Luteolin, a natural flavonoid, inhibits methylglyoxal induced apoptosis via the mTOR/4E-BP1 signaling pathway

Liu, Yi; Huang, Jie; Zheng, Xian; Yang, Xia; Ding, Yan; Fang, Tongyong; Zhang, Yuyun; Wang, Shuaishuai; Zhang, Xiaofei; Luo, Xuan; Guo, Anlei; Newell, Kelly A.; Yu, Yinghua; Huang, Xu‐Feng

doi:10.1038/s41598-017-08204-6

Cited by 29 publications

(12 citation statements)

References 58 publications

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“…mTOR, a highly conserved serine/threonine kinase, is a central regulator of cell death/survival, protein synthesis, and autophagy . In MLO‐Y4 osteocytes, fluid flow and PGE 2 were reported to activate the Akt/mTOR signals and regulate Hif‐1α expression involved in mechanosensory function .…”

Section: Discussionmentioning

confidence: 99%

CSF‐1 in Osteocytes Inhibits Nox4‐mediated Oxidative Stress and Promotes Normal Bone Homeostasis

et al. 2019

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CSF-1 is a key factor in regulating bone remodeling; osteocytes express CSF-1 and its receptor. Viable osteocytes are essential for bone remodeling through cell-cell contact and secretion of factors that regulate osteoblasts and osteoclasts. Increased oxidative stress contributes to osteocyte death and correlates with bone loss during aging. The NADPH oxidase Nox4 is a major source of ROS in bone. CSF-1 decreases Nox4, suggesting that CSF-1 protects against oxidative stress. Here, we show that osteocyte apoptosis previously reported in our global CSF-1KO mice is associated with increased Nox4, as well as 4-HNE expression in osteocytes. Osteocytes isolated from CSF-1KO mice were less viable and showed increased intracellular ROS, elevated NADPH oxidase activity/ Nox4 protein, activation of mTOR/S6K, and downstream apoptosis signals compared with WT osteocytes. Nox4 expression was also increased in CSF-1KO osteocytes and colocalized with MitoTracker Red in mitochondria. Notably, CSF-1 inhibited Nox4 expression and apoptosis cascade signals. In additional studies, shNox4 decreased these signals in CSF-1KO osteocytes, whereas overexpression of Nox4 in WT osteocytes activated the apoptosis pathway. To determine the role of CSF-1 in osteocytes, DMP1Cre-CSF-1cKO (CSF-1cKO) mice that lack CSF-1 in osteocytes/late osteoblasts were developed. Osteocyte defects in CSF-1cKO mice overlapped with those in CSF-1KO mice, including increased apoptosis, Nox4, and 4-HNE-expressing osteocytes. CSF-1cKO mice showed unbalanced cancellous bone remodeling with decreased bone formation and resorption. Continued exposure to high Nox4/ROS levels may further compromise bone formation and predispose to bone loss and skeletal fragility. Taken together, our findings suggest a novel link between CSF-1, Nox4-derived ROS, and osteocyte survival/function that is crucial for osteocyte-mediated bone remodeling. Results reveal new mechanisms by which CSF-1/oxidative stress regulate osteocyte homeostasis, which may lead to therapeutic strategies to improve skeletal health in aging.

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Section: Discussionmentioning

confidence: 99%

CSF‐1 in Osteocytes Inhibits Nox4‐mediated Oxidative Stress and Promotes Normal Bone Homeostasis

et al. 2019

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“…The inflammatory cytokines induce mitochondrial apoptosis, manifested by the release of the cytochrome C, the suppression of the B cell lymphoma 2 (Bcl-2), the activation of caspases [9,10]. It plays a significant role in neuronal apoptosis in neurodegenerative diseases by integrating death signals through Bcl-2/Bax and coordinates caspases through the release of Cytochrome C. Bcl-2 modulates the translocation of the pro-apoptotic protein Bax from the cytosol to the mitochondrial membrane, where it enhances mitochondrial membrane permeability and releases Cyt C, which further promotes pro-caspases activation [11].…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Potential Neuroprotective Effects of Luteolin against Aβ1–42-Induced Alzheimer’s Disease

Ahmad

Ikram

et al. 2021

IJMS

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The current study was undertaken to unveil the protective effects of Luteolin, a natural flavonoid, against amyloid-beta (Aβ1–42)-induced neuroinflammation, amyloidogenesis, and synaptic dysfunction in mice. For the development of an AD mouse model, amyloid-beta (Aβ1–42, 5 µL/5 min/mouse) oligomers were injected intracerebroventricularly (i.c.v.) into mice’s brain by using a stereotaxic frame. After that, the mice were treated with Luteolin for two weeks at a dose of 80 mg/kg/day. To monitor the biochemical changes, we conducted western blotting and immunofluorescence analysis. According to our findings, the infusion of amyloid-beta activated c-Jun N-terminal kinases (p-JNK), p38 mitogen-activated protein kinases, glial fibrillary acidic protein (GFAP), and ionized calcium adaptor molecule 1 (Iba-1) in the cortex and hippocampus of the experimental mice; these changes were significantly inhibited in Aβ1–42 + Luteolin-treated mice. Likewise, we also checked the expression of inflammatory markers, such as p-nuclear factor-kB p65 (p-NF-kB p65 (Ser536), tissue necrosis factor (TNF-α), and Interleukin1-β (IL-1β), in Aβ1–42-injected mice brain, which was attenuated in Aβ1–42 + Luteolin-treated mice brains. Further, we investigated the expression of pro- and anti-apoptotic cell death markers such as Bax, Bcl-2, Caspase-3, and Cox-2, which was significantly reduced in Aβ1–42 + Lut-treated mice brains compared to the brains of the Aβ-injected group. The results also indicated that with the administration of Aβ1–42, the expression levels of β-site amyloid precursor protein cleaving enzyme (BACE-1) and amyloid-beta (Aβ1–42) were significantly enhanced, while they were reduced in Aβ1–42 + Luteolin-treated mice. We also checked the expression of synaptic markers such as PSD-95 and SNAP-25, which was significantly enhanced in Aβ1–42 + Lut-treated mice. To unveil the underlying factors responsible for the protective effects of Luteolin against AD, we used a specific JNK inhibitor, which suggested that Luteolin reduced Aβ-associated neuroinflammation and neurodegeneration via inhibition of JNK. Collectively, our results indicate that Luteolin could serve as a novel therapeutic agent against AD-like pathological changes in mice.

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“…In addition, the other major regulator in hypoxia is mTOR, which promotes HIF-1α protein activation when hyperactivated (42,43). A previous study indicated that luteolin may inhibit the activation of Mtor (44). Therefore, the negative effect of luteolin and HIF-1α may contribute to the hyperactivation of mTOR.…”

Section: Discussionmentioning

confidence: 99%

Luteolin inhibits angiogenesis of the M2‑like TAMs via the downregulation of hypoxia inducible factor‑1α and the STAT3 signalling pathway under hypoxia

Fang

Chen

et al. 2018

Mol Med Report

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The imbalance between angiogenic inducers and inhibitors appears to be a critical factor in tumour pathogenesis. Angiogenesis serves a key role in the occurrence, invasion and metastasis of tumours. Macrophages are a major cellular component of human and rodent tumours, where they are usually termed tumour‑associated macrophages (TAMs). In malignant tumours, TAMs tend to resemble alternatively activated macrophages (M2‑like), promote TA angiogenesis, strengthen tumour migration and invasive abilities, and simultaneously inhibit antitumor immune responses. In our previous study, luteolin, commonly found in a wide variety of plants, had a strong antitumor effect under normoxia; however, it is unknown whether luteolin serves a similar role under hypoxia. In the present study, cobalt chloride (CoCl2) was used to simulate hypoxia. Hypoxia‑inducible factor‑1α (HIF‑1α), which is difficult to detect under normoxic conditions, was significantly increased. Additionally, vascular endothelial growth factor (VEGF) was also significantly increased in response to CoCl2 treatment. Subsequently, luteolin was applied with CoCl2 to examine the effects of luteolin. Luteolin decreased the expression of VEGF and matrix metalloproteinase‑9, which promote angiogenesis. In addition, luteolin also suppressed the activation of HIF‑1 and phosphorylated‑signal transducer and activator of transcription 3 (STAT3) signalling, particularly within the M2‑like TAMs. The results of the present study provide novel evidence that luteolin, under hypoxic conditions, has a strong anticancer effect via the HIF‑1α and STAT3 signalling pathways.

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Luteolin, a natural flavonoid, inhibits methylglyoxal induced apoptosis via the mTOR/4E-BP1 signaling pathway

Cited by 29 publications

References 58 publications

CSF‐1 in Osteocytes Inhibits Nox4‐mediated Oxidative Stress and Promotes Normal Bone Homeostasis

CSF‐1 in Osteocytes Inhibits Nox4‐mediated Oxidative Stress and Promotes Normal Bone Homeostasis

Deciphering the Potential Neuroprotective Effects of Luteolin against Aβ1–42-Induced Alzheimer’s Disease

Luteolin inhibits angiogenesis of the M2‑like TAMs via the downregulation of hypoxia inducible factor‑1α and the STAT3 signalling pathway under hypoxia

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