Frontiers in Endocrinology
·
2021
·
IF 5.555
Bai Yu,Du Qiang,Zhang Le,Li Ling,Wang Nana,Wu Bo,Li Ping,Li Ling
This study aims to investigate the effect of angiopoietin like 8 (ANGPTL8) on gestational diabetes mellitus (GDM) and insulin resistance (IR). The GDM model was induced by high fat diet in mice, and IR was observed. The expression and secretion of ANGPTL8 were promoted in placenta of GDM mice. IR was induced in trophoblast cell HTR-8/SVneo by treatment of high concentration of insulin, and the expression levels of ANGPTL8 were increased. Silencing of ANGPTL8 alleviated IR and decreased glucose uptake in HTR-8/SVneo cells. However, the inflammation and oxidative stress in IR cells were not restrained by ANGPTL8 knockdown. In addition, c-Jun N-terminal kinase (JNK) signaling was activated by IR, which was inhibited by silencing of ANGPTL8. The effect of ANGPTL8 knockdown on IR was attenuated by JNK antagonist, and aggravated by JNK agonist, suggesting that ANGPTL8 affected IR by regulating JNK signaling. In conclusion, we demonstrated that the silencing of ANGPTL8 ameliorated IR by inhibiting JNK signaling in trophoblast cells. These findings may provide novel insights for diagnosis and treatment of GDM in clinic.
研究领域:
内分泌学
·
妇产科学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2017
·
IF 4.48
Yuchao Sun,Mengqiao Lian,Yuan Lin,Bin Xu,Yanli Li,Jin Wen,Dapeng Chen,Ming Xu,Marwan Almoiliqy,Li Wang
Intestinal ischemia reperfusion (I/R) may cause inflammation-, oxidative stress-, and apoptosis-related tissue injuries and facilitate bacterial infection, leading to multiple organ failure. Myricetin , a flavonoid , is found to have diverse biological effects including anti-inflammatory, anti-oxidative, and anti-bacterial effects. Based on our pre-experiment, we proposed that myricetin pretreatment (25, 50 mg/kg) could ameliorate intestinal I/R injury and myricetin-induced modulation on MKK7/JNK signal pathway might play a key role in the amelioration. The present study was designed to verify the proposal by using both rat intestinal I/R model in vivo and hypoxia/reoxygenation (H/R)-injured intestinal epithelial cell line (IEC-6 cells) model in vitro. The results confirmed our proposal. Myricetin selectively ameliorated I/R- and H/R-induced injuries in vivo and in vitro respectively without significantly affecting the corresponding normal controls. Myricetin significantly alleviated I/R-induced rat intestinal injury by reducing the generation of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 and by reducing MPO activity. Myricetin significantly reduced oxidative stress through decreasing MDA level and increasing the levels of SOD and GSH in the intestinal tissues compared with I/R control rats. Myricetin significantly decreased apoptosis by selectively down-regulating the expression of p-MKK7 and p-JNK without affecting MKK7 and JNK, inhibiting Bax, caspase-3 protein expression, and up-regulating Bcl-2 protein expression in I/R-injured jejunum of rats. In vitro study indicated that MKK7 siRNA transfection significantly decreased both MKK7 and p-MKK7 and other apoptosis-related proteins, partially simulating myricetin-induced anti-apoptotic effects. MKK7 siRNA transfection + myricetin could not further decrease MKK7, p-MKK7, and other apoptosis-related proteins, suggesting that inhibition of MKK7/JNK pathway plays a key role in myricetin-induced protection against intestinal I/R. MKK7 overexpression by cDNA transfection abrogated myricetin-reduced apoptosis-related protein expression, confirming that the MKK7/JNK signal pathway is the key target for myricetin-induced amelioration. The present study indicated that pretreatment of myricetin induced selective protection against intestinal I/R injury without significantly affecting corresponding normal controls and p-MKK7 was the key target, suggesting that myricetin is worth further translational studies.
研究领域:
药理学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2022
·
IF 10.75
Li Zhang,Linyu Zhu,Xiaohan Yao,Xiaohan Lou,Jiajia Wan,Xixi Duan,Longze Pan,Anqi Li,Zhuoyu Gu,Ming Wang,Fazhan Wang,Zhihai Qin
Chemotherapeutic drugs have been successfully used to treat several cancers, including melanoma. However, metastasis occasionally occurs after chemotherapy. Here, we reported that paclitaxel (PTX) treatment for B16F10 tumour in mice led to an enhanced lymphatic metastasis of the melanoma cells, although a significant inhibition of tumour growth at the injection site was observed. Further study demonstrated that PTX upregulated the expression of C-C chemokine receptor type 7 (CCR7) in B16F10 cells, enhancing their migration through the activation of JNK and p38 signalling pathways. Loss of CCR7 or blockade of C-C motif chemokine ligand 21 (CCL21)/CCR7 axis abolished the pro-migration effect of PTX on B16F10 melanoma cells. Importantly, combination of PTX and CCR7 mAb could simultaneously delay the tumour growth and reduce the lymphatic metastasis in B16F10 melanoma. The blockade of CCL21/CCR7 axis may collectively serve as a strategy for lymphatic metastasis in some melanoma after chemotherapy.
研究领域:
肿瘤学
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免疫学
·
药理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Jie Wen,Lingmao Zhao,Zhuohan Li,Chao Pi,Xianhu Feng,Peng Shi,Hongru Yang,Ligang Chen,Xiaodong Wang,Furong Liu,Yumeng Wei,Ling Zhao
Chemotherapy remains the first choice of treatment for colon cancer despite the inevitable adverse effects. Curcumin (CU) possesses antitumor activity but has poor aqueous solubility, low bioavailability, and weak activity. To address this, nine novel monocarbonyl CU analogues were designed, synthesized, and evaluated in the present study. Among them, CA8 exhibited the highest water solubility, which was approximately 2.37 × 106 times that of CU. In addition, compared with CU, its cytotoxicity on Caco-2 cells (19.2 times/48 h) was stronger. Of note, CA8 arrestedthe cell cycle of Caco-2 cells at the G2/M phase and induced apoptosis. Meanwhile, acute toxicity experiments indicated that KM mice tolerated CA8 for up to 300 mg/kg CA8 (oral administration) and 50 mg/kg CA8 (intraperitoneal injection). The oral administration of CA8 to Sprague Dawley rats exhibited higher AUC (0-t) (6.23-fold) and longer MRT (0-t) (3.35-fold) than that of CU. CA8 also inhibited the proliferation and angiogenesis of tumor cells more than CU and tegafur. Finally, CA8 may exert anti-tumor effects through the activation of JNK pathway and inhibition of AKT pathway. These results suggest that CA8 is a safe and highly effective new drug for colon cancer treatment.
研究领域:
肿瘤学
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药理学
·
生物化学
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DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2021
·
IF 6.543
Peng Li,Changlian Xie,Jiankai Zhong,Zhongzhou Guo,Kai Guo,Qiuyun Tu
Endothelial dysfunction, which is characterized by damage to the endoplasmic reticulum (ER) and mitochondria, is involved in a variety of cardiovascular disorders. Here, we explored whether mitochondrial damage and ER stress are associated with endothelial dysfunction. We also examined whether and how melatonin protects against oxidized low-density lipoprotein- (ox-LDL-) induced damage in endothelial cells. We found that CHOP, GRP78, and PERK expressions, which are indicative of ER stress, increased significantly in response to ox-LDL treatment. ox-LDL also induced mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential, increased mitochondrial ROS levels, and downregulation of mitochondrial protective factors. In addition, ox-LDL inhibited antioxidative processes, as evidenced by decreased antioxidative enzyme activity and reduced Nrf2/HO-1 expression. Melatonin clearly reduced ER stress and promoted mitochondrial function and antioxidative processes in the presence of ox-LDL. Molecular investigation revealed that ox-LDL activated the JNK/Mff signaling pathway, and melatonin blocked this effect. These results demonstrate that ox-LDL induces ER stress and mitochondrial dysfunction and activates the JNK/Mff signaling pathway, thereby contributing to endothelial dysfunction. Moreover, melatonin inhibited JNK/Mff signaling and sustained ER homeostasis and mitochondrial function, thereby protecting endothelial cells against ox-LDL-induced damage.
研究领域:
心血管研究
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Pei Xie,Li-Jun Yan,Hong-Ling Zhou,Hui-Hui Cao,Yuan-Ru Zheng,Zi-Bin Lu,Hua-Yi Yang,Jia-Mei Ma,Yu-Yao Chen,Chuying Huo,Chunyang Tian,Jun-Shan Liu,Lin-Zhong Yu
Background: Acute lung injury (ALI) is a serious inflammatory disease with clinical manifestations of hypoxemia and respiratory failure. Presently, there is no effective treatment of ALI. Although emodin from Rheum palmatum L. exerts anti-ALI properties, the underlying mechanisms have not been fully explored.
Purpose: This study aimed to investigate the therapeutic effect and mechanism of emodin on LPS-induced ALI in mice.
Methods: RAW264.7 cells and zebrafish larvae were stimulated by LPS to establish inflammatory models. The anti-inflammatory effect of emodin was assessed by ELISA, flow cytometric analysis, and survival analysis. In vitro mechanisms were explored by using Western blotting, luciferase assay, electrophoretic mobility shift assay (EMSA), and small interfering RNA (siRNA) approach. The acute lung injury model in mice was established by the intratracheal administration of LPS, and the underlying mechanisms were assessed by detecting changes in histopathological and inflammatory markers and Western blotting in lung tissues.
Results: Emodin inhibited the inflammatory factor production and oxidative stress in RAW264.7 cells, and prolonged the survival of zebrafish larvae after LPS stimulation. Emodin suppressed the expression levels of phosphorylated JNK at Thr183/tyr182 and phosphorylated Nur77 at Ser351 and c-Jun, and increased the expression level of Nur77 in LPS-stimulated RAW264.7 cells, while these regulatory effects of emodin on Nur77/c-Jun were counteracted by JNK activators. The overexpression of JNK dampened the emodin-mediated increase in Nur77 luciferase activity and Nur77 expression. Moreover, the inhibitory effect of emodin on c-Jun can be attenuated by Nur77 siRNA. Furthermore, emodin alleviated LPS-induced ALI in mice through the regulation of the JNK/Nur77/c-Jun pathway.
Conclusions: Emodin protects against LPS-induced ALI through regulation on JNK/Nur77/c-Jun signaling. Our results indicate the potential of emodin in the treatment of ALI.Keywords: acute lung injury, inflammation, lipopolysaccharide, emodin, JNK/Nur77/c-Jun
研究领域:
药理学
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免疫学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Future Medicinal Chemistry
·
2026
·
IF 3.3
Ziyao Lu,Qinghong Liao,Yuetong Duan,Kaixuan Wang,Siyu He,Weiping Lyu,Xuehong Chen,Qi Li
Objective This study aims to investigate whether butyrylcholinesterase (BChE) inhibitor QY-54 can be used to treat glioblastoma (GBM) and exert a neuroprotective profile.Methods At the cellular level, the effects of QY-54 on the proliferation, invasion, and migration of GBM cells from different species were investigated. At the animal level, the safety of QY-54 in normal mice, its anti-tumor effects in GBM mice, and its effects on cognition protective function were examined.Results At the cellular level, QY-54 exhibited significant inhibitory effects on the proliferation, migration, and invasion of GBM cells derived from different species. At the animal level, QY-54 showed low toxicity in normal mice. Moreover, it significantly inhibited GBM tumor growth, promoted tumor cell apoptosis, suppressed neuroinflammation, protected neurons, and improved the general condition and cognitive function of GBM mice. In Western blot experiments, QY-54 upregulated c-jun N-terminal kinase (JNK) levels to exert an inhibitory effect on glioma.Conclusion QY-54 exhibits dual effects of anti-glioblastoma and cognitive improvement, by inhibiting BChE and activating the JNK signaling pathway. QY-54 is a highly promising drug for the treatment of glioblastoma with neuroprotective profile.
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DOI
PubMed
高影响因子
YONSEI MEDICAL JOURNAL
·
2019
·
IF 1.759
Huaxin Wang,Xuan Peng,Yayi Huang,Yeda Xiao,Zhuo Wang,Liying Zhan
Purpose The aim of this study was to investigate whether propofol could attenuate hypoxia/reoxygenation-induced apoptosis and autophagy in human renal proximal tubular cells (HK-2) by inhibiting JNK activation. Materials and methods HK-2 cells were treated with or without propofol or JNK inhibitor SP600125 for 1 hour and then subjected to 15 hours of hypoxia and 2 hours of reoxygenation (H/R). Cell viability and LDH release were measured with commercial kits. Cell apoptosis was evaluated by flow cytometry. The expressions of p-JNK, cleaved-caspase-3, Bcl-2, and autophagy markers LC3 and p62 were measured by Western blot or immunofluorescence. Results HK-2 cells exposed to H/R insult showed higher cell injury (detected by increased LDH release and decreased cell viability), increased cell apoptosis index and expression of cleaved-caspase-3, a decrease in the expression of Bcl-2 accompanied by increased expression of p-JNK and LC3II, and a decrease in expression of p62. All of these alterations were attenuated by propofol treatment. Similar effects were provoked upon treatment with the JNK inhibitor SP600125. Moreover, the protective effects were more obvious with the combination of propofol and SP600125. Conclusion These results suggest that propofol could attenuate hypoxia/reoxygenation induced apoptosis and autophagy in HK-2 cells, probably through inhibiting JNK activation.
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DOI
PubMed
高影响因子
Food Bioscience
·
2023
·
IF 5.2
Jiaxin Li,Hengju Ge,Yang Xu,Jiahong Xie,Naymul Karim,Fujie Yan,Jianling Mo,Wei Chen
Chlorogenic acid (CGA) is a phenylpropanoid compound in chrysanthemum, which has a variety of biological activities. Nevertheless, CGA has not yet been studied concerning oxidative stress in hepatocytes. Our research aims to investigate whether chlorogenic acid can improve hepatic oxidative stress, and further illustrated its detailed mechanism. The results of free radicals measurement and Western blot showed that CGA suppressed the activation of JNK (c-Jun NH2-teminal kinase) signaling pathway by ameliorating endoplasmic reticulum stress in H 2 O 2 -treated hepatocytes, thereby eliminating excess intracellular free radicals. In addition, through RT-qPCR, we found that miR-199a-5p down-regulated in H 2 O 2 -induced L02 cells, which was restored by CGA. By inhibiting the expression of miR-199a-5p to promote the transcription of GRP78 gene, the antioxidant capacity of CGA was greatly weakened in hepatocytes. Our findings suggest that CGA treatment alleviated the H 2 O 2 -induced oxidative stress by targeting miR-199a-5p, thereby ameliorating ER stress and inhibiting JNK phosphorylation for antioxidant capacity enhancement. Based on our available results, CGA may be an alternative compound to mitigate hepatic oxidative damage through the miR-199a-5p/GPR78 axis.
研究领域:
药理学
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分子生物学
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细胞生物学
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产品关联
DOI
高影响因子
Frontiers in Oncology
·
2022
·
IF 5.738
Wu Fengjiao,Shao Rongrong,Zheng Peisen,Zhang Tingting,Qiu Chenyu,Sui Hehuan,Li Shaotang,Jin Libo,Pan Huanle,Jin Xiance,Zou Peng,Cui Ri,Xie Congying
Colon cancer is one of the most common cancer in the world. Doxorubicin (DOX) is a classical anti-tumor drug which widely used in treatment of cancers, however, high toxicity limited its further clinical application. Thus, it is urgent to find new drugs with low toxicity and high efficiency to treat colon cancer. Isoalantolactone (IATL), an isomeric sesquiterpene lactone isolated from the plant of inula helenium, has been reported to have anti-cancer activity against a variety of cancer cells. However, the function of IATL in colon cancer remains unclear. Here, we demonstrated that IATL inhibited colon cancer cell growth by increasing cellular reactive oxygen species (ROS) production. Further study showed that ROS accumulation contributed to DNA damage and JNK signaling pathway activation. In addition, we found that IATL markedly enhanced DOX-induced cell cytotoxicity in colon cancer cells. IATL in combination with DOX significantly increased the ROS production, induced DNA damage and activated JNK signaling pathway. Taken together, our data suggested that combined treatment with IATL and DOX may serve as a potential therapeutics for colon cancer.
研究领域:
肿瘤学
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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
JOURNAL OF APPLIED TOXICOLOGY
·
2021
·Vol. 41
·期 12
·2011-2020
·
IF 3.446
Yuanyuan Zhang,Bingke Ma,Shuangshuang Hao,Jiaqi Wang,Ruichen Zhang,Muhammad Ishfaq,Chenxi Shi,Liang Yuan,Rui Li,Changwen Li,Fangping Liu
Drug-induced liver injury (DILI) is a serious and frequently occurring issue in drug development. The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in many diseases; hepatocyte nuclear factor-1α (HNF-1α) and glutathione S-transferase A1 (GSTA1) are important in regulating liver-specific genes expressions and affecting drug metabolism. Oltipraz is used to treat liver cirrhosis by improving liver function, and C2-ceramide is a pro-apoptotic lipid that regulates multiple signaling pathways. In this study, we investigated the function of the JNK signaling pathway with HNF-1α and GSTA1 in a cellular model of DILI and whether oltipraz and C2-ceramide exert effects via the JNK pathway. The results showed that inhibiting JNK could ameliorate APAP-induced hepatocyte injury, reduced oxidative stress, suppressed JNK and c-Jun activation, and hepatocyte apoptosis. Meanwhile, the mRNA and protein expressions of HNF-1α and GSTA1 were increased significantly compared to control conditions. The effect of oltipraz (8 μmol/L) was similar to a JNK inhibitor and significantly increased HNF-1α/GSTA1 expression, but oltipraz combined with JNK inhibitor did not show a synergistic effect. Although C2-ceramide (8 μmol/L) aggravated hepatocyte injury and apoptosis, exacerbated oxidative stress, increased phosphorylation of JNK and c-Jun, and markedly decreased HNF-1α/GSTA1 expression, C2-ceramide combined with JNK inhibitor could partially alleviate these alterations. These results demonstrated that the JNK signaling pathway with HNF-1α/GSTA1 are involved in the process of DILI. Inhibiting JNK up-regulated HNF-1α and GSTA1 expressions which could attenuate hepatocyte injury. Oltipraz and C2-ceramide might affect the expression of HNF-1α/GSTA1 though JNK signaling.
研究领域:
药理学
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肝脏病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
AAPS Journal
·
2017
·Vol. 19
·期 6
·1703-1714
·
IF 3.423
Cao Mingnan,Wang Huixia,Guo Limei,Yang Simin,Liu Chun,Khor Tin Oo,Yu Siwang,Kong Ah-Ng
Oxidative stress is an important pathogenic factor in various hepatic diseases. Nuclear factor-erythroid 2-related factor-2 (Nrf2), which coordinates the expression of an array of antioxidant and detoxifying genes, has been proposed as a potential target for prevention and treatment of liver disease. Dibenzoylmethane (DBM) is a minor ingredient in licorice that activates Nrf2 and prevents various cancers and oxidative damage. In the present study, the mechanisms by which DBM activates Nrf2 signaling were delineated, and its protective effect against carbon tetrachloride (CCl 4 )-induced liver injury was examined. DBM potently induced the expression of HO-1 in cells and in the livers of mice, but this induction was diminished in Nrf2-deficient mice and cells. Overexpression of Nrf2 enhanced DBM-induced HO-1 expression, while overexpression of a dominant-negative fragment of Nrf2 inhibited this induction. DBM treatment resulted in dissociation from Keap1 and nuclear translocation of Nrf2. Moreover, DBM activated Akt/protein kinase B, mitogen-activated protein kinases, and AMP-activated protein kinase and increased intracellular calcium levels. Inhibition of JNK, AMPK, or intracellular calcium signaling significantly suppressed the induction of HO-1 expression by DBM. Finally, DBM treatment significantly inhibited CCl 4 -induced acute liver injury in wild-type but not in Nrf2-deficient mice. Taken together, our results revealed the mechanisms by which DBM activates Nrf2 and induces HO-1 expression, and provide molecular basis for the design and development of DBM and its derivatives for prevention or treatment of liver diseases by targeting Nrf2.
研究领域:
药理学
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肝病学
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分子生物学
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毒理学
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DOI
PubMed
高影响因子
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