Fetal e-cigarette exposure programs a neonatal brain hypoxic-ischemic sensitive phenotype via altering DNA methylation patterns and autophagy signaling pathway

Author(s):  
Andrew Walayat ◽  
Yong Li ◽  
Yanyan Zhang ◽  
Yingjie Fu ◽  
Bailin Liu ◽  
...  

Maternal e-cigarette (e-cig) exposure is a pressing perinatal health concern. Emerging evidence reveals its potential adverse impacts on brain development in offspring, yet the underlying mechanisms are poorly understood. The present study tested the hypothesis that fetal e-cig exposure induces an aberrant DNA methylation profiles in the developing brain, leading to alteration of autophagic flux signaling and programming of a sensitive phenotype to neonatal hypoxic-ischemic encephalopathy (HIE). Pregnant rats were exposed to chronic intermittent e-cig aerosol. Neonates were examined at the age of 9-days-old. Maternal e-cig exposure decreased the body weight and brain weight but enhanced the brain-to-body weight ratio in the neonates. E-cig exposure induced a gender-dependent increase in hypoxic-ischemia-induced brain injury in male neonates associated with enhanced ROS activity. It differentially altered DNA methyltransferase expression and enhanced both global DNA methylation levels and specific CpG methylation at the autophagy-related gene 5 (ATG5) promoter. In addition, maternal e-cig exposure caused down-regulations of ATG5, microtubule associated protein 1 light chain 3 beta and sirtuin 1 expression in neonatal brains. Of importance, knockdown of ATG5 in neonatal pups exaggerated neonatal HIE. In conclusion, the present study reveals that maternal e-cig exposure downregulates autophagy-related gene expression via DNA hypermethylation, leading to programming of a hypoxic-ischemic sensitive phenotype in the neonatal brain.

2021 ◽  
Vol 11 ◽  
Author(s):  
Qianqian Tang ◽  
Mengjiang Lu ◽  
Bin Xu ◽  
Yaling Wang ◽  
Shengfeng Lu ◽  
...  

BackgroundPrevious studies had suggested that electroacupuncture (EA) can promote white adipose tissue (WAT) browning to counter obesity. But the mechanism was still not very clear.AimIn this study, we aim to study the effect of EA on promoting inguinal WAT (iWAT) browning and its possible mechanism.MethodThree-week-old rats were randomly divided into a normal diet (ND) group and a high-fat diet (HFD) group. After 10 weeks, the HFD rats were grouped into HFD + EA group and HFD control group. Rats in the EA group were electro-acupunctured for 4 weeks on Tianshu (ST25) acupoint under gas anesthesia with isoflurane, while the rats in HFD group were under gas anesthesia only. Body weight and cumulative food intake were monitored, and H&E staining was performed to assess adipocyte area. The effect of EA on WAT was assessed by qPCR, immunoblotting, immunoprecipitation and Co-immunoprecipitation. Mitochondria were isolated from IWAT to observe the expression of mitochondrial transcription factor A (TFAM).ResultsThe body weight, WAT/body weight ratio and cumulative food consumption obviously decreased (P < 0.05) in the EA group. The expressions of brown adipose tissue (BAT) markers were increased in the iWAT of EA rats. Nevertheless, the mRNA expressions of WAT genes were suppressed by 4-week EA treatment. Moreover, EA increased the protein expressions of SIRT-1, PPARγ, PGC-1α, UCP1 and PRDM16 which trigger the molecular conversion of iWAT browning. The decrease of PPARγ acetylation was also found in EA group, indicating EA could advance WAT-browning through SIRT-1 dependent PPARγ deacetylation pathway. Besides, we found that EA could activate AMPK to further regulate PGC-1α-TFAM-UCP1 pathway to induce mitochondrial biogenesis.ConclusionIn conclusion, EA can remodel WAT to BAT through inducing SIRT-1 dependent PPARγ deacetylation, and regulating PGC-1α-TFAM-UCP1 pathway to induce mitochondrial biogenesis. This may be one of the mechanisms by which EA affects weight loss.


Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 41
Author(s):  
Nouf Aljobaily ◽  
Michael J. Viereckl ◽  
David S. Hydock ◽  
Hend Aljobaily ◽  
Tsung-Yen Wu ◽  
...  

Background: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Methods: Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. Results: The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.


2016 ◽  
Vol 36 (9) ◽  
pp. 901-909 ◽  
Author(s):  
D Sheela ◽  
R Vijayaraghavan ◽  
S Senthilkumar

Buprenorphine drug cartridge was made for autoinjector device for use in emergency and critical situations to reduce the morbidity and mortality. Water-filled cartridges were prepared and buprenorphine was injected aseptically in the cartridge, to make 0.05 and 0.10 mg/mL. Rats were injected intraperitoneally, buprenorphine (0.3 and 0.6 mg/kg), repeatedly with the autoinjector and compared with manual injection (7 days and 14 days) using various haematological and biochemical parameters. No significant change was observed in the body weight, organ to body weight ratio and haematological variables in any of the experimental groups compared with the control group. Except serum urea and aspartate aminotransferase, no significant change was observed in glucose, cholesterol, triglycerides, bilirubin, protein, albumin, creatinine, uric acid, alanine aminotransferase, gamma glutamyltransferase and alkaline phosphatase. The autoinjectors deliver the drugs with spray effect and force for faster absorption. In the present study, the autoinjector meant for intramuscular injection was injected intraperitoneally in rats, and the drug was delivered with force on the vital organs. No significant difference was observed in the autoinjector group compared to the manual group showing tolerability and safety of the buphrenorphine autoinjector. This study shows that buprenorphine autoinjector can be considered for further research work.


2014 ◽  
Vol 66 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Maria Luisa Mansego ◽  
Fermin Ignacio Milagro ◽  
Maria Angeles Zulet ◽  
José Alfredo Martinez

The objective of this study was to examine whether 7 SNPs previously associated with obesity-related traits that add or remove potential sites of DNA methylation are accompanied by differential DNA methylation and subsequently affect adiposity variables or body weight reduction in WBC from obese subjects under an energy-restricted program. Material and Methods: Anthropometric measurements were assessed in 47 volunteers recruited within the RESMENA study (Spain). At baseline, DNA from white blood cells was isolated and 7 obesity-related trait CpG-SNPs were genotyped by TaqMan-PCR. Then, methylation levels of CpG-SNP sites were quantified by MassArray® EpiTyper™ or MS-HRM approaches. Results: Differential DNA methylation levels were observed by genotypes in all of the CpG-SNPs analyzed. The FTO and BDNF methylation levels were further correlated with baseline body weight and, BDNF mRNA levels and body weight change, respectively. Moreover, the rs7359397 (SH2B1) was associated with the body weight, body mass index, and truncal fat mass reduction. Conclusions: Our results reveal the interaction of epigenetic and genetic variations in CpG-SNPs, especially in BDNF and SH2B1 genes, and how allele-specific methylation may contribute to elucidate the possible molecular mechanisms as these SNPs are affecting the decrease of mRNA levels and contributing to a lower body weight reduction. © 2014 S. Karger AG, Basel


2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Soheb Anwar Mohammed ◽  
Bugga Paramesha ◽  
Yashwant Kumar ◽  
Ubaid Tariq ◽  
Sudheer Kumar Arava ◽  
...  

Allylmethylsulfide (AMS) is a novel sulfur metabolite found in the garlic-fed serum of humans and animals. In the present study, we have observed that AMS is safe on chronic administration and has a potential antihypertrophic effect. Chronic administration of AMS for 30 days did not cause any significant differences in the body weight, electrocardiogram, food intake, serum biochemical parameters, and histopathology of vital organs. Single-dose pharmacokinetics of AMS suggests that AMS is rapidly metabolized into Allylmethylsulfoxide (AMSO) and Allylmethylsulfone (AMSO2). To evaluate the efficacy of AMS, cardiac hypertrophy was induced by subcutaneous implantation of ALZET® osmotic minipump containing isoproterenol (~5 mg/kg/day), cotreated with AMS (25 and 50 mg/kg/day) and enalapril (10 mg/kg/day) for 2 weeks. AMS and enalapril significantly reduced cardiac hypertrophy as studied by the heart weight to body weight ratio and mRNA expression of fetal genes (ANP and β-MHC). We have observed that TBARS, a parameter of lipid peroxidation, was reduced and the antioxidant enzymes (glutathione, catalase, and superoxide dismutase) were improved in the AMS and enalapril-cotreated hypertrophic hearts. The extracellular matrix (ECM) components such as matrix metalloproteinases (MMP2 and MMP9) were significantly upregulated in the diseased hearts; however, with the AMS and enalapril, it was preserved. Similarly, caspases 3, 7, and 9 were upregulated in hypertrophic hearts, and with the AMS and enalapril treatment, they were reduced. Further to corroborate this finding with in vitro data, we have checked the nuclear expression of caspase 3/7 in the H9c2 cells treated with isoproterenol and observed that AMS cotreatment reduced it significantly. Histopathological investigation of myocardium suggests AMS and enalapril treatment reduced fibrosis in hypertrophied hearts. Based on our experimental results, we conclude that AMS, an active metabolite of garlic, could reduce isoproterenol-induced cardiac hypertrophy by reducing oxidative stress, apoptosis, and stabilizing ECM components.


2015 ◽  
Vol 308 (7) ◽  
pp. L672-L682 ◽  
Author(s):  
Martine Makanga ◽  
Hidekazu Maruyama ◽  
Celine Dewachter ◽  
Agnès Mendes Da Costa ◽  
Emeline Hupkens ◽  
...  

Congenital diaphragmatic hernia (CDH) has a high mortality rate mainly due to lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). Simvastatin has been shown to prevent the development of pulmonary hypertension (PH) in experimental models of PH. We, therefore, hypothesized that antenatal simvastatin would attenuate PPHN in nitrofen-induced CDH in rats. The efficacy of antenatal simvastatin was compared with antenatal sildenafil, which has already been shown to improve pathological features of PPHN in nitrofen-induced CDH. On embryonic day (E) 9.5, nitrofen or vehicle was administered to pregnant Sprague-Dawley rats. On E11, nitrofen-treated rats were randomly assigned to antenatal simvastatin (20 mg·kg−1·day−1 orally), antenatal sildenafil (100 mg·kg−1·day−1 orally), or placebo administration from E11 to E21. On E21, fetuses were delivered by cesarean section, killed, and checked for left-sided CDH. Lung tissue was then harvested for further pathobiological evaluation. In nitrofen-induced CDH, simvastatin failed to reduce the incidence of nitrofen-induced CDH in the offspring and to increase the body weight, but improved the lung-to-body weight ratio and lung parenchyma structure. Antenatal simvastatin restored the pulmonary vessel density and external diameter, and reduced the pulmonary arteriolar remodeling compared with nitrofen-induced CDH. This was associated with decreased lung expression of endothelin precursor, endothelin type A and B receptors, endothelial and inducible nitric oxide synthase, together with restored lung activation of apoptotic processes mainly in the epithelium. Antenatal simvastatin presented similar effects as antenatal therapy with sildenafil on nitrofen-induced CDH. Antenatal simvastatin improves pathological features of lung hypoplasia and PPHN in experimental nitrofen-induced CDH.


2009 ◽  
Vol 28 (12) ◽  
pp. 765-775 ◽  
Author(s):  
OM Aboyade ◽  
MT Yakubu ◽  
DS Grierson ◽  
AJ Afolayan

The toxicological effect of the aqueous extract of fresh, dried and boiled berries of Solanum aculeastrum Dunal at 1, 10 and 25 mg/kg body weight was investigated in male Wistar rats for 28 days. The parameters used were the body weight of the animals and absolute weights of the organs, haematological parameters, renal and liver functional endpoints. The animals gained appreciable weight and showed no signs of clinical toxicity. The dried (DB), boiled dried (BDB), fresh (FB) and boiled fresh berry (BFB) extracts reduced (p < .05) the heart-, liver-and spleen-body weight ratio of the animals whereas that of the lung was not altered. The kidney and testes-body weight ratios were specifically altered by the different extract. All these were not accompanied by any histomorphological changes. The extracts did not alter (p > .05) the levels of RBC, Hb, PCV and albumin of the animals. The platelets were decreased by the DB and FB whereas BFB increased this parameter. The FB and BFB at all the doses also reduced the mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC) of the animals. With the exception of the FB where the creatinine and chloride levels decreased, other extracts did not alter the level of these kidney parameters. Only FB increased the levels of uric acid and urea. All the extract decreased the serum alanine aminotransferase (ALT) of the animal. The levels of total protein, globulin, total and conjugated bilirubin were not altered by DB and BDB whereas these indices were increased by FB and BFB. The DB and BDB increased the serum alkaline phosphatase (ALP) activity whereas FB decreased the activity of the enzyme. In contrast, DB and BDB decreased the serum aspartate aminotransferase (AST) activity of the animals whereas FB and BFB increased the activity of the enzyme. The FB and BFB also increased the levels of potassium, magnesium and phosphorus of the animals. Overall, the alterations in the biochemical parameters by the various extracts of S. aculeastrum berries at these doses indicated that the normal functioning of these organs may be adversely affected. However, drying and boiling might reduce the toxic effect of the berries.


2019 ◽  
Vol 69 (4) ◽  
pp. 63-70
Author(s):  
Piotr Siermontowski ◽  
Wojciech Kozłowski ◽  
Katarzyna Pleskacz

AbstractThe prerequisite of development of pulmonary barotrauma [PB] is retention of the breathing mix in the lungs during a sudden decrease in external pressure or its administration into the airways under increased pressure or in a volume exceeding the maximum lung capacity. In such cases, the pulmonary parenchyma ruptures and air enters both the pleural cavity and/or the lumen of ruptured blood vessels located in the alveolar septa. The result is permanent disruption of the pulmonary parenchyma.The aim of the study was to assess the influence of post-PB lesions on the heart muscle and the importance of hyperbaric treatment on the exacerbation of such lesions in the heart. The hearts of 35 rabbits were used in the study. In animals of the experimental group, PB was induced in the pressure chamber using the proprietary method described in previous publications. Part of the animals in this group were treated with air hyperbaria. The comparison group consisted of animals, which did not undergo PB during a simulated dive. All animals were weighed, observed for four weeks and then put to death following the experiment. In autopsy, among others, whole hearts were collected and weighed after fixation. Subsequently, the C/S ratio, i.e. the body to heart weight ratio, was calculated. The measurement results were subject to statistical analysis. A statistically significant increase in the C/S ratio was found, indicating an increase in the share of heart weight in the total body weight in the group of animals with PB not treated with air hyperbaria as compared to the control group.


2009 ◽  
Vol 78 (1) ◽  
pp. 121-127 ◽  
Author(s):  
Štefan Juhás ◽  
Alexandra Bukovská ◽  
Štefan Čikoš ◽  
Soňa Czikková ◽  
Dušan Fabian ◽  
...  

Essential oils are plant secondary metabolites possessing various pharmacological properties, primarily anti-oxidative, antimicrobial or immunomodulative, but they can exhibit toxic and allergic effects as well. The aim of this study was to compare the effects of Rosmarinus officinalis essential oil dietary administration in carrageenan paw oedema and trinitrobenzene sulfonic acid (TNBS) colitis. ICR mice received rosemary essential oil at three concentrations (1 250, 2 500 and 5 000 ppm) in the standard laboratory diet starting two weeks before the experiments. The inflammation of paws induced by carrageenan application was evaluated by measurement of paw swelling, paw weight and myeloperoxidase activity. In the TNBS model the mice were killed by cervical dislocation 3 days after colitis induction and the mortality, changes in the body weight of mice, colon weight : body weight ratio, macroscopical scores and myeloperoxidase activity were analysed. Furthermore, IL-1β and IL-6 cytokine levels in colonic tissue were quantified using ELISA assay. Dietary supplementation with 5 000 ppm of rosemary essential oil initially after 2 h increased but after 24 h suppressed the extent of paw oedema. The same dose in the TNBS model exhibited protective effects on colonic mucosa and significantly decreased macroscopic scores for colonic inflammation. On the other hand, in colon samples from mice fed the diet with 1 250 ppm of rosemary essential oil we detected decreased myeloperoxidase activity and significantly lower levels of IL-6 compared to TNBS control animals. Our results indicate that rosemary essential oil is able to influence several variables of murine experimental inflammatory models depending on the concentration used. We conclude that the anti-inflammatory effects of rosemary essential oil should be interpreted carefully due to its timeand dose-related effects.


2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Francisco J. Valenzuela-Melgarejo ◽  
Claudia Caro-Díaz ◽  
Gerardo Cabello-Guzmán

Increased consumption of energy-dense foods such as fructose-rich syrups represents one of the significant, growing concerns related to the alarming trend of overweight, obesity, and metabolic disorders worldwide. Metabolic pathways affected by fructose involve genes related to lipogenesis/lipolysis, beta-oxidation, mitochondrial biogenesis, gluconeogenesis, oxidative phosphorylation pathways, or altering of circadian production of insulin and leptin. Moreover, fructose can be a risk factor during pregnancy elevating the risk of preterm delivery, hypertension, and metabolic impairment of the mother and fetus. Melatonin is a chronobiotic and homeostatic hormone that can modulate the harmful effects of fructose via clock gene expression and metabolic pathways, modulating the expression of PPARγ, SREBF-1 (SREBP-1), hormone-sensitive lipase, C/EBP-α genes, NRF-1, PGC1α, and uncoupling protein-1. Moreover, this hormone has the capacity in the rat of reverting the harmful effects of fructose, increasing the body weight and weight ratio of the liver, and increasing the body weight and restoring the glycemia from mothers exposed to fructose. The aim of this review is to show the potential crosstalk between fructose and melatonin and their potential role during pregnancy.


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