ONCOLOGY REPORTS
·
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
Toxins
·
2019
·Vol. 11
·期 3
·142
·
IF 3.895
Rui Wang,Zhaoyue Dong,Xiaolong Zhang,Jingxin Mao,Fancheng Meng,Xiaozhong Lan,Zhihua Liao,Min Chen
Pterocephalus hookeri(C. B. Clarke) Höeck, recorded in the Chinese Pharmacopoeia (2015 version) as a Tibetan medicine for the treatment of various diseases, especially rheumatoid arthritis, was believed to possess a slight toxicity. However, hardly any research has been carried out about it. The present study aimed to evaluate the toxicity in vivo and in vitro. Toxicity was observed by the evaluation of mice weight loss and histopathological changes in the liver. Then, the comparison research between ethyl acetate extract (EAE) and n-butanol extract (BUE) suggested that liver toxicity was mainly induced by BUE. The mechanical study suggested that BUE-induced liver toxicity was closely associated with necrosis detected by MTT and propidium iodide (PI) staining, via releasing lactate dehydrogenase (LDH), reducing the fluidity, and increasing the permeability of the cell membrane. Western blot analysis confirmed that the necrosis occurred molecularly by the up-regulation of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3), as well as the activation of the nuclear factor-kappa-gene binding (NF-κB) signaling pathway in vivo and in vitro. This finding indicated that the liver toxicity induced by BUE fromP. hookeriwas mainly caused by necrosis, which provides an important theoretical support for further evaluation of the safety of this folk medicine.Keywords:Pterocephalus hookeri;liver toxicity;n-butanol extract;necrosis;inflammationKey Contribution:(1)Pterocephalus hookericould induce liver toxicity in vivo and in vitro. (2) The liver toxicity was induced by n-butanol extract ofP. hookeri. (3) The liver toxicity was mainly caused by necrosis associated with inflammation. (4) This finding provides an important theoretical support for further evaluation of the safety of this Tibetan medicine.
研究领域:
药理学
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毒理学
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细胞生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Simin Tian,Guang Xin,Kun Zhang,Ao Wen,Xiuxiang Yu,Chengyang Ni,Yijiang Liu,Xiaojuan Li,Yu Cao,Wen Huang
Background Acute pancreatitis (AP) is an inflammatory disease of the pancreas marked by inflammation and acinar cell necrosis. Scutellariae Barbata (S. Barbata), a traditional Chinese herb for inflammation, has unclear efficacy for AP. Purpose This study examined the mechanism of eriodictyol, an active component of S. Barbata decoction, targeting pancreatic necrosis and inflammation for the first time. Study Design This study firstly evaluated the pharmacological effects of S. Barbata on AP. Transcriptomic analysis and pharmacological screening were performed to identify essential genes linked to pancreatic necrosis and specific bioactive compounds in S. Barbata. These candidates underwent thorough validation with multiple assays. Our findings strongly demonstrate effectiveness of S. Barbata in combating pancreatic necrosis and reveal the underlying mechanisms involved. Methods Animal experiments were conducted to assess the effects of S. Barbata on AP. Analysis of bulk and single-cell RNA-seq data identified PANoptosis. The protein-protein interaction network and Cytoscape were used to identify AP targets based on PANoptosis. The ConnectivityMap database was used to filter potential compounds from S. Barbatae based on specific targets. After quantifying eriodictyol, its binding to ZBP1 was confirmed through molecular docking, dynamic simulation, cellular thermal shift assay, mtDNA analysis, and ZBP1 overexpression in 266-6 cells. Experiments in vivo and in vitro assessed the effects of eriodictyol on AP. Results S. Barbata decoction reduced pancreatic inflammation and necrosis. Gene Set Enrichment Analysis of PANoptosis revealed that Zbp1, Nlpr3, Ripk1, Casp8, Gsdmd , and Mlkl are ZBP1-dependent targets for AP. Eriodictyol, the active compound in S. Barbata showed a strong affinity for ZBP1. Eriodictyol may enhance pancreatic conditions and reduce ZBP1-dependent protein expression, with minimal impact on mtDNA levels. Conclusion This study broadened the traditional use of S. Barbata suggested eriodictyol as a potential AP treatment candidate via ZBP1-dependent signaling.
研究领域:
药理学
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分子生物学
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中医药学
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2025
·
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
Cancers
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2022
·Vol. 14
·期 23
·5976
·
IF 6.575
Yuanhui Gao,Zhenyu Nie,Hui Cao,Denggao Huang,Mei Chen,Yang Xiang,Xiaolong Yu,Shufang Zhang
Simple SummaryScabertopin is one of the major sesquiterpene lactones fromElephantopus scaberL. Sesquiterpene lactones are thought to have fairly strong anti-cancer efficacy. However, there has not been any research report on the efficacy and mechanism of Scabertopin in the treatment of bladder cancer. The aim of this study is to evaluate the antitumor activity of scabertopin in bladder cancer and its potential molecular mechanism in vitro. In this study, we found that scabertopin can induce necroptosis in bladder cancer cells by promoting the production of mitochondrial reactive oxygen species, and also inhibit the migration and invasion ability of bladder cancer cells. At the same time, we also demonstrated that the half-inhibition rate of scabertopin on various bladder cancer cell lines is much lower than that on human ureteral epithelial immortalized cells. This shows that scabertopin is a safe and effective anti-bladder cancer drug.AbstractBladder cancer remains one of the most common malignant tumors that threatens human health worldwide. It imposes a heavy burden on patients and society due to the high medical costs associated with its easy metastasis and recurrence. Although several treatment options for bladder cancer are available, their clinical efficacy remains unsatisfactory. Therefore, actively exploring new drugs and their mechanisms of action for the clinical treatment of bladder cancer is very important. Scabertopin is one of the major sesquiterpene lactones found inElephantopus scaberL. Sesquiterpene lactones are thought to have fairly strong anti-cancer efficacy. However, the anticancer effect of sesquiterpenoid scabertopin on bladder cancer and its mechanism are still unclear. The aim of this study is to evaluate the antitumor activity of scabertopin in bladder cancer and its potential molecular mechanism in vitro. Our results suggest that scabertopin can induce RIP1/RIP3-dependent necroptosis in bladder cancer cells by promoting the production of mitochondrial reactive oxygen species (ROS), inhibit the expression of MMP-9 by inhibiting the FAK/PI3K/Akt signaling pathway, and ultimately inhibit the migration and invasion ability of bladder cancer cells. At the same time, we also demonstrated that the half-inhibition concentration (IC50) of scabertopin on various bladder cancer cell lines (J82, T24, RT4 and 5637) is much lower than that on human ureteral epithelial immortalized cells (SV-HUC-1). The above observations indicate that scabertopin is a potential therapeutic agent for bladder cancer that acts by inducing necroptosis and inhibiting metastasis.Keywords:scabertopin;bladder cancer;reactive oxygen species;necroptosis;Elephantopus scaberL.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2022
·
IF 7.31
Pingjun Zhu,Junyan Wang,Wenjuan Du,Jun Ren,Ying Zhang,Fei Xie,Guogang Xu
Mitochondrial dysfunction and necroptosis have been perceived as the primary molecular mechanisms underscoring acute lung injury. Meanwhile, nuclear receptor subfamily 4 group A member 1 (NR4A1) is considered a regulator of inflammation-related endothelial injury in lung tissue although the downstream molecular events remain elusive. In this study, we employed NR4A1-/- mice to decipher the role of NR4A1 in the onset and progression of acute lung injury with a focus on mitochondrial damage and necroptosis. Our results demonstrated that NR4A1 was significantly upregulated in lipopolysaccharide- (LPS-) treated lung tissues. Knockout of NR4A1 overtly improved lung tissue morphology, inhibited inflammation, and reduced oxidative stress in LPS-treated lung tissue. A cell signaling study suggested that NR4A1 deletion repressed levels of PGAM5 and attenuated LPS-mediated necroptosis in primary murine alveolar epithelial type II (ATII) cells, the effects of which were mitigated by PGAM5 overexpression. Moreover, LPS-mediated mitochondrial injury including mitochondrial membrane potential collapse and mitochondrial oxidative stress was drastically improved by NR4A1 deletion. Furthermore, NR4A1 deletion preserved mitochondrial homeostasis through activation of Opa1-related mitochondrial fusion. Silencing of Opa1 triggered mitochondrial dysfunction in NR4A1-deleted ATII cells. Taken together, our data identified NR4A1 as a novel regulator of LPS-related acute lung injury through regulation of mitochondrial fusion and necroptosis, indicating therapeutic promises of targeting NR4A1 in the treatment of acute lung injury in clinical practice.
研究领域:
分子生物学
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免疫学
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呼吸病学
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DOI
PubMed
高影响因子
Journal of Advanced Research
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2025
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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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产品关联
DOI
PubMed
高影响因子
IEEE SENSORS JOURNAL
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2024
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IF 4.3
Hao-Yuan Cao,Dandan Wei,Yingying Hu,Bin Liu,Yue Fu,Juan Liu,Xing-Dao He,Jinhui Yuan,Wenbo Xiao,Qiang Wu
In this paper, a high sensitivity U-shape single mode- tapered four core-single mode (STFS) optical fiber biosensor is proposed and investigated for tumor necrosis factor-alpha (TNF-α) detection in both Phosphate Buffered Saline (1x) (PBS) and diluted serum. The surface of U-shape STFS biosensor is immobilized with TNF-α antibody (10 μg/mL), which will specifically bind with target TNF-α. The results demonstrate a Hill curve relationship between wavelength shift and TNF-α concentration (from 10
1
to 10
4
pg/mL diluted in PBS). The lowest concentration of TNF-α detected in the experiment is 10 pg/mL, with an average wavelength shift of 0.389 nm. The average wavelength fluctuation of the sensor in PBS is 0.099 nm, and the corresponding limit of detection (LOD) is 4.35 pg/mL. Results for the detection of TNF-α in blood sample is also presented. It is found that the deviation of detected TNF-α concentrations (13.00–15.03 pg/mL, calibrated by measured results in PBS) is -0.7%~14.7% compared to standard TNF-α concentration of 13.09 pg/mL in blood. This biosensor, with its simple structure and high sensitivity, has the potential to serve as a valuable reference in disease diagnosis and medical drug usage, offering promising application prospects.
研究领域:
生物医学工程
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光学传感
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分子诊断
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产品关联
DOI
高影响因子
Journal of Clinical and Translational Hepatology
·
2024
·Vol. 13
·期 2
·105
·
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
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Wei Zhu,Sai Zhu,Shan Jiang,Jiuyu Yin,Yonggui Wu,Xiaomei Luo
Background Cisplatin (CIS), a widely administered chemotherapeutic agent, is associated with acute kidney injury (AKI). Lansoprazole (LPZ), commonly prescribed to mitigate chemotherapy-induced gastrointestinal complications, may further elevate AKI risk. Paeoniflorin (Pae), a bioactive compound derived from traditional Chinese medicine, demonstrates renal protective properties in AKI, yet its mechanism against CIS and LPZ induced AKI remains undefined. Methods A composite AKI model was established in vivo and in vitro using CIS and LPZ. The protective effect of Pae on the injury of renal tissue or renal tubular cells in mice was observed, followed by Pae pretreatment. The target of Pae was found through network pharmacology, and the binding ability of the target was verified by CETSA experiment and molecular docking. Finally, the target gene was knocked out or over expressed to verified whether Pae regulates necroptosis through this target. Results It was found that renal injury could be exacerbated by LPZ in the CIS induced AKI. Pae could alleviate CIS and LPZ induced AKI. The target gene of Pae was TNFAIP3, which played an important role in necroptosis. The TNFAIP3 could bind well to Pae in molecular docking and CETSA experiment. The necroptosis and inflammatory responses in AKI induced by CIS and LPZ could be also inhibited by Pae in vivo and in vitro. Overexpression of TNFAIP3 played the same cellular protective role as Pae preconditioning. In contrast, Pae could not continue to play a protective role after TNFAIP3 was knocked down. Conclusion The traditional Chinese medicine Pae holds promise as a potential therapeutic agent for AKI, with TNFAIP3 representing an effective therapeutic target in this pathology.
研究领域:
药理学
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分子生物学
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肾脏病学
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转化医学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
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2023
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IF 4.7
Hao Yin,Xingyan Fu,Hanyu Gao,Han Gao,Yannan Ma,Xitong Chen,Xueqi Zhang,Shan-Shan Du,Yun-Kun Qi
Liver cancer is the third leading cause of cancer-associated mortality globally, and >830,000 patients with liver cancer undergoing treatment succumbed to the disease in 2020, which indicates the urgent need to develop a more effective anti-liver cancer drug. In our previous study, nucleus-targeting hybrid peptides obtained from the fusion of LTX-315 and the rhodamine B group possessed potent anti-adherent cancer cell activity. Hybrid peptides accumulated in the cell nucleus and damaged the nuclear membrane, resulting in the transfer of reactive oxygen species (ROS) from the cytoplasm to the nucleus and the induction of apoptosis. However, the source of the high concentration of ROS within the cytoplasm is unclear. Moreover, although our previous study demonstrated that hybrid peptides possessed potent anticancer activity against adherent cancer cells, their efficacy on liver cancer remained unexplored. The current study found that the hybrid peptide NTP-217 killed liver cancer cells after 4-h treatment with a half-maximal inhibitory concentration of 14.6-45.7 μM. NTP-217 could stably accumulate in the liver tumor tissue and markedly inhibited liver tumor growth in mice. Furthermore, NTP-217 destroyed mitochondria and induced the leakage of mitochondrial contents, resulting in the generation of a substantial quantity of ROS. Unlike the apoptosis induced by 24 h of treatment by NTP-217, 4 h of treatment caused ROS-mediated necrotic cell death. These findings suggested that short-time treatment with hybrid peptides could trigger ROS-mediated rapid necrosis in liver cancer cells, and provided a basis for the future development of hybrid peptides as anti-liver cancer agents.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
AQUACULTURE
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2023
·
IF 4.5
Xiang Liu,Bing-Ke Li,Qin-Xue Liu,Peng-Fei Li,Fei Ling,Gao-Xue Wang
Viral nervous necrosis (VNN) caused by nervous necrosis virus (NNV) is a major threat to the global aquaculture industry, resulting in huge economic losses. In this study, we evaluated a naturally anthraquinone, rhein, as a potential therapeutic agent against NNV. Rhein effectively inhibited NNV-induced cytopathic effects (CPE) at a concentration of 18.84 μM, with an inhibitory concentration (IC 50 ) against NNV replication of 8.77 μM. Moreover, the study revealed a possible anti-NNV mechanism. Rhein could disrupt NNV-induced S-phase cell cycle arrest by inhibiting ATP synthesis, and cell cycle arrested in S phase is favorable for NNV replication, which in turn inhibits NNV replication. The therapeutic effect of rhein was also evaluated in vivo , where the survival rate of NNV infected grouper was increased by 26.7% with the treatment of 10 mg/kg rhein. Our findings demonstrated the potential of rhein as a pharmacological compound that exerts significant antiviral activity against NNV by modulating the cell cycle and ATP synthesis. Consequently, rhein has shown significant promise as a medication for the prevention and treatment of viral infections in aquaculture.
研究领域:
水产养殖
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病毒学
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药理学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）