Journal of Advanced Research
·
2025
·
IF 13
Longchen Yu,Qining Guo,Yaping Li,Mai Mao,Zhenping Liu,Tingting Li,Lei Wang,Xin Zhang
Introduction Pancreatic cancer (PC) cannot currently be completely cured and has a poor prognosis. Necroptosis is a distinct form of regulated cell death that differs from both necrosis and apoptosis. Understanding the role of necroptosis during PC progression would open new avenues for targeted therapy. Objectives The purpose of this study is to examine the impact of necroptosis on the progression of PC and related mechanisms. Methods RNA sequencing was performed to identify necroptosis-related genes that are differentially expressed in PC tissues. The biological functions of CHMP4C and its necroptosis effects were determined in vitro and in vivo . RNA immunoprecipitation, MeRIP-qPCR, Co-immunoprecipitation assays were conducted to evaluate the interaction among CHMP4C, YBX1 and caspase-8 mRNA. Extracellular vesicles were isolated using the differential ultracentrifugation method. The expression of CHMP4C, p-MLKL and CD117 were detected on a PC tissue microarray using multiplex immunofluorescence staining. Results CHMP4C was significantly overexpressed in PC cells and tissues. It promoted cell growth and suppressed necroptosis of PC cells in both in vivo and in vitro settings. Mechanistically, CHMP4C interacted with YBX1 to mediate m 5 C modification of caspase-8 mRNA, resulting in increased caspase-8 expression and inhibition of RIPK1/RIPK3/MLKL pathway phosphorylation. Furthermore, CHMP4C promoted extracellular exocytosis of p-MLKL to further suppress necroptosis. Additionally, PC cells used CHMP4C within extracellular vesicles to recruit and stimulate mast cells (MCs), which in turn promoted PC cell proliferation. In PC tissues, the expression of CHMP4C showed a negative correlation with p-MLKL and a positive association with CD117. High expression levels of CHMP4C in patients were associated with poorer overall survival outcomes. Conclusions CHMP4C promotes PC progression by inhibiting necroptosis, which has potential as a biomarker and therapeutic target in PC.
研究领域:
肿瘤学
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分子生物学
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医学
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DOI
PubMed
高影响因子
ONCOLOGY REPORTS
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2025
·Vol. 53
·期 5
·1-14
·
IF 3.9
Ying Hu,Xin Liu,Ziheng Yuan,Jianping He,Run Ma,Yuming Wang,Genfa Yi
Globally, lung adenocarcinoma (LUAD) remains the leading cause of cancer‑related mortality, highlighting the urgent need for innovative therapeutic approaches. Necroptosis has been recognized as a crucial mechanism for inhibiting cancer progression. Research has revealed a significant association between microRNA (miRNA)‑mediated necroptosis and tumor progression. The present study aimed to elucidate the role and underlying mechanisms of miR‑10b‑5p in regulating necroptosis in the context of LUAD. In an investigation of LUAD, miRNA sequencing was conducted on both LUAD and adjacent non‑tumor tissues, followed by the integration of external database information to identify specific target miRNAs. The expression of miR‑10b‑5p was verified in LUAD tissues and corresponding adjacent non‑cancerous tissues using immunohistochemistry. In vitro experiments, utilizing LUAD cell lines engineered to modulate miR‑10b‑5p levels, assessed its effects on cellular activities and necroptosis. The inhibition of PKP3 by miR‑10b‑5p was determined using a dual luciferase reporter system. Furthermore, alterations in miR‑10b‑5p levels were found to affect PKP3 expression and inhibit the RIPK3/MLKL signaling pathway, as evidenced by western blot analysis in LUAD cell lines. The effect of PKP3 knockdown on cell activity and necroptosis in LUAD cell lines with low miR‑10b‑5p expression levels was assessed using cell function assays. Finally, a nude mouse xenograft model was used to investigate the effect of miR‑10b‑5p on LUAD growth in vivo and its specific mechanism of action. It has been revealed that miR‑10b‑5p levels are significantly elevated in LUAD specimens. Further investigations demonstrated that an increase in miR‑10b‑5p enhances the proliferation of LUAD cells and suppresses the progression of necroptosis, as evidenced by in vitro experiments. Through dual luciferase reporter assays, PKP3 was confirmed as a direct target negatively regulated by miR‑10b‑5p, leading to reduced expression levels. Western blot analysis indicated that miR‑10b‑5p inhibits the RIPK3/MLKL pathway activation through downregulation of PKP3, which leads to increased cell proliferation and decreased necroptosis. However, knockdown of PKP3 reversed the inhibitory effect of miR‑10b‑5p inhibitors on cellular activity and inhibited necrosis by suppressing the RIPK3/MLKL signalling pathway. In addition, animal model studies demonstrated that inhibition of miR‑10b‑5p activated the RIPK3/MLKL pathway by promoting PKP3 expression and significantly reduced LUAD growth by promoting necroptosis. In conclusion, our studies have revealed that the miR‑10b‑5p functions as a tumorigenic factor, enhancing various cellular activities in LUAD cells and suppressing necroptosis by specifically targeting PKP3, thereby inhibiting activation of the RIPK3/MLKL pathway. Importantly, interventions using inhibitors that specifically target miR‑10b‑5p have shown significant success in impeding the progression of LUAD by promoting necroptosis in both cellular and animal models. Thus, targeting miR‑10b‑5p holds considerable potential as a therapeutic strategy for LUAD.
研究领域:
肿瘤学
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分子生物学
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医学遗传学
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DOI
PubMed
高影响因子
Cellular & Molecular Immunology
·
2024
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IF 21.8
Wu Xiaoxia,Zhao Xiaoming,Li Fang,Wang Yang,Ou Yangjing,Zhang Haiwei,Li Xiaoming,Wu Xuanhui,Wang Lingxia,Li Ming,Zhang Yue,Liu Jianling,Xing Mingyan,Liu Han,Tan Yongchang,Wang Yangyang,Xie Yangyang,Zhang Hanwen,Luo Yan,Li Hong,Wang Jing,Sun Liming,Li Yu,Zhang Haibing
The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT ), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3–MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.
研究领域:
免疫学
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病理生理学
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细胞生物学
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炎症
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血管生物学
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DOI
PubMed
高影响因子
Journal of Clinical and Translational Hepatology
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2024
·Vol. 13
·期 2
·105
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IF 3.1
Yimeng Zhou,Yang Ding,Yanwei Li,Qiuju Sheng,Chao Han,Yaoxin Fan,Ziyi Wang,Bingchao Lu,Xiaoguang Dou,Chong Zhang
Background and Aims Necroptosis is critical for regulating intestinal epithelial cells (IECs). Butyric acid (BA), produced during intestinal microbial metabolism, protects the intestinal epithelial barrier. However, whether necroptosis occurs in IECs during liver cirrhosis and whether sodium butyrate (NaB) can regulate necroptosis have not yet been reported. In this study, we aimed to investigate whether IECs undergo necroptosis in cirrhosis and whether NaB can regulate necroptosis and the related regulatory mechanisms. Methods Serum levels of RIPK3, MLKL, and Zonulin, as well as fecal BA levels, were measured and correlated in 48 patients with liver cirrhosis and 20 healthy controls. A rat model of liver cirrhosis was established, and NaB was administered. The expressions of MLKL, p-MLKL, and tight junction proteins were measured. We conducted an in vitro investigation of the effect of NaB on necroptosis in the HT29 cell line. Results Serum levels of RIPK3, MLKL, and Zonulin in the liver cirrhosis group were higher, while fecal BA levels were lower than those in the control group. Zonulin levels were positively correlated with RIPK3 and MLKL levels, while fecal BA levels were negatively correlated with serum MLKL levels, but not with RIPK3 levels. NaB reduced the mRNA and protein expression of MLKL but had no effect on RIPK1 and RIPK3 in vitro. Rescue experiments demonstrated that NaB inhibited necroptosis through E2F1-mediated regulation of MLKL. Conclusions NaB alleviates intestinal mucosal injury and reduces necroptosis in IECs in liver cirrhosis. It also inhibits the necroptosis of IECs and protects the intestinal barrier by reducing E2F1 expression and downregulating MLKL expression levels. These results can be employed to develop a novel strategy for treating complications arising from liver cirrhosis.
研究领域:
医学
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消化系统疾病
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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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2022
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IF 5.895
Yong Fan,Jing Lu,Zelin Yu,Xiao Qu,Shuang Guan
1,3-Dichloro-2-propanol (1,3-DCP), as a food pollutant, exists in a variety of foods. Studies have shown that it has nephrotoxicity. In the study, we found that 1,3-DCP caused renal injury with necroptosis in C57BL/6J mice. The mechanism of 1,3-DCP-caused nephrotoxicity was further explored in NRK-52E cells in vitro. We found that 1,3-DCP caused cell necroptosis with the increase in lactate dehydrogenase (LDH) levels and the expressions of RIPK3 and MLKL. But pretreatment with a ROS inhibitor N-acetyl-l-cysteine (NAC), a RIPK3 inhibitor GSK’872, or RIPK3 gene silencing alleviated 1,3-DCP-induced cell necroptosis. The data indicated that 1,3-DCP induced necroptosis through the ROS/RIPK3/MLKL pathway in NRK-52E cells. In further mechanistic studies, we explored how 1,3-DCP induced ROS production. We found that 1,3-DCP inhibited the expressions of nuclear and cytoplasmic Nrf2. But pretreatment with an Nrf2 activator dimethyl fumarate (DMF) up-regulated the expressions of nuclear and cytoplasmic Nrf2 and down-regulated ROS levels and RIPK3 and MLKL expressions. We also examined the effects of mitophagy on 1,3-DCP-induced ROS. The data manifested that 1,3-DCP suppressed mitophagy in NRK-52E cells by decreasing LC3-II, Pink1, and Parkin levels, increasing p62 levels, and decreasing colocalization of LC3 and Mito-Tracker Red. Pretreatment with an autophagy activator rapamycin (Rapa) decreased 1,3-DCP-induced ROS. Taken together, our data identified that 1,3-DCP caused renal necroptosis through the ROS/RIPK3/MLKL pathway.
研究领域:
毒理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
CURRENT MICROBIOLOGY
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2025
·Vol. 82
·期 11
·1-15
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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
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分子生物学
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感染性疾病
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真菌病理学
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细胞死亡机制
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产品关联
DOI
PubMed
高影响因子
Autophagy
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2024
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IF 14.6
Zhigang Zhang,Shuai Chen,Shirui Jun,Xirong Xu,Yuchuan Hong,Xifei Yang,Liangyu Zou,You-Qiang Song,Yu Chen,Jie Tu
Individuals with genetic elimination of MLKL (mixed lineage kinase domain like pseudokinase) exhibit an increased susceptibility to neurodegenerative diseases like Alzheimer disease (AD). However, the mechanism is not yet fully understood. Here, we observed significant compromise in macroautophagy/autophagy in the brains of mlkl knockout (KO) mice, as evidenced by the downregulation of BECN1/Beclin1 and ULK1 (unc-51 like autophagy activating kinase 1). We identified UBA52 (ubiquitin A-52 residue ribosomal protein fusion product 1) as the binding partner of MLKL under physiological conditions. Loss of Mlkl induced a decrease in ubiquitin levels by preventing UBA52 cleavage. Furthermore, we demonstrated that the deubiquitinase (DUB) USP7 (ubiquitin specific peptidase 7) mediates the processing of UBA52, which is regulated by MLKL. Moreover, our results indicated that the reduction of BECN1 and ULK1 upon Mlkl loss is attributed to a decrease in their lysine 63 (K63)-linked polyubiquitination. Additionally, single-nucleus RNA sequencing revealed that the loss of Mlkl resulted in the disruption of multiple neurodegenerative disease-related pathways, including those associated with AD. These results were consistent with the observation of cognitive impairment in mlkl KO mice and exacerbation of AD pathologies in an AD mouse model with mlkl deletion. Taken together, our findings demonstrate that MLKL-USP7-UBA52 signaling is required for autophagy in brain through maintaining ubiquitin homeostasis, and highlight the contribution of Mlkl loss-induced ubiquitin deficits to the development of neurodegeneration. Thus, the maintenance of adequate levels of ubiquitin may provide a novel perspective to protect individuals from multiple neurodegenerative diseases through regulating autophagy.Abbreviations: 4HB: four-helix bundle; AAV: adeno-associated virus; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; APOE: apolipoprotein E; APP: amyloid beta precursor protein; Aβ: amyloid β; BECN1: beclin 1; co-IP: co-immunoprecipitation; DEGs: differentially expressed genes; DLG4: discs large MAGUK scaffold protein 4; DUB: deubiquitinase; EBSS: Earle’s balanced salt solution; GFAP: glial fibrillary acidic protein; HRP: horseradish peroxidase; IL1B: interleukin 1 beta; IL6: interleukin 6; IPed: immunoprecipitated; KEGG: Kyoto Encyclopedia of Genes and Genomes; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MLKL: mixed lineage kinase domain like pseudokinase; NSA: necrosulfonamide; OPCs: oligodendrocyte precursor cells; PFA: paraformaldehyde; PsKD: pseudo-kinase domain; SYP: synaptophysin; UB: ubiquitin; UBA52: ubiquitin A-52 residue ribosomal protein fusion product 1; UCHL3: ubiquitin C-terminal hydrolase L3; ULK1: unc-51 like autophagy activating kinase 1; UMAP: uniform manifold approximation and projection; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; USP9X: ubiquitin specific peptidase 9 X-linked.
研究领域:
神经科学
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分子生物学
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细胞生物学
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遗传学
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DOI
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
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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
SCIENCE OF THE TOTAL ENVIRONMENT
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2025
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IF 8
Jing Lu,Hongdi Wei,Xinyu Yao,Yuelin Chen,Meitong Liu,Shuang Guan
Glycidol is a common food contaminant, and its main target organ is the kidney. However, the mechanism of nephrotoxicity of glycidol has not been fully elucidated. In this paper, we investigated the mechanism of glycidol toxicity in mice kidneys and NRK-52E cells. We found that glycidol exposure induced necroptosis in renal cells through the RIPK1/RIPK3/MLKL pathway. Mechanistically, it was further found that glycidol blocked renal cell autophagy and induced ectopic aggregation of p62. Accumulated p62 recruited RIPK1 and activated downstream RIPK1/RIPK3/MLKL necrosome production. At the same time, the accumulated p62 could also participate in the activation of intracellular NF-κB nuclear transcription factor by interacting with RIPK1 to form a signalling complex, which promoted the secretion of inflammatory factors TNF-α and IL-1β, and induced inflammation in the kidney. Our present study provided a new understanding of the complex mechanism of glycidol on renal injury.
研究领域:
毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 6
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IF 7.7
Han Meng,Wenchao Hu,Enming Kang,Qing Xu,Pengfei Wang,Xuyang Yi,Honghui Mao,Bowen Zhang,Xinyu Meng,Yanjin Wang,Yanchen Tan,Zhuqing Mao,Xingxing Zheng,Lina Niu,Ming Shi,Ceng Luo,Shengxi Wu,Rougang Xie,Yazhou Wang
Neutrophil-involved neuroinflammation in dorsal root ganglion (DRG) plays double-sword roles in chronic pain. How DRG neuron-neutrophil interaction contributes to chronic pain remains unclear. Here, we report that MLKL, a key molecule in necroptosis, is constitutively expressed in the nucleus of nociceptive neurons and binds to histone H3. Periphery inflammation disrupted MLKL/H3 interaction, leading to cytoplasmic translocation of MLKL and release of histone H3. Extracellular histone H3 induces neuronal hyperactivity, neutrophil extracellular trap (NET), and hyperalgesia, possibly through P2X7 receptor and Toll-like receptor 4. Nociceptive-specific depletion of Mlkl significantly decreased pain threshold and exacerbated NET formation independent of cell death. Neutralizing extracellular histone, clearing extracellular DNA or restoring nuclear localization of MLKL can reduce both NET formation and hyperalgesia in Mlkl −/− m ice. These data demonstrated that the nociceptive neuron-neutrophil interaction mediated by this MLKL-histone-NET cascade may serve as a potential therapeutic target for chronic inflammatory pain.
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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.
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2022
·Vol. 8
·期 1
·1-13
·
IF 7.109
Lian Ni,Chen Yujie,Chen Sihan,Xiao Ta,Song Changjun,Ke Yangying,Wei Xuecui,Gong Chunyan,Yu Hui,Gu Heng,Chen Qing,Li Min,Chen Xu
Keratinocyte necroptosis (with proinflammatory characteristic) is required for epidermal damage in contact hypersensitivity (CHS). In DNCB-induced CHS mice model, we observed the aggravated keratinocyte death and increased phosphorylation level of MLKL, RIPK3 and RIPK1. However, CHS skin lesion did not present in keratinocyte-specific Mlkl knockout mice. We validated that MLKL-mediated keratinocyte necroptosis is required for epidermal damage in response to immune microenvironment in CHS. Moreover, MLKL-mediated necroptosis deficiency or inhibition resulted in blocking recruitment and activation of inflammatory cells in CHS via reducing HMGB1 release in keratinocytes. This study suggests that MLKL-mediated keratinocyte necroptosis functions as a self-amplified actor in inflammatory responses and could be considered as an effective therapeutic target. It proposes an innovative prospective that inhibiting keratinocyte necroptosis can prevent the development of epidermal damage in CHS.
研究领域:
免疫学
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细胞生物学
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皮肤病学
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产品关联
DOI
PubMed
高影响因子
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