Endogenous leptin promotes autophagy in EBSS-induced PFCs

Jiao, Deling; Yang, Zhaohui; Wang, Lulu; Hu, Binyue; Wang, Jing; Xu, Anyong; Cheng, Wood-Hi; Jia, Baoyu; Qing, Yubo; Zhao, Hongyan; Wei, Hong‐Jiang

doi:10.1080/19768354.2019.1651766

Cited by 6 publications

(5 citation statements)

References 34 publications

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“…Moreover, the LC3 II/LC3 I ratios were unaffected up to 4 h after cells were treated with RSL3 and erastin (Figures 1D and S1C ). Immunofluorescence (IF) revealed that autophagosomes were induced in HepG2 cells incubated with EBSS, which triggers autophagy, 27 and such effects were blocked by Wort, an autophagy inhibitor (Figure S1D,E ). However, no significant enhancement of autophagosome formation was observed in parallel with the increase of RB1CC1 in HepG2 cells treated with RSL3 and erastin (Figure S1D,E ).…”

Section: Resultsmentioning

confidence: 99%

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

Xue

Zhang

et al. 2022

Clinical & Translational Med

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Background Ferroptosis, a form of regulated cell death, is an important topic in the field of cancer research. However, the signalling pathways and factors that sensitise tumour cells to ferroptosis remain elusive. Methods We determined the level of ferroptosis in cells by measuring cell death and lipid reactive oxygen species (ROS) production. The expression of RB1‐inducible coiled‐coil 1 (RB1CC1) and related proteins was analyzed by immunoblotting and immunohistochemistry. Immunofluorescence was used to determine the subcellular localization of RB1CC1. We investigated the mechanism of RB1CC1 nuclear translocation by constructing a series of RB1CC1 variants. To examine the ferroptosis‐ and RB1CC1‐dependent transcriptional program in tumour cells, chromatin immunoprecipitation sequencing was performed. To assess the effect of c‐Jun N‐terminal kinase (JNK) agonists on strenthening imidazole ketone erastin (IKE) therapy, we constructed cell‐derived xenograft mouse models. Mouse models of hepatocellular carcinoma to elucidate the importance of Rb1cc1 in IKE‐based therapy of liver tumourigenesis. Results RB1CC1 is upregulated by lipid ROS and that nuclear translocation of phosphorylation of RB1CC1 at Ser537 was essential for sensitising ferroptosis in tumour cells. Upon ferroptosis induction, nuclear RB1CC1 sharing forkhead box (FOX)‐binding motifs recruits elongator acetyltransferase complex subunit 3 (ELP3) to strengthen H4K12Ac histone modifications within enhancers linked to ferroptosis. This also stimulated transcription of ferroptosis‐associated genes, such as coiled‐coil–helix–coiled‐coil–helix domain containing 3 (CHCHD3), which enhanced mitochondrial function to elevate mitochondrial ROS early following induction of ferroptosis. FDA‐approved JNK activators reinforced RB1CC1 nuclear translocation and sensitised cells to ferroptosis, which strongly suggested that JNK is upstream of RB1CC1. Nuclear localisation of RB1CC1 correlated with lipid peroxidation in clinical lung cancer specimens. Rb1cc1 was essential for ferroptosis agonists to suppress liver tumourigenesis in mice. Conclusions Our findings indicate that RB1CC1‐associated signalling sensitises tumour cells to ferroptosis and that targeting RB1CC1 may be beneficial for tumour treatment.

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Section: Resultsmentioning

confidence: 99%

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

Xue

Zhang

et al. 2022

Clinical & Translational Med

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“…Studies reported that hypoxia could lead to placenta leptin gene expression and production [48], and abnormal placenta leptin level was associated with aberrant trophoblast proliferation or invasion, as well as endothelial dysfunction, hypertension and fetal growth restriction [49,50], which may lead to PE. The interacting relations between leptin and autophagy varies in a tissue-specific pattern [51]. Although, the evidence in placenta is scarce, it was reported that autophagy was active in the placenta of PE women and leptin could modulate autophagy in various tissue types [52][53][54][55].…”

Section: Discussionmentioning

confidence: 99%

Autophagy-related biomarkers in preeclampsia: the underlying mechanism, correlation to the immune microenvironment and drug screening

Wan,

Yao,

Wang

et al. 2024

BMC Pregnancy Childbirth

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Background Preeclampsia is a life-threatening disease of pregnancy that lacks effective pharmaceuticals which can target its pathogenesis. Since preeclampsia involves complex pathological processes, including autophagy, this study aims to explore autophagy-related mechanisms of preeclampsia and to screen potential drugs. Methods Firstly, the datasets GSE75010, GSE24129, GSE66273, and autophagic genes lists were downloaded from public databases. Then, a weighted gene co-expression network analysis (WGCNA) was applied to filter autophagic-related hub genes of preeclampsia. The differential expression levels of the hub genes were validated with datasets GSE24129 and GSE66273. Next, the GO and KEGG enrichment, protein-protein interacting (PPI) network, as well as the downstream pathways was analyzed via the starBase, STRING and Cytoscape to determine the functions and regulatory network of the hub genes. Additionally, the immune microenvironment of preeclampsia was investigated by the CIBERSORTX database. Finally, three herb ingredients, berberine, baicalein, and luteolin were screened by molecular docking in comparison to pravastatin, metformin, and aspirin, to predict potential drugs for treating preeclampsia. Results A total of 54 autophagy-related genes were filtered by WGCNA. After filtering with |GS| > 0.5 and |MM| > 0.8, three hub genes, namely PKM, LEP, and HK2, were identified and validated. Among these genes, PKM and LEP were overexpressed in women older than 35 years old ( p<0.05; p<0.05); the expression of PKM, LEP, and HK2 differed remarkably in women with different BMI (all p<0.05); PKM overexpressed in women with hypertension (p<0.05). The regulatory network of hub genes demonstrated that they were mainly enriched in metabolic pathways, including the AMPK signaling pathway, glucagon signaling pathway, adipocytokine signaling pathway, and central carbon metabolism. Then, immune microenvironment analysis turned out that M2 macrophages were reduced in preeclampsia women (p<0.0001) and were negatively correlated with the expression of PKM (r=-0.2, p<0.05), LEP (r=-0.4, p<0.0001), and HK2 (r=-0.3, p<0.001). Lastly, molecular docking showed baicalein and luteolin could bind intimately to hub genes. Conclusion PKM, LEP, and HK2 could be promising biomarkers for preeclampsia, which might regulate the pathogenesis of preeclampsia via metabolism pathways and immune microenvironment. Baicalein and luteolin could be potential therapeutics for preeclampsia.

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“…Rapamycin-and starvation-induced autophagy are two different processes with common mechanisms [39][40][41]. Therefore, we used both autophagy induction methods to demonstrate the regulatory role of TGF-β1 under different autophagic conditions.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 inhibits autophagy and collagen degradation in rat bronchial fibroblasts

Zhang,

Yu,

Zhang

et al. 2024

Preprint

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Chronic obstructive pulmonary disease (COPD) is a major global health concern with an increasing prevalence. Notably, autophagy plays a crucial role in the pathophysiology of airway remodeling. However, further research is required to determine the precise mechanism of autophagy in rat bronchial fibroblasts (RBFs). In this study, we investigated the role of transforming growth factor-β1 (TGF-β1) on RBF-related collagen degradation following autophagy. We established rapamycin- and starvation-induced autophagy models of RBFs and then analyzed the expression of autophagy-related proteins (LC3-II, Beclin-1, and P62) in RBFs treated with TGF-β1. We also measured the levels of matrix metalloproteinase-1 (MMP-1) and its inhibitor, matrix metalloproteinase inhibitor-1 (TIMP-1) in the RBF supernatant using an enzyme-linked immunosorbent assay. Our results showed that TGF-β1 promoted RBF growth in a concentration-dependent manner, while rapamycin lowered RBF survival rates. TGF-β1 downregulated LC3-II and Beclin-1 expression but increased P62 expression levels after rapamycin and starvation-induced autophagy in RBFs. Adding TGF-β1 elevated TIMP-1 protein levels and reduced MMP-1 protein levels. The present study showed for the first time that TGF-β1 reduces airway remodeling in RBFs by inhibiting autophagy and collagen degradation, suggesting the potential therapeutic value of TGF-β1 for the prevention and treatment of COPD.

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Endogenous leptin promotes autophagy in EBSS-induced PFCs

Cited by 6 publications

References 34 publications

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

Autophagy-related biomarkers in preeclampsia: the underlying mechanism, correlation to the immune microenvironment and drug screening

TGF-β1 inhibits autophagy and collagen degradation in rat bronchial fibroblasts

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