NATURE
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2025
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IF 48.5
Zhu Yunfeng,Xiao Fang,Wang Yiling,Wang Yufang,Li Jialin,Zhong Dongmei,Huang Zhilei,Yu Miao,Wang Zhirong,Barbara Joshua,Plunkett Christopher,Zeng Mengxue,Song Yiyan,Tan Tian,Zhang Ruibin,Xu Kezhen,Wang Zhongxing,Cai Changjie,Guan Xiangdong,Hammack Scott,Zhang Liang,Shi Zheng,Xiang Fu-li,Shao Feng,Xu Jie
Plasma membrane integrity is vital for nearly all aspects of cell functioning 1 . Mechanical forces can cause plasma membrane damage 2 , but it is not known whether there are large molecules that regulate plasma membrane integrity under mechanical strain. Here we constructed a 384-well cellular stretch system that delivers precise, reproducible strain to cultured cells. Using the system, we screened 10,843 siRNAs targeting 2,726 multi-pass transmembrane proteins for strain-induced membrane permeability changes. The screen identified NINJ1, a protein recently proposed to regulate pyroptosis and other lytic cell death 3,4 , as the top hit. We demonstrate that NINJ1 is a critical regulator for mechanical strain-induced plasma membrane rupture (PMR), without the need of stimulating any cell death programs. NINJ1 level on the plasma membrane is inversely correlated to the amount of force required to rupture the membrane. In the pyroptosis context, NINJ1 on its own is not sufficient to fully rupture the membrane, and additional mechanical force is required for full PMR. Our work establishes that NINJ1 functions as a bona fide determinant of membrane biomechanical properties. Our study also suggests that PMR across tissues of distinct mechanical microenvironments is subjected to fine tuning by differences in NINJ1 expression and external forces.
研究领域:
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
Genes & Genomics
·
2022
·Vol. 44
·期 11
·1385-1397
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IF 2.164
Zhang Xueluo,Chen Yanhua,Wang Xianping,Zhang Zhiping,Wang Jun,Shen Yan,Hu Yuanjing,Wu Xueqing
Background Trophoblasts are the most important parts of the placenta in early pregnancy. Trophoblast cell dysfunction can induce embryo implantation insufficiency, thereby resulting in multiple diseases, including recurrent spontaneous abortion (RSA). A previous study indicates higher nerve injury-induced protein 1 (NINJ1) RNA levels in the villi tissues of RSA patients. Objective This study aimed to investigate the effect of NINJ1 on trophoblast behaviors and pregnancy loss. Methods Fresh villi tissues were obtained from with RSA patients and patients with artificial selective abortion for personal reasons, and NINJ1 expression in these tissues was detected. Extravillous trophoblast cell line HTR-8/SVneo was transfected with small-interfering RNA targeting NINJ1 or NINJ1 overexpression vector to perform loss-/gain-of-function experiments. Spontaneous abortion (SA) was induced by mating CBA/J females with DBA/2 males and the pregnant females were intraperitoneally injected with adenovirus vector carrying NINJ1 short hairpin RNA. Results NINJ1 mRNA and protein levels were higher in the villi tissues of RSA patients than those of artificial selective abortion patients. NINJ1 knockdown promoted trophoblast cell proliferation, migration and invasion but inhibited cell apoptosis. Moreover, conditioned medium from NINJ1-depleted trophoblasts promoted the angiogenesis of human umbilical vein endothelial cells. NINJ1 knockdown also promoted activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway in trophoblasts, and STAT3 inhibitor reversed NINJ1 knockdown-induced effects on trophoblast behaviors. Furthermore, pregnancy loss was attenuated by NINJ1 inhibition. Conclusion NINJ1 contributes to the development of SA and triggers trophoblast cell dysfunction through inhibiting the STAT3 pathway. Graphical abstract
研究领域:
妇产科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2024
·Vol. 21
·期 1
·1-16
·
IF 9.3
Chen Lushu,Zhang HuiYing,Zhang Ying,Li Xiumiao,Wang MeiHuan,Shen Yaming,Cao Yuan,Xu Yong,Yao Jin
Retinal neovascularisation is a major cause of blindness in patients with proliferative diabetic retinopathy (PDR). It is mediated by the complex interaction between dysfunctional ganglion cells, microglia, and vascular endothelial cells. Notably, retinal microglia, the intrinsic immune cells of the retina, play a crucial role in the pathogenesis of retinopathy. In this study, we found that lysophosphatidylserines (LysoPS) released from injured ganglion cells induced microglial extracellular trap formation and retinal neovascularisation. Mechanistically, LysoPS activated the GPR34-PI3K-AKT-NINJ1 signalling axis by interacting with the GPR34 receptor on the microglia. This activation upregulated the expression of inflammatory cytokines, such as IL-6, IL-8, VEGFA, and FGF2, and facilitated retinal vascular endothelial cell angiogenesis. As a result, inhibition of the GPR34-PI3K-AKT-NINJ1 axis significantly decreased microglial extracellular trap formation and neovascularisation by suppressing LysoPS-induced microglial inflammatory responses, both in vitro and in vivo. This study reveals the crucial role of apoptotic ganglion cells in activating microglial inflammation in PDR, thereby enhancing our understanding of the pathogenesis of retinal neovascularisation.
研究领域:
眼科学
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免疫学
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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
Cell Death Discovery
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2025
·Vol. 11
·期 1
·1-15
·
IF 7
Zheng Xiao-Bo,Wang Xue,Gao Sheng-Qing,Gao Chao-Chao,Li Tao,Han Yan-Ling,Zhao Ran,Sun Yan,Miao Shu-Hao,Qiu Jia-Yin,Jin Wang-Xuan,Zhou Meng-Liang
Brain endothelial cell (bEC) dysfunction is the main factor of blood-brain barrier (BBB) breakdown, which triggers a vicious cycle of aggravating traumatic brain injury (TBI) pathogenesis. Previous studies have revealed that neutrophil extracellular traps (NETs) released by neutrophils can lead to BBB disruption, but there is a lack of research on the underlying mechanisms after TBI. Here, excessive NETs were found in both contused brain tissue and circulation following TBI. We found that NETs could activate the TLR4/NF-κB pathway to induce bEC pyroptosis, which led to BBB disruption after TBI. During this process, ninjurin-1 (NINJ1) was activated in pyroptotic bECs, and it mediated the release of high mobility group box 1 protein (HMGB1) via plasma membrane rupture (PMR) to promote NET formation. NINJ1-mediated release of HMGB1 aggravated NET accumulation by forming a vicious circle following TBI. Knockdown of NINJ1 rescued NET formation, attenuated BBB leakage, and improved neurological outcomes after TBI. NINJ1 may represent a promising target for alleviating NET-induced BBB destruction and other related injuries after TBI.
研究领域:
神经科学
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免疫学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2026
·
IF 11.3
Yi-lang Zhong,Zhi-qiang Liang,Can Hu,Chen-qin Xu,Miao-Miao Wang,Chao Ma,Cheng-lin Jia,Ye-min Cao,Yong-bing Cao,Ji Li,Jian-da Zhou,Jian Chen
Background Impaired healing of diabetic foot ulcers (DFU) is a major clinical challenge. This condition is driven by unresolved inflammation and cellular dysfunction. However, the specific role of macrophage ferroptosis in this process remains poorly defined. Purpose This study aimed to investigate the contribution of macrophage ferroptosis to DFU pathogenesis. We also evaluated the therapeutic effect and underlying mechanism of the Ruan Jian Qing Mai formula (RJQM). Our investigation focused on the NINJ1–ferroptosis–inflammation axis and its role in intercellular communication. Methods We combined single-cell RNA sequencing of human wound tissues with a streptozotocin-induced diabetic mouse model. The chemical composition of RJQM was characterized by HPLC-MS. For in vitro experiments, we used macrophages stimulated with high glucose and LPS to model diabetic conditions. Key markers for ferroptosis, inflammation, and signaling pathways were assessed using Western blot, qPCR, and flow cytometry. Finally, endothelial cell behavior was evaluated through migration and tube formation assays. Results Our analysis revealed that macrophages exhibited the highest ferroptosis activity in diabetic wounds. In diabetic mice, RJQM treatment accelerated wound healing in a ferroptosis-dependent manner. We identified 87 compounds in RJQM. These compounds effectively suppressed ferroptosis by enhancing GPX4/xCT expression while reducing lipid peroxidation and iron overload. Mechanistically, RJQM inhibited a positive feedback loop involving NINJ1 and ferroptosis, and also suppressed downstream STAT3 activation. Furthermore, conditioned media from RJQM-treated macrophages promoted endothelial migration and tube formation. This pro-angiogenic effect was reversed by NINJ1 overexpression, confirming its critical role. Conclusion RJQM promotes diabetic wound repair by targeting the NINJ1–STAT3–ferroptosis pathway in macrophages. This action reduces inflammation and restores the cells' pro-angiogenic functions. Our findings support RJQM as a promising therapeutic strategy for DFU.
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高影响因子
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