INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Chunling Yuan,Li Zheng,Hongxia Hu,Xue Cheng,Peng Liu
Background Investigate the effects of berbamine (BBM) on alleviating motor and cognitive impairment in animal models of Huntington's disease (HD). Methods Intraperitoneal injection of 3-nitropropionic acid (3-NP) mice and B6-hHTT130-N transgenic mice were used as the HD models. We evaluated the anti-HD effect of BBM through behavioral experiments and employed molecular biological techniques, network pharmacology analysis, to test the potential mechanisms. Results BBM improved motor and cognitive impairment in 3-NP-injected and B6-hHTT130-N mice. BBM improved pathological damage in the brain, reduced the expression of mHTT in B6-hHTT130-N mice. BBM increased the ATP and mtDNA content, attenuated PINK1/Parkin-mediated mitophagy suppression. Furthermore, network pharmacology analysis, molecular docking and CETSA identified two targets: Src and AKT1. By using the Src inhibitor KX2–391, AKT inhibitor MK-2206 and NFκB inhibitor QNZ, we found that BBM showed a similar experimental results to Src inhibitor in Q74 plasmid transfected BV2 cells. BBM could inhibit the Src/AKT1/NFκB/NLRP3 signaling pathway-mediated neuroinflammation, and enhance PINK1/Parkin expression may through inhibiting Src. Conclusion BBM ameliorates motor and cognitive impairments in HD model mice through inhibition of neuroinflammation and mHTT expression, maintenance of mitochondrial function, which was mediated by inhibiting Src/AKT1/NFκB signaling pathway and attenuating Src-mediated mitophagy suppression.
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高影响因子
CARDIOVASCULAR DRUGS AND THERAPY
·
2021
·Vol. 36
·期 6
·1075-1089
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IF 3.727
Wang Li,Peng Yunfan,Song Lijun,Xia Dasheng,Li Chao,Li Zhuqing,Li Qi,Yu Ao,Lu Chengzhi,Wang Yongjian
Purpose Anti-inflammatory therapy is important for reducing myocardial injury after acute myocardial infarction (MI). New anti-inflammatory drugs and their mechanism are necessary to be explored to improve clinical efficacy. We aimed to improve the efficacy of colchicine on attenuating MI injury by nano-drug delivery systems and to investigate the mechanism of anti-inflammatory. Methods A colchicine-containing delivery system based on calcium carbonate nanoparticles (ColCaNPs) was synthesized. The protection against MI by ColCaNPs was evaluated using an in vivo rat model established by ligating the left anterior descending coronary artery. Macrophage polarization and the levels of inflammatory cytokines were determined using immunohistochemistry, Western blot, and ELISA analysis. Results ColCaNP treatment showed about a 45% reduction in myocardial infarct size and attenuating myocardial fibrosis compared with groups without drug intervention after MI. Furthermore, ColCaNPs significantly decreased the levels of CRP, TNF-α, and IL-1β in serum and the expression of proinflammatory cytokine in myocardial tissues after MI ( p < 0.05). We also found that ColCaNPs notably restrained pyroptosis and inhibited inflammatory response by modulating on M1/M2 macrophage polarization and suppressing TLR4/NFκB/NLRP3 signal pathway. Conclusion Colchicine-containing nanoparticles can protect against MI injury in a clinically relevant rat model by reducing inflammation. In addition, calcium carbonate nanoparticles can increase the cardioprotective effects of colchicine.
研究领域:
心脏病学
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药学
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纳米技术
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炎症研究
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CONNECTIVE TISSUE RESEARCH
·
2023
·
IF 2.9
Gao-Feng Zhao,Le-Bin Huang
Aims Osteoarthritis (OA) is a chronic inflammatory disease, characterized by degradation of extracellular matrix, apoptosis of chondrocytes and inflammation in articular cartilage. Zinc finger E-box binding homebox 2 (ZEB2), a transcription repressor, has been demonstrated with anti-inflammatory role in some cells. The analysis from GEO data reveals that ZEB2 expression is upregulated in articular cartilage of OA patients and experimental OA rodents. This study aims to confirm the function of ZEB2 in OA process.Material and methods The experimental OA was induced by anterior cruciate ligament transaction (ACLT) in rats, and the adenovirus loaded with ZEB2 coding sequence was intra-articularly injected into rats (1 × 10 PFU). The primary articular chondrocytes were stimulated by interleukin-1β (IL-1β) (10 ng/ml) to mimic the osteoarthritic injury, and transfected with the adenovirus carrying ZEB2 coding or silencing sequence. The apoptosis, content of extracellular matrix, inflammation, and the activity of NFκB signaling in chondrocytes and cartilage were determined.Results ZEB2 was highly expressed in osteoarthritic cartilage tissues and IL-1β-treated chondrocytes. The overexpression of ZEB2 restrained ACLT- or IL-1β administration-induced apoptosis, matrix degradation and inflammation in vivo or in vitro, evidenced by changed levels of cleaved caspase-3/PARP, collagen-II, aggrecan, matrix metalloproteinase 3/13, tumor necrosis factor-α and interleukin-6. Additionally, the phosphorylation of NFκB p65, IκBα and IKKα/β, and the nuclear translocation of p65 was blocked by ZEB2, implying inactivation of this signaling.Conclusions ZEB2 mitigated osteoarthritic symptoms in rats and chondrocytes, and NFκB signaling might be involved. These findings may provide novel insights for clinical treatment of OA.
研究领域:
骨科
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分子生物学
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细胞生物学
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病理学
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Journal of Immunology Research
·
2023
·
IF 4.1
Hui Du,Shiwen Tong,Ge Kuang,Xia Gong,Ningman Jiang,Xian Yang,Hao Liu,Nana Li,Yao Xie,Yang Xiang,Jiashi Guo,Zhenhan Li,Yinglin Yuan,Shengwang Wu,Jingyuan Wan
Acetaminophen (APAP) overdose would lead to liver toxicity and even acute liver failure in severe cases by triggering an inflammatory response and oxidative stress. Sesamin has been reported to possess anti-inflammatory and antioxidant actions in several animal disease models. In the present study, the effects and mechanisms of sesamin on APAP-induced acute liver injury (ALI) were explored. The results showed that pretreatment with sesamin significantly alleviated APAP-induced ALI, as indicated by decreased serum aminotransferase activities, hepatic pathological damages, and hepatic cellular apoptosis. But sesamin has no significant effects on the expression of cytochrome P450 2E1 (CYP2E1), APAP-cysteine adducts (APAP-CYS) production, and glutathione content in the liver of APAP-administered mice. Moreover, APAP-induced liver oxidative stress and inflammatory response also were remarkedly attenuated by sesamin, including reducing hepatic reactive oxygen species levels, promoting antioxidant generation, and inhibiting the expression of TNF-α and IL-1β, as well as decreasing inflammatory cell recruitment. Notably, sesamin inhibited serum high-mobility group box 1 (HMGB1) releases and blocked hepatic activation of Toll-like receptor 4 (TLR4)-interleukin 1 receptor-associated kinase 3-nuclear factor kappa B (NF-κB) signaling pathway in APAP-administered mice. These findings indicated that sesamin could mitigate APAP-induced ALI through suppression of oxidative stress and inflammatory response, which might be mediated by the deactivation of HMGB1/TLR4/NF-κB signaling in mice.
研究领域:
肝病学
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药理学
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免疫学
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FISH & SHELLFISH IMMUNOLOGY
·
2023
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IF 4.7
Yihan Yu,Dandan Tian,Sanghyok Ri,Tongchol Kim,Kwangjin Ju,Jiongming Zhang,Shuangshuang Teng,Weixia Zhang,Wei Shi,Guangxu Liu
Although accumulating data demonstrated that gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter , plays an important regulatory role in immunity of vertebrates, its immunomodulatory function and mechanisms of action remain poorly understood in invertebrates such as bivalve mollusks . In this study, the effect of GABA on phagocytic activity of hemocytes was evaluated in a commercial bivalve species, Tegillarca granosa . Furthermore, the potential regulatory mechanism underpinning was investigated by assessing potential downstream targets. Data obtained demonstrated that in vitro GABA incubation significantly constrained the phagocytic activity of hemocytes. In addition, the GABA-induced suppression of phagocytosis was markedly relieved by blocking of GABA A and GABA B receptors using corresponding antagonists. Hemocytes incubated with lipopolysaccharides (LPS) and GABA had significant higher K + -Cl - cotransporter 2 (KCC2) content compared to the control. In addition, GABA treatment led to an elevation in intracellular Cl − , which was shown to be leveled down to normal by blocking the ionotropic GABA A receptor. Treatment with GABA A receptor antagonist also rescued the suppression of GABA A receptor-associated protein ( GABARAP ), KCC , TNF receptor associated factor 6 ( TRAF6 ), inhibitor of nuclear factor kappa-B kinase subunit alpha ( IKKα ), and nuclear factor kappa B subunit 1 ( NFκB ) caused by GABA incubation. Furthermore, incubation of hemocytes with GABA resulted in a decrease in cAMP content, an increase in intracellular Ca 2+ , and downregulation of cAMP-dependent protein kinase ( PKA ), calmodulin kinase II ( CAMK2 ), calmodulin ( CaM ), calcineurin ( CaN ), TRAF6 , IKKα , and NFκB . All these above-mentioned changes were found to be evidently relieved by blocking the metabotropic G-protein-coupled GABA B receptor. Our results suggest GABA may play an inhibitory role on phagocytosis through binding to both GABA A and GABA B receptors, and subsequently regulating corresponding downstream pathways in bivalve invertebrates.
研究领域:
免疫学
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分子生物学
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海洋生物学
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无脊椎动物生理学
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JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-17
·
IF 10.2
Ren Xunshan,Zhuang Huangming,Zhang Yuelong,Zhou Panghu
Background Tendon injuries have a high incidence and limited treatment options. Stem cell transplantation is essential for several medical conditions like tendon injuries. However, high local concentrations of reactive oxygen species (ROS) inhibit the activity of transplanted stem cells and hinder tendon repair. Cerium oxide nanoparticles (CeONPs) have emerged as antioxidant agents with reproducible reducibility. Results In this study, we synthesized polyethylene glycol-packed CeONPs (PEG-CeONPs), which were loaded into the human umbilical cord mesenchymal stem cells (hUCMSCs) to counteract oxidative damage. H 2 O 2 treatment was performed to evaluate the ROS scavenging ability of PEG-CeONPs in hUCMSCs. A rat model of patellar tendon defect was established to assess the effect of PEG-CeONPs-carrying hUCMSCs in vivo. The results showed that PEG-CeONPs exhibited excellent antioxidant activity both inside and outside the hUCMSCs. PEG-CeONPs protect hUCMSCs from senescence and apoptosis under excessive oxidative stress. Transplantation of hUCMSCs loaded with PEG-CeONPs reduced ROS levels in the tendon injury area and facilitated tendon healing. Mechanistically, NFκB activator tumor necrosis factor α and MAPK activator dehydrocrenatine, reversed the therapeutic effect of PEG-CeONPs in hUCMSCs, indicating that PEG-CeONPs act by inhibiting the NFκB and MAPK signaling pathways. Conclusions The carriage of the metal antioxidant oxidase PEG-CeONPs maintained the ability of hUCMSCs in the injured area, reduced the ROS levels in the microenvironment, and facilitated tendon regeneration. The data presented herein provide a novel therapeutic strategy for tendon healing and new insights into the use of stem cells for disease treatment. Graphical Abstract
研究领域:
生物医学工程
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干细胞生物学
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组织工程
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纳米技术
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高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Hui-Hui Guo,Yan-Xing Han,Xiao-Juan Rong,Zhen Shen,Hao-Ran Shen,Ling-Fei Kong,Yun-Dan Guo,Ji-Zhou Li,Bo Xu,Tian-Le Gao,Lu-Lu Wang,Cai Tie,Jian-Dong Jiang
Background Asthma affects 3% of the global population, leading to over 0.25 million deaths. Due to its complexity, asthma is difficult to cure or prevent, and current therapies have limitations. This has led to a growing demand for alternative asthma treatments. We found rosmarinic acid (RosA) as a potential new drug candidate from natural medicine. However, RosA has poor bioavailability and remains mainly in the gastrointestinal tract after oral administration, suggesting the involvement of gut microbiota in its bioactivity. Purpose To investigate the mechanism of RosA in alleviating allergic asthma by gut-lung axis. Methods We used 16S rRNA gene sequencing and metabolites analysis to investigate RosA's modulation of gut microbiota. Techniques of molecular biology and metabolomics were employed to study the pharmacological mechanism of RosA. Cohousing was used to confirm the involvement of gut microbiota in RosA-induced improvement of allergic asthma. Results RosA decreased cholate levels from spore-forming bacteria, leading to reduced 5-hydroxytryptamine (5-HT) synthesis, bronchoconstriction, vasodilation, and inflammatory cell infiltration. It also increased short-chain fatty acids (SCFAs) levels, facilitating the expression of intestinal tight junction proteins to promote intestinal integrity. SCFAs upregulated intestinal monocarboxylate transporters (MCTs), thereby improving their systemic delivery to reduce Th2/ILC2 mediated inflammatory response and suppress eosinophil influx and mucus production in lung. Additionally, RosA inhibited lipopolysaccharide (LPS) production and translocation, leading to reduced TLR4-NFκB mediated pulmonary inflammation and oxidative stress. Conclusions The anti-asthmatic mechanism of oral RosA is primarily driven by modulation of gut microbiota-derived 5-HT, SCFAs, and LPS, achieving a combined synergistic effect. RosA is a safe, effective, and reliable drug candidate that could potentially replace glucocorticoids for asthma treatment.
研究领域:
药理学
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免疫学
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微生物学
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呼吸医学
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高影响因子
Heliyon
·
2024
·
IF 3.4
Yinyin Zhao,Kangxiao Guo,Yongwang Yan,Binyuan Jiang
Cucurbitacin IIb, a member of the triterpenoid family, exerts beneficial effects on intestinal diseases, including enteritis and bacillary dysentery. However, its effects and mechanisms of action on colitis have not yet been explored. In this study, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis and explored the effects of cucurbitacin IIb on colitis symptoms, inflammatory responses, microbiota, and metabolite profiles. The results showed that cucurbitacin IIb alleviated colitis symptoms including body weight loss, an increase in the disease activity index, and elevated levels of myeloperoxidase and eosinophil peroxidase content. Additionally, it ameliorated intestinal morphology impairment, reduced the phosphorylation of NFκB protein, and mitigated accumulation of pro-inflammatory cytokines IL-6 and IL-1β. Furthermore, cucurbitacin IIb alleviated alterations in gut microbial composition and metabolites in DSS-treated mice. However, antibiotic treatment diminishes the beneficial effects of cucurbitacin IIb on colitis. We further found that transplantation of fresh feces or heat-inactivated feces from mice treated with cucurbitacin IIb to DSS-treated mice alleviated colitis, similar to the effects of cucurbitacin IIb. Collectively, our results suggest that cucurbitacin IIb exerted anti-inflammatory effects in colitis by regulating the microbiota composition and metabolites, thereby alleviating colitis symptoms.
研究领域:
胃肠病学
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免疫学
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微生物学
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药理学
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Food & Function
·
2020
·Vol. 11
·期 4
·3741-3748
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IF 4.171
Wei Li,Mingbo Gao,Ting Han
Impairment of the intestinal barrier often occurs in inflammatory bowel diseases, and pro-inflammatory factors play a vital role in the pathogenesis of intestinal diseases. In our study, the potential protective effects of Lycium barbarum polysaccharides (LBP) against intestinal barrier dysfunction evoked by pro-inflammatory factors and its anti-inflammatory effects were investigated. Caco-2 cells were stimulated with or without tumor necrosis factor (TNF)-α in the presence or absence of LBP. Our findings showed that LBP assuaged the increase of paracellular permeability and the decrease of transepithelial electrical resistance (TER) in Caco-2 cells. In addition, LBP also prevented the secretion of pro-inflammatory markers (IL-8, IL-6, ICAM-1 and MCP-1) in TNF-α-challenged Caco-2 cells. Moreover, LBP inhibited the overexpression of tight junction (TJ) proteins (claudin-1, ZO-3, and occludin) and the increase of MLCK, pMLC, p-IκBα and NFκBp65 protein expression evoked by TNF-α was suppressed by LBP pre-incubation. This finding indicated that LBP improve TNF-α-evoked intestinal barrier dysfunction via suppressing the MLCK-MLC signaling pathway mediated by NFκB.
研究领域:
药理学
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胃肠病学
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细胞生物学
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免疫学
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高影响因子
INTERNATIONAL JOURNAL OF ONCOLOGY
·
2023
·Vol. 62
·期 5
·1-21
·
IF 5.2
Ting Xue,Yaodong Chen,Jia Xu,Weiqin Du,Pengzhou Kong,Xinri Zhang
Lung cancer is the leading cause of cancer‑related mortality worldwide. Non‑small cell lung cancer (NSCLC) is the most common pathological subtype of lung cancer and is associated with low 5‑year overall survival rates. Therefore, novel and effective chemotherapeutic drugs are urgently required for improving the survival outcomes of patients with lung cancer. Cyclovirobuxine D (CVB‑D) is a natural steroidal alkaloid, used for the treatment of cardiovascular diseases in Traditional Chinese Medicine. Several studies have also demonstrated the antitumor effects of CVB‑D. Therefore, in the present study, the therapeutic effects of CVB‑D in lung cancer and the underlying mechanisms were investigated using the in vivo xenograft model of NSCLC in nude mice and in vitro experiments with the NSCLC cell lines. Bioinformatics analyses of RNA‑sequencing data, and cell‑based functional assays demonstrated that CVB‑D treatment significantly inhibited in vitro and in vivo NSCLC cell proliferation, survival, invasion, migration, angiogenesis, epithelial‑to‑mesenchymal transition and G2/M phase cell cycle. CVB‑D exerted its antitumor effects by inhibiting the KIF11‑CDK1‑CDC25C‑cyclinB1 G2/M phase transition regulatory oncogenic network and the NF‑κB/JNK signaling pathway. CVB‑D treatment significantly reduced the sizes and weights and malignancy of xenograft NSCLC tumors in the nude mice. In conclusion, the present study demonstrated that CVB‑D inhibited the growth and progression of NSCLC cells by inhibiting the KIF11‑CDK1‑CDC25C‑CyclinB1 G2/M phase transition regulatory network and the NF‑κB/JNK signaling pathway. Therefore, CVB‑D is a promising drug for the treatment of NSCLC patients.
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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细胞生物学
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高影响因子
CANCER LETTERS
·
2024
·
IF 9.1
Ying Ning,Yu Chen,Tian Tian,Xinyan Gao,Xiaolan Liu,Jia Wang,Huijun Chu,Chenyang Zhao,Yufei Yang,Ke Lei,He Ren,Zhumei Cui
Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
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高影响因子
Journal of Advanced Research
·
2024
·
IF 11.4
Dongwei Guan,Pengju Huang,Xinlei Liu,Qing Li,Xiaoxun Zhang,Nan Liu,Yong Wang,Ying Wan,Jin Chai,Shiying Cai,Rui Chen,Zhijia Ye
Introduction Niemann-Pick C1 (NPC1), a lysosomal cholesterol transport protein, is required for efficient efferocytosis. Patients with Npc1 mutation are frequently accompanied with hepatic symptoms, including hepatomegaly, elevated liver transaminases, or even acute liver failure, but the pathogenic mechanism remains unknown. Objectives Our work aims to characterize the functional role of myeloid NPC1 in liver injury and elucidate its underlying mechanism. Methods Analyses of injured livers from patients with liver diseases and mouse models were conducted to examine NPC1 expression. Myeloid cell-specific Npc1 knockout mice were constructed to determine the functional role of macrophage NPC1 in liver injury. Isolated macrophages were subjected to in vitro mechanistical assays. Results We found that NPC1 is mainly expressed in hepatic macrophages. Its mRNA and protein expression are significantly elevated in injured livers from both patients and mouse models. Tissue-specific deletion of myeloid Npc1 increased liver inflammation, levels of serum liver function enzymes, and liver fibrosis in mouse models of liver injury induced by carbon tetrachloride (CCl 4 ) injection and methionine-and-choline-deficient (MCD) diets. Further analyses indicate that Npc1 deficiency in mouse models of liver injury resulted in increased levels of serum HMGB1 and mitochondrial DNA, promoted hepatic macrophage proinflammatory activation, M1 polarization, led to overproduction of hepatic inflammatory cytokines/chemokines, e.g. CCL2 and STING/NFκB pathway activation. In vitro mechanistical studies reveal that Npc1 -deficient macrophages exhibited inefficient efferocytosis, partly due to impaired cargo degradation. Conclusions These findings indicate that elevated expression of myeloid NPC1 in liver diseases protects liver from injury by promoting macrophage efferocytosis of damaged cells. Dysfunction of NPC1 aggravates liver injury, suggesting that NPC1 may be a potential therapeutic target for treating liver diseases.
研究领域:
肝病学
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免疫学
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细胞生物学
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病理学
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