Ocular Surface
·
2024
·
IF 5.9
Xiaozhao Zhang,Guangjin Chen,Yan He,Qingming Tang,Ying Yin,Ying Jie
Secretory glands, responsible for tears and saliva production, play essential roles in maintaining ocular and oral well-being. Disruptions in gland secretion can arise from various factors, including rhythm disturbances associated with sleep disorders. However, the underlying mechanisms governing these disruptions remain largely unexplored. We demonstrate that BMAL1, a core component of the circadian system, plays a critical role in regulating secretory gland secretion. Loss of BMAL1 induces vacuolation and atrophy phenotypes in acinar cells, subsequently leading to cell apoptosis and gland hypofunction, but does not cause Sjogren's syndrome, which is characterized by localized inflammatory cell infiltration. Mechanically, BMAL1 directly modulates the transcription of ITPR2 and ITPR3, thereby altering the secretion of Lactoferrin and Lysozyme. Restoration of ITPR2 and ITPR3 expression in Bmal1 -deficient rats effectively alleviated the symptoms of lacrimal and parotid glands secretory dysfunction and significantly reduced dry mouth and dry eye conditions in rhythm-disordered rats. These findings highlight the essential role of BMAL1 in regulating salivary and lacrimal gland secretion and suggest a novel therapeutic approach for treating dry mouth and dry eyes associated with rhythm disorders.
研究领域:
昼夜生物学
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分泌生理学
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分子生物学
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治疗学
✓ 已验证
DOI
高影响因子
FASEB JOURNAL
·
2023
·Vol. 37
·期 10
·e23193
·
IF 4.8
Chaofan Wang,Yue Gao,Changjiao Luan,Wentao Sun,Sumin Ge,Yaru Li,Lei Xu,Qiu Du,Weili Liu,Guotao Lu,Weijuan Gong,Xingjie Ma
Cellular senescence is broadly known as a stable cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP). In the past decades, calcium signaling has emerged as a key mediator of cellular senescence. However, the transcriptional regulation of calcium signaling during cellular senescence remains partially understood. We have previously identified the nuclear receptor RXRA as a key senescence repressor through inhibiting the endoplasmic reticulum (ER) calcium release channel inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) mediated intracellular calcium signaling. Nevertheless, as a transcriptional recruiter, the mechanism by which RXRA inhibits ITPR2 during cellular senescence remains unclear. Here we identified the zinc finger protein ZBTB17 can interact with RXRA. Interestingly, knockdown of ZBTB17 induces a cascade of RXRA-dependent intracellular calcium signaling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) accumulation, DNA damages, and ultimately cellular senescence. Moreover, the signaling and senescence phenotype induced by knocking down of ZBTB17 can also be abolished after silencing ITPR2. Altogether, our work provides a new mechanism controlling intracellular calcium signaling and cellular senescence and unveils novel insight toward the role of zinc finger proteins.
研究领域:
细胞生物学
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分子生物学
·
转录调控
·
信号传导
✓ 已验证
DOI
PubMed
高影响因子
Science Advances
·
2022
·
IF 14.957
Jiaming Liu,Jia-Wen Mo,Xunda Wang,Ziqi An,Shuangyang Zhang,Can-Yuan Zhang,Peiwei Yi,Alex T. L. Leong,Jing Ren,Liang-Yu Chen,Ran Mo,Yuanyao Xie,Qianjin Feng,Wufan Chen,Tian-Ming Gao,Ed X. Wu,Yanqiu Feng,Xiong Cao
Major depressive disorder (MDD) is a devastating mental disorder that affects up to 17% of the population worldwide. Although brain-wide network-level abnormalities in MDD patients via resting-state functional magnetic resonance imaging (rsfMRI) exist, the mechanisms underlying these network changes are unknown, despite their immense potential for depression diagnosis and management. Here, we show that the astrocytic calcium-deficient mice, inositol 1,4,5-trisphosphate-type-2 receptor knockout mice (Itpr2−/− mice), display abnormal rsfMRI functional connectivity (rsFC) in depression-related networks, especially decreased rsFC in medial prefrontal cortex (mPFC)–related pathways. We further uncover rsFC decreases in MDD patients highly consistent with those of Itpr2−/− mice, especially in mPFC-related pathways. Optogenetic activation of mPFC astrocytes partially enhances rsFC in depression-related networks in both Itpr2−/− and wild-type mice. Optogenetic activation of the mPFC neurons or mPFC-striatum pathway rescues disrupted rsFC and depressive-like behaviors in Itpr2−/− mice. Our results identify the previously unknown role of astrocyte dysfunction in driving rsFC abnormalities in depression.
研究领域:
神经科学
·
精神病学
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功能性磁共振成像
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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