of HCC tumor cells. Furthermore, we found that LAGE3 exerted cancer-promoting effects by potentiating the JNK and ERK signaling pathway. An ERK inhibitor (10 μM SCH772984) or JNK inhibitor (25 μM SP600125) repressed the upregulated LAGE3-induced proliferation, migration, and invasion of HCC cells. Conclusions LAGE3 enhanced the malignant phenotypes of HCC by promoting the JNK and ERK signaling pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2024
·
IF 8.2
Peisen Zheng,Yiqun Xia,Xin Shen,Hui Lu,Yinghua Chen,Chenxin Xu,Chenyu Qiu,Yafei Zhang,Peng Zou,Ri Cui,Xiaoying Huang
Lung cancer is one of the most lethal diseases in the world. Although there has been significant progress in the treatment of lung cancer, there is still a lack of effective strategies for advanced cases. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, has achieved much attention due to its antitumor properties. Nevertheless, the use of lenvatinib is restricted by the characteristics of poor efficacy and drug resistance. In this study, we assessed the effectiveness of lenvatinib combined with thioredoxin reductase 1 (TrxR1) inhibitors in human lung cancer cells. Our results indicate that the combination therapy involving TrxR1 inhibitors and lenvatinib exhibited significant synergistic antitumor effects in human lung cancer cells. Moreover, siTrxR1 also showed significant synergy with lenvatinib in lung cancer cells. Mechanically, we demonstrated that ROS accumulation significantly contributes to the synergism between lenvatinib and TrxR1 inhibitor auranofin. Furthermore, the combination of lenvatinib and auranofin can activate endoplasmic reticulum stress and JNK signaling pathways to achieve the goal of killing lung cancer cells. Importantly, combination therapy with lenvatinib and auranofin exerted a synergistic antitumor effect in vivo . To sum up, the combination therapy involving lenvatinib and auranofin may be a potential strategy for treating lung cancer.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 11
·1296
·
IF 6
Yue Liu,Chunhong Chen,Zhihui Hao,Jianzhong Shen,Shusheng Tang,Chongshan Dai
Exposure to cadmium sulfate (CdSO4) can lead to neurotoxicity. Nevertheless, the precise molecular mechanisms underlying this phenomenon remain unclear, and effective treatment strategies are scarce. This study explored the protective effects of ellagic acid (EA), a natural polyphenolic compound, against CdSO4exposure-induced neurotoxicity in HT22 cells and the underlying molecular mechanisms. Our findings demonstrated that exposure of HT22 cells to CdSO4resulted in apoptosis, which was effectively reversed by EA in a dose-dependent manner. EA supplementation also decreased reactive oxygen species (ROS) and mitochondrial ROS production, reduced malondialdehyde (MDA) levels, and restored the activities of superoxide dismutase (SOD) and catalase (CAT). Additionally, EA supplementation at 5–20 μM significantly counteracted Cd-induced the loss of mitochondrial membrane potential and the decrease of ATP and reduced the ratio of Bax/Bcl-2 and cleaved-caspase-3 protein expression. Furthermore, EA supplementation resulted in the upregulation of Nrf2 and HO-1 protein and mRNAs while simultaneously downregulating the phosphorylation of JNK and p38 proteins. The pharmacological inhibition of c-Jun N-terminal kinase (JNK) partially attenuated the activation of the Nrf2/HO-1 pathway induced by CdSO4and exacerbated its cytotoxic effects. In conclusion, our findings suggest that ethyl acetate (EA) supplementation offers protective effects against CdSO4-induced apoptosis in HT22 cells by inhibiting oxidative stress and activating the Nrf2 signaling pathway. Furthermore, the activation of the JNK pathway appears to play a protective role in CdSO4-induced apoptosis in HT22 cells.
研究领域:
毒理学
·
药理学
·
细胞生物学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Jinping Wang,Jianmin Wu,Zishen Lin,Ning Ma,Zhaoyue Men,Chao Zhang,Xi Ma,Hongyu Zheng
The invasion of pathogens derived from diet or the environment triggers intestinal inflammation, which is a result of the host intestinal barrier damage and immune dysfunction, such as the decrease of host defense peptides (HDPs) and inhibition of cell proliferation. Herein, the siRNA interference demonstrated that a critical lysozyme, which was mainly induced by dietary supplementations of sodium butyrate and forskolin, improved cell proliferation by inhibiting p38 MAPK and JNK signaling pathways and reinforced the intestinal barrier. Moreover, we established a mouse model of intestinal inflammation with Citrobacter rodentium ( C. rodentium ). It was found that NaBu and FSK stimulated intestinal epithelial proliferation to repair barrier damage, and performed stronger disease resistance to C. rodentium infection on account of the lysozyme upregulation in colon. Therefore, this study revealed that NaBu and FSK prevented or alleviated the development of foodborne infections by promoting lysozyme expression, which may be mediated by the effect of lysozyme on promoting cell proliferation and improving barrier function.
研究领域:
胃肠病学
·
免疫学
·
分子生物学
·
微生物学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Dan Wang,Yimeng Zou,Tianqi Zhao,Weiyue Cao,Jiachi Han,Qing Wu,Zhitong Li,Xinyu Li,Peijing Liu,Lin Bai,Guiping Ren
Background The blood FGF21 expression has been previously suggested to increase in patients developing atopic dermatitis (AD) and asthma. However, its impact on atopic march is rarely analyzed. The present work focused on investigating the role of Fibroblast Growth Factor 21(FGF21) in atopic march mice and its underlying mechanisms. Methods The models were induced with Diisononyl phthalate (DINP) and OVA in wild-type C57BL/6 and FGF21 −/− mice. RAW264.7 cells were induced by LPS with/without FGF21 or KLB-SiRNA for in vitro analyses. Results The data indicated that there were more severe allergic reactions including IgE levels and the proportion of mast cells in the blood of FGF21 −/− mice in relative to WT model mice during the progression from AD to asthma. However, exogenous administration of FGF21 inhibited allergies. In this study, we reported that FGF21 mitigated AD-like lesions and Th1/2 or Th17/Treg cell imbalance in AD mice, and significantly decreased TSLP, IL-33, IL-4, IL-5, IL-13 and IL-17A expression on skin. During the asthma phase, FGF21 improved airway remodeling by downgrading inflammatory factors IL-4, IL-5, IL-13 and IL-17A; fibrotic markers α-SMA and Collagen I; and oxidative products MDA and ROS in wild-type model mice. Compared with WT model mice, the adverse consequences were aggravated in FGF21 −/− asthmatic mice. From the mechanistic perspective, FGF21 suppressed NF-κB/NLRP3, TGF-β1/Smad3 and JNK signaling pathways and increased Nrf2 expression in vivo and in vitro. In addition, β-Klotho knockdown attenuated the ameliorative impact of FGF21 on cellular damage. Blocking AMPKα in the LPS-treated RAW264.7 cells inhibited the reduction of FGF21 and the phosphorylation of JNK. Conclusions To conclude, FGF21 alleviated atopic march by inhibiting Th2/17 immune response, and reduced airway remodeling by regulating NF-κB/NLRP3, TGF-β1/Smad3 and AMPKα/JNK pathways. Moreover, this study provides a rationale and novel ideas for applying FGF21 in treating AD and asthma.
研究领域:
免疫学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2019
·
IF 3.17
Zhiyu Xi,Xibei Hu,Xiao Chen,Yong Yang,Jie Ren,Baofeng Wang,Zhihong Zhong,Yuhao Sun,Guo-Yuan Yang,Qingfang Sun,Liuguan Bian
Protocatechuic acid (PCA) has been well studied for its neuroprotection value in several diseases, but the effect in intracerebral haemorrhage (ICH) has not been reported. Here we verified the protection of PCA in ICH, and investigated the relative mechanisms. ICH model mice were established by injection of collagenase IV. The mice were treated with PCA once per day for 3 days, starting immediately after operation. The modified neurological severity score (mNSS) of mice at 1st, 3rd and 7th day after operation were recorded. And some of mice were euthanized at 3rd day to compare brain water content, pro-inflammatory cytokines expression, and cell apoptosis in perihematomal tissue. Additionally, SH-SY5Y cells were treated hemin to mimic secondary injury of ICH. Cells were incubated with PCA for treatment. The cell viability , ROS , apoptosis rate and protein expression of apoptosis-relative protein and MAPKs and NF-κB were detected and analysed. The results revealed PCA alleviated the cerebral oedema at 3rd post ICH, and significantly improved neurological functions. PCA also attenuated the protein and gene expression of TNF-а, IL-1β and IL-6 vivo. PCA dose-dependently decreased the generation of ROS and apoptosis rate. Furthermore, PCA treatment dose-dependently decreased the expression of bax, cleaved caspase-3, increased bcl-2 expression; PCA downregulated P38/JNK-NF-κB pathway. In conclusion, PCA effectively improves prognosis of ICH mice by inhibiting oxidative stress , inflammation and apoptosis. The mechanism possibly results of downregulating of P38/JNK-NF-κB pathway, and PCA can be a potential therapeutic agent for ICH.
研究领域:
神经科学
·
药理学
·
分子生物学
·
病理生理学
✓ 已验证
DOI
PubMed
高影响因子
STEROIDS
·
2020
·
IF 1.948
Jingwen Xu,Zhe Wang,Yuying Huang,Yihai Wang,Limin Xiang,Xiangjiu He
T-17, a bioactive spirostanol saponin extracted from Tupistra chinensis Baker, was previously reported with anti-inflammatory and cytotoxic activities. However, the mechanism underlying of its anti-proliferation activity remains to be elucidated. In this study, we investigated the anti-gastric cancer cell growth activity of T-17 in terms of cell viability, colony formation, cell cycle, induction of apoptosis/autophagy, and JNK pathway. T-17 showed dose-dependent cytotoxicity in SGC-7901 and AGS cell lines, it induced caspase-mediated apoptosis as well as G0/G1 phase arrest and modulation of cyclinE2 and p21 expression. In addition, T-17 promoted the cancer cell autophagy as evidenced with increased expression of Beclin-1 and decreased p62 in western blot and formation of GFP-LC3 puncta. Furthermore, T-17-induced autophagy decreased gastric cancer cell apoptosis as assessed by pharmacological autophagy inhibitors and ATG5 siRNA usage. Importantly, the activation of JNK pathway was simultaneously involved in T-17-induced apoptosis and autophagy. Taken together, the results suggest that T-17 is a promising cytotoxic agent for therapeutic treatment of human gastric adenocarcinoma, which provides a good foundation for further research and development of Tupistra chinensis Baker.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INFLAMMATION
·
2022
·Vol. 46
·期 2
·534-554
·
IF 4.657
Tong He,Wang Li,Zhang Kefan,Shi Jing,Wu Yongshuai,Bao Yulong,Wang Changshan
Noninfectious liver injury, including the effects of chemical material, drugs and diet, is a major cause of liver diseases worldwide. In chemical and drugs-induced liver injury, innate inflammatory responses are mediated by extracellular danger signals. The S100 protein can act as danger signals, which can promote the migration and chemotaxis of immune cells, promote the release of various inflammatory cytokines, and regulate the body’s inflammatory and immune responses. However, the role of S100A6 in inflammatory response in chemical and drugs-induced sterile liver injury remains unclear. We constructed the model of sterile liver injury induced by carbon tetrachloride (CCl 4 )/Paracetamol (APAP) and performed RNA sequencing (RNA-seq) on the liver tissues after injury (days 2 and 5). We analyzed inflammatory protein secretion in the liver tissue supernatant by enzyme-linked immunosorbent assay (ELISA), determined the inflammation response by bioinformatic analysis during sterile liver injury, and assessed mononuclear/macrophage infiltration by immunohistochemistry and flow cytometry. Immunohistochemistry was used to analyze the location of S100A6. We conducted inflammatory factor expression analysis and molecular mechanistic studies in Kupffer cells (KCs) induced by S100A6 using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), ELISA, and western blot in vitro experiments. We performed chemokine CCL2 expression analysis and molecular mechanism studies using the same method. We used a Transwell assay to show the infiltration of mononuclear/macrophage. We here observed that aggravated inflammatory response was shown in CCl 4 and APAP-administrated mice, as evidenced by enhanced production of inflammatory cytokines (TNF-α, IL-1β), and elevated mononuclear/macrophage infiltration and activation of immunity. The expression of S100A6 was significantly increased on day 2 after sterile liver injury, which is primarily produced by injured liver cells. Mechanistic studies established that S100A6 activates Kupffer cells (KCs) via the p -P38, p -JNK and P65 pathways to induce inflammation in vitro . Furthermore, TNF-α can stimulate liver cells via the p -P38 and p -JNK pathways to produce CCL2 and promote the infiltration of mononuclear/macrophage. In summary, we showed that S100A6 plays an important role in regulating inflammation, thus influencing sterile liver injury. Our findings provide novel evidence that S100A6 can as a danger signal that contributes to pro-inflammatory activation through p -P38 and p -JNK pathways in CCl 4 and APAP-induced sterile liver injury in mice. In addition, the inflammatory factor TNF-α induces a large amount of CCL2 production in normal liver cells surrounding the injured area through a paracrine action, which is chemotactic for blood mononuclear/macrophage infiltration. Graphical Abstract
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
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.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2025
·Vol. 55
·期 3
·1-14
·
IF 5.8
Qiumin Xie,Qin Yi,Jing Zhu,Bin Tan,Han Xiang,Rui Wang,Huiwen Liu,Tangtian Chen,Hao Xu
Sepsis is often a cause of mortality in patients admitted to the intensive care unit. Notably, the heart is the organ most susceptible to the impact of sepsis and this condition is referred to as sepsis‑induced cardiomyopathy (SIC). Low triiodothyronine (T3) syndrome frequently occurs in patients with sepsis, and the heart is one of the most important target organs for the action of T3. Phospholamban (PLN) is a key protein associated with Ca2+‑pump‑mediated cardiac diastolic function in the myocardium of mice with SIC, and PLN is negatively regulated by T3. The present study aimed to explore whether T3 can protect cardiac function during sepsis and to investigate the specific molecular mechanism underlying the regulation of PLN by T3. C57BL/6J mice and H9C2 cells were used to establish in vivo and in vitro models, respectively. Myocardial damage was detected via pathological tissue sections, a Cell Counting Kit-8 assay, an apoptosis assay and crystal violet staining. Intracellular calcium levels and reactive oxygen species were detected by Fluo‑4AM and DHE fluorescence. The protein and mRNA expression levels of JNK and c‑Jun were measured by western blotting and reverse transcription‑quantitative PCR to investigate the molecular mechanisms involved. Subsequently, 100 clinical patients were recruited to verify the clinical application value of PLN in SIC. The results revealed a significant negative correlation between PLN and T3 in the animal disease model. Furthermore, the expression levels of genes and proteins in the JNK/c‑Jun signaling pathway and PLN expression levels were decreased, whereas the expression levels of sarcoplasmic reticulum calcium ATPase were increased after T3 treatment. These results indicated that T3 alleviated myocardial injury in SIC by inhibiting PLN expression and its phosphorylation, which may be related to the JNK/c‑Jun signaling pathway. Accordingly, PLN may have clinical diagnostic value in patients with SIC.
研究领域:
心脏病学
·
内分泌学
·
重症医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL AND MOLECULAR PATHOLOGY
·
2020
·
IF 2.28
Zhaohui Shi,Min Xu,Xiaodong Chen,Jian Wang,Tianfeng Zhao,Dingjun Zha
Allergic rhinitis (AR) is tightly associated with type 2 inflammation. SFRP5 combined with WNT5A mainly inhibits chronic inflammatory response, atherosclerosis , and other metabolic disorders . However, the effect of SFRP5/WNT5A axis on recombinant human interleukin-13 (rhIL-13)-induced inflammation has not been studied. In this study, we aimed to investigate whether secreted frizzled-related protein 5 (SFRP5) could modulate the production of cytokines relevant to eosinophil infiltration and mucin secretion through blocking the activation of Wnt family 5A (WNT5A) signaling pathway . A mouse model of AR demonstrated low expression of SFRP5 and high expression of WNT5A, and indicated that the number of eosinophil and goblet cells was increased, concomitant with elevated IL-13, colony stimulating factor 2 (CSF2), chemokine ligand 11 (CCL11), Mucin 4 , and Mucin 5AC levels. Furthermore, lentivirus-SFRP5 overexpression up-regulated the expression of SFRP5 but down-regulated WNT5A level, and inhibited the activation of JNK pathway via decreasing p-JNK1/2 (Thr183/Tyr185) and p-c-Jun (Ser73) protein expressions in rhIL-13-treated human nasal epithelial cells (HNEpCs). Noticeably, SFRP5 overexpression markedly reduced rhIL-13-induced inflammatory protein and mucin generation through lowered CSF2, CCL11, Mucin 4, as well as Mucin 5AC levels. Taken together, these findings confirmed the regulatory role of SFRP5/WNT5A axis in rhIL-13-mediated inflammatory response in HNEpCs.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2017
·
IF 3.154
Jiarui Nie,Yaning Chang,Yujia Li,Yingjun Zhou,Jiawen Qin,Zhen Sun,Haibin Li
Caffeic acid phenethyl ester (CAPE), extracted from propolis, was evaluated for the ameliorative effects on insulin resistance and the mechanisms were identified, using non-insulin-dependent diabetes mellitus (NIDDM) model mice and insulin resistance (IR) model cells. After 5 weeks of CAPE supplementation, insulin sensitivity, hyperlipidemia, and peroxisome proliferator-activated receptor-α (PPAR-α) levels were improved in mice. Proinflammatory cytokines in serum and the expressions of tumor necrosis factor-alpha (TNF-α) mRNA in tissues were markedly downregulated from CAPE-treated mice. In vitro, CAPE supplement significantly improved glucose consumption, glucose uptake, glycogen content, and oxidative stress and decreased expression of glucose-6-phosphatase (G6Pase) mRNA in cells. Both in vivo and in vitro, CAPE enhanced p-Akt (Ser473) and p-insulin receptor substrate (IRS)-1 (Tyr612), but inhibited p-JNK (Thr183/Tyr185), p-NF-κB p65 (Ser536), and nuclear translocation of p-NF-κB p65 (Ser536). In summary, CAPE can ameliorate insulin resistance through modulation of JNK and NF-κB signaling pathway in mice and HepG2 cells.
✓ 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）