scholarly journals Administration of simvastatin halts progression of cirrhosis via up-regulating expression of miR-34a and interleukin-10 in rats

2021 ◽  
Author(s):  
Hui Yang ◽  
Xiaorong Zhou ◽  
Yonghua Wang ◽  
Yan Cheng ◽  
Zhao [email protected] ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Computational Analysis ◽  
Mrna Level ◽  
Underlying Mechanism ◽  
Interleukin 10 ◽  
Luciferase Assay ◽  
Protein Levels ◽  
Treatment Dose ◽  
Active Caspase ◽  
Complementary Binding

IntroductionSimvastatin (SIM) treatment has been found to be able to reduce the expression of miR-34a, and we found that interleukin-10 (IL-10) is a potential target gene of miR-34a by searching the online microRNA (miRNA) database. Furthermore, it has been shown that IL10 up-regulation could halt the progression of cirrhosis. The objective of this study was to explore the underlying mechanism of Simvastatin/miR-34a/IL-10 involved in HBV associated cirrhosis.Material and methodsReal-time PCR, western-blot analysis, immunohistochemistry, computational analysis, luciferase assay was carried out to explore the underlying mechanism of miR-34a involved in HBV associated cirrhosis.ResultsSIM treatment dose-dependently decreased the levels of miR-34a while increasing the levels of IL-10 mRNA and protein. Levels of IL-10 mRNA and protein were remarkably decreased, while miR-34a mRNA level and active caspase-3 protein level was apparently increased in Cirrhosis group compared with sham group. Accordingly, SIM treatment obstructed the dysregulated miR-34a expression and IL-10 expression in cirrhosis animals. By performing computational analysis, we identified that a complementary binding site of miR-34a was located in IL-10 3’ untranslated region (3’UTR), and miR-34a reduced luciferase activity of wild-type IL-10 3’UTR.ConclusionsOur data also suggested that SIM may become a new therapeutic strategy for HBV-associated cirrhosis via targeting the miR-34a/IL-10 axis.

scholarly journals Knockdown of Long Non-Coding RNA GAS5 Increases miR-23a by Targeting ATG3 Involved in Autophagy and Cell Viability

2018 ◽  
Vol 48 (4) ◽  
pp. 1723-1734 ◽  
Author(s):  
Lexing Li ◽  
Chunxiao Huang ◽  
Yulong He ◽  
Zhan Sang ◽  
Guoquan Liu ◽  
...  
Keyword(s):  
Complex Formation ◽  
Cell Viability ◽  
Mrna Level ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Protein Levels ◽  
Repressive Effect ◽  
Competing Endogenous Rnas ◽  
Reporter Assays ◽  
Direct Binding

Background/Aims: Autophagy is a process of evolutionarily conservative degradation, which could maintain cellular homeostasis and cope with various types of stress. LncRNAs are considered as competing endogenous RNAs (ceRNAs) contributing to autophagy. GAS5 has been suggested as a new potential factor to mediate autophagy pathway and the underlying mechanism remains to be further confirmed. This study was taken to identify the effect of GAS5/miR-23a/ATG3 axis on autophagy and cell viability. Methods: The western blotting assay was used to detecte the protein levels of LC3, mTOR, Beclin-1, ATG3, ATG5-ATG12 complex and p62. The mRNA level of Pre-miR-23a, Pri-miR-23a, miR-23a, GAS5, LC3, mTOR and ATG3 were quantified by real-time RT-PCR. Dual-luciferase reporter assays were performed to confirm the direct binding of miR-23a and ATG3 or GAS5. Cell viability was evaluated by CCK-8 and flow cytometry. Results: We showed that miR-23a could directly suppress ATG3 expression in 293T cells, which suggested that ATG3 was identified as a target of miR-23a. MiR-23a mimics could restrain LC3 II, Beclin1 levles and ATG5-ATG12 complex formation. Meanwhile, miR-23a also increased the expression of mTOR and p62. Notably, there was a putative miR-23a-binding site in GAS5. MiR-23a overexpression might suppress the GAS5 expression, but the repressive effect was abolished by mutation of binding sites. Importantly, overexpression of GAS5 could inhibit the mature miR-23a and has no effect on miR-23a precursors. Knockdown of GAS5 suppressed the expression of LC3 II, ATG3 and ATG5-ATG12 complex formation, whereas p62 and mTOR levels were promoted. The further results showed that miR-23a overexpression and GAS5 inhibition both significantly suppressed cell viability and promoted the apoptosis rate following LPS stimulation, and knockdown of miR-23a exhibited the opposite effects. Conclusions: Our study revealed that down-regulation GAS5 attenuated cell viability and inhibited autophagy through ATG3-dependent autophagy by regulating miR-23a expression. The results suggested that GAS5/miR-23a/ATG3 axis might be a novel regulatory network contributing to a better understanding of regulation on autophagy program and cell viability.

scholarly journals MiR-122 Targets SerpinB3 and Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma

2019 ◽  
Vol 8 (2) ◽  
pp. 171 ◽  
Author(s):  
Cristian Turato ◽  
Francesca Fornari ◽  
Daniela Pollutri ◽  
Matteo Fassan ◽  
Santina Quarta ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Strategy ◽  
Luciferase Assay ◽  
Cell Phenotype ◽  
Stem Cell Markers ◽  
Advanced Hepatocellular Carcinoma ◽  
Protein Levels ◽  
Low Levels ◽  
Patients Experience ◽  
The Relationship

The only first-line treatment approved for advanced hepatocellular carcinoma (HCC) is sorafenib. Since many patients experience drug resistance, the discovery of more effective therapeutic strategies represents an unmet clinical need. MicroRNA (MiR)-122 is downregulated in most HCCs, while oncogenic SerpinB3 is upregulated. Here, we assessed the relationship between miR-122 and SerpinB3 and their influence on cell phenotype and sorafenib resistance in HCC. A bioinformatics analysis identified SerpinB3 among hypothetical miR-122 targets. In SerpinB3-overexpressing HepG2 cells, miR-122 transfection decreased SerpinB3 mRNA and protein levels, whereas miR-122 inhibition increased SerpinB3 expression. Luciferase assay demonstrated the interaction between miR-122 and SerpinB3 mRNA. In an HCC rat model, high miR-122 levels were associated with negative SerpinB3 expression, while low miR-122 levels correlated with SerpinB3 positivity. A negative correlation between miR-122 and SerpinB3 or stem cell markers was found in HCC patients. Anti-miR-122 transfection increased cell viability in sorafenib-treated Huh-7 cells, while miR-122 overexpression increased sorafenib sensitivity in treated cells, but not in those overexpressing SerpinB3. In conclusion, we demonstrated that miR-122 targets SerpinB3, and its low levels are associated with SerpinB3 positivity and a stem-like phenotype in HCC. MiR-122 replacement therapy in combination with sorafenib deserves attention as a possible therapeutic strategy in SerpinB3-negative HCCs.

scholarly journals MiR-599 Protects Cardiomyocytes against Oxidative Stress-Induced Pyroptosis

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Xiaoying Fan ◽  
Enbo Zhan ◽  
Yuan Yao ◽  
Ruoxi Zhang ◽  
Yong Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Cardiac Injury ◽  
Luciferase Assay ◽  
Inflammatory Factors ◽  
Protein Levels ◽  
Promising Therapeutic Approach ◽  
Oxidative Condition ◽  
Complementary Binding

Oxidative stress is a crucial factor and key promoter of a variety of cardiovascular diseases associated with cardiomyocyte injury. Emerging literatures suggest that pyroptosis plays a key role in cardiac damages. However, whether pyroptosis contributes to cardiomyocyte injury under oxidative stress and the underlying molecular mechanisms are totally unclear. This study was designed to investigate the potential role of pyroptosis in H2O2-induced cardiomyocyte injury and to elucidate the potential mechanisms. Primary cardiomyocytes from neonatal Wistar rats were utilized. These myocytes were treated with different concentrations of H2O2 (25, 50, and 100 μM) for 24 h to induce oxidative injury. Our results indicated that mRNA and protein levels of ASC were remarkably upregulated and caspase-1 was activated. Moreover, the expressions of inflammatory factors IL-1β and IL-18 were also increased. Luciferase assay showed that miR-599 inhibited ASC expression through complementary binding with its 3 ′ UTR. MiR-599 expression was substantially reduced in H2O2-treated cardiomyocytes. Upregulation of miR-599 inhibited cardiomyocyte pyroptosis under oxidative stress, and opposite results were found by decreasing the expression of miR-599. Consistently, miR-599 overexpression ameliorated cardiomyocyte injury caused by H2O2. Therefore, miR-599 could be a promising therapeutic approach for the management of cardiac injury under oxidative condition.

Identification of N-Substituted Triazolo-azetidines as Novel Antibacterials using pDualrep2 HTS Platform

2019 ◽  
Vol 22 (5) ◽  
pp. 346-354
Author(s):  
Yan A. Ivanenkov ◽  
Renat S. Yamidanov ◽  
Ilya A. Osterman ◽  
Petr V. Sergiev ◽  
Vladimir A. Aladinskiy ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Large Scale ◽  
Underlying Mechanism ◽  
Luciferase Assay ◽  
Reporter System ◽  
E Coli ◽  
Starting Point ◽  
High Concentrations ◽  
Mic Value

Aim and Objective: Antibiotic resistance is a serious constraint to the development of new effective antibacterials. Therefore, the discovery of the new antibacterials remains one of the main challenges in modern medicinal chemistry. This study was undertaken to identify novel molecules with antibacterial activity. Materials and Methods: Using our unique double-reporter system, in-house large-scale HTS campaign was conducted for the identification of antibacterial potency of small-molecule compounds. The construction allows us to visually assess the underlying mechanism of action. After the initial HTS and rescreen procedure, luciferase assay, C14-test, determination of MIC value and PrestoBlue test were carried out. Results: HTS rounds and rescreen campaign have revealed the antibacterial activity of a series of Nsubstituted triazolo-azetidines and their isosteric derivatives that has not been reported previously. Primary hit-molecule demonstrated a MIC value of 12.5 µg/mL against E. coli Δ tolC with signs of translation blockage and no SOS-response. Translation inhibition (26%, luciferase assay) was achieved at high concentrations up to 160 µg/mL, while no activity was found using C14-test. The compound did not demonstrate cytotoxicity in the PrestoBlue assay against a panel of eukaryotic cells. Within a series of direct structural analogues bearing the same or bioisosteric scaffold, compound 2 was found to have an improved antibacterial potency (MIC=6.25 µg/mL) close to Erythromycin (MIC=2.5-5 µg/mL) against the same strain. In contrast to the parent hit, this compound was more active and selective, and provided a robust IP position. Conclusion: N-substituted triazolo-azetidine scaffold may be used as a versatile starting point for the development of novel active and selective antibacterial compounds.

The Natural Flavonoid Naringenin Inhibits the Cell Growth of WilmsTumorinChildren by Suppressing TLR4/NF-κB Signaling

2020 ◽  
Vol 20 ◽  
Author(s):  
Hongtao Li ◽  
Peng Chen ◽  
Lei Chen ◽  
Xinning Wang
Keyword(s):  
Cell Growth ◽  
Western Blot ◽  
Wilms Tumor ◽  
Critical Role ◽  
Time Dependent ◽  
Luciferase Assay ◽  
Dependent Manner ◽  
Tlr4 Expression ◽  
Protein Levels

Background: Nuclear factor kappa B (NF-κB) is usually activated in Wilms tumor (WT) cells and plays a critical role in WT development. Objective: The study purpose was to screen a NF-κB inhibitor from natural product library and explore its effects on WT development. Methods: Luciferase assay was employed to assess the effects of natural chemical son NF-κB activity. CCK-8 assay was conducted to assess cell growth in response to naringenin. WT xenograft model was established to analyze the effect of naringenin in vivo. Quantitative real-time PCR and Western blot were performed to examine the mRNA and protein levels of relative genes, respectively. Results: Naringenin displayed significant inhibitory effect on NF-κB activation in SK-NEP-1 cells. In SK-NEP-1 and G-401 cells, naringenin inhibited p65 phosphorylation. Moreover, naringenin suppressed TNF-α-induced p65 phosphorylation in WT cells. Naringenin inhibited TLR4 expression at both mRNA and protein levels in WT cells. CCK-8 staining showed that naringenin inhibited cell growth of the two above WT cells in dose-and time-dependent manner, whereas Toll-like receptor 4 (TLR4) over expression partially reversed the above phenomena. Besides, naringenin suppressed WT tumor growth in dose-and time-dependent manner in vivo. Western blot found that naringenin inhibited TLR4 expression and p65 phosphorylation in WT xenograft tumors. Conclusion: Naringenin inhibits WT development viasuppressing TLR4/NF-κB signaling

HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages Through the SIK/CRTC3 Pathway

2021 ◽  
Author(s):  
Yong Fu ◽  
Gailing Ma ◽  
Yuqian Zhang ◽  
Wenli Wang ◽  
Tongguo Shi ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Experimental Colitis ◽  
Underlying Mechanism ◽  
Interleukin 10 ◽  
Camp Response Element Binding ◽  
Cellular Level ◽  
Trinitrobenzene Sulfonic Acid ◽  
Murine Colitis ◽  
Anti Inflammatory

Abstract Background Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that plays a pivotal role in maintaining mucosal immune homeostasis. As a novel synthetic inhibitor of salt-inducible kinases (SIKs), HG-9-91-01 can effectively enhance IL-10 secretion at the cellular level, but its in vivo immunoregulatory effects remain unclear. In this study, we investigated the effects and underlying mechanism of HG-9-91-01 in murine colitis models. Methods The anti-inflammatory effects of HG-9-91-01 were evaluated on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-, dextran sulfate sodium–induced colitis mice, and IL-10 knockout chronic colitis mice. The in vivo effector cell of HG-9-91-01 was identified by fluorescence-activated cell sorting and quantitative real-time polymerase chain reaction. The underlying mechanism of HG-9-91-01 was investigated via overexpressing SIKs in ANA-1 macrophages and TNBS colitis mice. Results Treatment with HG-9-91-01 showed favorable anticolitis effects in both TNBS- and DSS-treated mice through significantly promoting IL-10 expression in colonic macrophages but failed to protect against IL-10 KO murine colitis. Further study indicated that HG-9-91-01 markedly enhanced the nuclear level of cAMP response element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3), whereas treatment with lentiviruses encoding SIK protein markedly decreased the nuclear CRTC3 level in HG-9-91-01–treated ANA-1 macrophages. In addition, intracolonic administration with lentiviruses encoding SIK protein significantly decreased the nuclear CRTC3 level in the lamina propria mononuclear cells and ended the anti-inflammatory activities of HG-9-91-01. Conclusions We found that HG-9-91-01 promoted the IL-10 expression of colonic macrophages and exhibited its anticolitis activity through the SIK/CRTC3 axis, and thus it may represent a promising strategy for inflammatory bowel disease therapy.

Contribution of Growth Arrest-Specific 5/miR-674 to the Hypothalamus Pituitary Adrenal Axis Regulation Effect by Electroacupuncture following Trauma

2021 ◽  
pp. 1-13
Author(s):  
Jing Zhu ◽  
Chunxia Guo ◽  
Pingping Lu ◽  
Shuijin Shao ◽  
Bing Tu
Keyword(s):  
Hpa Axis ◽  
Interleukin 1 ◽  
Growth Arrest ◽  
Luciferase Assay ◽  
Function Evaluation ◽  
Protein Levels ◽  
Adrenal Axis ◽  
Post Surgery ◽  
Hypothalamus Pituitary Adrenal Axis ◽  
Pituitary Adrenal Axis

<b><i>Background:</i></b> Electroacupuncture (EA) can improve trauma-induced hypothalamus pituitary adrenal axis (HPA) hyperactivity. However, the mechanism underlying the EA effect has not been fully understood. <b><i>Methods and Study Design:</i></b> This study was undertaken to explore the role of hypothalamic growth arrest-specific 5 (Gas5) in the regulation of EA on HPA axis function post-surgery. Paraventricular nuclear Gas5 levels were upregulated in rats using an intracerebroventricular injection of pAAV-Gas5. Primary hypothalamic neurons and 293T cells were cultured for miRNA and siRNAs detection. Radioimmunoassay, PCR, Western blot, and immunohistochemistry were used for HPA axis function evaluation. <b><i>Results:</i></b> The overexpression of Gas5 abolished the effect of EA on the regulation of trauma-induced HPA axis hyperactivity. Using a bioinformatics analysis and dual luciferase assay, we determined that miRNA-674 was a target of Gas5. Additionally, miRNA-674 levels were found to have decreased in trauma rats, and this effect was reversed after EA intervention. TargetScan analysis showed that serum and glucocorticoid inducible kinase 1 (SGK1) were targets of miR-674. Moreover, we found that SGK1 protein levels increased in trauma rats and SGK1 expression inhibition alleviated HPA axis abnormality post-surgery. EA could improve the number of hypothalamus iba-1 positive cells and hypothalamic interleukin 1 beta protein expression. <b><i>Conclusions:</i></b> Our study demonstrated the involvement of the hypothalamic Gas5/miRNA-674/SGK1 signaling pathway in EA regulation of HPA axis function after trauma.

scholarly journals Maternal obesity during pregnancy leads to adipose tissue ER stress in mice via miR-126-mediated reduction in Lunapark

Diabetologia ◽  
2021 ◽  
Author(s):  
Juliana de Almeida-Faria ◽  
Daniella E. Duque-Guimarães ◽  
Thomas P. Ong ◽  
Lucas C. Pantaleão ◽  
Asha A. Carpenter ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Er Stress ◽  
Maternal Obesity ◽  
Luciferase Assay ◽  
Whole Body ◽  
Mrna Levels ◽  
Protein Levels ◽  
Novel Targets

Abstract Aims/hypothesis Levels of the microRNA (miRNA) miR-126-3p are programmed cell-autonomously in visceral adipose tissue of adult offspring born to obese female C57BL/6J mice. The spectrum of miR-126-3p targets and thus the consequences of its dysregulation for adipocyte metabolism are unknown. Therefore, the aim of the current study was to identify novel targets of miR-126-3p in vitro and then establish the outcomes of their dysregulation on adipocyte metabolism in vivo using a well-established maternal obesity mouse model. Methods miR-126-3p overexpression in 3T3-L1 pre-adipocytes followed by pulsed stable isotope labelling by amino acids in culture (pSILAC) was performed to identify novel targets of the miRNA. Well-established bioinformatics algorithms and luciferase assays were then employed to confirm those that were direct targets of miR-126-3p. Selected knockdown experiments were performed in vitro to define the consequences of target dysregulation. Quantitative real-time PCR, immunoblotting, histology, euglycaemic–hyperinsulinaemic clamps and glucose tolerance tests were performed to determine the phenotypic and functional outcomes of maternal programmed miR-126-3p levels in offspring adipose tissue. Results The proteomic approach confirmed the identity of known targets of miR-126-3p (including IRS-1) and identified Lunapark, an endoplasmic reticulum (ER) protein, as a novel one. We confirmed by luciferase assay that Lunapark was a direct target of miR-126-3p. Overexpression of miR-126-3p in vitro led to a reduction in Lunapark protein levels and increased Perk (also known as Eif2ak3) mRNA levels and small interference-RNA mediated knockdown of Lunapark led to increased Xbp1, spliced Xbp1, Chop (also known as Ddit3) and Perk mRNA levels and an ER stress transcriptional response in 3T3-L1 pre-adipocytes. Consistent with the results found in vitro, increased miR-126-3p expression in adipose tissue from adult mouse offspring born to obese dams was accompanied by decreased Lunapark and IRS-1 protein levels and increased markers of ER stress. At the whole-body level the animals displayed glucose intolerance. Conclusions/interpretation Concurrently targeting IRS-1 and Lunapark, a nutritionally programmed increase in miR-126-3p causes adipose tissue insulin resistance and an ER stress response, both of which may contribute to impaired glucose tolerance. These findings provide a novel mechanism by which obesity during pregnancy leads to increased risk of type 2 diabetes in the offspring and therefore identify miR-126-3p as a potential therapeutic target. Graphical abstract

scholarly journals Anti–Na+/K+-ATPase immunotherapy ameliorates α-synuclein pathology through activation of Na+/K+-ATPase α1–dependent autophagy

2021 ◽  
Vol 7 (5) ◽  
pp. eabc5062
Author(s):  
Lei Cao ◽  
Siping Xiong ◽  
Zhiyuan Wu ◽  
Lei Ding ◽  
Yebo Zhou ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tyrosine Hydroxylase ◽  
Neurodegenerative Diseases ◽  
Motor Function ◽  
Therapeutic Strategy ◽  
Underlying Mechanism ◽  
Behavioral Tests ◽  
Behavioral Deficits ◽  
Cellular Homeostasis ◽  
Beneficial Effects

Na+/K+-ATPase (NKA) plays important roles in maintaining cellular homeostasis. Conversely, reduced NKA activity has been reported in aging and neurodegenerative diseases. However, little is known about the function of NKA in the pathogenesis of Parkinson’s disease (PD). Here, we report that reduction of NKA activity in NKAα1+/− mice aggravates α-synuclein–induced pathology, including a reduction in tyrosine hydroxylase (TH) and deficits in behavioral tests for memory, learning, and motor function. To reverse this effect, we generated an NKA-stabilizing monoclonal antibody, DR5-12D, against the DR region (897DVEDSYGQQWTYEQR911) of the NKAα1 subunit. We demonstrate that DR5-12D can ameliorate α-synuclein–induced TH loss and behavioral deficits by accelerating α-synuclein degradation in neurons. The underlying mechanism for the beneficial effects of DR5-12D involves activation of NKAα1-dependent autophagy via increased AMPK/mTOR/ULK1 pathway signaling. Cumulatively, this work demonstrates that NKA activity is neuroprotective and that pharmacological activation of this pathway represents a new therapeutic strategy for PD.

scholarly journals Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus

2017 ◽  
Vol 59 (1) ◽  
pp. 81-92 ◽  
Author(s):  
Long The Nguyen ◽  
Sonia Saad ◽  
Yi Tan ◽  
Carol Pollock ◽  
Hui Chen
Keyword(s):  
Endoplasmic Reticulum ◽  
Body Weight ◽  
Er Stress ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Mrna Level ◽  
Metabolic Stress ◽  
High Fat ◽  
Chemical Chaperone ◽  
Protein Levels

Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect. In this study, we show that offspring born to high-fat diet-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning. Hypothalamic mRNA level of the orexigenic neuropeptide Y (NPY) was increased, while the levels of the anorexigenic pro-opiomelanocortin (POMC), NPY1 receptor (NPY1R) and melanocortin-4 receptor (MC4R) were significantly downregulated. In association, the expression of unfolded protein response (UPR) markers including glucose-regulated protein (GRP)94 and endoplasmic reticulum DNA J domain-containing protein (Erdj)4 was reduced. By contrast, protein levels of autophagy-related genes Atg5 and Atg7, as well as mitophagy marker Parkin, were slightly increased. The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased activating transcription factor (ATF)4, immunoglobulin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity.

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