scholarly journals Orphan receptor GPR158 controls stress-induced depression

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Laurie P Sutton ◽  
Cesare Orlandi ◽  
Chenghui Song ◽  
Won Chan Oh ◽  
Brian S Muntean ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Orphan Receptor ◽  
Dependent Manner ◽  
Depression And Anxiety ◽  
Major Depressive ◽  
Protein Levels ◽  
Pharmacological Target ◽  
Decisive Action

Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress-responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid-dependent manner. Viral overexpression of GPR158 in the PFC induced depressive-like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant-like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression.

scholarly journals Distinct Amino Acid Availability-Dependent Regulatory Mechanisms of MepS and MepM Levels in Escherichia coli

2021 ◽  
Vol 12 ◽  
Author(s):  
Yung Jae Kim ◽  
Byoung Jun Choi ◽  
Si Hyoung Park ◽  
Han Byeol Lee ◽  
Ji Eun Son ◽  
...  
Keyword(s):  
Amino Acid ◽  
Minimal Medium ◽  
Molecular Mechanisms ◽  
Aromatic Amino Acids ◽  
Normal Growth ◽  
Regulatory Mechanisms ◽  
Dependent Manner ◽  
Bacterial Physiology ◽  
Protein Levels ◽  
Amino Acid Availability

Peptidoglycan (PG) hydrolases play important roles in various aspects of bacterial physiology, including cytokinesis, PG synthesis, quality control of PG, PG recycling, and antibiotic resistance. However, the regulatory mechanisms of their expression are poorly understood. In this study, we have uncovered novel regulatory mechanisms of the protein levels of the synthetically lethal PG endopeptidases MepS and MepM, which are involved in PG synthesis. A mutant defective for both MepS and MepM was lethal in an amino acid-rich medium, whereas it exhibited almost normal growth in a minimal medium, suggesting the expendability of MepS and MepM in a minimal medium. Protein levels of MepS and MepM dramatically decreased in the minimal medium. Although MepM was revealed as a substrate of Prc, a periplasmic protease involved in the proteolysis of MepS, only the decrease in the MepS level in the minimal medium was affected by the prc depletion. Phenotypic and biochemical analyses showed that the presence of aromatic amino acids in the medium induced the accumulation of MepS, but not MepM, while the presence of glutamate increased the level of MepM, but not MepS. Together, these results demonstrate that the protein levels of the two major PG endopeptidases are regulated in an amino acid availability-dependent manner, but their molecular mechanisms and signaling are significantly distinct.

scholarly journals IcarisideII facilitates the differentiation of ADSCs to SCs via let-7i/STAT3 axis to preserve erectile function

2019 ◽  
Vol 52 (1) ◽  
Author(s):  
Pingyu Ge ◽  
Yinxue Guo ◽  
Jun Shen
Keyword(s):  
Cell Proliferation ◽  
Erectile Function ◽  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Regulatory Relationship ◽  
Rat Models ◽  
Protein Levels ◽  
Dose Dependent

Abstract Background IcarisideII (ICAII) could promote the differentiation of adipose tissue-derived stem cells (ADSCs) to Schwann cells (SCs), leading to improvement of erectile function (EF) and providing a realistic therapeutic option for the treatment of erectile dysfunction (ED). However, the underlying molecular mechanisms of ADSCs and ICAII in this process remain largely unclear. Methods ADSCs were treated with different concentrations of ICAII. Cell proliferation was determined by MTT assay. qRT-PCR and western blot were performed to detect expressions of SCs markers, signal transducer and activator of transcription-3 (STAT3), and microRNA-let-7i (let-7i). Luciferase reporter assay was conducted to verify the regulatory relationship between let-7i and STAT3. The detection of intracavernosal pressure (ICP) and the ratio of ICP/mean arterial pressure (MAP) were used to evaluate the EF in bilateral cavernous nerve injury (BCNI) rat models. Results ICAII promoted cell proliferation of ADSCs in a dose-dependent manner. The mRNA and protein levels of SCs markers were increased by ICAII treatment in a dose-dependent manner in ADSCs. Moreover, let-7i was significantly decreased in ICAII-treated ADSCs and upregulation of let-7i attenuated ICAII-induced promotion of SCs markers. In addition, STAT3 was a direct target of let-7i and upregulated in ICAII-treated ADSCs. Interestingly, overexpression of STAT3 abated the let-7i-mediated inhibition effect on differentiation of ADSCs to SCs and rescued the ICAII-mediated promotion effect on it. Besides, combination treatment of ADSCs and ICAII preserved the EF of BCNI rat models, which was undermined by let-7i overexpression. Conclusion ICAII was effective for preserving EF by promoting the differentiation of ADSCs to SCs via modulating let-7i/STAT3 pathway.

scholarly journals Twist Modulates Human Trophoblastic Cell Invasion via Regulation of N-Cadherin

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 925-936 ◽  
Author(s):  
York Hunt Ng ◽  
Hua Zhu ◽  
Peter C. K. Leung
Keyword(s):  
Cell Invasion ◽  
Small Interfering Rna ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Trophoblastic Cell ◽  
Protein Levels ◽  
Bewo Cells ◽  
Interfering Rna ◽  
Tgf Β1

The invasion of extravillous cytotrophoblasts (EVT) into the underlying maternal tissues and vasculature is a key step in human placentation. The molecular mechanisms involved in the development of the invasive phenotype of EVT include many that were first discovered for their role in cancer cell metastasis. Previous studies have demonstrated that N-cadherin and its regulatory transcription factor Twist play important roles in the onset and progression of cancers, but their roles in human trophoblastic cell invasion is not clear. The goal of the study was to examine the role of Twist and N-cadherin in human trophoblastic cell invasion. Twist and N-cadherin mRNA and protein levels were determined by RT-PCR and Western blotting in human placental tissues, highly invasive EVT, and poorly invasive JEG-3 and BeWo cells. Whether IL-1β and TGF-β1 regulate Twist mRNA and protein levels in the EVT was also examined. A small interfering RNA strategy was employed to determine the role of Twist and N-cadherin in HTR-8/SVneo cell invasion. Matrigel assays were used to assess cell invasion. Twist and N-cadherin were highly expressed in EVT but were poorly expressed in JEG-3 and BeWo cells. IL-1β and TGF-β1 differentially regulated Twist expression in EVT in a time- and concentration-dependent manner. Small interfering RNA specific for Twist decreased N-cadherin and reduced invasion of HTR-8/SVneo cells. Similarly, a reduction in N-cadherin decreased the invasive capacity of HTR-8/SVneo cells. Twist is an upstream regulator of N-cadherin-mediated invasion of human trophoblastic cells.

scholarly journals “Insulin-Like” Effects of Palmitate Might Contribute to the Development of Insulin Resistance in Hypothalamic Neurons

2018 ◽  
Author(s):  
Martin Benzler ◽  
Jonas Benzler ◽  
Sigrid Stoehr ◽  
Cindy Hempp ◽  
Mohammed Z. Rizwan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Saturated Fatty Acids ◽  
Dependent Manner ◽  
Omega 3 ◽  
Protein Levels

Saturated fatty acids are implicated in the development of metabolic diseases, including obesity and type 2 diabetes. There is evidence, however, that polyunsaturated fatty acids can counteract the pathogenic effects of saturated fatty acids. To gain insight into the early molecular mechanisms by which fatty acids influence hypothalamic inflammation and insulin resistance, we performed time-course experiments in a hypothalamic cell line, using different durations of treatment with the saturated fatty acid palmitate, and the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). Western blot analysis revealed that palmitate elevated the protein levels of phospho(p)AKT in a time-dependent manner. This effect seems involved in the pathogenicity of palmitate, as temporary inhibition of the PI3K/AKT pathway by selective PI3K inhibitors prevented palmitate-induced insulin resistance. Similarly to palmitate, DHA also increased levels of pAKT, but to a weaker extent. Co-administration of DHA with palmitate decreased pAKT close to the basal level after 8 h, and prevented palmitate-induced insulin resistance after 12 h. Measurement of the inflammatory markers pJNK and pNFκB-p65 revealed tonic elevation of both markers in the presence of palmitate alone. DHA alone transiently induced elevation of pJNK, returning to basal levels by 12 h treatment. Co-administration of DHA with palmitate prevented palmitate-induced inflammation after 12 h, but not at earlier time points.

scholarly journals Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme

2019 ◽  
Vol 117 (1) ◽  
pp. 677-688 ◽  
Author(s):  
Gonzalo S. Tejeda ◽  
Ellanor L. Whiteley ◽  
Tarek Z. Deeb ◽  
Roland W. Bürli ◽  
Stephen J. Moss ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Neurodegenerative Diseases ◽  
Movement Disorders ◽  
Intracellular Trafficking ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Protein Levels ◽  
Recessive Mutations ◽  
Phosphodiesterase 10A

A robust body of evidence supports the concept that phosphodiesterase 10A (PDE10A) activity in the basal ganglia orchestrates the control of coordinated movement in human subjects. Although human mutations in the PDE10A gene manifest in hyperkinetic movement disorders that phenocopy many features of early Huntington’s disease, characterization of the maladapted molecular mechanisms and aberrant signaling processes that underpin these conditions remains scarce. Recessive mutations in the GAF-A domain have been shown to impair PDE10A function due to the loss of striatal PDE10A protein levels, but here we show that this paucity is caused by irregular intracellular trafficking and increased PDE10A degradation in the cytosolic compartment. In contrast to GAF-A mutants, dominant mutations in the GAF-B domain of PDE10A induce PDE10A misfolding, a common pathological phenotype in many neurodegenerative diseases. These data demonstrate that the function of striatal PDE10A is compromised in disorders where disease-associated mutations trigger a reduction in the fidelity of PDE compartmentalization.

Cerebrovascular ETB, 5-HT1B, and AT1 receptor upregulation correlates with reduction in regional CBF after subarachnoid hemorrhage

2007 ◽  
Vol 293 (6) ◽  
pp. H3750-H3758 ◽  
Author(s):  
Saema Ansar ◽  
Petter Vikman ◽  
Marianne Nielsen ◽  
Lars Edvinsson
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Molecular Mechanisms ◽  
Cerebral Arteries ◽  
Temporal Correlation ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Ang Ii ◽  
Contractile Responses ◽  
Protein Levels ◽  
Receptor Mrna

We hypothesize that cerebral ischemia leads to enhanced expression of endothelin (ET), 5-hydroxytryptamine (5-HT), and angiotensin II (ANG II) receptors in the vascular smooth muscle cells. Our aim is to correlate the upregulation of cerebrovascular receptors and the underlying molecular mechanisms with the reduction in regional and global cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH). SAH was induced by injecting 250 μl blood into the prechiasmatic cistern in rats. The cerebral arteries were removed 0, 1, 3, 6, 12, 24, and 48 h after the SAH for functional and molecular studies. The contractile responses to ET-1, 5-carboxamidotryptamine (5-CT), and ANG II were investigated with myograph. The receptor mRNA and protein levels were analyzed by quantitative real-time PCR and immunohistochemistry, respectively. In addition, regional and global CBFs were measured by an autoradiographic method. As a result, SAH resulted in enhanced contractions to ET-1 and 5-CT. ANG II [via ANG II type 1 (AT1) receptors] induced increased contractile responses [in the presence of the ANG II type 2 (AT2) receptor antagonist PD-123319]. In parallel the ETB, 5-HT1B, and AT1 receptor, mRNA and protein levels were elevated by time. The regional and global CBF showed a successive reduction with time after SAH. In conclusion, the results demonstrate for the first time that SAH induces the upregulation of ETB, 5-HT1B, and AT1 receptors in a time-dependent manner both at functional, mRNA, and protein levels. These changes occur in parallel with a successive decrease in CBF. Thus there is a temporal correlation between the changes in receptor expression and CBF reduction, suggesting a linkage.

scholarly journals N6-Methyladenosine Methyltransferase METTL3 Promotes Angiogenesis and Atherosclerosis by Upregulating the JAK2/STAT3 Pathway via m6A Reader IGF2BP1

2021 ◽  
Vol 9 ◽  
Author(s):  
Guo Dong ◽  
Jiangbo Yu ◽  
Gaojun Shan ◽  
Lide Su ◽  
Nannan Yu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Chorioallantoic Membrane ◽  
Tube Formation ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Stat3 Pathway ◽  
Protein Levels ◽  
Chick Chorioallantoic Membrane

Atherosclerosis (AS) is a life-threatening vascular disease. RNA N6-methyladenosine (m6A) modification level is dysregulated in multiple pathophysiologic processes including AS. In this text, the roles and molecular mechanisms of m6A writer METTL3 in AS progression were explored in vitro and in vivo. In the present study, cell proliferative, migratory, and tube formation capacities were assessed through CCK-8, Transwell migration, and tube formation assays, respectively. RNA m6A level was examined through a commercial kit. RNA and protein levels of genes were measured through RT-qPCR and western blot assays, respectively. VEGF secretion level was tested through ELISA assay. JAK2 mRNA stability was detected through actinomycin D assay. The relationship of METTL3, IGF2BP1, and JAK2 was investigated through bioinformatics analysis, MeRIP, RIP, RNA pull-down, and luciferase reporter assays. An AS mouse model was established to examine the effect of METTL3 knockdown on AS development in vivo. The angiogenetic activity was examined through chick chorioallantoic membrane assay in vivo. The results showed that METTL3 was highly expressed in ox-LDL-induced dysregulated HUVECs. METTL3 knockdown inhibited cell proliferation, migration, tube formation, and VEGF expression/secretion in ox-LDL-treated HUVECs, hampered AS process in vivo, and prevented in vivo angiogenesis of developing embryos. METTL3 positively regulated JAK2 expression and JAK2/STAT3 pathway in an m6A dependent manner in HUVECs. IGF2BP1 positively regulated JAK2 expression through directly binding to an m6A site within JAK2 mRNA in HUVECs. METTL3 knockdown weakened the interaction of JAK2 and IGF2BP1. METTL3 exerted its functions through JAK2/STAT3 pathway. In conclusion, METTL3 knockdown prevented AS progression by inhibiting JAK2/STAT3 pathway via IGF2BP1.

Developmental regulation of genes mediating murine brain glucose uptake

1999 ◽  
Vol 276 (3) ◽  
pp. R892-R900 ◽  
Author(s):  
Janine Y. Khan ◽  
Rosario A. Rajakumar ◽  
Robert A. McKnight ◽  
Uday P. Devaskar ◽  
Sherin U. Devaskar
Keyword(s):  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Developmental Regulation ◽  
Cellular Growth ◽  
Neuronal Membrane ◽  
Dependent Manner ◽  
Glut 1 ◽  
Protein Levels ◽  
Age Dependent ◽  
Murine Brain

We examined the molecular mechanisms that mediate the developmental increase in murine whole brain 2-deoxyglucose uptake. Northern and Western blot analyses revealed an age-dependent increase in brain GLUT-1 (endothelial cell and glial) and GLUT-3 (neuronal) membrane-spanning facilitative glucose transporter mRNA and protein concentrations. Nuclear run-on experiments revealed that these developmental changes in GLUT-1 and -3 were regulated posttranscriptionally. In contrast, the mRNA and protein levels of the mitochondrially bound glucose phosphorylating hexokinase I enzyme were unaltered. However, hexokinase I enzyme activity increased in an age-dependent manner suggestive of a posttranslational modification that is necessary for enzymatic activation. Together, the postnatal increase in GLUT-1 and -3 concentrations and hexokinase I enzymatic activity led to a parallel increase in murine brain 2-deoxyglucose uptake. Whereas the molecular mechanisms regulating the increase in the three different gene products may vary, the age-dependent increase of all three constituents appears essential for meeting the increasing demand of the maturing brain to fuel the processes of cellular growth, differentiation, and neurotransmission.

scholarly journals Metformin’s Effects on Apoptosis of Esophageal Carcinoma Cells and Normal Esophageal Epithelial Cells: An In Vitro Comparative Study

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Jianwei Peng ◽  
Xubin Jing ◽  
Jialing Wu ◽  
Danmian Hong ◽  
Xi Hu ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Cell Line ◽  
Molecular Mechanisms ◽  
Carcinoma Cells ◽  
Cell Counting ◽  
Epithelial Cell Line ◽  
Dependent Manner ◽  
Real Time Quantitative Pcr ◽  
Protein Levels

The effect of metformin on human esophageal normal and carcinoma cells remains poorly understood. We aim to investigate the different antiproliferation effects and underlying distinct molecular mechanisms between these two types of cells. Human esophageal squamous cell carcinoma cell line, EC109, and normal esophageal epithelial cell line, HEEC, were used in the experiment. The cell survival rate was determined by cell counting kit-8 (CCK-8). Cell apoptosis was analyzed by flow cytometry. The mRNA and protein levels of signal transducer and activator of transcription 3 (Stat3) were detected by real-time quantitative PCR and western blot. Interleukin-6 (IL-6) was added to activate Stat3. The level of intracellular reactive oxygen species (ROS) was assessed by a DCFH-DA fluorescent probe. Metformin had more significant inhibitory effects on cell proliferation in EC109 cells than HEECs. Metformin induced apoptosis of EC109 cells in a dose-dependent manner instead of HEECs. The expression of Stat3 in both mRNA and protein levels was higher in EC109 cells than HEECs. Further study revealed that metformin may attenuate the phosphorylation of the Stat3 and the Bcl-2 expression, which was restored by IL-6 partly in EC109 cells but not HEECs. On the contrary, metformin increased the level of ROS in both the cell lines, but this intracellular ROS variation had no effect on apoptosis. Metformin has different functional roles on the apoptosis in esophageal carcinoma cells and normal esophageal cells. Therefore, the Stat3/Bcl-2 pathway-mediated apoptosis underlies the cell-type-specific drug sensitivity, suggesting metformin possesses a therapeutic activity and selectivity on esophageal cancer.

Influence of testosterone on regulation of ODC, antizyme, and N1-SSAT gene expression in mouse kidney

2003 ◽  
Vol 285 (3) ◽  
pp. F498-F506 ◽  
Author(s):  
Olivier Levillain ◽  
Anna Greco ◽  
Jean-Jacques Diaz ◽  
Roger Augier ◽  
Anne Didier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Polyamine Biosynthesis ◽  
Testosterone Treatment ◽  
Female Mice ◽  
Protein Levels ◽  
Time Courses

Polyamines are involved in the control of the cell cycle and cell growth. In murine kidney, testosterone enhances gene expression of ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis. In this study, we document the time course effect of testosterone on 1) gene expression of ODC, antizyme 1 (AZ1), and spermidine/spermine- N1-acetyltransferase ( N1-SSAT); 2) ODC activity in proximal convoluted tubules (PCT) and cortical proximal straight tubules (CPST); and 3) renal polyamine levels. Female mice were treated with testosterone for a period of 1, 2, 3, and 5 consecutive days. ODC gene expression was extremely low in kidneys of untreated female mice compared with that of males. Consequently, the renal putrescine level was sevenfold lower in females than in males, whereas spermidine and spermine levels did not differ between sexes. In female kidneys, testosterone treatment sharply increased ODC mRNA and protein levels as well as ODC activity. Testosterone increased the expression of ODC in PCT and CPST over different time courses, which suggests that ODC activity is differentially regulated in distinct tubules. The expression of AZ1 and N1-SSAT mRNA was similar in male and female mouse kidneys. Testosterone treatment enhanced AZ1 and N1-SSAT mRNA levels in a time-dependent manner by unknown molecular mechanisms. Putrescine and spermidine levels increased after testosterone treatment in female kidneys. Surprisingly, although ODC protein and activity were undetectable in female kidneys, the levels of AZ1 mRNA and protein were similar to those in males. Therefore, one may propose that ODC protein could be continuously degraded by AZ1 in female kidneys.

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