BIOCHEMICAL PHARMACOLOGY
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2025
·
IF 5.6
Heng Wang,Guojiang Zhang,Cai Zhao,Youan Xue,Di Zhu,Yan Chang
While interferon-alpha (IFN-α) demonstrates potent antineoplastic activity against hepatocellular carcinoma (HCC), but many patients have a low response rate and may even develop resistance to it. It is necessary to find new strategies to reduce IFN-α resistance and improve its efficacy. RAR-related orphan receptor gamma t (RORγt) agonists exhibit dual immunomodulatory functions, demonstrating both immunosuppression-reducing and immune-activating properties. In this study, we demonstrated that the combination of the RORγt agonist-LYC-55716 and IFN-α significantly promoted cytotoxic T cell 17 (Tc17 cell) differentiation and interleukin-17a (I1-17a) expression through activation of the Akt/Stat3 signal pathway. The combination therapy markedly enhanced the tumoricidal activity of differentiated Tc17 cells against hepatoma carcinoma cells. Moreover, this therapeutic strategy showed superior antitumor efficacy in multiple HCC models while maintaining a favorable safety profile compared to single-agent treatment. Importantly, our findings revealed that the combination treatment significantly enhanced CD8 + T cells infiltration into tumor tissues. Moreover, our mechanistic studies revealed that the observed synergistic antitumor effect was mediated by enhanced CD8 + T cell tumor infiltration, which was facilitated by the C-X-C motif chemokine ligand 10 (Cxcl10)- C-X-C motif chemokine receptor 3 (Cxcr3) interaction. Collectively, these findings support a novel immunoregulatory strategy that leverages RORγt agonists to enhance the efficacy of IFN-α in HCC therapy
研究领域:
肿瘤免疫学
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肝脏疾病
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分子生物学
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药物开发
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高影响因子
Frontiers in Bioengineering and Biotechnology
·
2024
·
IF 4.3
Ruijie Wang,Ning Zhou,Jinfang Xue,Yan Li,Yang Wang,Huadong Zhu,Chuanzhu Lv
Background: In sepsis, the lung is one of the worst affected organs, often leading to acute lung injury (ALI). More and more evidence suggests that macrophages are also involved in the pathogenesis of ALI. In our previous study, we successfully synthesized Iron-capsaicin-based nanoparticles (Fe-CAP NPs) and found that it could inhibit the secretion of inflammatory cytokines to alleviate ALI. Here, we further explore the anti-inflammatory mechanism of Fe-CAP NPs.Methods: Bone marrow-derived macrophages (BMDM) and C57 mice were divided into four groups: control group, lipopolysaccharide (LPS) group, CAP + LPS group and Fe-CAP + LPS group. Western blot and Immunofluorescence were used to detect the expression of macrophage phenotypic markers CD86 and CD206 in BMDM and lung tissue. Fluorescence microbeads, Transwell and ROS kit were used to detect the phagocytosis, migration and ROS clearing capability of BMDM. Western blot was used to detect the expression of JAK2/STAT3 pathway and apoptosis proteins in BMDM. TUNEL kit and H&E staining were used to evaluate apoptosis and pathological changes in lung tissue.Results: In vitro, CD86 expression was increased in LPS, but decreased after Fe-CAP pretreatment. CD206 expression was the opposite. Fe-CAP reduced phagocytosis, migration and scavenged ROS in LPS-treated BMDM. Fe-CAP inhibited P-JAK2 and P-STAT3 expression and reduced apoptosis. In vivo, Fe-CAP improved lung histopathology and reduced apoptosis in lung tissue of LPS group. CD86 expression was increased in lung tissue of LPS group, but decreased in Fe-CAP preconditioning, and CD206 expression was reversed.Conclusion: Fe-CAP NPs could alleviate sepsis-induced ALI by regulating the polarization and function of macrophages, reducing ROS level and apoptosis.
研究领域:
免疫学
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药理学
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肺病学
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纳米技术
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高影响因子
TOXICOLOGY
·
2024
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IF 4.8
Ruoyun Dong,Li Li,Hongmei Chang,Guanling Song,Sixiu Liu
Titanium dioxide nanoparticles (TiO 2 NPs) can reduce sperm number, but the mechanisms of defective spermatogenesis induced by TiO 2 NPs have not been studied through cell-cell interactions at present. A kind of biomimetic three-dimensional blood−testis barrier microfluidic chip capable of intercellular communication was constructed with soft lithography techniques, including Sertoli cell (TM4), spermatogonia (GC-1) and vascular endothelial cell units, to study the mechanisms of TiO 2 NPs-induced defective spermatogenesis. TM4 and GC-1 cells cultured in TiO 2 NPs exposure and control chips were collected for transcriptomics and metabonomics analysis, and key proteins and metabolites in changed biological processes were validated. In TM4 cells, TiO 2 NPs suppressed glucose metabolism, especially lactate production, which reduced energy substrate supply for spermatogenesis. TiO 2 NPs also decreased the levels of key proteins and metabolites of lactate production. In GC-1 cells, TiO 2 NPs disturbed chemokine signaling pathways regulating cell proliferation and interfered with glutathione metabolism. The Cxcl13, Stat3 and p-Stat3 levels and cell proliferation rate were decreased, and the GSR, GPX4 and GSH contents were increased in GC-1 cells in chips under TiO 2 NPs treatment. The decrease in energy substrate supply for spermatogenesis and inhibition of spermatogonia proliferation could be the main mechanisms of defective spermatogenesis induced by TiO 2 NPs.
研究领域:
纳米技术
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生殖生物学
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细胞生物学
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分子生物学
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毒理学
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高影响因子
CURRENT MOLECULAR MEDICINE
·
2017
·Vol. 17
·期 5
·381-387
·
IF 2.345
Zhu F.,Guan Y.,Zhang R.
Rationale: Studies have implied the positive association of JAK2/STAT3 signaling with the onset and severity of acute pancreatitis (AP). However, definitive functional study of JAK2/STAT3 signaling in the pathogenesis of acute pancreatitis in vivo is missing and its potential as a therapeutic
target and the underlying mechanisms remain to be determined. Objectives: The aim of this study was to explore the role of JAK2/STAT3 signaling in the pathogenesis of hyperlipidemia-intensified caerulin-induced AP and its potential as a therapeutic target. Methods and Results: Using
the caerulin-induced acute pancreatitis rat model, we showed that JAK2/STAT3 signaling was activated in pancreas and systemic inflammation was increased during AP. Pharmacological suppression of JAK2 by its inhibitor AG490 robustly protected against tissue damage, attenuated JAK2/STAT3 signaling
and inflammatory responses. Local pancreatic tissue damage and phosphor- JAK2 in the pancreatic tissue were enhanced in animals fed with high fat diet compared to chow-diet fed animals. Interestingly, JAK2 inhibitor AG490 significantly inhibited pancreas necrosis and systemic inflammation
in animals fed with high fat or chow-diet, but did not affect STAT3 signaling. Conclusion: These results establish that JAK2 activation plays a significant role in the pathogenesis of caerulin-induced AP in animals on both chow and high-fat diets by regulating necrosis and systemic inflammation.
Thus, our results not only clarify novel signaling mechanisms in AP but also suggest that JAK2 might constitute a target in the management of hyperlipidemia-intensified caerulin-induced AP.
研究领域:
胃肠病学
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药理学
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分子生物学
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炎症
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PubMed
高影响因子
Cell Communication and Signaling
·
2025
·Vol. 23
·期 1
·1-21
·
IF 8.9
Jia Yifan,He Muchen,Wang Fan,Zhan Yaqing,Deng Qiwen,Shen Jiantong,Wang Xiwen,Ran Qi,Huang Wenqi,Ling Yihong,Wen Shihong
Background & Aims Dysfunction of the intestinal epithelial barrier (IEB) and gut vascular barrier (GVB) contributes to the development of intestinal ischemia/reperfusion (IR) injury. Tryptophan (TRP), an essential amino acid, plays a crucial role in maintaining intestinal homeostasis, yet its regulatory effects on the GVB following IR remain unexplored. We aimed to better define the role of TRP in intestinal IR in vivo and in vitro. Methods Mice underwent intestinal ischemia/reperfusion (IR) and were fed control, TRP-recommended (TRP-r), or TRP-sufficient (TRP-s) diets. Fecal metagenomic sequencing analyzed microbial composition, and targeted metabolomics quantified tryptophan and its metabolites in intestinal and serum samples. ILA’s effects on barrier integrity were assessed via tight junction protein expression and FITC-dextran permeability assays. RNA sequencing of intestinal endothelial cells elucidated mechanisms by which ILA modulated GVB function. The STAT3-claudin 2 relationship was validated in vitro by ChIP-qPCR. Results TRP supplementation significantly reshaped the gut microbiota, mitigated tissue damage and enhanced the integrity of both the IEB and GVB. Indole-3-lactic acid (ILA), a key tryptophan metabolite, was identified as an important factor in preserving GVB function. Mechanistically, our results show that the aryl hydrocarbon receptor (AhR)/Nrf2/signal transducer and activator of transcription 3 (STAT3) pathway is essential for ILA-mediated improvement of GVB integrity and downregulation of the pore-forming protein claudin 2. Conclusions Our findings highlight the dual role of ILA in reinforcing both IEB and GVB functions and shed light on the molecular mechanisms underlying ILA’s GVB-protective effects. This study implicates that ILA or other AhR-activating metabolites may serve as promising pharmacological agents for alleviating IR-induced intestinal damage. Graphical
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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
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药理学
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分子生物学
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癌症研究
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高影响因子
NEUROSCIENCE LETTERS
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2026
·
IF 2.2
Qiang Zhang,Yilin Wang
Background Rheumatoid arthritis (RA) discomfort is linked to spinal cord microglia activation. Manual acupuncture (MA, twirling manipulation) reduces RA pain. MA’s ability to relieve RA discomfort was examined in this study. Methods After receiving complete Freund’s adjuvant (CFA), RA rats received acupuncture (with or without twisting manipulation). Paw withdrawal latency (PWL), nociceptive threshold, and hematoxylin and eosin (H&E) staining assessed arthritis severity. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate the levels of inflammatory factors (IL-1β, TNF-α and IL-6) in the spinal dorsal horn. Immunofluorescence was used to assess the expression of p-p38 and Iba-1 in the ipsilateral hippocampus and ipsilateral (right) dorsal root ganglia (DRG). Western blot was used to evaluate the expression of proteins linked to the nuclear factor kappa-B (NF-κB) /signal transducer and activator of transcription 3 (STAT3) pathway. Results MA treatment enhanced PWL, inhibited the expression of spinal dorsal horn inflammatory factor and the activation of ipsilateral DRG or ipsilateral hippocampal microglia, also down-regulated NF-κB/STAT3 pathway proteins. The effect of MA on RA symptoms was better than acupuncture alone. Conclusions Our findings demonstrate that MA significantly ameliorates pain in CFA-induced RA rats. The novelty of this study lies in identifying that this analgesic effect is achieved through the inhibition of the NF-κB/STAT3 signaling pathway, leading to a marked reduction in spinal microglia activation
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EXPERIMENTAL AND MOLECULAR PATHOLOGY
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2020
·
IF 2.28
Chunyan Tian,Fengli Gao,Xing Li,Zhuying Li
Asthma is a chronic inflammatory airway disease. Icariside II has been reported to exert anti-inflammatory effect in multiple human diseases . The present study aimed to investigate the effects and mechanisms of Icariside II on airway inflammation and remodeling in asthma. We established an asthma mouse model with ovalbumin (OVA) immunization. Histological analysis using H&E, PAS and Masson staining showed that administration of Icariside II attenuated OVA-induced airway inflammation and remodeling. Icariside II reduced the numbers of total white blood cells and eosinophils in bronchoalveolar lavage fluid (BALF). The levels of interleukin (IL)-4, IL-5, IL-13 and transforming growth factor (TGF)-β1 in peripheral blood and the expression of α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), eotaxin-1, CC-chemokine receptor-3 (CCR-3), Toll-like receptor (TLR)-2 and TLR-4 were significantly down-regulated in lung tissues of OVA-induced mouse model. These results suggested that Icariside II inhibited eosinophil activation and thus decreased eosinophils-induced airway inflammation and remodeling in asthma. Moreover, Icariside II suppressed TGF-β1-induced cell proliferation , migration, and CTGF expression in airway smooth muscle cells (ASMCs). In both OVA-induced mouse model of asthma and TGF-β1-induced ASMCs, Icariside II decreased IκBα degradation, nuclear translocation of NF-κB p65 and STAT3 phophorylation, indicating an inactivation of NF-κB and STAT3 in the presence of Icariside II. Therefore, we demonstrate that Icariside II attenuates eosinophils-induced airway inflammation and remodeling in asthmatic mice and inhibits TGF-β1-induced cell proliferation and migration in ASMCs via suppressing NF-κB and STAT3 signalings.
研究领域:
免疫学
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药理学
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呼吸医学
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PubMed
高影响因子
BRITISH JOURNAL OF CANCER
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2026
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IF 7.8
Zhao Kun,Zhang Jian,Wang Ran,Wang Bin,Ye Dongfan,Huang XiaoOu,Qiu Lingxiao,Duan Yi,Xu Zhi
Background EGFR-tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with non-small cell lung cancer (NSCLC); however, drug resistance limits their long-term efficacy. The role of STAT3 signaling in EGFR-TKI resistance is not completely understood. Methods Using immunohistochemistry, we assessed changes in STAT3 phosphorylation levels in NSCLC before and after EGFR-TKIs treatment. Through gene editing and transcriptome sequencing experiments, we investigated the mechanism by which STAT3 signaling mediates drug resistance. We conducted cell proliferation and nude mice tumorigenesis experiments to verify whether STAT3 inhibitors enhanced the anti-tumor effect of EGFR-TKIs on NSCLC. Results We found that inhibition of the MAPK pathway by EGFR-TKIs triggers the rapid activation of STAT3 in NSCLC. RNA-seq analysis and cellular experiments confirmed that STAT3 regulates the expression of stemness markers, which contribute to drug resistance. Cancer stemness maintenance depends on telomerase. We found that STAT3 also mediates NSCLC resistance by regulating telomerase expression. Finally, we demonstrated in both cellular and animal models that icaritin, an anti-hepatocellular carcinoma agent, significantly potentiates the anti-tumor efficacy of EGFR-TKIs against NSCLC by inhibiting STAT3 activation. Conclusions The combination of EGFR-TKIs and STAT3 inhibitors has the potential to be a better therapeutic strategy for EGFR-mutant NSCLC than EGFR-TKI monotherapy. The alternative text for this image may have been generated using AI.
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ONCOGENE
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2026
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IF 9.1
Liu Pengpeng,Wang Huizhen,Yu Kexun,Ma Mengdi,Yang Xiongwei,Wang Yuexiang,Li Yongxiang
Lymphangiogenesis drives gastric cancer lymph node (GC LN) metastasis via neuro-immune-cancer interactions in the tumor microenvironment. However, the underlying mechanisms remain incompletely understood. Here, we demonstrate that chronic stress (CS) in GC patients correlates with poorer short-term prognosis, perineural/lymphovascular invasion, and advanced LN staging. Mechanistically, CS-induced neutrophil extracellular traps (NETs) are key mediators of LN metastasis. Inhibiting NETs suppressed popliteal LN metastasis and lymphangiogenesis. In vitro and in vivo experiments revealed that CS upregulated acetylcholine (ACh) and choline acetyltransferase (ChAT) levels, with ACh directly inducing NETs formation in a dose-dependently. Exogenous ACh increased LN metastasis (volume), whereas gastric vagotomy attenuated CS-mediated orthotopic tumor growth. Functional assays confirmed that ACh-driven NETs enhanced GC cell malignant behaviors, accelerated adhesive suspension state transformation via extracellular matrix remodeling, and activated a feedforward ACh-NGF axis. This triggered PKC-γ/STAT3-S100A8/A9-ROS cascade, mediating NETs formation and upregulating VEGFA/C. Protein analysis showed CD300ld overexpression in CS + GC tissues, independent of ACh signaling. Notably, combined targeting of the NGF/TrkA and CD300ld exerted synergistic anti-LN metastatic and lymphangiogenic effects. Collectively, this study elucidates a CS-driven mechanism regulating NETs to promote GC LN metastasis and identifies NGF/TrkA and CD300ld as therapeutic targets for GC LN metastasis.
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Yu Yang,Hongda Liu,Junling Ren,Lin Liu,Hui Sun,Li Wang,Guangli Yan,Ying Han,Xijun Wang
Ethnopharmacological relevance Danggui Buxue Decoction (DBD) is a classic traditional Chinese medicine formula that has shown significant efficacy in treating blood deficiency syndrome (BDS), though its mechanisms of action remain unclear. Aim of the study To identify the absorbed bioactive components of DBD and elucidate its molecular mechanisms in BDS by integrating metabolomics and bioinformatics. Materials and methods Using a benzene induced BDS mouse model, we analyzed serum-absorbed components of DBD via UPLC-Q/TOF-MS. A multi-omics approach combining metabolomics, molecular docking, and dynamics simulations was utilized to identify therapeutic targets and bioactive components, followed by experimental validation using pharmacological assays, Western blot, and cellular thermal shift assay (CETSA). Results In the BDS mouse model, DBD primarily corrected nicotinate and nicotinamide metabolism and improved hematopoietic function. Furthermore, it significantly decreased the levels of inflammatory cytokines that activate the STAT3 signaling pathway, including interleukin-6 (IL-6), interleukin-17 (IL-17), and transforming growth factor-β (TGF-β). It also suppressed the expression of p-JAK2/JAK2 and p-STAT3/STAT3. Under the effective status of DBD, we identified eleven prototype components and three metabolites derived from DBD, among which astragaloside IV was a high-affinity binder to STAT3, with molecular dynamics simulations and CETSA confirming its binding stability. Conclusion Our integrated approach suggests that DBD may alleviate BDS by normalizing metabolic imbalance and suppressing the IL-6/JAK2/STAT3 signaling pathway. A role for astragaloside IV as a potent bioactive compound of DBD with high-affinity binder to STAT3 is supported by molecular dynamics simulations and CETSA experiments. These findings provide a mechanistic foundation for DBD's therapeutic effects in treating BDS.
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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.
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