JOURNAL OF IMMUNOLOGY
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2024
·
IF 3.6
Zhu Yiqiang,Zhou Lu,Mo Lengshan,Hong Cansheng,Pan Lingxia,Lin Jie,Qi Yanwei,Tan Simin,Qian Manhongtian,Hu Tengfei,Zhao Yi,Qiu Huaina,Lin Peibin,Ma Xiancai,Yang Quan
Myeloid-derived suppressor cells (MDSCs), the negative immune regulators, have been demonstrated to be involved in immune responses to a variety of pathological conditions, such as tumors, chronic inflammation, and infectious diseases. However, the roles and mechanisms underlying the expansion of MDSCs in malaria remain unclear. In this study, the phenotypic and functional characteristics of splenic MDSCs during Plasmodium yoelii NSM infection are described. Furthermore, we provide compelling evidence that the sera from P. yoelii–infected C57BL/6 mice containing excess IL-6 and granulocyte-macrophage colony-stimulating factor promote the accumulation of MDSCs by inducing Bcl2 expression. Serum-induced MDSCs exert more potent suppressive effects on T cell responses than control MDSCs within both in vivo P. yoelii infection and in vitro serum-treated bone marrow cells experiments. Serum treatment increases the MDSC inhibitory effect, which is dependent on Arg1 expression. Moreover, mechanistic studies reveal that the serum effects are mediated by JAK/STAT3 signaling. By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti–Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii–infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria.
研究领域:
免疫学
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传染病学
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细胞生物学
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疟疾
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DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2023
·
IF 4.4
Shao-Liang Jiang,Wan-Jun Wang,Zhe-Ying Hu,Rong-Juan Zhang,Jie-Hua Shi
The primary coverage of this paper is to investigate the molecular interaction of JAK2 inhibitor, fedratinib (FED) with BSA/HAG proteins through multispectral approaches and molecular docking as well as MD calculation. Arrival at a conclusion, the endogenous fluorescence of BSA/HAG protein was quenched separately in the form of static and mixed quenching. The FED-BSA and FED-HAG complexes with the stoichiometric ratio of 1:1 were formed in the interaction process. And, The K b values of these complexes were of 10 4 –10 5 M −1 and 10 5 –10 6 M −1 , respectively, representing that the FED-HAG complex exhibited a comparatively high affinity compared to the FED-BSA complex. It is confimed that FED inserted into the interface area between subdomain IIA and IIB of BSA (marked as site II') and the bucket-shaped hydrophobic cavity of HAG, respectively, resulting in the slight alteration in the secondary structure of BSA/HAG and the micro-environment round Tyr and Trp residues. The expetimental results also confirmed that van der Waals forces (VDW), hydrogen bonds and hydrophobic interaction played a dominant role in the formation of two stable complexes. The above experimental results were supplemented and verified through molecular docking and MD simulation. Meanwhile, the effects of common ions on affinity were explored. This study could shine a light on evaluating the pharmacological properties of the JAK inhibitor FED, understanding the distribution and operation of the drug in the body, and leading to the development of the creation of novel medication devise.
研究领域:
药理学
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生物化学
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计算生物学
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PubMed
高影响因子
ONCOLOGY REPORTS
·
2025
·Vol. 53
·期 3
·1-14
·
IF 3.9
Dongsheng Lv,Xu Han,Liang Hao,Zhimin Sun,Aobo Zhang,Jing Liu,Liang Liu,Liqiang Liu
Cysteine‑ and glycine‑rich protein 2 (CSRP2) are closely associated with tumor invasion and metastasis. CSRP2 is significantly upregulated in glioma tissues and is associated with the clinical stage of the tumor. Overexpression of CSRP2 in glioma cells promotes the proliferation and metastasis of cancer cells, whereas CSRP2 knockdown inhibits the biological functions of tumor cells. Transcriptome sequencing of CSRP2‑knockdown U251M cells revealed that silencing of CSRP2 inhibited the JAK‑STAT1 signaling pathway, and differentially expressed genes were significantly enriched in cell processes related to necroptosis. Experiments on necroptosis in glioma cells using flow cytometry, Hoechst 33342/PI dual staining and transmission electron microscopy indicated that CSRP2 overexpression inhibited necroptosis in glioma cells. Western blotting results showed that overexpression of CSRP2 activated the JAK‑STAT1 signaling pathway, while the addition of the pathway inhibitor ruxolitinib promoted the phosphorylation of necroptosis proteins RIPK1, RIPK3 and MLKL. Therefore, it was hypothesized that CSRP2 maintains JAK‑STAT1 activation by inhibiting the protein inhibitor of activated STAT1, which then inhibits the necrotizing apoptosis of glioma cells.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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神经肿瘤学
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PubMed
高影响因子
EUROPEAN JOURNAL OF HISTOCHEMISTRY
·
2023
·
IF 2
Hui Yang,Yunlong Zhang,Desheng Zhang,Liping Qian,Tianxing Yang,Xiaocheng Wu
Crocin has been reported to have therapeutic effects on multiple cancers including colon cancer, but its specific mechanism is still ambiguous and needs to be further explored. Human colorectal adenocarcinoma cells (HCT- 116) and human normal colonic epithelial cells (CCD841) were first treated with increasing concentrations of crocin. Subsequently, with 150 and 200 μM of crocin, the cell vitality was examined by cell counting kit 8. Cell apoptosis and proliferation were tested by TUNEL staining and colony formation assay, respectively. The expression of Ki-67 was assessed by immunofluorescence. Enzyme-linked immunosorbent assay was used to evaluate the level of inflammation- and oxidative-related factors. The reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) were examined by flow cytometry. Janus kinase (JAK), signal transducer and activator of transcription 3 (STAT3), and extracellular regulated protein kinases (ERK) in HCT-116 cells were tested by Western blot. Different concentrations of crocin barely affected the CCD841 cell vitality, while crocin restrained the HCT-116 cells vitality, proliferation and the expression of Ki-67, while inducing apoptosis in a concentration-dependent manner. Moreover, the contents of inflammation- and oxidative- related factors in HCT-116 cells were largely blunted by crocin that enhanced ROS, restrained the MMP and suppressed p-JAK2/JAK2, p-STAT3/STAT3, and p-ERK/ERK expression. Crocin induced apoptosis and restored mitochondrial function in HCT-116 cells via repressing the JAK pathway. If the therapeutic effect works in patients, it could herald a new, effective treatment for colon cancer, improving the patients’ prognosis and quality of life.
研究领域:
癌症生物学
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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
Frontiers in Pharmacology
·
2024
·
IF 4.4
Huan Yu,Dan Zhou,Wei Wang,Qingxia Wang,Min Li,Xiaoyun Ma
Background and Purpose: The damage or apoptosis of retinal ganglion cells (RGCs) is one of the leading causes of various blinding eye diseases, such as glaucoma, diabetic retinopathy, optic neuritis, and ischemic optic neuropathy. Oxidative stress is involved in RGCs death. Baicalin, a flavonoid compound extracted from Scutellaria baicalensis, has various beneficial effects, including anti-inflammatory, anti-apoptotic, and antioxidant properties. However, the effects of baicalin on RGCs and the underlying mechanisms require further investigation.Methods: In this study, a glutamate-induced oxidative stress damage model of R28 cells and a rat retinal injury model were established to investigate the effects of baicalin on oxidative stress damage to RGCs and try to elucidate the underlying mechanism.Results: In vitro experiments demonstrated that the survival rate of R28 cells after glutamate treatment dropped to 33.4%, while 10 μM baicalin significantly inhibited glutamate-induced damage in RGCs (P < 0.001) and enhanced cell viability through decreasing ROS levels, increasing antioxidant enzyme activity, and suppressing the expression of inflammatory factors iNOS, TNF-α, IL-6, and IL-1β (P < 0.001). In vivo, baicalin effectively mitigated structural damage to retinal tissue and RGCs morphology induced by glutamate, increasing the thickness of the retinal ganglion cell layer, improving RGCs density, and reducing overall retinal thinning in rats (P < 0.001) in a time- and dose-dependent effects. Mechanistic studies revealed that glutamate evaluated the phosphorylation levels of JAK/STAT, while baicalin effectively inhibited the activation of the JAK/STAT signaling pathway.Conclusion: This study confirmed that baicalin protects against glutamate-induced oxidative stress damage in RGCs. It effectively alleviates oxidative stress and inflammatory responses, reduces cell apoptosis, and improves the pathological changes in the retina of rat models of RGCs damage, thereby decreasing RGCs death. Further exploration of its mechanism revealed that baicalin effectively inhibits the JAK/STAT signaling pathway, protecting RGCs from oxidative stress damage. This provides an experimental basis for the application of baicalin in the treatment of RGCs damage.
研究领域:
眼科学
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药理学
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细胞生物学
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神经科学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2016
·Vol. 39
·期 2
·307-316
·
IF 2.348
Yongsheng Yang,Qiumei Dong,Rongheng Li
The induction of apoptosis-resistant rheumatoid synovial tissue cells has been related to constitutively active Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in rheumatoid arthritis (RA). The excessive proliferation and inherent resistance to apoptosis of fibroblast-like synoviocytes (FLS) is an important mechanism by which RA originates. However, the effects of matrine on FLS in RA is unclear. The present study aimed to investigate the mechanism of action of matrine in a rat model of collagen‑induced arthritis (CIA). The CIA model was established using bovine type II collagen. FLS were isolated from control and CIA rats, cultured in vitro, and confirmed to harbor fibroblast‑like characteristics. After treatment of FLS with varying concentrations of matrine, the JAK2 inhibitor AG490, or a combination of both drugs, cell proliferation, apoptosis rate, expression of apoptotic markers and the activation of the JAK/STAT pathway were assessed. Additionally, CIA rats were administered either matrine or methotrexate by oral gavage to examine the effects of therapeutic intervention on arthritis pathogenesis. The arthritis index (AI) was measured and ankle joint structure was analyzed histologically to determine the severity of CIA. Furthermore, expression levels of apoptotic markers and members of the JAK/STAT family were also examined in vivo. Compared with the CIA group, matrine reduced AI and improved ankle pathology. Matrine also inhibited FLS proliferation, induced G0/G1 cell cycle arrest, and increased the rate of apoptosis in vitro. The effects of matrine on apoptosis induction were further confirmed by observations that Bcl-2 levels were decreased, whereas Bax and caspase-3 levels were increased in the matrine-treated synovial tissues and FLS. Finally, matrine treatment also diminished the phosphorylation, and hence activation of JAK2, STAT1 and STAT3. Our results suggest that matrine induces the apoptosis of FLS from rats with CIA by inhibiting activation of the JAK/STAT signaling pathway.
研究领域:
药理学
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免疫学
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风湿病学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 17
·8678
·
IF 4.9
Yamin Zhang,Jiajia Lin,Xiaomei Xu,Xuehua Lu,Lisha Li,Yuezhen Yang,Wenjin Lin
This study aimed to compare the therapeutic effects of fresh (CMF) and dried (CMD) Centipeda minima against allergic rhinitis (AR), elucidate their underlying molecular mechanisms, and identify the bioactive compounds responsible for their immunomodulatory actions. An ovalbumin-induced AR mouse model was treated with CMF or CMD extracts, followed by evaluation of nasal symptoms, serum biomarkers (IgE, histamine, cytokines), and nasal mucosa histopathology. Transcriptomics and widely targeted metabolomics were integrated with network pharmacology to identify differentially expressed genes and bioactive components, which were further validated in RAW264.7 and RBL-2H3 cells. CMF and CMD exhibited distinct anti-AR mechanisms: CMF predominantly suppressed Th2 responses (reducing IgE, IL-6, and histamine while elevating IL-10), whereas CMD enhanced Th1 activity (increasing IFN-γ). Metabolomic analysis revealed CMF was rich in amino acids while CMD contained higher flavonoids, with neocnidilide and 6-gingerol identified as key bioactive compounds that modulated TNF-α, IL-6, and IL-10 via NF-κB and JAK-STAT pathways. These findings demonstrate that CMF and CMD exert complementary anti-inflammatory effects through Th2 inhibition and Th1 activation, respectively, providing a molecular basis for the traditional use of Centipeda minima and highlighting its bioactive compounds as potential therapeutics for inflammatory diseases.
研究领域:
药理学
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免疫学
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民族药理学
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分子生物学
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植物学
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生物医学
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PubMed
高影响因子
Probiotics and Antimicrobial Proteins
·
2025
·
IF 4.4
Niu Lingdi,Li Hai,Guo Junjie,Jia Zheng,Chang Qingru,Liu Ning,Zhang Shuhe,Ge Junwei
The gut microbiota plays a complex role in immune system maturation and function. The induction of memory in innate immune cells appears to be part of a co-adaptation between the host and microbiome. As important gut commensals, certain Lactobacillus have been shown to induce innate immune memory. However, the universality, phenotypic characteristics, mechanisms of Lactobacillus -induced innate immune memory, and its potential applications in vaccine immunology remain poorly understood. Here, we discovered that specific strains of the gut commensal Lactobacillus can induce innate immune memory, resulting in a more balanced trained immunity phenotype through SOCS activation. Upon secondary stimulation, macrophages exhibited increased expression of IL-6 , IL-1β , IL-10 , IL-12 , IFN-β , and TGF-β . Peptidoglycan and components in the secretome sensitive to pancreatic enzymes were identified as key elements in inducing trained immunity. Furthermore, mice that underwent training demonstrated rapid resistance to S. aureus infection. Additionally, Lactobacillus -induced trained immunity significantly enhanced the protective efficacy of vaccines against MRSA. Our findings demonstrate that certain Lactobacillus strains can activate non-classical trained immunity, offering potential for enhancing vaccine efficacy. Our study provides new insights into the role of some gut commensals in immune modulation and suggests a novel approach to vaccine enhancement through trained immunity induced by specific gut commensals.
研究领域:
免疫学
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微生物组研究
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疫苗学
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固有免疫
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分子生物学
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宿主-微生物相互作用
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PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2022
·
IF 2.65
Li Li,Ru Liu,Jing He,Jing Li,Juan Guo,Yun Chen,Ke Ji
Objective. Microglial BV-2 cells are activated in the brain following insomnia. Naringin (NAR) is a polymethoxylated flavonoid that is also commonly found in citrus fruits and is known for its antioxidant potential. However, the effect of NAR on microglial cells has rarely been studied in the brain of an organism after insomnia. This study aimed to investigate the effects and potential mechanisms of action of NAR on microglial cell activation and inflammation. Methods. BV-2 cells were obtained from the China Center for Type Culture Collection and randomly divided into five treatment groups: control, model, NAR (10 μM), WP1066 (5 μM), and NAR + WP1066. With the exception of the control group, all groups were stimulated with LPS (1 μg/mL) for 6 h. CCK8 was used to quantify cell viability and a scratch test was performed to detect cell migration. The expression levels of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), nterleukin 10 (IL-10), and insulin like growth factor (1IGF-1) were measured by ELISA. Western blotting was performed to determine the levels of p-STAT3 and p-JAK. The Focalcheck™ Thin-Ring Fluorescent Microspheres kit was used to detect cell phagocytosis. Immunofluorescence was used to observe the expression of iNOS and arginase1 in BV-2 cells. Results. Compared with the control group, cell migration, cell viability, and the expression of IL-1β, IL-6, TNF-α, and iNOS were significantly increased in the model group, whereas the expression levels of IL-10, IGF-1, and arginase 1, as well as cell phagocytosis were reduced. With the increase in NAR concentration, cell migration, cell viability, the expression levels of IL-1β, IL-6, TNF-α, and iNOS decreased, while the expression of IL-10, IGF-1, and arginase 1 increased. Compared with the control group, p-STAT3, and p-JAK expression in the model group were significantly increased (P<0.05). Compared with the model group, the expression of p-STAT3 and p-JAK in the NAR, NAR + WP1066, and WP1066 groups was significantly decreased (). Conclusion. NAR treatment inhibited the proliferation, migration, and inflammation of BV-2 cells as well as the activation of microglia to the M1 phenotype. Conversely, NAR treatment promoted the activation of microglia to the M2 phenotype and enhanced the phagocytic function of BV-2 cells by regulating the activity of the JAK/STAT3 pathway.
研究领域:
神经科学
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免疫学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 4
·2018
·
IF 6.208
Yan Zhang,Pei Ma,Zhiguang Duan,Yannan Liu,Yu Mi,Daidi Fan
Lung adenocarcinoma (LAC) is a common lung cancer with a high malignancy that urgently needs to be treated with effective drugs. Ginsenoside Rh4 exhibits outstanding antitumor activities. However, few studies reported its effects on growth, metastasis and molecular mechanisms in LAC. Here, Rh4 is certified to show a strong anti-LAC efficiency in vitro and in vivo. Results of flow cytometry and Western blot are obtained to exhibited that Rh4 markedly restrained cellular proliferation and colony formation by arresting the cell cycle in the G1 phase. Results from a wound healing assay and transwell assays demonstrated that Rh4 is active in the antimigration and anti-invasion of LAC. The analysis of Western blot, immunofluorescence and RT-qPCR confirmed that Rh4 reverses the epithelial–mesenchymal transition (EMT) through upregulating the gene expression of E-cadherin and downregulating that of snail, N-cadherin and vimentin. In vivo results from immunohistochemistry show consistent trends with cellular studies. Furthermore, Rh4 suppresses the Janus kinases2/signal transducer and activator of the transcription3 (JAK2/STAT3) signaling pathway stimulated by TGF-β1. Silencing the STAT3 signal or co-treating with AG490 both enhanced the EMT attenuation caused by Rh4, which revealed that Rh4 suppressed EMT via inhibiting the JAK2/STAT3 signaling pathway. These findings explore the capacity and mechanism of Rh4 on the antimetastasis of LAC, providing evidence for Rh4 to LAC therapy.Keywords:ginsenoside Rh4;lung adenocarcinoma;metastasis;cell cycle;JAK/STAT signaling
研究领域:
肿瘤学
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分子生物学
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药理学
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PubMed
高影响因子
Antioxidants
·
2022
·Vol. 11
·期 2
·426
·
IF 7.675
Tian Wei,Lei Wu,Xiaowen Ji,Yan Gao,Guiran Xiao
Ursolic acid (UA) is a bioactive molecule widely distributed in various fruits and vegetables, which was reported to play a therapeutic role in ulcerative colitis (UC) induced by toxic chemicals. However, the underlying mechanism has not been well clarified in vivo. Here, using aDrosophilaUC model induced by sodium dodecyl sulfate (SDS), we investigated the defensive effect of UA on intestinal damage. The results showed that UA could significantly protectDrosophilafrom the damage caused by SDS exposure. Further, UA alleviated the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA) induced by SDS and upregulated the activities of total superoxide dismutase (T-SOD) and catalase (CAT). Moreover, the proliferation and differentiation of intestine stem cells (ISCs) as well as the excessive activation of the c-Jun N-terminal kinase (JNK)-dependent JAK/STAT signaling pathway induced by SDS were restored by UA. In conclusion, UA prevents intestine injury from toxic compounds by reducing the JNK/JAK/STAT signaling pathway. UA may provide a theoretical basis for functional food or natural medicine development.Keywords:ursolic acid;ulcerative colitis;JNK;JAK/STAT;Drosophila
研究领域:
药理学
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分子生物学
·
胃肠病学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Fangfei Zhou,Qingge Lu,Lingyu Kong,Sitong Wang,Haixia Zhang,Meng Zhao,Yue Hu,Fanwu Wu,Chenxi Wu
Background: Cancer is a global public health crisis and the leading cause of death among middle-aged and older individuals, with its incidence increasingly shifting toward younger populations. Approximately 90% of the patients succumb to advanced metastasis, and effective treatments remain elusive. The specific molecular mechanisms underlying cancer cell invasion and migration remain poorly understood, hindering the development of effective targeted therapies. Therefore, inhibiting or reversing cancer cell invasion and migration may be crucial for reducing mortality. Our previous research revealed that the five drugs (FD), derived from Xuefu Zhuyu Decoction (XFZYD), play a significant role in inhibiting cell migration.Hypothesis/purpose: This study aims to explore the main drug components of FD and investigate the underlying mechanism in inhibiting cell migration.Methods: We used the Drosophila ptc>scrib-IR cell migration model to investigate the effects of FD. FD was disassembled and analyzed using an orthogonal design. Drug extracts were prepared and administered to Drosophila larvae. We assessed the effects of FD on cell migration, reactive oxygen species (ROS) levels, and gene expression.Results: In FD disassembled recipes and orthogonal test design, a significant difference was observed in the intervention with or without Glycyrrhiza uralensis Fisch. (GUF) in migrating cell number (P < 0.01), which emerged as a more potent inhibitor of FD from XFZYD in cell migration. High-performance liquid chromatography revealed that GUF and its extract contained effective medicinal components, namely glycyrrhizic acid, liquiritin, liquiritigenin, and glycyrrhetinic acid. Moreover, GUF at 4.0 mg/mL displayed strong inhibitory effect in migrating cell number and distance when compared with model, XFZYD or FD. Excessive ROS can activate the JAK/STAT signaling pathway and promote the EMT process. GUF inhibited ptc>scrib-IR-induced cell migration by reducing ROS levels, JAK/STAT signalling, and the transcription of upd2, upd3, hop and socs36E. Finally, GUF rescued the altered expressions of the epithelial-mesenchymal transition (EMT)-related proteins, including matrix metalloproteinase 1 (MMP1), β-integrin and E-cadherin, triggered by cell migration.Conclusion: Our findings demonstrate that GUF may serve as a promising candidate for targeting advanced metastatic tumors by suppressing ROS-mediated JAK/STAT signaling and EMT.
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高影响因子
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