Marine Drugs
·
2020
·Vol. 18
·期 6
·328
·
IF 4.073
Jing Ye,Donghui Chen,Zhicheng Ye,Yayan Huang,Na Zhang,Edmund M. K. Lui,Changhu Xue,Meitian Xiao
Fucoidan has been reported to have a variety of biological activities. However, different algae species, extraction methods, harvesting seasons, and growth regions lead to the structural variation of fucoidan, which would affect the bioactivities of fucoidan. To date, the anti-inflammatory properties and the underlying mechanism of fucoidan from brown algaSaccharina japonica(S. japonica) remain limited. The aims of the present study were to investigate the structure, the anti-inflammatory properties, and the potential molecular mechanisms of fucoidan isolated fromS. japonica(SF6) against lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. SF6 was characterized using high performance liquid gel permeation chromatography (HPGPC), Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR), and observed to be rich in fucose, galactose, and sulfate. Additionally, results showed that SF6 remarkably inhibited LPS-induced production of various inflammatory mediators and pro-inflammation cytokines, including nitric oxide (NO), NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-β (IL-β), and interleukin-6 (IL-6). A mechanism study showed that SF6 could effectively inhibit inflammatory responses through blocking LPS-induced inflammation pathways, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase (JAK)-2 and signal transducer and activator of transcription (STAT)-1/3 pathways. These results suggested that SF6 has the potential to be developed as an anti-inflammatory agent applied in functional food.Keywords:fucoidan;Saccharina japonica;anti-inflammation;mechanism
研究领域:
药理学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Ruipeng Lu,Jingjing Hong,Tong Fu,Yu Zhu,Ruiqi Tong,Di Ai,Shuai Wang,Qingsong Huang,Ceshi Chen,Zhiming Zhang,Rui Zhang,Huiling Guo,Boan Li
Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B). PyVT-Ovol2 knockout mice develop a higher number of primary breast tumors with accelerated growth and increased lung-metastases. Furthermore, treatment with FAO inhibitors effectively reduces stemness characteristics of tumor cells, breast tumor initiation, and metastasis, especially in OVOL2-deficient breast tumors. The findings suggest that targeting JAK/STAT3 pathway and FAO is a promising therapeutic strategy for OVOL2-deficient TNBC.
研究领域:
肿瘤学
·
分子生物学
·
癌症生物学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR BIOCHEMISTRY
·
2018
·Vol. 120
·期 6
·9147-9158
·
IF 2.959
Ya-Jun Song,Jun-Ying Cao,Zhuang Jin,Wen-Gang Hu,Rong-Hua Wu,Lu-Hai Tian,Bo Yang,Jin Wang,Ya Xiao,Chi-Bing Huang
Interstitial cystitis (IC) is a heterogeneous syndrome with unknown etiology, and microRNAs (miRs) were found to be involved in IC. In our study, we aim to explore the role of miR-132 in the inflammatory response and detrusor fibrosis in IC through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway in rat models. A rat model of IC was established and treated with the miR-132 mimic, miR-132 inhibitor, and/or JAK-STAT signaling pathway inhibitor AG490. Enzyme-linked immunosorbent assay was applied to measure the expression of interleukin (IL)-6, IL-10, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1). The urodynamic test was performed to assess urodynamic parameters, and reverse transcription quantitative polymerase chain reaction and Western blot analysis for the expression of miR-132, STAT4, suppressors of cytokine signaling 3 (SOCS3), JAK2, vascular endothelial growth factor (VEGF), IFN-γ, and TNF-α. IC rats treated with miR-132 inhibitor and AG490 had decreased collagen fiber, inflammatory cell infiltration, and mast cells, lower expression of IL-6, IL-10, IFN-γ, TNF-α, ICAM-1, collagens I and III, and alleviated urodynamic parameters and decreased expression of STAT4, VEGF, JAK2, IFN-γ, TNF-α, and increased expression of SOCS3. Taken together, our data indicate that downregulation of miR-132 alleviates inflammatory response and detrusor fibrosis in IC via the inhibition of the JAK-STAT signaling pathway.
研究领域:
泌尿学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Pharmaceuticals
·
2022
·Vol. 16
·期 1
·9
·
IF 5.215
Chunyu Wu,Chenping Sun,Xianghui Han,Yiyi Ye,Yuenong Qin,Sheng Liu
Sanyin formula (SYF) is used as a complementary treatment for triple-negative breast cancer (TNBC). The purpose of this study was to identify the potential functional components and clarify the underlying molecular mechanisms of SYF in TNBC. High-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) was used to identify the main components of SYF extracts. Network pharmacology and bioinformatic analyses were carried out to identify potential candidate targets of SYF in TNBC. Cell proliferation was determined with a Celigo imaging cytometer. Wound-healing and Transwell assays were adopted to evaluate cell migration. A Transwell cell-invasion assay was performed with Matrigel-coated membranes. In vivo bioluminescence imaging (BLI) and pathological analyses illustrated the effect of SYF on cancer cell metastasis in tumour-bearing mice. The inhibitory mechanism of SYF was investigated via quantitative PCR (qPCR) and Western blotting. We found that 3,4-dihydroxyphenyllactic acid, kaempferol, p-coumaric acid, and vanillic acid may be the active components of SYF. Molecular docking confirmed that kaempferol, p-coumaric acid, vanillic acid, and 3,4-dihydroxyphenyllactic acid bound stably to proteins such as AKR1C3, MMPs, and STAT3. SYF extract suppressed TNBC cell proliferation, migration, invasion, and metastasis by inhibiting JAK/STAT3 signalling and then regulating downstream genes, such as MMP-2/MMP-9. SYF regulates the expression of genes involved in cell proliferation, migration, and invasion by regulating the JAK/STAT3 signalling pathway and finally inhibits tumour cell metastasis in TNBC. The present study clarifies the mechanism by which SYF inhibits TNBC metastasis and lays an experimental foundation for the continued clinical development of SYF targeting the JAK/STAT3 pathway.Keywords:Sanyin formula (SYF);triple-negative breast cancer (TNBC);signal transducer and activator of transcription 3 (STAT3) pathway;cancer cell metastasis;network pharmacology
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2017
·
IF 4.593
Shimei Qi,Zunyong Feng,Qiang Li,Zhilin Qi,Yao Zhang
Myricitrin, a naturally occurring polyphenol hydroxy flavonoid, has been reported to possess anti-inflammatory properties. However, the precise molecular mechanism of myricitrin’s effects on LPS-induced inflammation is unclear. In the present study, myricitrin significantly alleviated acute lung injury in mice. Myricitrin also markedly suppressed the production of NO, TNF-α, IL-6, and MCP-1 in RAW264.7 macrophage cells. The inhibition of NO was concomitant with a decrease in the protein and mRNA levels of iNOS. The phosphorylation of JAKs and STAT-1 was abrogated by myricitrin. Furthermore, myricitrin inhibited the nuclear transfer and DNA binding activity of STAT1. The JAK-specific inhibitor ruxolitinib simulated the anti-inflammatory effect of myricitrin. However, myricitrin had no impact on the MAPK signalling pathway. Myricitrin attenuated the generation of intracellular ROS by inhibiting the assembly of components of the gp91phox and p47phox. Suppression of ROS generation using NAC or apocynin or by silencing gp91phox and p47phox all demonstrated that decreasing the level of ROS inhibited the LPS-induced inflammatory response. Collectively, these results confirmed that myricitrin exhibited anti-inflammatory activity by blocking the activation of JAKs and the downstream transcription factor STAT1, which may result from the downregulation of NOX2-dependent ROS production mediated by myricitrin.
研究领域:
药理学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Crystals
·
2022
·Vol. 12
·期 12
·1722
·
IF 2.67
Yujiang Xie,Genpei Shi,Jie Sun,Si Li,Wei Gao,Yimin Hu,Chang Zu,Weiwei Tang,Junbo Gong
Developing multicomponent crystal forms, especially cocrystals and salts, is becoming a promising pathway to improve the solubility and bioavailability of drugs. Herein, new multicomponent crystals of SHR0302, a new generation of Janus Kinase (JAK) inhibitor that suffers from poor solubility, were developed based on a cooperative approach of computational and experimental coformer screenings. Virtual screening methods, including the conductor-like screening model for realistic solvents (COSMO-RS) and molecular complementary (MC) analysis, were employed to predict the binding affinity between SHR0302 and selected coformers. The developed screening method was capable of reducing the screening database to 30 coformers from a total of 42 proposed coformers. The proof-of-concept experimental screening study was performed to demonstrate the efficiency of computational screening, wherein three new multicomponent crystalline forms were found and fully characterized by powder X-ray diffraction, thermal analysis, and IR and1H-NMR spectroscopy. Further, the measurements of the solubility property of these new multicomponent crystal forms reveal an apparent promotion compared with the drug alone. Finally, the receiver operator characteristic (ROC) curve was used to assess the prediction performance of the COSMO-RS model. It was found that the established screening model can effectively shorten the experimental screening time and efforts.Keywords:multicomponent crystals;cocrystals;COSMO-RS;cocrystal prediction;solubility enhancement
研究领域:
药物化学
·
计算化学
✓ 已验证
产品关联
DOI
高影响因子
PeerJ
·
2022
·
IF 3.061
Jinhuang Shen,Xinhua Ma,Yubin He,Yanjun Wang,Tianhua Zhong,Yonghong Zhang
Background Ulcerative colitis is a unique inflammatory bowel disease with ulcerative lesions of the colonic mucosa. Melianodiol (MN), a triterpenoid, isolated from the fruits of the Chinese medicinal plant Melia azedarach , possesses significant anti-inflammatory properties. Objective The present study investigated the protective effects of MN on lipopolysaccharide (LPS)-induced macrophages and DSS-mediated ulcerative colitis in mice. Methods In the study, mice were given MN (50, 100, and 200 mg/kg) and 5-ASA (500 mg/kg) daily for 9 days after induction by DSS for 1 week. The progress of the disease was monitored daily by observation of changes in clinical signs and body weight. Results The results showed that MN effectively improved the overproduction of inflammatory factors (IL-6, NO, and TNF- α ) and suppressed the activation of the NF- κ B signalling cascade in LPS-mediated RAW264.7 cells. For DSS-mediated colitis in mice, MN can reduce weight loss and the disease activity index (DAI) score in UC mice, suppress colon shortening, and alleviate pathological colon injury. Moreover, MN treatment notably up regulated the levels of IL-10 and down regulated those of IL-1 β and TNF- α , and inhibited the protein expression of p-JAK2, p-STAT3, iNOS, NF- κ B P65, p-P65, p-IKK α/β , and p-I κ B α in the colon. After MN treatment, the levels of MDA and NO in colonic tissue were remarkably decreased, whereas the levels of GSH, SOD, Nrf-2, Keap-1, HO-1, I κ B α , and eNOS protein expression levels were significantly increased. Conclusion These results indicate that MN can activate the Nrf-2 signalling pathway and inhibit the JAK/STAT, iNOS/eNOS, and NF- κ B signalling cascades, enhance intestinal barrier function, and effectively reduce the LPS-mediated inflammatory response in mouse macrophages and DSS-induced intestinal injury in UC.
研究领域:
药理学
·
免疫学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Annals of Translational Medicine
·
2022
·
IF 3.616
Huili Huang,Ying Tong,Tong Fu,Danmei Lin,Hansheng Li,Li Xu,Senyue Zhang,Yanzhe Yin,Yiran Gao
Background To use network pharmacology and gut microbiota sequencing to investigate the probable mechanism of Bining decoction (BN) in the treatment of gouty nephropathy (GN). Methods Firstly, the mechanism of therapeutic effects of BN on GN were collected by integrating network pharmacology. Secondly, the treatment effects of BN against GN in 30 Institute of Cancer Research (ICR) mice were evaluated by performing biochemical tests [uric acid, blood urea nitrogen, and creatinine (UA, BUN, and Cr)] and evaluating the renal weight index. Finally, 16S rRNA sequencing was utilized for elucidating the therapeutical effect of BN in GN. Results The results of gut microbiota sequencing analysis showed the abundance of Faecalibaculum , Romboutsia , Bifidobacterium , Bacteroides , Odoribacter , Lachnospiraceae NK4A136 group, unclassified_f__ Lachnospiraceae , Roseburia , norank_f__ Lachnospiraceae , Lactobacillus , Dubosiella , norank_f__ Muribaculaceae , and Turicibacter in the BN group had a significant changed between-group comparisons. Using a network pharmacology-related database, 413 active components of BN were identified, as well as 1,085 GN-associated targets. The 118 targets of disease targets and component targets were mapped, of which the top 10 genes were selected. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that 157 pathways were enriched, which was partially consistent with the metabolic pathways of gut microbiota sequencing analysis. Conclusions Combining 16S rRNA gene sequencing and network pharmacology analysis, similar signaling pathways were followed: “Pathways in cancer” and “Adipocytokine signaling pathway”. The results reveal that BN increases the abundance of Turicibacter , regulates the expression of JAK2 in the JAK/STAT pathway, increases the beneficial bacteria Turicibacter associated with intestinal butyric acid, which could enhance the intestinal barrier, and exert anti-inflammatory effects.
研究领域:
药理学
·
微生物学
·
分子生物学
·
肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2026
·
IF 3.7
Wen Qiang,Yuan Yi,Liu Zhihua,Wang Lei,Pan Chunguo
Lung cancer (LC) is a leading cause of cancer-related mortality worldwide. While the chemokine CCL25 is implicated in the tumor microenvironment, its specific role in LC is not fully understood. Here, we identify CCL25 as a key promoter of tumor progression through a novel macrophage-mediated signaling axis. Bioinformatics and clinical analyses revealed that CCL25 is highly expressed in LC and correlates with M2 macrophage infiltration and poorer patient survival. In vitro, tumor-derived CCL25 drove M2 polarization of macrophages by upregulating its receptor CCR9. Functionally, these CCL25-CCR9-induced M2 macrophages secreted TGF-β1 and significantly enhanced the proliferation, migration, and invasion of LC cells. Mechanistically, this effect was mediated through the activation of the JAK/STAT signaling pathway and the subsequent upregulation of the downstream oncogene PIM2 in tumor cells. Both pharmacological inhibition of JAK/STAT and genetic knockdown of PIM2 reversed the tumor-promoting crosstalk. Single-cell transcriptomics confirmed the presence of a TGF-β1-expressing CCR9 + M2 macrophage subset in human tumors and revealed co-expression of CCR9 and PIM2 in tumor cells. In vivo, CCL25 overexpression accelerated tumor growth and M2 macrophage infiltration. Collectively, our findings define a complete CCL25-CCR9-TGF-β1-JAK/STAT-PIM2 signaling circuit wherein tumor cells educate macrophages to, in turn, fuel their own malignant progression, highlighting this axis as a potential therapeutic target in lung cancer.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2022
·
IF 6.064
Sun Jingjun,Zhu Shuangjiu,Xu Weixuan,Jiang Guoqin
The combination of chemo-photothermal therapy has a wide application prospect in the intensive treatment of cancer. In this study, we developed a complex nanoparticle consist of polypyrrole, cystine dihydrochloride and hyaluronan. The polypyrrole nanoparticles loaded with paclitaxel exhibited good photothermal effects, and the drug release can be triggered by combined response of temperature and redox. In vitro biological studies indicated the nanoparticles could effectively induced apoptosis of MDA-MB-231 breast cancer cells involved in the potential mechanism of inhibition of biological expression of heat shock proteins and JAK-STAT signaling pathway. In addition, the nanoparticles have a significant inhibitory effect on cancer growth in breast tumor-bearing mice model, indicating that they have great potential for synergistic chemo-photothermal therapy.
研究领域:
纳米技术
·
癌症治疗
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Annals of Translational Medicine
·
2020
·
IF 3.297
Li Li,Xingfeng He,Xingtong Wang,Yu Sun,Guosheng Wu,He Fang,Chen Wang,Pengfei Luo,Zhaofan Xia
Background Ruxolitinib is an inhibitor of Janus kinases (JAK) 1/2. It was authorised recently by the U.S. Food and Drug Administration (FDA) as a new Myelofibrosis treatment. In this study, we identified ruxolitinib as a new inhibitor of nitric oxide (NO) production in response to lipopolysaccharide (LPS)stimulation of RAW 264.7 cells. Methods In vitro direct effects of ruxolitinib were determined through NO production on RAW 264.7 cells. Also the expression level of iNOS, TNF-α and IL-6 were detected by Western Blotting and qRT-PCR. In vivo therapeutic effects of ruxolitinib on sepsis were evaluated by an endotoxemia model with C57 mice. The survival was calculated and histopathological damage of organs was observed by HE. Cytokines in serum were detected by Mouse Cytokine Array Panel. Results Ruxolitinib was found to significantly reduce NO production, inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 expression, suggesting that ruxolitinib blocks LPS signaling that leads to pro-inflammatory factor expression. Furthermore, the inhibitory effects of ruxolitinib contributed to the survival of septic mice by 70% and pro-inflammatory cytokines in serum declined apparently. The results taken together indicate that ruxolitinib can significantly suppress LPS-stimulated NO production and improve the survival of septic mice, perhaps by interfering with the NF-κB pathway. Conclusions These findings suggest ruxolitinib might be a possible therapeutic candidate for sepsis therapy.
研究领域:
药理学
·
免疫学
·
传染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Jiahao Wang,Liang Zhang,Lingjun Wang,Jincheng Tang,Wei Wang,Yichang Xu,Ziang Li,Zhouye Ding,Xinzhao Jiang,Kun Xi,Liang Chen,Yong Gu
Targeting macrophages can facilitate the site-specific repair of critical bone defects. Herein, a composite hydrogel, gelatin- Bletilla striata polysaccharide-mesoporous bioactive glass hydrogel (GBM gel ), is constructed via the self-assembly of mesoporous bioactive glass on polysaccharide structures, through the Schiff base reaction. GBM gel can efficiently capture macrophages and drive the recruitment of seed stem cells and vascular budding required for regeneration in the early stages of bone injury, and the observed sustained release of inorganic silicon ions further enhances bone matrix deposition, mineralization, and vascular maturation. Moreover, the use of macrophage-depleted rat calvarial defect models further confirms that GBM gel , with ligand-selective macrophage targeting, increases the bone regeneration area and the proportion of mature bone. Mechanistic studies reveal that GBM gel upregulates the TLR4/NF-κB and MAPK macrophage pathways in the early stages and the JAK/STAT3 pathway in the later stages; thus initiating macrophage polarization at different time points. In conclusion, this study is based on the endogenous self-healing properties of bone macrophages, which enhances stem cell homing, and provides a research and theoretical basis upon which bone tissue can be reshaped and regenerated using the body's immune power, providing a new strategy for the treatment of critical bone defects.
研究领域:
生物医学工程
·
组织工程
·
免疫学
·
再生医学
·
材料科学
✓ 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）