Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts

Nakashima, Akitoshi; Cheng, Shi-Bin; Kusabiraki, Tae; Motomura, Kenichiro; Aoki, Aiko; Ushijima, Akemi; Ono, Yuichi; Tsuda, S.; Saito, Tomoko; Yokosuka, Osamu; Sago, Haruhiko; Matsumoto, Kenji; Sharma, Surendra; Saito, Shigeru

doi:10.1038/s41598-019-47607-5

Cited by 79 publications

(73 citation statements)

References 49 publications

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“…miR-129-5p may directly regulate ATG7 and reduce white adipogenic differentiation. Endoplasmic reticulum (ER) stress inhibits autophagic flux by blocking autophagosome-lysosome fusion in trophoblast cells [28]. ER-phagy helps to ameliorate the effect of ER stress through the degradation of ER membranes [29].…”

Section: Discussionmentioning

confidence: 99%

miR-129-5p Inhibits Adipogenesis through Autophagy and May Be a Potential Biomarker for Obesity

Jin

Han

et al. 2019

International Journal of Endocrinology

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Introduction Obesity has an unclear pathogenesis. MicroRNAs (miRNAs) may function as biologically active molecules for obesity through regulating adipocyte differentiation. This study aimed to identify how miR-129-5p (a specific miRNA) regulates adipogenesis in vitro and explore its possible role in the pathogenesis of obesity in humans. Materials and Methods The miR-129-5p expression was detected in obese mouse models. The effect of miR-129-5p on adipocyte differentiation was observed, and the adipose markers were analyzed. Bioinformatics and dual-luciferase reporter assay were applied to predict and confirm the target genes of miR-129-5p. The human serum samples were detected and analyzed. Results miR-129-5p is highly expressed in adipose tissues of db/db mice. Gain- and loss-of-function studies show that miR-129-5p could significantly inhibit adipocyte differentiation and white adipocyte browning in vitro and decreases the level of specific markers, such as FABP4, UCP1, and PPARγ, in mature white and brown adipocytes. miR-129-5p directly targets ATG7 which is predicted with bioinformatics and confirmed by dual-luciferase reporter assay. Serum miR-129-5p level was evidently elevated in patients with simple obesity (p < 0.01) and correlates with obesity indices, including BMI (r = 0.407, p < 0.029) and fat percentage (r = 0.394, p < 0.038). Conclusion miR-129-5p might target on the ATG7-related autophagy signaling network that regulates white and brown adipogenesis. Importantly, the aforementioned results suggest serum miR-129-5p might be a potential biomarker and therapeutic target for obesity.

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Section: Discussionmentioning

confidence: 99%

miR-129-5p Inhibits Adipogenesis through Autophagy and May Be a Potential Biomarker for Obesity

Jin

Han

et al. 2019

International Journal of Endocrinology

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“…54 Furthermore, autophagy inhibition using chemical inhibitors enhances ER stress in trophoblasts. 54 Thus, impairment of autophagy would exaggerate ER stress in trophoblasts, or vice versa. Lysosomal-associated membrane protein 1 and betagalactosidase (a hydrolase in lysosomes), which are associated with the reduction of lysosomes by ER stress in trophoblasts, and which are secreted into the cultured medium, also show a significant decrease in the sera of women suffering from preeclampsia, when compared with those of normal pregnant women.…”

Section: Er Stress Autophagy Inhibition and Serum Markersmentioning

confidence: 99%

Placental autophagy failure: A risk factor for preeclampsia

Nakashima

Saito

Aoki

et al. 2020

J of Obstet and Gynaecol

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Hypertensive disorders of pregnancy, including preeclampsia, directly affect maternal and perinatal morbidity and mortality. As the pathophysiology of preeclampsia is multi-factorial and has been studied using different approaches, we have demonstrated that impaired autophagy is an intertwined risk factor for preeclampsia. This concept has been verified in both in vitro and in vivo experiments. Autophagy is primarily involved in maintaining cellular homeostasis, and in immune regulation, longevity, cytokines secretion and a variety of other biological functions. Here, we review the role of autophagy in normal embryogenesis and placentation. Once placental autophagy is impaired by metabolic stress such as hypoxia, endoplasmic reticulum stress or starvation, placental development could be disrupted, resulting in functional maladaptations at the maternal-fetal interface. These malfunctions may result in fetal growth restriction or preeclampsia.

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“…LAMP1 is involved in lysosome biogenesis and autophagy [49]. Endoplasmic reticulum stress (ERS) inhibits lysosomal exocytosis and the secretion of lysosomal-associated membrane protein 1 (LAMP1) [50]. ERS is activated under stress in the hippocampus [51].…”

Section: Discussionmentioning

confidence: 99%

Hippocampal and Cerebellar Changes in Acute Restraint Stress and the Impact of Pretreatment with Ceftriaxone

et al. 2020

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Acute restraint stress (ARS) is an unavoidable stress situation and may be encountered in different clinical situations. The aim of the current study was to investigate the effects of ARS on the hippocampus and cerebellum, assess the impact of these effects on the behavior and cognitive function, and determine whether pretreatment with ceftriaxone would attenuate the damages produced by ARS on the hippocampus and cerebellum. Four groups of male mice were included in this study: The control group, ARS group, ceftriaxone group, and ARS + ceftriaxone group. Tail suspension test, Y-maze task, and open field tests were used to assess depression, working spatial memory, and anxiety. The biochemical analyses included measurements of serum cortisol, tumor necrotic factor (TNF), interleukin-6, hippocampal expression of bone morphogenetic protein 9 (BMP9), lysosomal-associated membrane protein 1 (LAMP1), glutamate transporter 1 (GLT1), heat shock protein 90, cerebellar expression of S100 protein, glutamic acid decarboxylase (GAD), and carbon anhydrase. Histopathological examination of the brain sections was conducted on the hippocampus and cerebellum by hematoxylin and eosin stains in addition to ultrastructure evaluation using electron microscopy. Our results suggested that ceftriaxone had neuroprotective properties by attenuating the effects of ARS on the hippocampus and cerebellum in mice. This effect was demonstrated by the improvement in the cognitive and behavioral tests as well as by the preservation of the hippocampal and cerebellar architecture.

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Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts

Cited by 79 publications

References 49 publications

miR-129-5p Inhibits Adipogenesis through Autophagy and May Be a Potential Biomarker for Obesity

miR-129-5p Inhibits Adipogenesis through Autophagy and May Be a Potential Biomarker for Obesity

Placental autophagy failure: A risk factor for preeclampsia

Hippocampal and Cerebellar Changes in Acute Restraint Stress and the Impact of Pretreatment with Ceftriaxone

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