CTRP9 decreases high glucose‑induced trophoblast cell damage by reducing endoplasmic reticulum stress

Zhang, Lianxiao; Ding, Huiqing; Shi, Yubo; Zhang, Duoyi; Yang, Xue

doi:10.3892/mmr.2022.12701

Cited by 8 publications

(4 citation statements)

References 39 publications

(31 reference statements)

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“…Prior research has supported our observations. For instance, it has been reported that CTRP9, when applied to high glucose‐induced HTR8/SVneo cells, enhances cell viability by mitigating ERS, ultimately ameliorating gestational diabetes mellitus 32 . Additionally, Yoshida et al.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, it has been reported that CTRP9, when applied to high glucose-induced HTR8/SVneo cells, enhances cell viability by mitigating ERS, ultimately ameliorating gestational diabetes mellitus. 32 Additionally, Yoshida et al proposed that TM administration significantly hampers HTR8/Svneo cell invasion, underscoring the potential of ERS to suppress EVT invasion capability and promote hypertensive disorders of pregnancy. 33 These studies further corroborate the significance of our findings.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the endoplasmic reticulum stress‐associated IRE‐1 pathway alleviates preterm birth

Qiu,

Liu,

Chen

et al. 2024

American J Rep Immunol

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BackgroundPremature birth (PTB) remains a major global health concern due to its association with neonatal morbidity and mortality. The unfolded protein response (UPR) within the endoplasmic reticulum (ER) is tightly regulated by Inositol‐requiring enzyme type 1 (IRE‐1), a pivotal cellular modulator. This study seeks to elucidate the role of the ER stress (ERS)‐related IRE‐1 pathway in PTB.MethodsHuman placental trophoblast cells HTR8/Svneo were exposed to the ER‐stress inducer tunicamycin (TM). The expression of IRE‐1 and ERS‐associated proteins ATF6, GRP78, and XBP‐1 was assessed in placental tissues and TM‐treated cells. Cellular viability, migration, invasion, and apoptosis were evaluated through a series of experimental assays. Additionally, various methods were employed to assess and verify the activation of autophagy, using the autophagy marker, microtubule‐associated protein 1A/1B‐light chain 3 (LC3). Additionally, TUDCA (an ERS inhibitor) was used to assess its potential to counteract the TM‐induced cell effects.ResultsElevated levels of ATF6, GRP78, and XBP‐1 were observed in PTB tissues and cells. TM treatment substantially reduced cell viability, migration, and invasion while promoting apoptosis. Treatment with TUDCA (an ERS inhibitor) counteracted the effects of TM on the cells. Furthermore, we identified an overexpression of IRE‐1 in PTB tissues and cells and its knockdown enhanced cell viability, migration, and invasion while suppressed apoptosis and autophagy under TM stimulation. Notably, IRE‐1 was found to modulate the activity of the IRE‐1/XBP1/CHOP signaling pathway in TM‐treated cells.ConclusionThe upregulation of IRE‐1 in PTB placental tissues is implicated in the pathogenesis of PTB. Importantly, inhibiting the ERS‐associated IRE‐1/XBP1/CHOP pathway may be a good strategy in mitigating PTB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of the endoplasmic reticulum stress‐associated IRE‐1 pathway alleviates preterm birth

Qiu,

Liu,

Chen

et al. 2024

American J Rep Immunol

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“…Research has demonstrated that an over‐activated ERS is the primary cause of abnormal trophoblast differentiation and placental development in patients with PE (Capatina et al, 2021). Inhibition of ERS has been shown to reduce trophoblast damage (Zhang et al, 2022). In the present study, we found that hypoxic stimulation decreased trophoblast viability but promoted inflammation.…”

Section: Discussionmentioning

confidence: 99%

Phenylbutyric acid inhibits hypoxia‐induced trophoblast apoptosis and autophagy in preeclampsia via the PERK/ATF‐4/CHOP pathway

Li,

Guo,

et al. 2024

Molecular Reproduction Devel

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Preeclampsia (PE) is a common pregnancy complication with a high mortality rate. Abnormally activated endoplasmic reticulum stress (ERS) is believed to be responsible for the destruction of key placental cells‐trophoblasts. Phenylbutyric acid (4‐PBA), an ERS inhibitor, is involved in regulating the development of ERS‐related diseases. At present, how 4‐PBA affects trophoblasts and its mechanisms is still unclear. In this study, PE cell models were established by stimulating HTR‐8/SVneo cells with hypoxia. To verify the underlying mechanisms of 4‐PBA on PE, CCT020312, an activator of PERK, was also used. The results showed that 4‐PBA restored hypoxia‐induced trophoblast viability, inhibited HIF‐1α protein expression, inflammation, and PERK/ATF‐4/CHOP pathway. Hoechst 33342 staining and flow cytometry results confirmed that 4‐PBA decreased hypoxia‐induced apoptosis in trophoblasts. The results of the JC‐1 analysis and apoptosis initiation enzyme activity assay also demonstrated that 4‐PBA inhibited apoptosis related to the mitochondrial pathway. Furthermore, by detecting autophagy in trophoblasts, an increased number of autophagic vesicles, damaged mitochondria, enhanced dansylcadaverine fluorescence, enhanced levels of autophagy proteins Beclin‐1, LC3II, and decreased p62 were seen in hypoxia‐stimulated cells. These changes were reversed by 4‐PBA. Furthermore, it was observed that CCT020312 reversed the effects of 4‐PBA on the viability, apoptosis, and autophagosome number of hypoxia‐induced trophoblasts. In summary, 4‐PBA reduces autophagy and apoptosis via the PERK/ATF‐4/CHOP pathway and mitochondrial pathway, thereby restoring the viability of hypoxic trophoblasts. These findings provide a solid evidence base for the use of 4‐PBA in PE treatment and guide a new direction for improving the outcomes of patients with PE.

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“…TM is a classical ER stress inducer [12]. HTR-8/SVneo cells were induced with DMSO and 0.078 µg/ml TM, respectively [13][14]. ELISA revealed that the expression level of Aβ 1−42 was enhanced in TM-induced HTR-8/SVneo cells (Fig.…”

Section: Cell Autophagy and Upregulation Of Aβ 1−42 Induced By Er Stressmentioning

confidence: 90%

Aβ1-42 stimulates an increase in autophagic activity through tunicamycin-induced endoplasmic reticulum stress in HTR-8/SVneo cells and pre-eclampsia

Gao,

Cheng,

Cai

et al. 2024

Preprint

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Environmental changes can trigger endoplasmic reticulum (ER) stress and misfolded protein accumulation, potentially leading to Pre-eclampsia (PE). Amyloid-β (Aβ) is a crucial misfolded protein that can overactivate autophagy. Our study assessed the expression of Aβ1−42 and autophagic activity in PE placental tissues and trophoblasts under ER stress. Placental tissues were surgically collected from normal pregnant women (NP) and pregnant women with PE delivering through cesarean section. The expression levels of Aβ1−42 were detected in both PE and NP placental tissues, as well as in tunicamycin (TM)-induced HTR-8/SVneo cells. Autophagy-related proteins, such as Beclin-1, the ratio of LC3-II to LC3-I, ATG5, and SQSTM1/p62 in the placental tissues and HTR-8/SVneo cells were measured by Western blot. The number and morphology of autophagosomes were observed using transmission electron microscopy (TEM). Potential targets associated with the unfolded protein response (UPR) in the placental tissues of NP and PE cases were screened using PCR Arrays. The misfolded protein was significantly upregulated in the PE group. In both Pre-eclampsia (PE) placental tissues and TM-induced HTR-8/SVneo cells, not only was Aβ1–42 upregulated, but also Beclin-1, ATG5, and LC3BII/I were significantly increased, accompanied by an increase in autophagosome count, while SQSTM1/P62 was downregulated. A total of 17 differentially expressed genes (DEGs) associated with the UPR were identified, among which elevated calnexin (CANX) was validated in the placenta from both PE and TM-induced HTR-8/SVneo cells. Autophagy is significantly upregulated in PE cases due to ER stress-induced Aβ1−42 accumulation, likely mediated by autophagy-related proteins involved in the UPR.

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CTRP9 decreases high glucose‑induced trophoblast cell damage by reducing endoplasmic reticulum stress

Cited by 8 publications

References 39 publications

Inhibition of the endoplasmic reticulum stress‐associated IRE‐1 pathway alleviates preterm birth

Inhibition of the endoplasmic reticulum stress‐associated IRE‐1 pathway alleviates preterm birth

Phenylbutyric acid inhibits hypoxia‐induced trophoblast apoptosis and autophagy in preeclampsia via the PERK/ATF‐4/CHOP pathway

Aβ1-42 stimulates an increase in autophagic activity through tunicamycin-induced endoplasmic reticulum stress in HTR-8/SVneo cells and pre-eclampsia

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