CURRENT MICROBIOLOGY
·
2025
·Vol. 82
·期 11
·1-15
·
IF 2.6
Shen Wei,Wang Meng,Han Ting,Yao Yan,Ying Xinyi,Cui Yuyue,Du Peng
Previous research has indicated that the exopolysaccharide galactosaminogalactan (GAG) from Aspergillus fumigatus plays a pivotal role in the pathogenesis of experimental invasive aspergillosis by promoting virulence. However, it remains unclear whether the exopolysaccharide is directly virulent to host cells. In this study, we established a co-incubation system using human THP-1-derived macrophages and GAG extracted from A. fumigatus ATCC 1022 to assess the capacity of GAG to induce necroptosis in THP-1 cells, as well as to elucidate the underlying mechanisms of this process. Our findings indicate that the proportion of N-acetylgalactosamine in the GAG fraction derived from strain ATCC 1022 was lower, while GAG demonstrated a significantly greater ability to induce the production of the pro-inflammatory cytokines TNF-α and IL-1β, which was accompanied by the induction of necroptosis. Western blotting analysis revealed a significant increase in the phosphorylation of RIP1, RIP3, and MLKL proteins in GAG-treated THP-1 cells, and RIP1-RIP3-MLKL signaling activation and GAG-induced caspase activity-independent cell death were effectively inhibited by the TNF-α receptor-1 (TNFR1) inhibitor R-7050, the neutralizing antibody against TNF-α or necroptosis inhibitor Necrostatin-1. It's worth noting that the expression of CLEC4E, the gene encoding the Mincle receptor in macrophages, was elevated in the co-incubation system, potentially enhancing TNF-α-mediated necroptotic cell death. In addition to the RIP1-RIP3-MLKL axis, BAX, cleaved PARP, and JNK were also activated following GAG treatment, warranting further investigation into their roles in the regulation of necroptosis. Our findings demonstrate that GAG produced by A. fumigatus conidia during germination triggers necroptotic cell death in human THP-1 cells via TNF-α-mediated RIP1-RIP3-MLKL signaling.
研究领域:
微生物学
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免疫学
·
分子生物学
·
感染性疾病
·
真菌病理学
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细胞死亡机制
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Bo Xu,Jiaqi Fang,Jianguang Wang,Xuehan Jin,Shengfu Liu,Kaihang Song,Ping Wang,Junjian Liu,Shuhao Liu
The disruption of the blood spinal cord barrier (BSCB) after spinal cord injury (SCI) can trigger secondary tissue damage. Edaravone is likely to protect the BSCB as a free radical scavenger, whereas it has been rarely reported thus far. In this study, the protective effect of edaravone was investigated with the use of compression spinal cord injured rats and human brain microvascular endothelial cells (HBMECs) injury. As indicated by the result of this study, edaravone treatment facilitated functional recovery after rats were subjected to SCI, ameliorated the vascular damage, and up-regulated the expression of BSCB-associated proteins. In vitro results, edaravone improved HBMECs viability, restored intercellular junctions, and promoted cellular angiogenic activities. It is noteworthy that autophagy was activated and RIP1/RIP3/MLKL phosphorylation was notably up-regulated. However, edaravone treatment exhibited the capability of mitigating above-mentioned tendency in vivo and in vitro. Moreover, rapamycin (Rapa) treatment deteriorated the protective effect of edaravone while aggravating the phosphorylation of RIP1/RIP3/MLKL expression. In the model of necrotic activator-induced HBMECs, autophagic expression was increased, whereas edaravone prevented autophagy and phosphorylation of RIP1/RIP3/MLKL. In general, our results suggested that edaravone is capable of reducing the destruction of BSCB and promoting functional recovery after SCI. The possible underlying mechanism is that edaravone is capable of protecting angiogenic activity and improving autophagy and the phosphorylation of RIP1/RIP3/MLKL, as well as their mutual deterioration. Accordingly, edaravone can be a favorable option for the treatment of SCI.
研究领域:
神经科学
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药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RENAL FAILURE
·
2025
·
IF 3
Shu Zhang,Xin Dong,Gangyi Chen,Chao Wang
Background Oxidative stress is a critical pathological mechanism in septic acute kidney injury (AKI). Tanshinone IIA (Tan IIA), a bioactive compound derived from Salvia miltiorrhiza, exhibits antioxidative properties. This study aimed to explore the protective mechanisms of Tan IIA in septic AKI.Methods A mouse model of lipopolysaccharide (LPS)-induced AKI was established, with Tan IIA administered prior to LPS injection. Renal function was assessed by serum creatinine and urea nitrogen levels, while histopathological damage and apoptosis were evaluated using PAS and TUNEL staining. Oxidative stress was assessed by SOD activity, ROS levels, and 8-OHdG staining. In vitro, LPS-stimulated HK-2 cells were treated with Tan IIA or RIP3 siRNA. The expression of RIP3, p-RIP3, Nrf2, HO-1, KEAP1, and downstream antioxidant genes (NQO1, GCLC) was analyzed by qRT-PCR, immunohistochemistry, and Western blot. Apoptosis was further evaluated by Annexin V-FITC/PI flow cytometry and detection of apoptosis-related proteins (Bax, cleaved caspase-3, Bcl-2). Co-immunoprecipitation was performed to examine RIP3–Nrf2 interaction.Results In vivo, Tan IIA significantly improved renal function and alleviated tubular damage. It decreased ROS production and 8-OHdG positivity while restoring SOD activity. In vitro, Tan IIA or RIP3 silencing decreased ROS levels, enhanced SOD activity, promoted Nrf2 nuclear translocation, and upregulated antioxidant genes. Flow cytometry confirmed reduced apoptotic cell populations, and Western blot showed reversal of LPS-induced pro-apoptotic protein changes. The co-immunoprecipitation confirmed an interaction between RIP3 and Nrf2 under LPS stimulation.Conclusion These findings suggest that Tan IIA protects against LPS-induced AKI by inhibiting RIP3 expression and restoring Nrf2-mediated antioxidant defenses, thereby attenuating oxidative stress and apoptosis.
研究领域:
药理学
·
肾脏病学
·
分子生物学
·
氧化应激研究
·
炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2026
·
IF 2.6
Xiaojing Wei,Binjing Zhao,Xinyi Jiang,Lunli Lan,Rui Wang,Yuanyuan Li
Vladimiria souliei(Franch.)Ling is used as medicine with dried roots, which is a perennial herb in Asteraceae family. It has been generally applied as traditional Chinese medicine with relieving abdominal swelling or pain, and treatment of digestive system disease. However, the pharmacological mechanism of alleviating gastric ulcer (GU) for this herb were still unknown. UPLC-Q-TOF/MS was performed to analyze the main components of Vladimiria souliei extract (VSE). Based on the results of histopathological observation, cytokines assay, and immunohistochemistry staining, the therapeutic effect of VSE on ethanol-induced GU was appraised. Meanwhile, the CCK-8, LDH assay and crystal violet staining were assessed to evaluate the appropriate concentration of VSE in vitro. In GES-1 cells induced by ethanol, the cell viability, ROS and cell membrane damage assay were detected after the interference of VSE. Then, several pivotal proteins relating to necroptosis in GES-1 were evaluated through immunofluorescence staining to illustrate the further pharma-cological mechanisms. As a result, VSE significantly restrained the expansion of ulcer area, reduced the pepsin activity, restored the levels of SOD, decreased the levels of MDA, ROS, TNF-α, IL-1β, IL-6, and IL-18, ultimately ameliorated the gastric mucosa injury. Further analysis exhibited that VSE significantly inhibited the cellular necroptosis by down-regulating the levels of RIP1, RIP3 and MLKL. Conclusions: This research clarified that the VSE could improve gastric mucosal injury through inhibition of RIP1-RIP3-MLKL necrosome activation, which might provide scientific evidences on the application of Vladimiria souliei as a ethnic herb to ameliorate GU.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2019
·
IF 2.705
Qing Shan,Xiaoyu Li,Mei Zheng,Xi Lin,Guotao Lu,Dongming Su,Xiang Lu
Doxorubicin (DOX) is an antitumor drug widely used in hematological tumors and various solid tumors. However, the cardiotoxicity elicited by DOX severely limits its clinical treatment. Dimethyl itaconate (DI), a common form of itaconate, is found many potential targets for prevent heart injury. Here we employed wild type and Nrf2 knockout mice and induced a cardiotoxicity model by administration of DOX to clarify the effects of DI. After treatment with DI, we found that it could effectively alleviate the cardiotoxicity by analyzing morphology, LDH levels and heart weight/body weight ratio changes. Meanwhile we demonstrated that RIP3, a key protein of necrosis, was significantly decreased in DI treated group. Further we observed that treatment with DI could suppress oxidative stress by altering Nrf2/HO-1. Compared with vehicle group, DI could increase the tissue SOD and GSH, and reduce MDA levels, then DHE staining revealed that the level of ROS in DI group reduced by half. Finally, transmission electron microscope (TEM) data showed that treatment with DI obviously decreased the mitochondrial damage. While Nrf2 was ablated in mice, the protective effects of DI were vanished and SOD, GSH, MDA became unchanged related to vehicle group. This report provides the evidence for the protective effects of DI treatment in cardiotoxicity induced by DOX. On mechanisms, DI could reduce the oxidative stress by altering Nrf2/HO-1 pathway and prevent mitochondrial from damage. Taken together, these findings of this paper will afford the new therapeutic targets in DOX related cardiotoxicity.
研究领域:
药理学
·
心脏病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2023
·
IF 5.8
Zhidan Liu,Kang Kang,Shulin Shan,Shuai Wang,Xianjie Li,Hui Yong,Zhengcheng Huang,Yiyu Yang,Zhaoxiong Liu,Yanan Sun,Yao Bai,Fuyong Song
Exposure to carbon disulfide (CS 2 ) has been associated with an increased incidence of parkinsonism in workers, but the mechanism underlying this association remains unclear. Using a rat model, we investigated the effects of chronic CS 2 exposure on parkinsonian pathology. Our results showed that CS 2 exposure leads to significant motor impairment and neuronal damage, including loss of dopaminergic neurons and degeneration of the substantia nigra pars compacta (SNpc). The immunoassays revealed that exposure to CS 2 induces aggregation of α-synuclein and phosphorylated α-synuclein, as well as activation of necroptosis in the SNpc. Furthermore, in vitro and in vivo experiments demonstrated that the interaction between α-synuclein and the necrosome complex (RIP1, RIP3, and MLKL) is responsible for the loss of neuronal cells after CS 2 exposure. Taken together, our results demonstrate that CS 2 -mediated α-synuclein aggregation can induce dopaminergic neuron damage and parkinsonian behavior through interaction with the necrosome complex.
研究领域:
神经科学
·
毒理学
·
病理学
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Chenyu Zhang,Zutao Chen,Guohua Qi,Yu Tian,Xiongjian Zheng,Xingkang Diao,Jiao Kong,Xingkai Ju,Jing Li,Shaojun Dong,Yongdong Jin
Accompanying the occurrence of inflammatory reaction to release cytokines, pyroptosis can activate an immune response for resistance against cancer. Consequently, elevated levels of cytokines released by cancer cells are highly correlated with the effectiveness of cancer treatment. Herein, a noninvasive surface-enhanced Raman spectroscopy (SERS) immunosensor was developed to sensitively and specifically measure the tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, during the cell pyroptosis process. The sandwiched structure of the sensor is functionalized with a TNF-α binding antibody for detecting TNF-α at concentrations as low as 1 pg/mL. Importantly, electrical stimulation (ES) can fleetly trigger cancer cell pyroptosis to induce the overexpression of receptor interacting protein 3 (RIP3), which is a significant protein that regulates the inflammatory response. The overexpression of RIP3 can activate caspase-1 to promote the upregulation of cytokine levels. Notably, the cytokine levels of TNF-α released from cancer cells (MCF-7 cells) were apparently higher than those of normal cells (MCF-10A cells) during pyroptosis detected by the SERS immunosensors. Due to its obvious superiorities of simple fabrication and fast readout without sample pretreatment, the developed SERS platform has a potential application value for diagnosis and treatment of cancer.
研究领域:
生物医学工程
·
癌症生物学
·
免疫学
·
分析化学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Yanan Wang,Deyao Qian,Xinyuan Wang,Xue Zhang,Zerui Li,Xinlei Meng,Liangmin Yu,Xuefeng Yan,Zhiyu He
Developing strategies to target injured pancreatic acinar cells (PACs) in conjunction with primary pathophysiology-specific pharmacological therapy presents a challenge in the management of acute pancreatitis (AP). We designed and synthesized a trypsin-cleavable organosilica precursor bridged by arginine-based amide bonds, leveraging trypsin’s ability to selectively identify guanidino groups on arginine via Asp189 at the active S1 pocket and cleave the carboxy-terminal (C-terminal) amide bond via catalytic triads. The precursors were incorporated into the framework of mesoporous silica nanoparticles (MSNs) for encapsulating the membrane-permeable Ca2+ chelator BAPTA-AM with a high loading content (∼43.9%). Mesenchymal stem cell membrane coating and surface modification with PAC-targeting ligands endow MSNs with inflammation recruitment and precise PAC-targeting abilities, resulting in the highest distribution at 3 h in the pancreas with 4.7-fold more accumulation than that of naked MSNs. The outcomes transpired as follows: After bioinspired MSNs’ skeleton biodegradation by prematurely and massively activated trypsin, BAPTA-AM was on-demand released in injured PACs, thereby effectively eliminating intracellular calcium overload (reduced Ca2+ level by 81.3%), restoring cellular redox status, blocking inflammatory cascades, and inhibiting cell necrosis by impeding the IκBα/NF-κB/TNF-α/IL-6 and CaMK-II/p-RIP3/p-MLKL/caspase-8,9 signaling pathways. In AP mice, a single dose of the formulation significantly restored pancreatic function (lipase and amylase reduced more by 60%) and improved the survival rate from 50 to 91.6%. The formulation offers a potentially effective strategy for clinical translation in AP treatment.
研究领域:
纳米医学
·
药学
·
生物医学工程
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分子生物学
·
炎症研究
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）