Genes & Diseases
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2025
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IF 9.4
Hui Gan,Mi Zhang,Yuhao Duan,Palahati Ailiyaer,Qi He,Junyi Tan,Yong Li,Xuan Zhai,Jing Zhao
Microglial activation triggers the inflammatory cascade and exacerbates brain injury following ischemic stroke. Middle cerebral artery occlusion (MCAO) modeling increased the expression of nuclear factor of activated T cells 5 (NFAT5) in microglia. However, the role of microglial NFAT5 in ischemic stroke remains unclear. Here, our findings indicated that microglial NFAT5 knockdown reduced the expression of pro-inflammatory factors, microglial activation, and neutrophil infiltration, ultimately ameliorating cerebral infarction and neurological deficits in mice following MCAO. Additionally, we treated hippocampal neuronal cells (HT22) with a conditioned culture medium from a microglia cell line (BV2) to simulate microglia-induced neuronal injury in vitro . We observed that NFAT5 knockdown attenuated the expression of pro-inflammatory factors in BV2 cells and reduced apoptosis in HT22 cells. Previously, our published work reported that the NOD-like receptor pyrin domain-containing 6 (NLRP6) inflammasome contributed to inflammatory injury after MCAO. In this study, we discovered that NFAT5 promoted the transcriptional activity of the Nlrp6 promoter through its −1527 bp to −1518 bp element. Notably, our results also demonstrated that NFAT5 regulated the stability of NLRP6 mRNA via the 5'UTR of Nlrp6 . Thus, our findings reveal the pivotal role and partial mechanism of microglial NFAT5 in neuroinflammation following ischemic stroke.
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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DOI
PubMed
高影响因子
World Journal of Diabetes
·
2024
·Vol. 15
·期 12
·2338
·
IF 4.2
Lu-Sha Cen,Yi Cao,Yi-Mai Zhou,Jing Guo,Jing-Wen Xue
BACKGROUND Shikonin is a natural remedy that is effective at treating diabetic wounds. NFAT5 is a potential therapeutic target for diabetes, and mitochondrial function is essential for wound healing. However, the relationship among Shikonin, NFAT5, and mitochondrial function has not been thoroughly studied. Here, we offer new perspectives on the advantages of shikonin for managing diabetes. AIM To assess the therapeutic mechanism of shikonin in diabetic wounds, its relationship with NFAT5, and its protection of mitochondrial function. METHODS Hypertonic cell and diabetic wound mouse models were established. NFAT5 expression was measured through western blotting and immunofluorescence, in vivo and in vitro . Mitochondrial function was evaluated using reactive oxygen species (ROS) detection and JC-1 and Calcein AM dyes. Mitochondrial structures were observed using transmission electron microscopy. The NFAT5/AMPK pathway was analyzed using a transfection vector and an inhibitor. The effect of shikonin on cells under hypertonic conditions via the NFAT5/AMPK pathway was assessed using western blotting. RESULTS Shikonin treatment preserved HaCaT cell viability, while significantly reducing cyclooxygenase-2 expression levels in a high-glucose environment ( P < 0.05). Additionally, shikonin maintained mitochondrial morphology, enhanced membrane potential, reduced membrane permeability, and decreased ROS levels in HaCaT cells under hyperosmolar stress. Furthermore, shikonin promoted wound healing in diabetic mice ( P < 0.05). Shikonin also inhibited NFAT5, in vivo and in vitro ( P < 0.05). Shikonin treatment reduced NFAT5 expression levels, subsequently inhibiting AMPK expression in vitro ( P < 0.05). Finally, shikonin inhibited several key downstream molecules of the NFAT5/AMPK pathway, including mammalian target of rapamycin, protein kinase B, nuclear factor kappa-light-chain-enhancer of activated B cells, and inducible nitric oxide synthase ( P < 0.05). CONCLUSION Shikonin protects mitochondria via the NFAT5/AMPK-related pathway and enhances wound healing in diabetes.
研究领域:
药理学
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内分泌学
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细胞生物学
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分子生物学
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糖尿病研究
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Gong Chen,Panyang Gu,Wenfang Wu,Yuan Yin,Liangyu Pan,Shu Huang,Wei Lin,Meichun Deng
Histone methylations play a crucial role in the development of neuropathic pain, and SET domain containing 2 (SETD2), a histone methyltransferase, serves as the sole tri-methylase known to catalyze H3K36me3 at the gene body. The N -methyl- d -aspartate receptor (NMDAR) is activated and mediates excitatory synaptic transmission in neuropathic pain. Nevertheless, the involvement of SETD2 in neuropathic pain and the specific regulatory mechanisms affecting NMDARs remain poorly understood. The expression levels of SETD2 were significantly decreased in the spinal cord and dorsal root ganglion (DRG) of rodents undergoing neuropathic pain induced by sciatic nerve chronic constrictive injury. Lentiviral shRNA-mediated SETD2 knockdown and conditional knockout in sensory neurons caused sustained NMDAR upregulation in DRG and spinal cord, which resulted in heightened neuronal excitability and increased pain hypersensitivity. SETD2 deficiency also led to reduced H3K36me3 deposition within the Grin1 (glutamate ionotropic receptor NMDA type subunit 1) gene body, thereby promoting aberrant transcription of the NMDARs subunit GluN1. The absence of SETD2 in the DRG potentiated neuronal excitability and increased presynaptic NMDAR activity in the spinal dorsal horn. Chromatin immunoprecipitation sequencing targeting H3K36me3 identified NFAT5 as a co-transcription factor in the transcriptional regulation of Grin1 . These findings highlight SETD2 as a key regulator in pain signal transmission and offered new perspectives on the development of analgesics through the targeted modulation of epigenetic mechanisms.
研究领域:
神经科学
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表观遗传学
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疼痛研究
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DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-19
·
IF 16.6
Li Yatian,Gao Zhenyue,Wang Yuhong,Pang Bo,Zhang Binbin,Hu Ruxin,Wang Yuqing,Liu Chao,Zhang Xuebin,Yang Jingxuan,Mei Mei,Wang Yongzhi,Zhou Xuan,Li Min,Ren Yu
Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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神经肿瘤学
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DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2022
·Vol. 19
·期 9
·e202200447
·
IF 2.745
Ling Guo,Yanling Jin,You Yang,Jing Liu,Chunyan Liu,Yan Zeng,Qulian Guo,Wenjun Liu
Purple sweet potato is considered an abundant, inexpensive, and ideal source of anthocyanins. Purple sweet potato anthocyanins (PSPAs) have been shown to possess high antimutagenicity and antitumor effects due to the abundance of acylated anthocyanins. However, the effect and underlying mechanism of PSPA effects in acute lymphoblastic leukemia (ALL), especially T-cell acute lymphoblastic leukemia (T-ALL), remain unclear. In this study, the antileukemic effects of PSPAs and the underlying molecular mechanisms were evaluated by in vitro and in silico assays. PSPAs extracted from ten cultivars were analyzed and quantified. Anthocyanins from Nanzi 018, which showed the best antileukemic effect, were selected to analyze the underlying mechanism. First, the PSPAs potently reduced cell viability and induced apoptosis. Additionally, the PSPAs sharply increased intracellular Ca 2+ levels, which resulted in calcium overload in T-ALL cells. Furthermore, on the basis of bioinformatics analyses, we focused on an osmotically regulated transcription factor, NFAT5. Molecular docking preliminarily indicated that PSPA molecules bound and interacted with the NFAT5 protein. Western blot analyses confirmed that PSPAs elicited calcium overload by nonosmotic regulation of NFAT5/S100A4-S100A9 pathway activation. Moreover, pretreatment with a NFAT5 inducer confirmed that PSPAs targeted NFAT5 and affected p38/NF-κB/Bcl-2/Caspase-3 axis activation. This study demonstrates that PSPAs exert their antileukemic effects through calcicoptosis induction by targeting NFAT5.
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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生物化学
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DOI
PubMed
高影响因子
Life Science Alliance
·
2024
·Vol. 7
·期 4
·e202302375
·
IF 3.3
Jialing Bao,Yunlin Tang,Yebo Chen,Jiangyan Jin,Xue Wang,Guozhen An,Lu Cao,Huarui Zhang,Gong Cheng,Guoqing Pan,Zeyang Zhou
Microsporidia are difficult to be completely eliminated once infected, and the persistence disrupts host cell functions. Here in this study, we aimed to elucidate the impairing effects and consequences of microsporidia on host DCs. Enterocytozoon hellem, one of the most commonly diagnosed zoonotic microsporidia species, was applied. In vivo models demonstrated that E. hellem-infected mice were more susceptible to further pathogenic challenges, and DCs were identified as the most affected groups of cells. In vitro assays revealed that E. hellem infection impaired DCs’ immune functions, reflected by down-regulated cytokine expressions, lower extent of maturation, phagocytosis ability, and antigen presentations. E. hellem infection also detained DCs’ potencies to prime and stimulate T cells; therefore, host immunities were disrupted. We found that E. hellem Ser/Thr protein phosphatase PP1 directly interacts with host p38α (MAPK14) to manipulate the p38α(MAPK14)/NFAT5 axis of the MAPK pathway. Our study is the first to elucidate the molecular mechanisms of the impairing effects of microsporidia on host DCs’ immune functions. The emergence of microsporidiosis may be of great threat to public health.
研究领域:
免疫学
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微生物学
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病理学
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DOI
PubMed
高影响因子
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