PHYTOMEDICINE
·
2021
·
IF 5.34
Xiaohan Wei,Baoping Zhang,Xiao Liang,Changshun Liu,Ting Xia,Yingjie Xie,Xue Deng,Xiaomei Tan
ABSTRACT Background Allergic rhinitis (AR) is an inflammatory, immunoglobulin E (IgE)-mediated disease characterized by the typical symptoms of sneezing, rhinorrhea , nasal itching , and congestion. Higenamine (HG) is a plant-based alkaloid, possesses a wide range of activities, including vascular and tracheal relaxation, antioxidative, antiapoptotic , anti-inflammatory, and immunomodulatory activities. So far, the effect and the underlying mechanism of HG on AR have not been studied. Hypothesis/Purpose The purpose of this study was to evaluate the effects of HG on AR and investigate its underlying mechanism. Methods The effects of HG on AR were evaluated in an ovalbumin-induced AR mouse model. Network pharmacology-based methods such as target prediction, protein-protein interaction (PPI) network analysis, pathway analysis, and molecular docking were used to identify the likely HG targets. Finally, we validated the mechanism of action of HG through its effects on these targets in human nasal epithelial cells (HNEpCs). Results Oral administration of 30, 60, and 120 mg/kg HG significantly alleviated rubbing and sneezing in AR mice and attenuated histopathological changes in the lung and nasal tissues . Additionally, HG reduced the levels of IgE, histamine, and IL-4 in the serum of AR mice, and regulated imbalance in Th1/Th2 cells. Using network pharmacology-based methods, we identified 29 HG targets related to AR. These targets are mainly involved in the PD-L1, relaxin, estrogen, HIF-1, Th1 and Th2 cell differentiation , T cell receptor , and the Th17 cell differentiation signaling pathways . Molecular docking showed that HG may well be suited to the receptor binding pockets of key target AKT1 , EGFR, c-Jun, NOS2 , and JAK2 . In HNEpCs, HG inhibited the histamine-induced mRNA expression and secretion of interleukin (IL)-6, and IL-8, as well as the expression of MUC5AC and the phosphorylation of NF-κB. Moreover, HG affected the changes of AKT1, EGFR, c-Jun, iNOS, and JAK2 induced by histamine. Conclusion Overall, our results suggest that HG may alleviate AR by activating AKT1 and suppressing the EGFR/JAK2/c-JUN signaling. HG, therefore, has great potential as a therapeutic agent for the treatment of AR.
研究领域:
免疫学
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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
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2019
·Vol. 46
·期 12
·1194-1200
·
IF 2.336
Di Wu,Wei Zhang,Ying Chen,Hong Ma,Mengchang Wang
Multiple myeloma (MM) is a malignancy characterized by the proliferation of malignant plasma cells. Platycodin D (PLD) is a triterpenoid saponin that exerts anti-tumour activity through multiple mechanisms. However, the role of PLD in MM remains unknown. Here, we investigated the effect of PLD on MM cell lines NCI-H929 and U266B1, and elucidated the underlying molecular mechanism. Cell Counting Kit-8 assay showed that the proliferation of NCI-H929 and U266B1 cells was significantly decreased after PLD treatment. Transwell assay confirmed that PLD treatment suppressed migration of NCI-H929 and U266B1 cells. Flow cytometry results indicated that the apoptotic rates of bortezomib (BTZ)-treated NCI-H929 and U266B1 cells were markedly increased after PLD treatment. Western blot analysis revealed that bcl-2 expression was decreased, while bax expression was increased in PLD-treated NCI-H929 and U266B1 cells compared with that in BTZ-treated cells. Furthermore, PLD treatment blocked the activation of nuclear factor-kappa B (NF-κB) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signalling pathways in NCI-H929 cells. Taken together, these data showed that PLD inhibited proliferation and migration, and enhanced chemosensitization to BTZ through inactivation of the NF-κB and JAK2/STAT3 pathways in MM cell lines. These findings indicated that PLD might serve as a novel therapeutic agent for the treatment of MM.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Guanghui Xu,Huiqi Wan,Litao Yi,Wei Chen,Youhua Luo,Yiqi Huang,Xiaojuan Liu
Accumulating evidence showed that berberine possessed the anti-inflammatory action in various diseases caused by inflammation. However, it was still unclear whether both inhalation and injection with berberine produced pulmonary protective role in acute respiratory distress syndrome (ARDS). This study was aimed to evaluate the effects of both administration routes including inhalation and injection with berberine in ARDS induced by lipopolysaccharide (LPS) inhalation. Histopathological examination and weight of lung were evaluated. Phosphorylation of NF-κB, JAK2 and STAT3 were measured to assess the activity of inflammation related signaling pathways. Proinflammatory cytokines including interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) and serum were also detected. The results showed that LPS caused the lung injury, while both administration routes with berberine attenuated the injury and improved the pulmonary morphology. In addition, the primary TLR4/NF-κB and secondary JAK2/STAT3 signaling pathways which were activated by LPS in lung were totally inhibited by berberine administration. Moreover, proinflammatory cytokines in both BALF and serum were decreased by berberine. Considering that molecular docking simulation indicated that berberine could bind with TLR4, the present suggested that the inhibition of the inflammation related TLR4/NF-κB and JAK2/STAT3 signaling pathways might be involved in the pulmonary protective effect of berberine in LPS-induced ARDS.
研究领域:
药理学
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呼吸医学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Jie-Fang Gao,Liu Tang,Fei Luo,Yi-Yuan Zhang,Lu Chen,Hong Ding,Zu-Dong Meng
Background and purpose Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by pruritus and impaired skin barrier function. The pathology of AD involves in immune dysfunction and epidermal barrier disruption. Reactive oxygen species (ROS) are found to be associated with AD, and play a role in the immunological abnormalities and dysfunctional skin barrier. Nicotinamide mononucleotide (NMN) plays an important role in oxidative stress related diseases, but its role in AD is unclear. Methods KM mice were treated with DNFB to induce AD-like lesion and typical applied with NMN for two weeks. The dermatitis score, the degree of itching and TEWL were evaluated during modeling. Epidermal thickness of skin lesions and histopathological changes were detected. Further, inflammatory factors, epidermal differentiation-related genes, oxidative stress indicators and JAK2/STAT5 signaling pathway were evaluated. NHEK cells were stimulated by TNF-α/IFN-γ after pre-treatment with NMN, then ROS levels, inflammatory factors and JAK2/STAT5 signaling pathway were detected. Results NMN exhibited potent anti-atopic activities, shown by alleviated AD-like symptoms, inhibited the increased expression of inflammatory cytokines and restored proteins and mRNA level of skin barrier genes. In addition, NMN inhibited TNF-α/IFN-γ-stimulated elevation of inflammatory chemokines, which was associated with blocking the activation of ROS-mediated JAK2/STAT5 pathway. Conclusion NMN may have a positive effect on relieving symptoms of AD.
研究领域:
皮肤病学
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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
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2016
·
IF 2.551
Zhilin Qi,Shimei Qi,Liefeng Ling,Jun Lv,Zunyong Feng
Salidroside (SAL) is an active ingredient isolated from the Rhodiola rosea , has potent anti-inflammatory effect, but the mechanism is still elusive. The purpose of this study is to verify the effects of SAL on LPS-induced inflammatory response and investigate the possible underlying molecular mechanism. RAW264.7 cells were pre-incubated with SAL for 2 h, then stimulated with or without LPS for another 16 h. The levels of TNF-α, MCP-1, IL-6, and PGE2 were detected by ELISA , and the production of NO was determined by nitrite analysis. The expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected by Western blotting . In RAW264.7 cells and murine peritoneal macrophages, the activation of signal molecules was also measured by Western blot. The nuclear translocation of STAT3 was determined by Laser confocal and nucleocytoplasmic separation experiments. Our results showed that SAL attenuated the productions of TNF-α, IL-6, MCP-1, PGE2 and NO dose dependently. SAL also suppressed LPS-induced expressions of iNOS and COX-2 significantly. Further studies revealed that SAL down-regulated the phosphorylation of JAK2-STAT3 signaling pathway and reduced the nuclear translocation of STAT3 induced by LPS in RAW264.7 cells and primary peritoneal macrophages. In addition, consistent with the results in vitro, in the model of mice acute lung injury (ALI) induced by LPS, SAL reduced the infiltration of inflammatory cells and decreased the levels of serum TNF-α and IL-6 obviously. Taken together, these data indicated that SAL exerted anti-inflammatory action via down-regulating LPS-induced activation of JAK2-STAT3 pathway and suppressing STAT3 transfer into the nucleus at least in part.
研究领域:
药理学
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免疫学
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细胞生物学
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炎症
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2017
·
IF 2.759
Yang Liu,Lei Wang,Yang Du,Zhiyuan Chen,Jia Guo,Xiaodong Weng,Xiao Wang,Min Wang,Danyang Chen,Xiuheng Liu
The aim of our study is to investigate the protective effect of apigenin and the role of the JAK2/STAT3 signaling pathway in renal ischemia/reperfusion injury (IRI) in rats. For in vivo experiments, rat kidneys were subjected to 45 min of ischemia , followed by 24 h of reperfusion. The kidneys were pretreated for 24 h with apigenin (4 mg/kg) intraperitoneally in the absence or presence of the JAK2 kinase-specific inhibitor AZD1480 (30 mg/kg). The serum creatinine and urea nitrogen levels were analyzed. Histologic examinations were evaluated. Expression of p-JAK2, p-STAT3, Bcl-2, Bax and Caspase-3 was detected by immunohistochemistry or western blot . For In vitro experiments, NRK-52E cells were exposed to I/R in the absence or presence of apigenin and JAK2 siRNA was used to explore JAK2/STAT3 activity. Cell viability , cell apoptosis and expression of p-JAK2, p-STAT3, Bcl-2, Bax and Caspase-3 were examined in NRK-52E culture after I/R. Consequently, apigenin conferred a renoprotective effect on the kidneys against IRI, as evidenced by decreased serum creatinine and urea nitrogen, mitigated renal histologic damage, improved NRK-52E cell viability and a decreased apoptotic index, including up-regulation of the anti-apoptotic protein Bcl-2 and down-regulation of the pro-apoptotic proteins Bax and Caspase3. However, AZD1480 and JAK2 siRNA blocked the apigenin-mediated renoprotective effects by attenuating the JAK2/STAT3 signaling pathway as well as abolished the effect of anti-oxidative stress and anti-apoptosis of apigenin. Our study demonstrates that apigenin pretreatment can protect against renal IRI via the activation of the JAK2/STAT3 signaling pathway.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2019
·
IF 2.086
Rui-Li Zhu,Ying-Kun Zhi,Lang Yi,Jin-Fang Luo,Jing Li,Sha-Sha Bai,Liang Liu,Pei-Xun Wang,Hua Zhou,Yan Dong
Objective: To investigate the cellular mechanism that sinomenine (SIN) inhibits inflammation in macrophages induced by LPS through α7 nicotinic acetylcholine receptor (α7nAChR).Materials and methods: RAW264.7 cells were stimulated with LPS and treated by SIN or nicotine (Nic). A selective antagonist of α7nAChR, α-bungarotoxin (BTX) was used to block α7nAChR. AG490 was used to inhibit JAK2 activation. ELISA was performed to detect the levels of TNF-α and MCP-1. Western blotting was used to analyze the expression of MIF, MMP-9, CD14, TLR4, STAT3 and p-STAT3. Intracellular-free calcium level was measured by Fluorescent probe fluo-3/AMResults: SIN inhibited the production of TNF-α, MCP-1, MIF, and MMP-9, decreased the expression of CD14 and TLR4, and inhibited the release of intracellular-free calcium from intracellular stores in RAW 264.7 cells stimulated by LPS. JAK-specific inhibitor AG490 attenuated the inhibitory effect of SIN on TNF-α. SIN increased the phosphorylation of STAT3. And the above effects of SIN were attenuated by antagonist of α7nAChR.Conclusions: SIN can decrease the expression of CD14/TLR4 and intracellular free calcium level, activate JAK2/STAT3 pathway to inhibit inflammatory response through α7nAChR in macrophages.
研究领域:
免疫学
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药理学
·
细胞生物学
·
炎症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2019
·
IF 4.527
Yuezhu Zhang,Shuyue Wang,Tianyang Zhao,Liwei Yang,Shuangyu Guo,Yanbin Shi,Xueting Zhang,Liting Zhou,Lin Ye
Mono-2-ethylhexyl phthalate (MEHP), as the major metabolite of Di-(2-ethylhexyl) phthalate (DEHP), can induce lipid accumulation in hepatocytes and further leads to non-alcoholic fatty liver disease (NAFLD), while the underlying mechanism is unclear. We aim to clarify the effects of JAK2/STAT5 pathway on lipid accumulation induced by MEHP and the role of oxidation stress in NAFLD. BRL-3A hepatocytes were exposed to MEHP (0, 10, 50, 100 and 200 μM) for 24 h and 48 h. Then the lipid droplets in cells were observed by Oil-Red-O staining and quantified by isopropyl alcohol . The levels of TG, SOD, TBARS, AST and ALT were all detected by commercial kits. RT-PCR was used to detect mRNA expression, and western blotting was used to detect the expression of proteins encoded by JAK2/STAT5 pathway genes and lipid metabolism-related genes. As a result, MEHP promoted the lipid synthesis and accumulation in BRL-3A cells. MEHP down-regulated the expression and inhibited the activation of JAK2/STAT5. Moreover, the lipid metabolism-related kinases levels were elevated after MEHP exposure. In addition, the SOD levels were gradually decreased and the TBARS levels were increased in MEHP-treated groups. The lipid metabolism-related proteins levels were correlated with the oxidation stress levels. Furthermore, the ALT and AST levels were elevated after MEHP exposure. Therefore, we concluded that MEHP led to lipid accumulation through inhibiting JAK2/STAT5 pathway, resulted in damaging liver parenchyma and NAFLD by aggravating oxidation stress.
研究领域:
毒理学
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细胞生物学
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肝病学
✓ 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
·
分子生物学
·
癌症研究
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Kai Zhou,Hua Chen,Xiao-yu Wang,Yan-mei Xu,Yu-feng Liao,Yuan-yuan Qin,Xue-wan Ge,Ting-ting Zhang,Zhong-lin Fang,Bei-bei Fu,Qing-Zhong Xiao,Feng-qin Zhu,Si-rui Chen,Xue-sheng Liu,Qi-chao Luo,Shan Gao
Background and purpose Xin-Ji-Er-Kang (XJEK) is traditional Chinese formula presented excellent protective effects on several heart diseases, but the potential components and targets are still unclear. The aim of this study is to elucidate the effective components of XJEK and reveal its potential mechanism of cardioprotective effect in myocardial ischemia-reperfusion (MIR) injury. Experimental approach Firstly, the key compounds in XJEK, plasma and heart tissue were analyzed by high resolution mass spectrometry. Bioinformatics studies were also involved to disclose the potential targets and the binding sites for the key compounds. Secondly, to study the protective effect of XJEK on MIR injury and related mechanism, mice subjected to MIR surgery and gavage administered with XJEK for 6 weeks. Cardiac function parameters and apoptosis level of cardiac tissue were assessed. The potential mechanism was further verified by knock down of target protein in vitro. Results Pharmacokinetics studies showed that Sophora flavescens alkaloids, primarily composed with matrine, are the key component of XJEK. And, through bioinformatic analysis, we speculated JAK2 could be the potential target for XJEK, and could form stable hydrogen bonds with matrine. Administration of XJEK and matrine significantly improved heart function and reduced apoptosis of cardiomyocytes by increasing the phosphorylation of JAK2 and STAT3. The anti-apoptosis effect of XJEK and matrine was also observed on AC16 cells, and could be reversed by co-treatment with JAK2 inhibitor AG490 or knock-down of JAK2. Conclusion XJEK exerts cardioprotective effect on MIR injury, which may be associated with the activation of JAK2/STAT3 signaling pathway.
研究领域:
药理学
·
心脏病学
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中医
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生物信息学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2023
·
IF 5.2
Qiaoli Wu,Bing Liu,Rongxian Yu,Xiaoling Sun,Ziyan Wang,Jun Zhou,Chenyang Lu,Jing Zhang,Jiaojiao Han,Xiurong Su
Osteoarthritis (OA) is a chronic disease associated with bone and muscle degeneration that causes great disturbances to daily lives. Skipjack tuna elastin peptides (STEP) is a kind of small molecule mixed peptides extracted from skipjack tuna bulbus cordis that have multiple active functions, including anti-inflammatory activity. However, it is ambiguous whether STEP reduce OA inflammation. Zebrafish served as a model in the present research for verifying the anti-inflammatory efficacy of STEP. Then, the composition of STEP was figured out by LC-MS/MS analysis, and the potential anti-inflammatory peptides were screened by molecular docking and microscale thermophoresis (MST). Finally, in vitro experiments were conducted on the potential peptides. According to the in vivo findings, STEP protected the cartilage tissues of zebrafish and regulated the expression of inflammatory factors and the JAK2/STAT3 signaling pathway . The in vitro results showed that the potential peptides (LGVGSPPGK, GFDPSR and PGAPGGGFDI) positively regulated the inflammatory responses and the JAK2/STAT3 signaling pathway and were effective in inhibiting extracellular matrix (ECM) degeneration and chondrocyte apoptosis. As a consequence, STEP possess anti-inflammatory and chondroprotective effects and could be a functional product for the alleviation of OA.
研究领域:
药理学
·
生物技术
·
生物化学
·
炎症研究
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骨科
✓ 已验证
产品关联
DOI
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-13
·
IF 3.8
Yao Fei,Yuan Qin,Yan Yichao,Liang Guoqiang,Zhou Liang,Xu Heng,Gao Shaomei,Zou Ting,Zhang Lurong
Yu-Ping-Feng-San (YPF) is a famous classical Chinese medicine formula known for its ability to boost immunity. YPF has been applied to enhance the immune status of tumor patients in clinical practice. However, there is still a lack of research on its immune regulatory effects and mechanisms in the tumor microenvironment. This study was designed to investigate the effects and mechanism of YPF on improving the immune suppression state of hepatocellular carcinoma (HCC) microenvironment. In an orthotopic mouse model of HCC, YPF improved the immune microenvironment of HCC immunosuppression, enhanced the maturation of dendritic cells (DCs), promoted the release of IL-12, and decreased the presence of JAK2, p-JAK2, STAT3, and p-STAT3 proteins in both tumor tissue and paracancerous tissues. YPF also could promote the maturation and reduce the activation of JAK2, p-JAK2, STAT3, and p-STAT3 proteins of mouse bone marrow-derived DCs induced by culture medium or tumor supernatant in vitro . Transient transfection of siRNA-STAT3 with DCs resulted in an increase in its maturation and its secretion of IL-12. On the whole, these combined effects of YPF served to ameliorate the HCC immune suppression microenvironment, which conducive to immune cells play the role of immune surveillance and killing liver cancer cells. The mechanisms of these combined effects were, at least in part, related to its inhibition of the activated JAK2-STAT3 signaling pathway in DCs within the HCC microenvironment.
研究领域:
肿瘤学
·
免疫学
·
药理学
✓ 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）