Theranostics
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2023
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IF 12.4
Lianxia Guo,Haobin Cen,Jiaxian Weng,Yiting He,Xiaocao Guo,Di He,Kaisheng Liu,Shuyi Duan,Jing Yang,Xiaojian Zhang,Zifei Qin,Yong Wan,Zhiyong Chen,Baojian Wu
Rationale: The role of circadian clock in pituitary tumorigenesis remains elusive. Here we investigate whether and how circadian clock modulates the development of pituitary adenomas. Methods and Results: We found altered expression of pituitary clock genes in patients with pituitary adenomas. In particular, PER2 is prominently upregulated. Further, jetlagged mice with PER2 upregulation have accelerated growth of GH3 xenograft tumor. Conversely, loss of Per2 protects mice against developing estrogen-induced pituitary adenoma. Similar antitumor effect is observed for SR8278, a chemical that can decrease pituitary PER2 expression. RNA-seq analysis suggests involvement of cell cycle disturbance in PER2 regulation of pituitary adenoma. Subsequent in vivo and cell-based experiments validate that PER2 induces pituitary expression of Ccnb2 , Cdc20 and Espl1 (three cell cycle genes) to facilitate cell cycle progression and inhibit apoptosis, thereby promoting pituitary tumorigenesis. Mechanistically, PER2 regulates the transcription of Ccnb2 , Cdc20 and Espl1 through enhancing the transcriptional activity of HIF-1α. HIF-1α trans-activates Ccnb2 , Cdc20 and Espl1 via direct binding to its specific response element in the gene promoters. Conclusion: PER2 integrates circadian disruption and pituitary tumorigenesis. These findings advance our understanding of crosstalk between circadian clock and pituitary adenomas and highlight the relevance of clock-based approaches in disease management.
研究领域:
肿瘤学
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内分泌学
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分子生物学
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昼夜节律
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PubMed
高影响因子
Communications Biology
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2025
·Vol. 8
·期 1
·1-16
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IF 5.1
Bie Pengfei,Su Dongpo,Gao Yang,Wu Liang,Niu Zhanfeng,Zhao Yanbin,He He,Jiang Zhanfeng,Zeng Zhong,Zhang Yaolin,Fan Heng,Xia Hechun
Microglia play significant roles in spinal cord injury (SCI) progression. Previous studies have suggested that ferroptosis plays a crucial role in exacerbating neuronal death following SCI; however, the role of microglial ferroptosis in SCI and the underlying mechanisms remain elusive. Here, we elucidate that lipid droplets accumulate in microglia to facilitate microglial ferroptosis after SCI. Notably, microglial ferroptosis peaks at 3 days post-injury, after which it decreases. Microglial Period 2 (Per2) expression is elevated after SCI in vivo; this change is highly synchronized with the changes in microglial ferroptosis. Microglia-specific Per2 knockout promoted neurological function recovery by suppressing microglial ferroptosis. In vitro, Per2 overexpression and deficiency amplified and mitigated microglial ferroptosis, respectively. RNA-seq indicated that Gpx4 was downregulated by Per2. Coimmunoprecipitation demonstrated that Per2 directly interacted with PPARα. Overall, our results indicate that Per2 determines the susceptibility of microglial ferroptosis via the PPARα-Gpx4 axis after SCI.
研究领域:
神经科学
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细胞生物学
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分子生物学
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免疫学
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高影响因子
Frontiers in Pharmacology
·
2025
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IF 4.8
Hailiang Li,Zheng Ma,Wanfu Yang,Yifan Zhang,Jinping Sun,Haifeng Jiang,Faxuan Wang,Li Hou,Hechun Xia
Introduction Glioblastoma multiform (GBM) is considered the deadliest brain cancer. Standard therapies are followed by poor patient’s survival outcomes, so novel and more efficacious therapeutic strategies are imperative to tackle this scourge. Metformin has been reported to have anti-cancer effects. However, the precise mechanism underlying these effects remains elusive. A better understanding of its underlying mechanism will inform future experimental designs exploring metformin as a potential adjuvant therapy for GBM. This research aimed to elucidate the potential molecular mechanism of metformin in GBM by integrating proteomics and transcriptomics. Methods The study examined the effects of metformin on GBM cell lines using various methods. The U87, U251 and HA1800 were cultured and modified through PER2 knockdown and overexpression. Cell viability was assessed using the CCK8 assay, and G6PDH activity and intracellular NADPH + levels were measured with specific kits. ROS levels, mitochondrial membrane potential, cell cycle distribution and apoptosis were analyzed by flow cytometry. RNA was extracted for transcriptomic analysis through RNA sequencing, while proteomic analysis was performed on total protein from treated cells. WB detected specific proteins, and RT-qPCR quantified gene expression. In vivo experiments, GBM xenograft on nude mice treated with metformin combining radiotherapy was evaluated and received IHC and TUNEL staining for protein expression and apoptosis assessment. Statistical analyses were conducted using Prism software to identify significant group differences. Results We found that differential expressional genes and proteins relating to circadian rhythm were enriched in proteomic or transcriptomic. The expression of PER2, the key circadian gene, was up-regulated in GBM cell lines when treated with metformin. Furthermore, the expression of silent information regulator 2(SIRT2) was down-regulated, while the expression of the G6PD protein just slightly increased in GBM cell lines. Meanwhile, NADPH+ production and G6PDH enzyme activity significantly decreased. Further study validated that metformin inhibited the cell growth of GBM cell lines through up-regulating PER2 and inhibited SIRT2/G6PD signaling pathway, enhancing radiotherapy(RT) sensitivity. We also found that the inhibition of SIRT2 caused by metformin is mediated by PER2. Discussion We found the pivotal role of metformin as an effective circadian rhythm regulator. Targeting circadian clock gene to modify and rescue the dysfunctional circadian clock of GBM cells at molecular level might be an innovative way to administer cancer chronotherapy and maintain metabolic homeostasis in real world practice.
研究领域:
肿瘤学
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分子生物学
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药理学
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
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IF 5.6
Xuejun Jiang,Pengcheng Wu,Hui Chen,Jialu Cui,Xiting Lv,Linna Ha,Mingyang Wu,Min Chen,Baojian Wu,Haiman Xu,Dong Dong
Intestinal bowel disease (IBD), prevalent among sleep-deprived populations, is closely associated with circadian rhythm disruptions. Evidence suggests that sleep deprivation (SD) exacerbates colitis; however, the mechanisms is remains poorly understood. We subjected mice with Dextran sulfate sodium (DSS) induced acute and chronic colitis to 6 h-SD per day. It was observed that mild SD significantly aggravated both acute and chronic colitis, involving progressive body weight loss, increased Disease Activity Index (DAI), shortened colon length, histopathological deterioration, and elevated levels of inflammatory cytokines. Circadian gene screening identified PER2 as a pivotal mediator in SD aggravating colitis. Both SD and colitis independently suppressed Per2 expression in mice colon. Notably, the inhibitory effect on PER2 was most pronounced in cases of colitis accompanied by SD. Consistent with this, Per2 deficiency heightened the susceptibility of mice to DSS-induced colitis. Furthermore, transcriptomic analysis revealed that the disordered arachidonic acid (AA) metabolism pathway was implicated in the exacerbation of colitis due to Per2 deficiency. Specifically, Ptgs2 , a gene coding AA metabolism enzyme COX-2, was significantly upregulated in both Per2 -/- colitis mice and SD colitis mice. The elevated PGE 2 levels in plasma and colon supported the involvement of COX-2 mediated proinflammatory conversion of AA during episodes of SD-related colitis aggravation. Mechanistically, in vitro experiments in CT-26 cells suggested Per2 suppressed COX-2 transcription via BMAL1. In summary, SD inhibited the expression of clock factor PER2 in colon, leading to disorder of COX-2-mediated AA metabolism; this process released more pro-inflammatory mediators thereby aggravating colitis
研究领域:
免疫学
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分子生物学
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胃肠病学
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时间生物学
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炎症研究
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高影响因子
Cell Death Discovery
·
2026
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IF 10.4
Yin Shilin,Yang Fang,Zhang Zhiwei,Liu Mingyuan,Tang Hong,Yang Kai
Dysregulation of cholesterol homeostasis is closely associated with the development of various cancers, but the underlying mechanisms remain unclear. This study found that the circadian clock gene Period 2 (PER2) is downregulated in oral squamous cell carcinoma (OSCC), promoting intracellular cholesterol synthesis and cell proliferation. Conversely, PER2 overexpression inhibits cell proliferation by suppressing intracellular cholesterol synthesis. Mechanistically, PER2 binds to Myosin Heavy Chain 9 (MYH9) and recruits Tripartite Motif Containing-21 (TRIM21) to promote ubiquitin-dependent degradation of MYH9, thereby inhibiting the cholesterol synthesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), reducing intracellular cholesterol synthesis, and suppressing OSCC proliferation. In OSCC xenograft models, overexpression of PER2 or treatment with the HMGCR inhibitor simvastatin significantly inhibited OSCC growth, with the combination showing markedly enhanced anti-OSCC efficacy compared to either approach alone. To explore the circadian regulatory role of PER2, overexpression or silencing experiments in OSCC demonstrated that PER2 modulates the circadian rhythms of HMGCR expression, intracellular cholesterol, and cell proliferation. Further investigations in subcutaneous OSCC mouse models revealed sex-specific circadian rhythms in PER2 and HMGCR expression, intracellular cholesterol, cell proliferation, and tumor growth in OSCC cells. Specifically, the acrophases of these indicators in OSCC of male mice were delayed relative to females, and the mesors of HMGCR expression, intracellular cholesterol, and cell proliferation were significantly higher than in females. The anticancer efficacy of simvastatin against OSCC in mice varied up to 2.5-fold across six different time points within 24 h, with broader time windows for optimal therapeutic efficacy and adverse effects in female mice than in males. This study identified a novel mechanism by which PER2 reprograms intracellular cholesterol, demonstrating that PER2 upregulation combined with simvastatin represents a potential novel strategy to improve the prognosis of OSCC patients, and clarifies that the anti-OSCC effect of simvastatin exhibits time-dependent and sex differences.
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高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Dihao Xie,Simin Zhong,Meixue Luo,Jiahao Xu,Ruoyan Zheng,Jiading Luo,Yiting Wang,Yongxing Guo,Lianxia Guo,Baojian Wu,Danyi Lu
Background Aristolochic acid I (AAI), an emerging biogenic contaminant widely present in Aristolochic plants, has been implicated in the progression of tubulointerstitial disease, known as aristolochic acid nephropathy (AAN). The circadian clock, a vital regulator of organ homeostasis, is susceptible to external chemical cues, including toxins. However, the reciprocal interactions between AAI and the circadian clock remain unexplored. Methods We initially assessed sex- and time-dependent nephropathy and behavioral responses in C57BL/6J mice exposed to AAI. Subsequently, we evaluated changes in the expression of circadian clock genes following treatment with AAI or its bioactive metabolite, aristolactam I, using real-time quantitative PCR and immunoblotting in renal tissues and cells. Additionally, real-time reporter assays were conducted on kidney explants from PER2::Luc knock-in reporter mice and Per2-dLuc / Bmal1-dLuc reporter cell lines. To further elucidate the regulatory role of circadian clocks in AAI-induced nephropathy, mice with global or kidney-specific knockout of Bmal1 , as well as mice subjected to experimental jetlag, were utilized. Results Our findings revealed a sex-dependent nephrotoxicity of AAI, with males exhibiting greater vulnerability. AAI-induced nephropathy was accompanied by impaired spatial cognitive function, disruptions in free-running locomotor activity, altered renal expression of multiple core clock genes, and disturbances in the circadian rhythm of renal PER2::Luc activity. Notably, kidney-specific ablation of the core clock gene Bmal1 significantly exacerbated renal injury and inflammation, whereas disruptions to the central clock, either genetically (through conventional knockout of Bmal1 ) or environmentally (mimicking jetlag), had minimal effects on AAI nephrotoxicity. Furthermore, both AAI and its bioactive metabolite aristolactam I demonstrated the ability to disrupt circadian clocks in human osteosarcoma cells (U2OS) and mouse renal tubular epithelial cells (mRTEC). Conclusion Collectively, these findings highlight the detrimental impact of aristolochic acids on local renal circadian clocks, ultimately exacerbating kidney damage. This study provides novel insights into the molecular mechanisms underlying AAI nephrotoxicity, potentially opening avenues for therapeutic interventions aimed at modulating the renal circadian clock to treat AAN.
研究领域:
肾病学
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药理学
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分子生物学
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时间生物学
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毒理学
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DOI
PubMed
高影响因子
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