Higenamine mitigates interleukin-1β-induced human nucleus pulposus cell apoptosis by ROS-mediated PI3K/Akt signaling

Zhu, Xiaojuan; Liu, Shichao; Cao, Zhijiao; Yang, Lei; Lü, Fang; Li, Yulan; Hu, Lin; Bai, Xiaoliang

doi:10.1007/s11010-021-04197-z

Cited by 16 publications

(15 citation statements)

References 35 publications

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“…Moreover, NAC preconditioning could alleviate FGFC1-induced ROS accumulation and block the upregulation of intrinsic pro-apoptotic proteins induced by FGFC1, suggesting that FGFC1 triggered apoptosis of erlotinib-resistant H1975 NSCLC cells via inducing the mitochondrial dysfunction and ROS accumulation ( Figures 3F–I ). Additionally, given the close relationship between ROS and PI3K/Akt pathway ( Zhang and Yang, 2013 ; Zhang et al, 2017 ; Zhu et al, 2021 ), then we researched the effect of FGFC1 on this pathway. The results showed that FGFC1 decreased the phosphorylation of Akt, whereas NAC indeed alleviated the inhibition of Akt phosphorylation induced by FGFC1 ( Figure 3H ), demonstrating that the PI3K/Akt signaling pathway might be involved in the FGFC1-induced cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway

et al. 2022

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Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been used as a first-line treatment for patients harboring with EGFR mutations in advanced NSCLC. Nevertheless, the drug resistance after continuous and long-term chemotherapies considerably limits its clinical efficacy. Therefore, it is of great importance to develop new chemotherapeutic agents and treatment strategies to conquer the drug resistance. FGFC1 (Fungi fibrinolytic compound 1), a type of bisindole alkaloid from a metabolite of the rare marine fungi Starchbotrys longispora. FG216, has exhibited excellent fibrinolytic and anti-inflammatory activity. However, the potent efficacy of FGFC1 in human cancer therapy requires further study. Herein, we demonstrated that FGFC1 selectively suppressed the growth of NSCLC cells with EGFR mutation. Mechanistically, FGFC1 treatment significantly induced the apoptosis of erlotinib-resistant NSCLC cells H1975 in a dose-dependent manner, which was proved to be mediated by mitochondrial dysfunction and elevated accumulation of intracellular reactive oxygen species (ROS). Scavenging ROS not only alleviated FGFC1-induced apoptosis but also relieved the decrease of phospho-Akt. We further confirmed that FGFC1 significantly decreased the phosphorylation of protein EGFR, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) in H1975 cells. Notably, PI3K inhibitor (LY294002) could promote the accumulation of ROS and the expression levels of apoptosis-related proteins induced by FGFC1. Molecular dynamics simulations indicated that FGFC1 can inhibit EGFR and its downstream PI3K/Akt/mTOR pathway through directly binding to EGFR, which displayed a much higher binding affinity to EGFRT790M/L858R than EGFRWT. Additionally, FGFC1 treatment also inhibited the migration and invasion of H1975 cells. Finally, FGFC1 effectively inhibited tumor growth in the nude mice xenograft model of NSCLC. Taken together, our results indicate that FGFC1 may be a potential candidate for erlotinib-resistant NSCLC therapy.

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Section: Discussionmentioning

confidence: 99%

FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway

et al. 2022

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“…The PI3K/Akt pathway plays a key role in modulating biological processes. The activated PI3K/Akt pathway participates in the processes of cell proliferation, apoptosis, and differentiation through interactions with downstream proteins under physiological and pathological conditions [ 18 – 22 , 52 – 54 ]. Previous studies have found that the PI3K/Akt pathway participates in the proliferation and apoptotic processes of NPMSCs [ 18 – 20 , 24 ], and 1,25(OH) 2 D 3 can modulate biological processes through PI3K/Akt pathway [ 21 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

1,25(OH)2D3 Mitigates Oxidative Stress-Induced Damage to Nucleus Pulposus-Derived Mesenchymal Stem Cells through PI3K/Akt Pathway

Wang

Zhu

Shi

et al. 2022

Oxidative Medicine and Cellular Longevity

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Intervertebral disc degeneration (IVDD) is one of the main causes of low back pain. The local environment of the degenerated intervertebral disc (IVD) increases oxidative stress and apoptosis of endogenous nucleus pulposus-derived mesenchymal stem cells (NPMSCs) and weakens its ability of endogenous repair ability in degenerated IVDs. A suitable concentration of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been certified to reduce oxidative stress and cell apoptosis. The current study investigated the protective effect and potential mechanism of 1,25(OH)2D3 against oxidative stress-induced damage to NPMSCs. The present results showed that 1,25(OH)2D3 showed a significant protective effect on NPMSCs at a concentration of 10-10 M for 24 h. Protective effects of 1,25(OH)2D3 were also exhibited against H2O2-induced NPMSC senescence, mitochondrial dysfunction, and reduced mitochondrial membrane potential. The Annexin V/PI apoptosis detection assay, TUNEL assay, immunofluorescence, western blot, and real-time quantitative polymerase chain reaction assay showed that pretreatment with 1,25(OH)2D3 could alleviate H2O2-induced NPMSC apoptosis, including the apoptosis rate and the expression of proapoptotic-related (Caspase-3 and Bax) and antiapoptotic-related (Bcl-2) proteins. The intracellular expression of p-Akt increased after pretreatment with 1,25(OH)2D3. However, these protective effects of 1,25(OH)2D3 were significantly decreased after the PI3K/Akt pathway was inhibited by the LY294002 treatment. In vivo, X-ray, MRI, and histological analyses showed that 1,25(OH)2D3 treatment relieved the degree of IVDD in Sprague–Dawley rat disc puncture models. In summary, 1,25(OH)2D3 efficiently attenuated oxidative stress-induced NPMSC apoptosis and mitochondrial dysfunction via PI3K/Akt pathway and is a promising candidate treatment for the repair of IVDD.

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“…Recent research demonstrated that NAC could block ROS production and further reversed LC3 II accumulation which triggered by coenzyme Q 0 , and the same mechanism of NAC also occurred in chrysin-induced autophagy [ 50 , 51 ]. We used NAC, an efficient ROS inhibitor [ 52 , 53 ]. Modulation of antioxidant enzymes (SOD, GSH, and MDA) indicated inhibition of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Streptococcus lutetiensis Induces Autophagy via Oxidative Stress in Bovine Mammary Epithelial Cells

Chen

Yang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Streptococcus lutetiensis, an emerging pathogen causing bovine mastitis, has not been well characterized. We reported that S. lutetiensis was pathogenic both in vivo and in vitro and caused inflammatory reactions in the mammary gland. However, roles of autophagy and oxidative stress in the pathogenesis of S. lutetiensis-induced mastitis are unclear. In this study, an autophagy model of S. lutetiensis-infected bovine mammary epithelial cells (bMECs) was used to assess oxidative stress and autophagy flux. Expressions of Beclin1, light chain 3II, and Sequestosome 1/p62 were elevated in bMECs after S. lutetiensis infection. In addition, autophagosome and lysosome formation confirmed autophagy occurred. Based on LysoTracker Red and acridine orange, lysosome degradation was blocked, and lower expressions of lysosomal-associated membrane protein 2, cathepsins D, and cathepsins L confirmed lysosomal damage. Concurrently, the nuclear factor erythroid 2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (Keap1), heme oxygenase 1 (HO1), and NAD (P)H: quinone oxidoreductase 1 (NQO1), and basilic proteins associated with the Nrf2/Keap1 signaling pathway, were detected. Decreased keap1 and increased Nrf2, HO1, NQO1, and reactive oxygen species (ROS) indicated increased oxidative stress. Treatment with N-Acetyl-L-cysteine (NAC), an ROS inhibitor, decreased both oxidative stress and autophagy. Therefore, we concluded that S. lutetiensis caused intracellular oxidative stress and autophagy in bMECs. In addition, crosstalk between autophagy and oxidative stress affected the autophagic flux and blocked downstream autophagy. The Nrf2-keap1-p62 pathway participated in this process, with ROS acting upstream of these effects, interfering with normal cell functions.

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Higenamine mitigates interleukin-1β-induced human nucleus pulposus cell apoptosis by ROS-mediated PI3K/Akt signaling

Cited by 16 publications

References 35 publications

FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway

FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway

1,25(OH)2D3 Mitigates Oxidative Stress-Induced Damage to Nucleus Pulposus-Derived Mesenchymal Stem Cells through PI3K/Akt Pathway

Streptococcus lutetiensis Induces Autophagy via Oxidative Stress in Bovine Mammary Epithelial Cells

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