Frontiers in Pharmacology
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2025
·
IF 4.8
Qian Feng,Cai-Zhi Li,Yi-Hua Zou,Xue-Yu Wang,Xia Yang,Rong Zhang*,Zhong-Qiu Liu*,Rong-Rong Zhang
Introduction: Brain metastasis (BM) is the most common and serious complication of breast cancer (BC). There is significant interest in investigating the crosstalk between BC cells and immune cells. β-elemene is the main pharmacodynamic component of Curcumae Rhizoma, a traditional Chinese medicine that is commonly used for the clinical treatment and prevention of various tumors. However, the specific underlying mechanism of β-elemene in BC-BM is still unclear.Methods: An intracardiac (ICT) injection model was used to establish specific BC-BM cells, then an intracarotid (ICD) injection model was used to verify the inhibitory effect of β-elemene in BC-BM. Tumor-cell-conditioned media, a primary microglia co-culture model, and an in vitro recruitment experiment were used to explore crosstalk between BC cells and immune cells. TMT-based quantitative proteomic, ELISA, IF, and other molecular biotechnologies were used to investigate the mechanisms.Results: The BC-BM cells established in our study not only increased BM rates but also exhibit mesenchymal phenotype and activated the JAK–STAT signaling pathway. Microglia, particularly M2 microglia, were enriched in BM lesions and secreted high levels of both IL6 and CCL2. Hypersecretory IL6 reversed the MET process of BC cells by regulating the JAK2/STAT3 signaling pathway to promote colonization in the brain. Increased levels of CCL2 significantly recruited monocytic myeloid-derived suppressor cells (M-MDSCs) to induce an immunosuppressive brain microenvironment. β-elemene could significantly inhibit BC-BM in mice by regulating the IL6/STAT3 signaling pathway and suppressing the M-MDSC recruitment.Conclusion: Our work first demonstrated that β-elemene regulated the IL6/STAT3 axis and M-MDSC recruitment to reconstruct immunosuppressive brain microenvironment to suppress BC-BM.
研究领域:
肿瘤学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
INFLAMMATION RESEARCH
·
2014
·Vol. 63
·期 7
·597-608
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IF 2.143
Pan Xiaolong,Cao Xiang,Li Na,Xu Yimiao,Wu Qiuyue,Bai Jing,Yin Zhimin,Luo Lan,Lan Lei
Objective Forsythin (FOR) is an active ingredient extracted from the fruit of the medicinal plant Forsythia suspensa (Thunb.) Vahl. Here, we investigated the effect of FOR on LPS-induced inflammatory response and the underlying molecular mechanisms in RAW264.7 macrophages. Materials and methods RAW264.7 cells were pre-treated with or without FOR and then stimulated with or without LPS. The productions of TNF-α, IL-1β, IL-6, PGE 2 and NO were determined by ELISA and nitrite analysis, respectively. The expressions of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were measured by Western blotting and RT-PCR analysis. The activations of signaling molecules were detected by Western blotting using phosphorylation specific antibodies. Reactive oxygen species (ROS) production was determined by ROS assay. Results LPS-induced productions of IL-1β, IL-6, TNF-α, NO and PGE 2 were inhibited by FOR in a dose-dependent manner. FOR also suppressed the LPS-elevated expressions of iNOS and COX-2. Further investigations revealed that FOR significantly inhibited the LPS-induced activations of JAK-STATs and p38 MAPKs, but not of IKKα/β in LPS-stimulated RAW264.7 cells. Additionally, FOR interfered with both JAK-STATs and p38 MAPKs signaling pathways to modulate the expressions of IL-1β, IL-6, TNF-α, iNOS and COX-2. Furthermore, FOR reduced the LPS-induced ROS accumulation, validating that FOR serves as an antioxidant. Conclusions Our data suggested that FOR exerts anti-inflammatory action, at least in part, via suppressing LPS-induced activation of JAK-STATs and p38 MAPKs signalings and production of ROS in macrophage cells.
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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分子生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Jiaxiang Zhang,Haitao Ma,Yongjie Yang,Liyin Liu,Dasheng Luo,Defu Yu,Tao Chen
Excessive intake of essential and toxic metals affects the pathological process of osteoporosis. At present, the effects of single forms of iron (Fe), lead (Pb) and other metals on bone injury have been widely studied. However, these metal elements usually do not exist in the environment in a separate form. They are ingested in various ways and are often found together in the human body. However, the mechanism of bone damage caused by Fe and Pb mixed exposure is still unclear at this stage. At present, the combined analysis of multi-omics is the conventional method to explore the molecular mechanism behind the disease. Therefore, we attempted to combine proteomics and metabolomics to explain the mechanism of bone damage caused by mixed Fe and Pb exposure. Differential proteins and metabolites were found to be predominantly enriched in the JAK-STAT signalling pathway, inflammatory bowel disease (IBD), and osteoclast differentiation. Combined analysis showed that Fpr2, Lifr, Lisofylline, 7-Ketocholesterol, LacCer (d18: 1/14:0) and other substances may be involved in the process of bone injury mediated by mixed metal exposure. In summary, we hypothesise that mixed exposure to Fe and Pb leads to osteoclast activation via the JAK-STAT signalling pathway in situ and indirectly via the gut-bone axis, resulting in bone damage. In general, our study potentially suggests that bone injury induced by mixed exposure of Fe and Pb may be related to osteoclast proliferation mediated by changes in inflammatory levels in vivo .
研究领域:
分子生物学
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毒理学
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骨代谢研究
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DOI
PubMed
高影响因子
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
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2026
·Vol. 40
·期 1
·e70661
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IF 2.8
Li Yao,Xin-ze Qiu,Jun Zou,Jing-rong Liang,Meng-bin Qin,Jin-xiu Zhang,Peng Peng,Jie-an Huang
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a leading cause of chronic liver disease with no available therapies. Currently, the pathogenesis of MASLD remains to be further elucidated. Ferroptosis and ferroptosis-related genes may play a vital role in the development of MASLD. Thus, this study investigated the role of heme oxygenase-1 (HMOX1/HO-1) in ferroptosis associated with MASLD. Here, we applied bioinformatics to identify ferroptosis-related genes. HMOX1 expression was validated by immunohistochemistry. Mice fed a methionine-choline-deficient diet for 8 weeks were treated with hemin, followed by biochemical and histological analyses. HL7702 cells were transfected to overexpress HMOX1, exposed to oleic acid, and treated with erastin or AZD1480. Iron, ROS, lipid peroxidation, and mitochondrial damage were assessed by ELISA, flow cytometry, and electron microscopy. Western blotting explored molecular mechanisms. HMOX1 was identified as a ferroptosis-related hub gene in MASLD datasets and was decreased in patient liver tissues. MCD-fed mice developed hepatic steatosis with elevated ALT, AST, TG, LDL, Fe²⁺, MDA, and ROS, along with reduced HMOX1 and GSH. Hemin ameliorated MASLD and inhibited ferroptosis. Cell experiments showed JAK/STAT pathway activation in MASLD. HMOX1 upregulation reduced lipid peroxidation, inhibited ferroptosis, and downregulated JAK/STAT, whereas erastin reversed these effects. AZD1480 reversed the effects of erastin and improved MASLD. Collectively, our results suggest that HMOX1 protects against MASLD by suppressing ferroptosis through JAK/STAT pathway inhibition.
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产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2023
·
IF 4.1
Zhihai Wu,Zhiqiang Luo,Wen Sun,Yuanyuan Shi,Qi Ding
Allergic asthma is a prevalent form of asthma that is characterized primarily by airway inflammation. Jiegeng decoction (JGT) is a traditional Chinese herbal formula known for its anti-inflammatory properties and has been used to treat respiratory diseases for centuries. This study aimed to investigate the biological effects and mechanisms of action of JGT in improving allergic asthma. An experimental allergic asthma mouse model was established using ovalbumin. The results showed that JGT significantly improved inflammation cell infiltration in the lung tissue of allergic asthmatic mice and the inflammatory environment of Th2 cells in the bronchoalveolar lavage fluid while also reducing serum IgE levels. Subsequently, 38 components of JGT were identified through liquid chromatography–mass spectrometry. Network pharmacology revealed that regulating inflammation and immune responses is the primary biological process by which JGT improves allergic asthma, with Th2 cell differentiation and the JAK-STAT signaling pathway being the key mechanisms of action. Finally, qPCR, flow cytometry, and Western blotting were used to validate that JGT inhibited Th2 cell differentiation by blocking the JAK1-STAT6 signaling pathway in CD4+ T cells, ultimately improving allergic asthma. This study provides a novel perspective on the therapeutic potential of JGT in the treatment of allergic asthma.
研究领域:
药理学
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免疫学
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中医
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
·
IF 6.7
Donglei Zheng,Xiaojuan Xin,Hui Ouyang,Lulu Ma,Hao Wang,Xin Liu,Xiangxin Liao,Xinzi Chu,Ying Gao,Jiaying Huo,Shugang Li
Ovotransferrin (OVT) is a functionally active protein demonstrated to alleviate ulcerative colitis (UC), although its mechanism remains incompletely understood. Notably, UC is closely associated with dysbiosis of the gut microbiota. This study investigates the potential of OVT to alleviate colitis by reshaped gut microbiota composition in a DSS-induced UC mouse model. Specifically, Ligilactobacillus murinus (L. murinus) was isolated from the gut microbiota of OVT-treated UC mice and stimulated by OVT in vitro. Integrated whole-genome sequencing and targeted metabolomics revealed that L. murinus encodes bile salt hydrolase, thereby driving secondary bile acid biosynthesis. Mechanistically, fermentation products (FP) derived from coculture of L. murinus with bile exerts potent anti-inflammatory in both Caco-2 cells and a colitis model by Ptgs2 (COX-2) downregulation and the JAK-STAT signaling pathway inhibition. These results established the “OVT-L. murinus-bile acids-Ptgs2/JAK-STAT” axis as a novel mechanism for UC treatment, providing a foundation for high-value applications of OVT in functional foods.
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DOI
PubMed
高影响因子
PLoS Genetics
·
2021
·Vol. 17
·期 7
·e1009649
·
IF 5.917
Kun Wu,Yiming Tang,Qiaoqiao Zhang,Zhangpeng Zhuo,Xiao Sheng,Jingping Huang,Jie’er Ye,Xiaorong Li,Zhiming Liu,Haiyang Chen
The differentiation efficiency of adult stem cells undergoes a significant decline in aged animals, which is closely related to the decline in organ function and age-associated diseases. However, the underlying mechanisms that ultimately lead to this observed decline of the differentiation efficiency of stem cells remain largely unclear. This study investigated Drosophila midguts and identified an obvious upregulation of caudal ( cad ), which encodes a homeobox transcription factor. This factor is traditionally known as a central regulator of embryonic anterior-posterior body axis patterning. This study reports that depletion of cad in intestinal stem/progenitor cells promotes quiescent intestinal stem cells (ISCs) to become activate and produce enterocytes in the midgut under normal gut homeostasis conditions. However, overexpression of cad results in the failure of ISC differentiation and intestinal epithelial regeneration after injury. Moreover, this study suggests that cad prevents intestinal stem/progenitor cell differentiation by modulating the Janus kinase/signal transducers and activators of the transcription pathway and Sox21a-GATAe signaling cascade. Importantly, the reduction of cad expression in intestinal stem/progenitor cells restrained age-associated gut hyperplasia in Drosophila . This study identified a function of the homeobox gene cad in the modulation of adult stem cell differentiation and suggested a potential gene target for the treatment of age-related diseases induced by age-related stem cell dysfunction.
Adult stem cells undergo an aging-related decline of differentiation efficiency in aged animals. However, the underlying mechanisms that ultimately lead to this observed decline of differentiation efficiency in stem cells still remain largely unclear. By using the Drosophila midgut as a model system, this study identified the homeobox family transcription factor gene caudal ( cad ), the expression of which is significantly upregulated in intestinal stem cells (ISCs) and progenitor cells of aged Drosophila . Depletion of cad promoted quiescent ISCs to become activate and produce enterocytes (ECs) in midguts under normal gut homeostasis conditions; However, overexpression of cad resulted in the failure of ISC differentiation and intestinal epithelial regeneration after injury. Moreover, cad prevents ISC-to-EC differentiation by inhibiting JAK/STAT signaling, and the expressions of Sox21a and GATAe . Reduction of cad expression in intestinal stem/progenitor cells restrained age-associated gut hyperplasia in Drosophila . These findings enable a detailed understanding of the roles of homeobox genes in the modulation of adult stem cell aging in humans. This will be beneficial for the treatment of age-associated diseases that are caused by a functional decline of stem cells.
研究领域:
发育生物学
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干细胞生物学
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衰老研究
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分子遗传学
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DOI
PubMed
高影响因子
ENVIRONMENTAL RESEARCH
·
2026
·
IF 8.2
Jiawei Yang,Qiong Zhang,Haichen Zhang,Tao Zhou,Lening Chen,Qianqian Xiao,Qinghe Meng,Jianjun Jiang,Weidong Hao,Xuetao Wei
Bis(2-ethylhexyl) tetrabromophthalate (TBPH), an emerging brominated flame retardant, has raised environmental concern due to its endocrine-disrupting potential. While epidemiological evidence and our previous animal studies have linked TBPH to thyroid disruption, the molecular mechanisms remain unclear. This study aimed to identify potential molecular targets and downstream pathways involved in TBPH-induced effects on thyroid. We found that TBPH (100 nM) significantly upregulated the expression of key thyroid hormone synthesis markers PAX-8, TPO, and TG in human thyroid follicular cells (Nthy-ori 3-1). In silico docking identified S1PR3 as a potential interactor with moderate predicted affinity, and cellular thermal shift assay (CETSA) provided initial evidence of target engagement. S1 pr 3 knockdown partially attenuated TBPH-induced marker upregulation. Mechanistically, TBPH increased interleukin-10 (IL-10) in an S1PR3-dependent manner, coupled with activation of a non-canonical JAK-STAT pathway (JAK3, TYK2, STAT2, and STAT5). Further, overexpression of Il-10 enhanced downstream effector expression, whereas overexpression of Jak3 similarly promoted PAX-8 and TPO levels; conversely, Tyk2 knockdown reduced these markers, supporting a functional role for this alternative signaling cascade. Importantly, key elements of this pathway were recapitulated in thyroid tissues of TBPH-treated rats, providing in vivo corroboration for the cellular observations. Collectively, our results suggest a S1PR3/IL-10/non-canonical JAK-STAT axis as a candidate mechanism for TBPH-induced thyroid marker upregulation, providing a hypothesis-generating framework for future toxicological investigations of TBPH and related emerging brominated flame retardants.
✓ 已验证
DOI
高影响因子
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
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免疫学
·
分子生物学
✓ 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
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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
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分子生物学
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药理学
✓ 已验证
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
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分子生物学
·
肾病学
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产品关联
DOI
PubMed
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
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免疫学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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