International Journal of Oral Science
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2026
·Vol. 18
·期 1
·32
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IF 17.6
Zhang Zhongyin,Shan Zerui,Chen Xinyu,Xia Yu,Meng Li,Zhang Yuxin,Wu Caihong,Yuan Lichan,Ma Junqing
Post-translational modifications (PTMs) have been gradually elucidated in congenital malformations such as cleft palate. Among them, O-GlcNAcylation as a dynamic PTM of proteins regulates various critical biological processes including transcription, translation, and cell fate determination. In this study, a substantial decline in O-linked β-D-N-acetylglucosamine (O-GlcNAc) levels was detected within the palatine plates of all-trans retinoic acid (atRA)-induced cleft palate mice. The role of O-GlcNAc transferase (OGT), the sole enzyme responsible for catalyzing O-GlcNAcylation, was investigated in the process of palatal development. In a zebrafish model, the loss of O-GlcNAc resulted in an elevated prevalence of cleft palate and compromised palatal bone formation. Mechanistically, O-GlcNAcylation of myeloid ecotropic viral integration site 2 (MEIS2), which is mediated by OGT, was found to maintain osteogenic homeostasis by modulating its protein stability through inhibition of ubiquitination. Notably, the serine 237 residue (Ser237) was identified as a critical site for MEIS2 O-GlcNAcylation. Together, the present study uncovers the important function of MEIS2 O-GlcNAcylation in palatal bone development and establishes a novel theoretical framework for understanding the regulatory network of palatal development. This finding may provide novel avenues for the future diagnosis and prevention of cleft palate.
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ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Zhang Chen-chun,Li Yuan,Jiang Chang-you,Le Qiu-min,Liu Xing,Ma Lan,Wang Fei-fei
The O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced apoptosis remain to be elucidated. Here, we show that treatment with H 2 O 2 inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved caspase 3 and accelerated apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H 2 O 2 -induced apoptosis, respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished OSMI-1-induced apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H 2 O 2 -treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H 2 O 2 -induced apoptosis of N2a cells.
研究领域:
细胞生物学
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分子生物学
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神经科学
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 23
·e70940
·
IF 4.2
Hao Tan,Cao Fang,Yiyun Tan,Zhi Wang,Yun Zhou,Xing Li
Astragalus polysaccharides (APS) are a crucial bioactive component known for their various pharmacological properties. Abnormal O‐linked β‐N‐acetylglucosamine modification (O‐GlcNAcylation) is noted in cases of intervertebral disc degeneration (IVDD). Nonetheless, it remains uncertain whether APS regulates the process of O‐GlcNAcylation associated with IVDD. We employed molecular docking, cycloheximide chase assay, immunohistochemistry, and immunoprecipitation to investigate APS‐mediated OGT/O‐GlcNAcylation regulation of Nrf2. The effects of APS and its role in promoting the O‐GlcNAcylation of Nrf2 in IVDD through both in vivo and in vitro studies are discussed. In vitro investigations demonstrated an increase in the levels of OGT and O‐GlcNAcylation in nucleus pulposus cells (NPCs) following exposure to tert‐butyl hydroperoxide (TBHP). APS further facilitated improvements in OGT expression and O‐GlcNAcylation processes, restoring the viability of NPCs inhibited by TBHP and promoting the synthesis of collagen II and aggrecan, while reducing apoptosis. Mechanistically, APS promotes the expression of OGT by targeting it. Furthermore, O‐GlcNAcylation mediated by OGT stabilizes the expression of Nrf2 via the ubiquitin‐proteasome pathway. Rescue experiments indicated that the disruption of either OGT or Nrf2 expression negated the protective role of APS on NPCs. Ultimately, both in vitro and in vivo studies indicated that APS significantly enhanced OGT expression and O‐GlcNAcylation, which subsequently improved Nrf2 expression and contributed to the alleviation of IVDD in rats. APS promotes O‐GlcNAcylation through OGT, thereby stabilizing the expression of Nrf2, which in turn contributes to the improvement of IVDD.
研究领域:
药理学
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分子生物学
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骨科学
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细胞生物学
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天然产物研究
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高影响因子
Communications Biology
·
2026
·
IF 5.8
Gu Xunhu,Liu Xu,Xiong Yong,Chen Xuefen,Zhang Yancai,Zheng Li-Li,Wang Wei
Major depressive disorder is associated with impaired excitatory synaptic transmission, but the molecular mechanisms linking chronic stress to altered AMPA receptor trafficking remain incompletely understood. Here we show that chronic mild stress increases OGT-mediated O-GlcNAcylation of PIN at serine 88, which stabilizes PIN and enhances its interaction with nitric oxide synthase. This suppresses nitric oxide synthase activity, reduces stargazin S-nitrosylation, weakens stargazin-GluA1 binding, and impairs GluA1-containing AMPA receptor trafficking. Genetic or pharmacological inhibition of OGT restores this signaling pathway and alleviates stress-induced depression-like behaviors in mice. These findings identify the OGT-PIN-NOS-stargazin axis as a regulator of stress-induced synaptic dysfunction and suggest that targeting OGT may help restore AMPA receptor trafficking in depression-related conditions.
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
HuiNa Yang,Qiao Peng,Ruonan Shuang,Zihang Guo,Hao Yang,Chang Chen,Weiwei Tao,Li Liu
Ethnopharmacological relevance Depression in traditional Chinese medicine is mechanistically linked to neuroinflammation–a key pathogenesis driving depressive disorders. Baixian Houpo Decoction (BXHPD), originating from the classical TCM text Jinkui Yaolue, is prescribed for depression attributable to “phlegm-qi stagnation”. While modern pharmacological studies confirm its potent anti-inflammatory properties, the molecular pathways underpinning BXHPD’s therapeutic effects against neuroinflammation remain undefined. Objective We aimed to evaluate the antidepressant effect of BXHPD in a cortical corticosterone (CORT)-induced mouse model of depression and its potential molecular mechanisms. Materials and Methods Male C57BL/6 wild-type and Aldh1l1-Cre/ERT2 mice received CORT injections to induce depression. Behavioral tests included sucrose preference (SPT), tail suspension (TST), forced swim (FST), and open field (OFT) tests. Hippocampal neuropathology was assessed via Nissl staining for neuronal damage and ELISA for pro-inflammatory (IL-1β, IL-6, TNF-α) and anti-inflammatory (IL-10, IL-4) cytokines. Molecular analyses involved CO-IP for O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT)-Cathepsin B (CTSB) interaction, O-GlcNAcylation, and NLRP3 inflammasome activation; western blotting for protein expression; immunofluorescence for OGT/GFAP and CTSB/LAMP1 colocalization; and DHE staining for ROS detection. Results BXHPD alleviated depressive-like behaviors, reduced neuronal damage, and inhibited pro-inflammatory cytokine release in depressed mice. Mechanistically, BXHPD downregulated OGT, thereby reducing CTSB O-GlcNAcylation to promote its maturation. This decrease in O-GlcNAcylation lowered ROS levels, attenuated lysosomal membrane permeabilization (LMP), limited cytoplasmic CTSB leakage, and ultimately suppressed NLRP3 inflammasome activation. Conclusion BXHPD targets astrocytes in the medial prefrontal cortex via the OGT /CTSB/NLRP3 pathway to alleviate neuroinflammation and improve depressive-like behaviors.
研究领域:
民族药理学
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神经科学
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分子生物学
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中医中药
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炎症研究
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高影响因子
TALANTA
·
2020
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IF 5.339
Nan Yin,Ruihuan Zhao,Jie Zhang,Dingding Yang,Zhimin Guo,Rui Liu,Xin Yao
Abnormal O-linked N-acetylglucosamine (O-GlcNAc) concentrations have been associated with many diseases, but the lack of accurate detection method limited O-GlcNAc to be used as a biomarker in clinical diagnosis. Then O-GlcNAc transferase (OGT) has drawn researchers’ attention as it closed related to the level of O-GlcNAc and be considered to be a promising new target for diseases diagnosis. Nevertheless, the existing OGT detection methods are either need labeling or the sensitity can not meet the needs of clinic testing. Herein, a label-free and sensitive SPR biosensor was developed for accurate detection of OGT based on a multi-functional peptide. The designed peptide contains three recognition sites, one is the cleavage site of protease K, one is the O-GlcNAcylated site by OGT, and another is six histidine which be used as the signal report probe to recognize Ni 2+ . The immobilized peptide would be cleavaged by proteinase K, then the His-tag residue part will leave the surface of Au film, resulting less His-tag could bind to Ni 2+ and a small SPR signal would be record. If the peptide is O-GlcNAcylated by OGT, the cleaving reaction would be limited due to the adjacent site of O-GlcNAcylation. Then more His-tag can be left on the Au film and a bigger SPR signal could be record, this signal is associated with the concentration of OGT. Utilizing the change of the peptide configuration as a signal report probe for OGT detection not only avoids labeling of peptide, but also makes the method more sensitive. The determination linear range of OGT is from 2.00 × 10 −13 to 5.00 × 10 −8 M with a detection limit of 1.19 × 10 −13 M, and the separation of two enzyme reactions ensured the high selectivity of the method. Finally, the sensing system was successfully used for OGT detection in blood samples with satisfied recovery. In summary, the label-free SPR platform for accurate detection of OGT in real samples is helpful to promote OGT serve as a biomarker for early clinical diagnosis of O-GlcNAc related diseases.
研究领域:
生物化学
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分析化学
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生物传感器
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临床诊断
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Jiajun Yang,Siyu Hou,Yuhui Zhao,Zhaoyang Sun,Lilin Zhang,Yan Deng,Xiaoli Shang,Hanjie Yu,Zheng Li,Hongmei Li
The antidiabetic activity of the novel Buckwheat protein-derived peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) and its associated protein glycosylation have been verified. Our preliminary study demonstrates the potential of AFYRW as a therapeutic agent for diabetes, but the mechanism needs further investigation. Given the vital role of O-linked N -acetylglucosamine transferase (OGT) in diabetes mellitus and insulin resistance (IR), we focused on the underlying molecular mechanisms of them in ameliorating IR. We found AFYRW protects against hyperglycemia in diabetic mice and improves glucose metabolism in an IR cell model. Mechanistically, we demonstrated that AFYRW decreases glutamine-fructose-6-phosphate amidotransferase (GFAT) expression via X-box binding protein 1 (XBP1) in the hexosamine biosynthesis pathway (HBP), consequently decreasing OGT and stimulating the SIRT1/PGC1α pathway. Of note, the overlapping roles of increased SIRT1 and decreased OGT caused by AFYRW ameliorated IR. The data presented here show that AFYRW contributes to metabolism by directly controlling glucose homeostasis. Taken together, our study unveils that AFYRW protects against both insulin resistance and diabetes mellitus-induced hyperglycemia through OGT to regulate the SIRT1/PGC1α pathway, which provides a mechanistic basis for novel AFYRW to be a potential therapeutic agent.
研究领域:
内分泌学
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分子生物学
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糖尿病研究
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药理学
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