scholarly journals Alcohol Exposure during the Developmental Period Induces β-Endorphin Neuronal Death and Causes Alteration in the Opioid Control of Stress Axis Function

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2828-2834 ◽  
Author(s):  
Dipak K. Sarkar ◽  
Peter Kuhn ◽  
Jasson Marano ◽  
Cuiping Chen ◽  
Nadka Boyadjieva
Keyword(s):  
Neuronal Death ◽  
Arcuate Nucleus ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Developmental Period ◽  
Stress Axis ◽  
Mrna Levels ◽  
Arcuate Nuclei ◽  
Tgf Β1

Proopiomelanocortin-producing neurons in the arcuate nucleus of the hypothalamus secrete β-endorphin (β-EP), which controls varieties of body functions including the feedback regulation of the CRH neuronal activity in the paraventricular nucleus of the hypothalamus. Whether ethanol exposure in developing rats induces β-EP neuronal death and alters their influence on CRH neurons in vivo has not been determined. We report here that binge-like ethanol exposures in newborn rats increased the number of apoptotic β-EP neurons in the arcuate nucleus of the hypothalamus. We also found that immediately after ethanol treatments there was a significant reduction in the expression of proopiomelanocortin and adenylyl cyclases mRNA and an increased expression of several TGF-β1-linked apoptotic genes in β-EP neurons isolated by laser-captured microdissection from arcuate nuclei of young rats. Several weeks after the ethanol treatment, we detected a reduction in the number of β-EP neuronal perikarya in arcuate nuclei and in the number of β-EP neuronal terminals in paraventricular nuclei of the hypothalamus in the treated rats. Additionally, these rats showed increased response of the hypothalamic CRH mRNA to the lipopolysaccharide challenge. The ethanol-treated animals also showed incompetent ability to respond to exogenous β-EP to alter the lipopolysaccharide-induced CRH mRNA levels. These data suggest that ethanol exposure during the developmental period causes β-EP neuronal death by cellular mechanisms involving the suppression of cyclic AMP production and activation of TGF-β1-linked apoptotic signaling and produces long-term structural and functional deficiency of β-EP neurons in the hypothalamus.

scholarly journals Acetaldehyde accelerates HCV-induced impairment of innate immunity by suppressing methylation reactions in liver cells

2015 ◽  
Vol 309 (7) ◽  
pp. G566-G577 ◽  
Author(s):  
Murali Ganesan ◽  
Jinjin Zhang ◽  
Tatiana Bronich ◽  
Larisa I. Poluektova ◽  
Terrence M. Donohue ◽  
...  
Keyword(s):  
Alcohol Exposure ◽  
Liver Cells ◽  
Ethanol Exposure ◽  
Ethanol Metabolism ◽  
In Vivo Studies ◽  
Temporary Increase ◽  
Hcv Rna ◽  
Induced Apoptosis ◽  
Induced Defects

Alcohol exposure worsens the course and outcomes of hepatitis C virus (HCV) infection. Activation of protective antiviral genes is induced by IFN-α signaling, which is altered in liver cells by either HCV or ethanol exposure. However, the mechanisms of the combined effects of HCV and ethanol metabolism in IFN-α signaling modulation are not well elucidated. Here, we explored a possibility that ethanol metabolism potentiates HCV-mediated dysregulation of IFN-α signaling in liver cells via impairment of methylation reactions. HCV-infected Huh7.5 CYP2E1+ cells and human hepatocytes were exposed to acetaldehyde (Ach)-generating system (AGS) and stimulated with IFN-α to activate IFN-sensitive genes (ISG) via the Jak-STAT-1 pathway. We observed significant suppression of signaling events by Ach. Ach exposure decreased STAT-1 methylation via activation of protein phosphatase 2A and increased the protein inhibitor of activated STAT-1 (PIAS-1)-STAT-1 complex formation in both HCV+ and HCV− cells, preventing ISG activation. Treatment with a promethylating agent, betaine, attenuated all examined Ach-induced defects. Ethanol metabolism-induced changes in ISGs are methylation related and confirmed by in vivo studies on HCV+ transgenic mice. HCV- and Ach-induced impairment of IFN signaling temporarily increased HCV RNA levels followed by apoptosis of heavily infected cells. We concluded that Ach potentiates the suppressive effects of HCV on activation of ISGs attributable to methylation-dependent dysregulation of IFN-α signaling. A temporary increase in HCV RNA sensitizes the liver cells to Ach-induced apoptosis. Betaine reverses the inhibitory effects of Ach on IFN signaling and thus can be used for treatment of HCV+ alcohol-abusing patients.

scholarly journals Endocannabinoid signaling in the lateral habenula regulates pain and alcohol consumption

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rao Fu ◽  
Ying Tang ◽  
Wenfu Li ◽  
Zhiheng Ren ◽  
Ding Li ◽  
...  
Keyword(s):  
Analgesic Effect ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Alcohol Exposure ◽  
Ethanol Vapor ◽  
Ethanol Exposure ◽  
Mrna Levels ◽  
Air Exposure ◽  
Lateral Habenula ◽  
Protein Levels

AbstractHyperalgesia, which often occurs in people suffering from alcohol use disorder, may drive excessive drinking and relapse. Emerging evidence suggests that the lateral habenula (LHb) may play a significant role in this condition. Previous research suggests that endocannabinoid signaling (eCBs) is involved in drug addiction and pain, and that the LHb contains core components of the eCBs machinery. We report here our findings in rats subjected to chronic ethanol vapor exposure. We detected a substantial increase in endocannabinoid-related genes, including Mgll and Daglb mRNA levels, as well as monoacylglycerol lipase (MAGL) protein levels, as well as a decrease in Cnr1 mRNA and type-1 cannabinoid receptor (CB1R) protein levels, in the LHb of ethanol-exposed rats. Also, rats withdrawing from ethanol exposure displayed hypersensitivity to mechanical and thermal nociceptive stimuli. Conversely, intra-LHb injection of the MAGL inhibitor JZL184, the fatty acid amide hydrolase inhibitor URB597, or the CB1R agonist WIN55,212-2 produced an analgesic effect, regardless of ethanol or air exposure history, implying that alcohol exposure does not change eCB pain responses. Intra-LHb infusion of the CB1R inverse agonist rimonabant eliminated the analgesic effect of these chemicals. Rimonabant alone elicited hyperalgesia in the air-, but not ethanol-exposed animals. Moreover, intra-LHb JZL184, URB597, or WIN55,212-2 reduced ethanol consumption in both homecages and operant chambers in rats exposed to ethanol vapor but not air. These findings suggest that LHb eCBs play a pivotal role in nociception and facilitating LHb eCBs may attenuate pain in drinkers.

scholarly journals Therapeutic Targeting of Nrf2 Signaling by Maggot Extracts Ameliorates Inflammation-Associated Intestinal Fibrosis in Chronic DSS-Induced Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Rong Wang ◽  
Daojuan Wang ◽  
Hongwei Wang ◽  
Tingyu Wang ◽  
Yajing Weng ◽  
...  
Keyword(s):  
Pathological Feature ◽  
Mrna Levels ◽  
Protective Effects ◽  
Clinical Markers ◽  
Chronic Colitis ◽  
Intestinal Fibrosis ◽  
Nrf2 Expression ◽  
Tgf Β1

Intestinal fibrosis is induced by excessive myofibroblast proliferation and collagen deposition, which has been regarded as a general pathological feature in inflammatory bowel disease (IBD). Therefore, identifying clinical markers and targets to treat and prevent intestinal fibrosis is urgently needed. The traditional Chinese medicine maggot, commonly known as “wu gu chong”, has been shown to reduce oxidative stress and alleviate inflammation in chronic colitis. This study investigated the mechanisms underlying the effects of maggot extract (ME) on inflammation-associated intestinal fibrosis in TGF-β1-stimulated human intestinal fibroblasts (CCD-18Co cells) and dextran sodium sulphate (DSS)-induced chronic colitis murine model. To assess the severity of inflammation and fibrosis, histological and macroscopic evaluation were carried out. The results showed that ME was a significant inhibitor of body weight loss and colon length shortening in mice with chronic colitis. In addition, ME suppressed the intestinal fibrosis by downregulating TGF-β1/SMADs pathway via upregulation of Nrf2 expression at both protein and mRNA levels. ME markedly increased the expression of Nrf2, thus resulting in a higher level of HO-1. After treatment with Nrf2 inhibitor (ML385) or siRNA-Nrf2 for deactivating Nrf2 pathway, the protective effects of ME were abolished both in vitro and in vivo. Moreover, the histopathological results for the major organs of DSS mice treated with ME showed no signs of clinically important abnormalities. Treatment with ME had no effect on the viability of CCD-18Co cells, suggesting its low in vitro cytotoxicity. Furthermore, ME could mediate intestine health by keeping the balance of the gut microbes through the enhancement of beneficial microbes and suppression of pathogenic microbes. In conclusion, this is the first ever report demonstrating that ME ameliorates inflammation-associated intestinal fibrosis by suppressing TGF-β1/SMAD pathway via upregulation of Nrf2 expression. Our findings highlight the potential of Nrf2 as an effective therapeutic target for alleviating intestinal fibrosis.

scholarly journals Binge Alcohol Exposure in Adolescence Impairs Normal Heart Growth

2020 ◽  
Vol 9 (9) ◽  
Author(s):  
Lizhuo Ai ◽  
Edith Perez ◽  
AnnaDorothea Asimes ◽  
Theerachat Kampaengsri ◽  
Maxime Heroux ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Troponin I ◽  
Systolic Function ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Whole Body ◽  
Cellular Hypertrophy ◽  
Before And After ◽  
Male Wistar Rats

Background Approximately 1 in 6 adolescents report regular binge alcohol consumption, and we hypothesize it affects heart growth during this period. Methods and Results Adolescent, genetically diverse, male Wistar rats were gavaged with water or ethanol once per day for 6 days. In vivo structure and function were assessed before and after exposure. Binge alcohol exposure in adolescence significantly impaired normal cardiac growth but did not affect whole‐body growth during adolescence, therefore this pathology was specific to the heart. Binge rats also exhibited signs of accelerated pathological growth (concentric cellular hypertrophy and thickening of the myocardial wall), suggesting a global reorientation from physiologic to pathologic growth. Binge rats compensated for their smaller filling volumes by increasing systolic function and sympathetic stimulation. Consequently, binge alcohol exposure increased PKA (protein kinase A) phosphorylation of troponin I, inducing myofilament calcium desensitization. Binge alcohol also impaired in vivo relaxation and increased titin‐based cellular stiffness due to titin phosphorylation by PKCα (protein kinase C α). Mechanistically, alcohol inhibited extracellular signal‐related kinase activity, a nodal signaling kinase activating physiology hypertrophy. Thus, binge alcohol exposure depressed genes involved in growth. These cardiac structural alterations from binge alcohol exposure persisted through adolescence even after cessation of ethanol exposure. Conclusions Alcohol negatively impacts function in the adult heart, but the adolescent heart is substantially more sensitive to its effects. This difference is likely because adolescent binge alcohol impedes the normal rapid physiological growth and reorients it towards pathological hypertrophy. Many adolescents regularly binge alcohol, and here we report a novel pathological consequence as well as mechanisms involved.

Alcohol exposure during late ovine gestation alters fetal liver iron homeostasis without apparent dysmorphology

2013 ◽  
Vol 304 (12) ◽  
pp. R1121-R1129 ◽  
Author(s):  
Foula Sozo ◽  
Anna M. Dick ◽  
Jonathan G. Bensley ◽  
Kelly Kenna ◽  
James F. Brien ◽  
...  
Keyword(s):  
Gene Expression ◽  
Iron Homeostasis ◽  
Ferric Iron ◽  
Fetal Liver ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Fetal Life ◽  
Mrna Levels ◽  
Liver Morphology ◽  
Iron Concentrations

High levels of alcohol (ethanol) exposure during fetal life can affect liver development and can increase susceptibility to infection after birth. Our aim was to determine the effects of a moderate level of ethanol exposure in late gestation on the morphology, iron status, and inflammatory status of the ovine fetal liver. Pregnant ewes were chronically catheterized at 91 days of gestation (DG; term ∼145 DG) for daily intravenous infusion of ethanol (0.75 g/kg maternal body wt; n = 8) or saline ( n = 7) over 1 h from 95 to 133 DG. At necropsy (134 DG), fetal livers were collected for analysis. Liver weight, general liver morphology, hepatic cell proliferation and apoptosis, perivascular collagen deposition, and interleukin ( IL) -1β, IL-6, or IL-8 mRNA levels were not different between groups. However, ethanol exposure led to significant decreases in hepatic content of ferric iron and gene expression of the iron-regulating hormone hepcidin and tumor necrosis factor ( TNF) -α (all P < 0.05). In the placenta, there was no difference in transferrin receptor, divalent metal transporter 1, and ferritin mRNA levels; however, ferroportin mRNA levels were increased in ethanol-exposed animals ( P < 0.05), and ferroportin protein tended to be increased ( P = 0.054). Plasma iron concentration was not different between control and ethanol-exposed groups; control fetuses had significantly higher iron concentrations than their mothers, whereas maternal and fetal iron concentrations were similar in ethanol-exposed animals. We conclude that daily ethanol exposure during the third-trimester-equivalent in sheep does not alter fetal liver morphology; however, decreased fetal liver ferric iron content and altered hepcidin and ferroportin gene expression indicate that iron homeostasis is altered.

scholarly journals The oncogenic TBX3 is a downstream target and mediator of the TGF-β1 signaling pathway

2013 ◽  
Vol 24 (22) ◽  
pp. 3569-3576 ◽  
Author(s):  
Jarod Li ◽  
Marc S. Weinberg ◽  
Luiz Zerbini ◽  
Sharon Prince
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Preliminary Evidence ◽  
Transforming Growth Factor Β1 ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
Breast Epithelial ◽  
Tgf Β1

The T-box transcription factor, TBX3, plays an important role in embryonic development, and haploinsufficiency of TBX3 causes ulnar–mammary syndrome. Overexpression of TBX3, on the other hand, is associated with several cancers, and preliminary evidence suggests that increased levels of TBX3 may inhibit cell proliferation but promote tumor migration and invasion. Although this suggests that deregulated levels of TBX3 are deleterious in development and promotes disease, very little is known about the signaling pathways that regulate TBX3 expression. Here we show that overexpressing TBX3 inhibits proliferative ability while promoting the migration of breast epithelial cells. We demonstrate that the transforming growth factor β1 (TGF-β1) pathway up-regulates TBX3 protein and mRNA levels and show a detailed transcriptional mechanism by which this occurs. Using in vitro and in vivo assays, we show that Smad3/4 and JunB bind and cooperatively regulate TBX3 promoter activity through a Smad-binding element at −67 base pairs. Further, we show that TBX3 plays a pivotal role in mediating the antiproliferative and promigratory role of TGF-β1 in breast epithelial and skin keratinocytes. This study identifies the TGF-β1 signaling pathway as a potentially important player in the regulation of TBX3 in development and cancer.

scholarly journals Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Fan Wu ◽  
Yan Zhao ◽  
Qingqing Shao ◽  
Ke Fang ◽  
Ruolan Dong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Renal Fibrosis ◽  
Cell Model ◽  
Smooth Muscle Actin ◽  
Collagen I ◽  
Mrna Levels ◽  
Smad Signaling ◽  
Tgf Β1

Objectives: Natural product, osthole, has been proven to have a protective effect on organ fibrosis, including renal fibrosis. All of these studies are mainly focused on the regulation of TGF-β/Smad signaling pathway. However, due to the pleiotropic roles of TGF-β/Smad signaling, direct TGF-β-targeted treatments are unlikely to be therapeutically feasible in clinic. Recently, the downstream IL-11/ERK1/2 signaling of TGF-β has become an attractive therapeutic target without upstream disadvantages. Based on that, this study was designed to identify the potential effects of osthole on IL-11/ERK1/2 signaling pathway in renal fibrosis.Methods: The renal fibrosis model was established in vivo and in vitro, we investigated the effects of osthole on unilateral ureteral obstruction (UUO)-induced renal fibrosis and TGF-β-induced HK-2 cells. After preliminarily confirming the antifibrogenic effects of osthole and the link between its antifibrogenic effects and the inhibition of IL-11/ERK1/2 signaling, we applied a direct IL-11-induced HK-2 cells fibrosis model to further explore the inhibitory effects of osthole on IL-11/ERK1/2 signaling pathway.Results: Our results confirmed that osthole can decrease the secretion of fibrosis proteins, such as α-smooth muscle actin (α-SMA), collagen I, and fibronectin, ameliorate experimental renal fibrosis in vivo and in vitro, and the effect was associated with suppressing TGF-β1/Smad signaling. More importantly, we found that IL-11/ERK1/2 signaling in UUO-induced renal fibrosis and TGF-β-induced HK-2 cell model was obviously upregulated, and osthole treatment also significantly inhibited the abnormal IL-11/ERK1/2 signaling activation. Given the direct link between TGF-β/Smad signaling and IL-11/ERK1/2 signaling pathway, we have verified that osthole has a direct inhibitory effect on IL-11/ERK1/2 signaling independent of TGF-β signaling by using an IL-11-induced HK-2 cells fibrosis model. Osthole treatment decreased the protein expression of α-SMA, collagen I and fibronectin without changing their mRNA levels in IL-11-induced HK-2 cells. Moreover, it was observed that the IL-11/ERK1/2 inhibitor, U0126, partly blocked the antifibrogenic effects of osthole.Conclusion: In this study, we found that osthole has a previously unrecognized role in inhibiting IL-11/ERK1/2 signaling pathway. Our work demonstrated that the antifibrogenic effect of osthole is not only mediated by TGF-β/Smad2/3 signaling, but also directly mediated by IL-11/ERK1/2 signaling pathway independent of TGF-β1 signaling.

scholarly journals Panax notoginseng Saponin Promotes Bone Regeneration in Distraction Osteogenesis via the TGF-β1 Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Di Liu ◽  
Zhenchen Zhao ◽  
Weidong Jiang ◽  
Peiqi Zhu ◽  
Xiaoning An ◽  
...  
Keyword(s):  
Bone Regeneration ◽  
Osteogenic Differentiation ◽  
Distraction Osteogenesis ◽  
Panax Notoginseng ◽  
Osteogenic Potential ◽  
Mrna Levels ◽  
Alizarin Red ◽  
Smad Pathway ◽  
Tgf Β1

Distraction osteogenesis (DO) is an efficient strategy that is employed for the treatment of large bone defects in craniomaxillofacial surgery. Despite its utility, however, DO is associated with a prolonged consolidation phase and a high complication rate that hinder its more widespread utilization. Panax notoginseng saponin (PNS) is a traditional Chinese medicine that is frequently administered for the treatment of a range of conditions. Herein, we explored the ability of PNS treatment to influence osteogenic differentiation using both rabbit bone marrow mesenchymal cells (BMSCs) and a model of mandibular DO. BMSC proliferation was assessed via CCK-8 assay, while osteogenic differentiation was monitored through ALP and alizarin red S staining. A PCR approach was used to evaluate the expression of genes associated with osteogenesis (ALP, Runx2, and OCN) and genes linked to the TGF pathway (TβR-II, SMAD2, SMAD3, and PPM1A). For in vivo experiments, treated BMSCs were locally injected into the DO gap, with PNS being injected into treated rabbits every other day throughout the experimental period. The quality of the regenerative process was assessed via scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), X-ray imaging, and hematoxylin and eosin (H&E) staining. These analyses revealed that PNS was able to promote BMSC osteogenesis and mandibular generation, driving the upregulation of osteogenesis-related genes at the mRNA levels through the modulation of the TGF-β1/Smad pathway. Consistently, the overexpression or silencing of TβR-II in PNS-treated BMSCs was sufficient to modulate their osteogenic potential. Analyses of in vivo mandibular DO outcomes revealed significantly augmented new bone growth in the PNS-treated group relative to control animals, with maximal osteogenesis in the group overexpressing rabbit TβR-II. Together, these results highlight the PNS as a promising and cost-effective therapeutic tool with the potential to enhance bone regeneration in clinical contexts through the modulation of the TGF-β1/Smad pathway.

scholarly journals Grid1 Regulates the Onset of Puberty in Female Rats

2020 ◽  
Author(s):  
Jing Ye ◽  
Ping Qin ◽  
Hailing Li ◽  
Tiezhu Kang ◽  
Wenyu Si ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Female Rats ◽  
Mrna Levels ◽  
Vaginal Opening ◽  
Ionotropic Receptor ◽  
Delta Type ◽  
Periventricular Nucleus ◽  
Old Rats ◽  
Puberty Onset

Abstract The present study aimed to investigate whether Grid1, encoding the glutamate ionotropic receptor delta type subunit 1(GluD1), influences the onset of puberty in female rats. First, we detected the expression of Grid1 mRNA and its protein in the hypothalamus from infancy to puberty. Second, we evaluated the suppression of Grid1 expression by Lentivirus-Grid1 (LV-Grid1) in primary hypothalamus cells through measuring the expression level of Grid1. Finally, LV-Grid1 was intracerebroventricular injected (ICV) into 21-day-old rats and to investigate the effect of Grid1 suppression on puberty onset in vivo. Results showed that GluD1 immunoreactivity could be detected in the arcuate nucleus (ARC), paraventricular nucleus (PVN), and periventricular nucleus (PeN). Grid1 mRNA levels were the lowest at prepuberty. Treatment of hypothalamic neurons with LV-Grid1 decreased the mRNA expression levels of Grid1 and Rfrp-3 (encoding RFamide-related peptide 3, RFRP 3), but increased that of Gnrh (encoding gonadotropin-releasing hormone, GnRH). After 7 days of ICV LV-Grid1 into rats, the Grid1 mRNA was significantly reduced (by 46%), Gnrh mRNA expression was significantly increased, but Rfrp-3 mRNA levels were decreased. The time of rat vaginal opening (VO) was earlier in the LV-Grid1 group; the concentrations of luteinizing hormone (LH), estradiol (E2), and progesterone (P4) in serum were significantly increased; and the ovaries were significantly larger. Our study revealed that Grid1 affects the onset of puberty by regulating the level of GnRH and RFRP3.

In vivo effects of TGF-β1 in lung surfactant regulation, lung meachanics amd structure

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
E Lopez-Rodriguez ◽  
C Boden ◽  
S Knippenberg ◽  
A Pascual ◽  
J Perez-Gil ◽  
...  
Keyword(s):  
Lung Surfactant ◽  
In Vivo Effects ◽  
Tgf Β1
Sign in / Sign up

Export Citation Format

Share Document