BRAIN BEHAVIOR AND IMMUNITY
·
2025
·
IF 7.6
Xiaoyu Yu,Tingting Yang,Di Wu,Chenxue Xu,Zhuoran Li,Ao Sun,Shulei Gao,Heng Li,Zhenyu Fan,Rongrong Huang
Microglial inflammation has been implicated in the pathophysiology of major depressive disorder; however, the underlying biological mechanisms remain inadequately understood. Consequently, we conducted a screening of the Poly ADP-ribose (PAR) polymerase (PARP) family expression in the hippocampus of chronic unpredictable stress (CUS) mouse models and investigated the specific role of PARP14 in microglial inflammation and its association with depression. Here, this study demonstrated the elevated PARP14 expression in the hippocampus of CUS mice. The knockdown of PARP14 in the hippocampus did not mitigate depressive-like behaviors in mice, whereas overexpression of PARP14 significantly mitigated these behaviors. Furthermore, PARP14 was abundant in microglia, and microglial-targeted PARP14 overexpression significantly alleviated depressive-behaviors in CUS, reduced microglial activation, and inhibited the central inflammatory responses. Mechanistically, PARP14 positively regulated nicotinamide nucleotide transhydrogenase (NNT) expression in microglia, and the inflammatory response of microglia induced by PARP14 knockdown was suppressed through NNT overexpression. Additionally, deficiency in NNT led to an accumulation of reactive oxygen species (ROS) and subsequent microglial inflammation, which was effectively inhibited by the ROS inhibitor N-Acetylcysteine. These findings suggest that PARP14 alleviates depressive-like behaviors in mice by inhibiting microglial activation via NTT-mediated clearance of ROS.
研究领域:
神经科学
·
免疫学
·
药理学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
·
2022
·Vol. 97
·期 2
·441-456
·
IF 6.168
Xu Chi,Jiang Shuyun,Ma Xingyu,Jiang Zeyong,Pan Youguang,Li Xiang,Zhang Liying,Zhou Hao,Chen Shen,Xing Xiumei,Chen Liping,Fu Wenfan,Wang Qing,Chen Wen,Li Daochuan
Cisplatin is recommended as a first-line chemotherapeutic agent against advanced non-small cell lung cancer (NSCLC), but acquired resistance substantially limits its clinical efficacy. Recently, DNA methylation has been identified as an essential contributor to chemoresistance. However, the precise DNA methylation regulatory mechanism of cisplatin resistance remains unclear. Here, we found that nicotinamide nucleotide transhydrogenase ( NNT ) was silenced by DNA hypermethylation in cisplatin resistance A549 (A549/DDP) cells. Also, the DNA hypermethylation of NNT was positively correlated to poor prognosis in NSCLC patients. Overexpression of NNT in A549/DDP cells could reduce their cisplatin resistance, and also suppressed their tumor malignancy such as cell proliferation and clone formation. However, NNT enhanced sensitivity of A549/DDP cells to cisplatin had little to do with its function in mediating NADPH and ROS level, but was mainly because NNT could inhibit protective autophagy in A549/DDP cells. Further investigation revealed that NNT could decrease NAD + level, thereby inactivate SIRT1 and block the autophagy pathway, while re-activation of SIRT1 through NAD + precursor supplementation could antagonize this effect. In addition, targeted demethylation of NNT CpG island via CRISPR/dCas9-Tet1 system significantly reduced its DNA methylation level and inhibited the autophagy and cisplatin resistance in A549/DDP cells. Thus, our study found a novel chemoresistance target gene NNT , which played important roles in cisplatin resistance of lung cancer cells. Our findings also suggested that CRISPR-based DNA methylation editing of NNT could be a potential therapeutics method in cisplatin resistance of lung cancer.
研究领域:
肿瘤学
·
分子生物学
·
表观遗传学
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产品关联
DOI
PubMed
高影响因子
HEREDITAS
·
2026
·Vol. 163
·期 1
·77
·
IF 2.6
Jian Fanghua,Fu Jun,Li Dan,Bao Weiqiang
Background Severe pneumonia (SP) threatens the quality of life and well-being of children. This study aims to explore the serum NNT-AS1 expression in SP children and its impact on lipopolysaccharide (LPS)-induced injury in human embryonic lung fibroblasts. Methods The study included 69 SP children, 62 mild pneumonia (MP) children and 75 healthy controls. A pneumonia cell model was constructed with LPS-induced MRC-5 cells. Loss-of-function experiments were performed using si-NNT-AS1 and miR-23a-3p inhibitor. The NNT-AS1 and miR-23a-3p expression was detected by real-time quantitative polymerase chain reaction. The diagnostic effect and prognostic value of NNT-AS1 were evaluated by receiver operating characteristics curves and Kaplan-Meier method. Cell viability and apoptosis were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Inflammatory factors were measured by enzyme-linked immunosorbent assay. The interaction between NNT-AS1 and miR-23a-3p was verified by luciferase reporter gene and RNA immunoprecipitation assays. Pearson correlation coefficient was used to analyze the correlation. Results NNT-AS1 was upregulated in SP children and showed good diagnostic efficacy (area under the curve (AUC) = 0.815). High NNT‑AS1 expression predicted a poorer survival. Silencing of NNT-AS1 increased cell viability, decreased apoptosis, and alleviated inflammatory responses. MiR-23a-3p was a target of NNT-AS1. Inhibition of miR-23a-3p partially reversed the protective effects of NNT-AS1 silencing on LPS-induced MRC-5 cell injury. Conclusions Serum NNT-AS1 is upregulated in SP patients, and its expression is correlated with clinical prognosis. NNT-AS1 participates in LPS-induced cellular damage by regulating miR-23a-3p. These findings provide a new theoretical basis for understanding the pathogenesis of SP.
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高影响因子
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