Inhibition of ASCT2 induces hepatic stellate cell senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis

Wang, Feixia; Li, Zhanghao; Chen, Li; Yang, Ting; Liang, Baoyu; Zhang, Zili; Xu, Xuefen; Yin, Guoping; Wang, Shijun; Ding, Hai; Zhang, Feng; Zheng, Shizhong

doi:10.1016/j.apsb.2022.03.014

Cited by 24 publications

(11 citation statements)

References 51 publications

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“…First, we confirmed the specificity of cultured chondrocytes using the specific markers Collagen II (Figure 3a). Based on the literature (Wang, Li, et al, 2022) and our preliminary data (Figure S1), 40 μM and 100 μM AT‐III doses were selected for in vitro studies. When passage‐6 chondrocytes were treated with these concentrations, the ratio of SA‐β‐gal‐positive cells and the P16 and P53 concentrations identified by Western blotting were all reduced relative to the control group (Figure 3b,c).…”

Section: Resultsmentioning

confidence: 99%

“…It is also reported to have significant anti‐senescence actions (Han et al, 2017; Zhu et al, 2018). As an active sesquiterpenoid compound of Atractylodes macrocephala , atractylenolide‐III (AT‐III) has been found to treat pulmonary (Chen et al, 2021), renal (Wang et al, 2019), and liver (Wang, Li, et al, 2022) fibrosis effectively; however, its effects on senescence have not been investigated. There is evidence that AT‐III acts via NF‐κB signaling (Gong et al, 2019; Ji et al, 2016), which is known to be a vital modulator of cellular senescence in joint tissue (Chen et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Atractylenolide‐III alleviates osteoarthritis and chondrocyte senescence by targeting NF‐κB signaling

Xu,

Hu,

Cai

et al. 2023

Phytotherapy Research

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Atractylenolide‐III (AT‐III) is well known as its role in antioxidant and anti‐inflammatory. Present study was aimed to figure out its effects on osteoarthritis and potential mechanisms. Rat model, human osteoarthritis cartilage explants as well as rat/human chondrocyte cultures were prepared to test AT‐III's effects on osteoarthritis progression and chondrocyte senescence. Potential targeted molecules of AT‐III were predicted using network pharmacology and molecular docking, assessed by Western blotting and then verified with rescue experiments. AT‐III treatment alleviated osteoarthritis severity (shown by OARSI grading score and micro‐CT) and chondrocyte senescence (indexed by levels of SA‐β‐gal, P16, P53, MMP13, ROS and ratio of healthy/collapsed mitochondrial membrane potentials). Network pharmacology and molecular docking suggested that AT‐III might play role through NF‐κB pathway. Further experiments revealed that AT‐III reduced phosphorylation of IKKα/β, IκBα and P65 in NF‐κB pathway. As well as nuclear translocation of p65. Both in vivo and in vitro experiments indicated that AT‐III's effects on osteoarthritis and anti‐senescence were reversed by an NF‐κB agonist. AT‐III could alleviate osteoarthritis by inhibiting chondrocyte senescence through NF‐κB pathway, which indicated that AT‐III is a prospective drug for osteoarthritis treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Atractylenolide‐III alleviates osteoarthritis and chondrocyte senescence by targeting NF‐κB signaling

Xu,

Hu,

Cai

et al. 2023

Phytotherapy Research

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“…injection with a mixture of carbon tetrachloride (CCl 4 ) and olive oil [1:9 (v/v)] at a dose of 5 mL/kg for 4 weeks (3 times/week). Vitamin A-liposome-LDH-A short hairpin RNA (shRNA) and vitamin A-liposome-LDH-A overexpression plasmids were prepared according to the well-established methods, 15 which have been successfully used in our studies 16 . Vitamin A-liposome-LDH-A shRNA and vitamin A-liposome-LDH-A overexpression plasmids were administrated to mice through tail vein to achieve HSC-specific knockdown or overexpression of LDH-A according to the established methods 17 .…”

Section: Methodsmentioning

confidence: 99%

“…Vitamin A-liposome-LDH-A short hairpin RNA (shRNA) and vitamin A-liposome-LDH-A overexpression plasmids were prepared according to the wellestablished methods, [15] which have been successfully used in our studies. [16] Vitamin A-liposome-LDH-A shRNA and vitamin A-liposome-LDH-A overexpression plasmids were administrated to mice through tail vein to achieve HSC-specific knockdown or overexpression of LDH-A according to the established methods. [17] Briefly, in study 1, 40 mice were randomly divided into 4 groups (n = 10 per cage).…”

Section: Animal Experimentsmentioning

confidence: 99%

Canonical Wnt signaling promotes HSC glycolysis and liver fibrosis through an LDH-A/HIF-1α transcriptional complex

Wang,

Chen,

Kong

et al. 2023

Hepatology

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Background and Aims: Aerobic glycolysis reprogramming occurs during HSC activation, but how it is initiated and sustained remains unknown. We investigated the mechanisms by which canonical Wnt signaling regulated HSC glycolysis and the therapeutic implication for liver fibrosis. Approach and Results: Glycolysis was examined in HSC-LX2 cells upon manipulation of Wnt/β-catenin signaling. Nuclear translocation of lactate dehydrogenase A (LDH-A) and its interaction with hypoxia-inducible factor-1α (HIF-1α) were investigated using molecular simulation and site-directed mutation assays. The pharmacological relevance of molecular discoveries was intensified in primary cultures, rodent models, and human samples. HSC glycolysis was enhanced by Wnt3a but reduced by β-catenin inhibitor or small interfering RNA. Wnt3a-induced rapid transactivation and high expression of LDH-A dependent on TCF4. Wnt/β-catenin signaling also stimulated LDH-A nuclear translocation through importin β2 interplay with a noncanonical nuclear location signal of LDH-A. Mechanically, LDH-A bound to HIF-1α and enhanced its stability by obstructing hydroxylation-mediated proteasome degradation, leading to increased transactivation of glycolytic genes. The Gly28 residue of LDH-A was identified to be responsible for the formation of the LDH-A/HIF-1α transcription complex and stabilization of HIF-1α. Furthermore, LDH-A-mediated glycolysis was required for HSC activation in the presence of Wnt3a. Results in vivo showed that HSC activation and liver fibrosis were alleviated by HSC-specific knockdown of LDH-A in mice. β-catenin inhibitor XAV-939 mitigated HSC activation and liver fibrosis, which were abrogated by HSC-specific LDH-A overexpression in fibrotic mice. Conclusions: Inhibition of HSC glycolysis by targeting Wnt/β-catenin signaling and LDH-A had therapeutic promise for liver fibrosis.

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“…ATL III improved hepatic steatosis and reduced hepatic inflammation, fibrosis, and oxidative stress in mice with high-fat-diet-induced NAFLD, and reduced lipid accumulation and ROS production in free fatty acid-treated HepG2 cells by activating the hepatic AdipoR1-mediated AMPK/SIRT1 signaling pathway [ 89 ]. In addition, ATL III can inhibit the production of ASCT2 in activated hepatic stellate cells aHSC by inhibiting the cGAS/IL-1α/NF-κB pathway so as to enhance the expression of SASP, promote the aging of aHSC, and produce the anti-fibrosis effect, which may be related to the OH group in ATL III [ 90 , 91 ].…”

Section: Pharmacological Effects Of Atractylenolidesmentioning

confidence: 99%

Chemical Constitution, Pharmacological Effects and the Underlying Mechanism of Atractylenolides: A Review

Xie

Lin

et al. 2023

Molecules

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Atractylenolides, comprising atractylenolide I, II, and III, represent the principal bioactive constituents of Atractylodes macrocephala, a traditional Chinese medicine. These compounds exhibit a diverse array of pharmacological properties, including anti-inflammatory, anti-cancer, and organ-protective effects, underscoring their potential for future research and development. Recent investigations have demonstrated that the anti-cancer activity of the three atractylenolides can be attributed to their influence on the JAK2/STAT3 signaling pathway. Additionally, the TLR4/NF-κB, PI3K/Akt, and MAPK signaling pathways primarily mediate the anti-inflammatory effects of these compounds. Atractylenolides can protect multiple organs by modulating oxidative stress, attenuating the inflammatory response, activating anti-apoptotic signaling pathways, and inhibiting cell apoptosis. These protective effects extend to the heart, liver, lung, kidney, stomach, intestine, and nervous system. Consequently, atractylenolides may emerge as clinically relevant multi-organ protective agents in the future. Notably, the pharmacological activities of the three atractylenolides differ. Atractylenolide I and III demonstrate potent anti-inflammatory and organ-protective properties, whereas the effects of atractylenolide II are infrequently reported. This review systematically examines the literature on atractylenolides published in recent years, with a primary emphasis on their pharmacological properties, in order to inform future development and application efforts.

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Inhibition of ASCT2 induces hepatic stellate cell senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis

Cited by 24 publications

References 51 publications

Atractylenolide‐III alleviates osteoarthritis and chondrocyte senescence by targeting NF‐κB signaling

Atractylenolide‐III alleviates osteoarthritis and chondrocyte senescence by targeting NF‐κB signaling

Canonical Wnt signaling promotes HSC glycolysis and liver fibrosis through an LDH-A/HIF-1α transcriptional complex

Chemical Constitution, Pharmacological Effects and the Underlying Mechanism of Atractylenolides: A Review

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