Phospholipid peroxidation-driven modification of chondrogenic transcription factor mediates alkoxyl radicals-induced impairment of embryonic bone development.
Phospholipid peroxidation-driven modification of chondrogenic transcription factor mediates alkoxyl radicals-induced impairment of embryonic bone development.
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磷脂过氧化驱动的软骨形成转录因子修饰介导烷氧基自由基诱导的胚胎骨发育损伤
DOI：
10.1016/j.redox.2022.102437
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发表时间：
2022-10
期刊：
影响因子：
11.4
通讯作者：
He, Rong-Rong
中科院分区：
文献类型：
--
作者：
Niu, Jie;Wan, Xin;Yu, Gui-Yuan;Jiang, Shan;Yi, Ruo-Nan;Wu, Yan-Ping;Ouyang, Shu-Hua;Liang, Lei;Kurihara, Hiroshi;Sun, Wan-Yang;Zhu, Xiao-Feng;Zhang, Rong-Hua;Cao, Yun-Feng;He, Jian-Bo;Duan, Wen-Jun;Li, Yi-Fang;He, Rong-Rong
关键词：
母亲压力与不良的出生结果有关，包括早产、婴儿死亡率和低出生体重。母体应激导致的胚胎骨发育障碍被认为是通过氧化应激损伤介导的。各种自由基，例如烷氧基，可以通过子宫内的内源性氧化还原反应或外源性刺激形成并传递给胚胎。然而，这些自由基是否会导致胎儿骨骼发育异常尚不清楚。在这里，我们证明产前骨生长迟缓和软骨细胞铁死亡相关信号是由经典烷氧基自由基发生器诱导的。我们还表明，烷氧基自由基通过胚胎中铁介导的芬顿反应导致软骨细胞中氧化磷脂的大量积累。我们进一步证明了脂质过氧化终产物 4-HNE 的作用，它与关键的软骨形成转录因子 SOX9 形成加合物，导致其降解，从而抑制软骨形成。我们的数据确定了磷脂过氧化在烷氧基自由基引起的异常软骨形成中的关键作用，并指出它是治疗氧化应激相关骨发育障碍的精确靶点。烷氧基自由基阻碍胚胎骨骼发育。烷氧基自由基诱导的氧化磷脂积累会抑制软骨形成。烷氧基自由基通过铁介导的芬顿反应引发磷脂过氧化。脂质过氧化终产物 4-HNE 与 SOX9 形成加合物，促进其泛素依赖性降解。
Maternal stress has been associated with poor birth outcomes, including preterm birth, infant mortality, and low birth weight. Bone development disorders in the embryo as a result of maternal stress are believed to be mediated through oxidative stress damage. Various species of free radicals, such as alkoxyl radicals, can be formed through endogenous redox response or exogenous stimuli in the womb and transmitted to embryos. Yet, whether these free radicals lead to abnormal fetal bone development is unclear. Here, we demonstrate prenatal bone growth retardation and ferroptosis-related signals of chondrocytes were induced by classic alkoxyl radical generators. We also show that alkoxyl radicals lead to significant accumulation of oxidized phospholipids in chondrocytes, through the iron-mediated Fenton reaction in embryos. We further demonstrate a role for the lipid peroxidation end product, 4-HNE, which forms adducts with the pivotal chondrogenesis transcription factor SOX9, leading to its degradation, therefore dampening chondrogenesis. Our data define a critical role for phospholipid peroxidation in alkoxyl radicals-evoked abnormal chondrogenesis, and pinpoint it being a precise target for treating oxidative stress-related bone development disorders. Alkoxyl radicals retard embryonic skeleton development. Alkoxyl radicals-induced accumulation of oxidized phospholipids dampen chondrogenesis. Alkoxyl radicals trigger phospholipid peroxidation via iron-mediated Fenton reaction. Lipid peroxidation end product, 4-HNE, forms adducts with SOX9 to promote its ubiquitin-dependant degradation.
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影响因子：
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作者：
Jilka RL;Almeida M;Ambrogini E;Han L;Roberson PK;Weinstein RS;Manolagas SC
通讯作者：
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影响因子：
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作者：
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DOI：
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DOI：
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发表时间：
2021-12
期刊：
Acta pharmaceutica Sinica. B
影响因子：
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DOI：
10.1080/14767058.2020.1869934
发表时间：
2020-12-29
影响因子：
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作者：
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通讯作者：
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