scholarly journals Maternal nicotinamide supplementation causes global DNA hypomethylation, uracil hypo-incorporation and gene expression changes in fetal rats

2014 ◽  
Vol 111 (9) ◽  
pp. 1594-1601 ◽  
Author(s):  
Yan-Jie Tian ◽  
Ning Luo ◽  
Na-Na Chen ◽  
Yong-Zhi Lun ◽  
Xin-Yi Gu ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Epigenetic Modification ◽  
Fetal Liver ◽  
Female Rats ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Chow Diet ◽  
Dna Hypomethylation

Recent evidence shows that excess nicotinamide can cause epigenetic changes in developing rats. The aim of the present study was to investigate the effects of maternal nicotinamide supplementation on the fetus. Female rats were randomised into four groups fed a standard chow diet (control group) or diets supplemented with 1 g/kg of nicotinamide (low-dose group), 4 g/kg of nicotinamide (high-dose group) or 4 g/kg of nicotinamide plus 2 g/kg of betaine (betaine group) for 14–16 d before mating and throughout the study. Fetal tissue samples were collected on the 20th day of pregnancy. Compared with the control group, the high-dose group had a higher fetal death rate, and the average fetal body weight was higher in the low-dose group but lower in the high-dose group. Nicotinamide supplementation led to a decrease in placental and fetal hepatic genomic DNA methylation and genomic uracil contents (a factor modifying DNA for diversity) in the placenta and fetal liver and brain, which could be completely or partially prevented by betaine. Moreover, nicotinamide supplementation induced tissue-specific alterations in the mRNA expression of the genes encoding nicotinamideN-methyltransferase, DNA methyltransferase 1, catalase and tumour protein p53 in the placenta and fetal liver. High-dose nicotinamide supplementation increased fetal hepatic α-fetoprotein mRNA level, which was prevented by betaine supplementation. It is concluded that maternal nicotinamide supplementation can induce changes in fetal epigenetic modification and DNA base composition. The present study raises the concern that maternal nicotinamide supplementation may play a role in the development of epigenetic-related diseases in the offspring.

scholarly journals Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis

2020 ◽  
Vol 22 (1) ◽  
pp. 176
Author(s):  
Toshiaki Iba ◽  
Jerrold H. Levy ◽  
Koichiro Aihara ◽  
Katsuhiko Kadota ◽  
Hiroshi Tanaka ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Leukocyte Adhesion ◽  
Endothelial Glycocalyx ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Protective Effects ◽  
Circulating Levels

(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.

Carcinogenesis Bioassay of Propyl Gallate in F344 Rats and B6C3FJ Mice

1983 ◽  
Vol 2 (6) ◽  
pp. 425-433 ◽  
Author(s):  
K. M. Abdo ◽  
J. E. Huff ◽  
J. K. Haseman ◽  
M. P. Dieter ◽  
G. A. Boorman ◽  
...  
Keyword(s):  
Propyl Gallate ◽  
Dose Group ◽  
Low Dose ◽  
Female Rats ◽  
Male Rats ◽  
High Dose Group ◽  
High Dose ◽  
Preputial Gland ◽  
Rats And Mice ◽  
F344 Rats

Chronic toxicity studies were conducted by maintaining groups of 50 F344 rats and 50 B6C3F1 mice of each sex on nutritionally complete diets containing 0%, 0.6%, or 1.2% propyl gallate for 103 weeks. Survival of rats and mice of both sexes was not significantly affected by the administration of this compound. Dosed rats and mice showed growth retardation and reduced feed utilization efficiency. Increased incidence of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate gland were observed in dosed male rats and were considered to be related to propyl gallate administration. Tumors of the preputial gland, islet ceil tumors of the pancreas, and pheochromocytoma of the adrenal gland were observed with significantly (p < 0.05) higher incidence in the low-dose male rats; however, there was little evidence of a dose response or of an effect in the high-dose group. Rare tumors (an astrocytoma and a glioma) were found in the brains of two low-dose female rats but none was found in the high-dose group. Malignant lymphoma occurred with a significant (p < 0.05) positive trend in male mice and the incidence in the high-dose group was significantly (p < 0.05) higher than that of the concurrent controls. However, the high-dose incidence was not significantly different from the historical control rate for the laboratory that conducted the bioassay. Under the conditions of the bioassay, propyl gallate was not considered to be clearly carcinogenic for F344 rats, although the increased incidence of preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytoma of the adrenal glands in low-dose male rats may have been related to compound administration. Thus, the evidence for carcinogenicity in male rats is regarded as being equivocal, while there was no indication of a carcinogenic response in female rats. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice, although the increased incidence of malignant lymphoma in dosed male mice may have been related to administration of the test compound.

Effect of High or Low Dose Phenoxybenzamine on Per-Operative Hemodynamics in Pheochromocytoma

2020 ◽  
Author(s):  
Randi Ugleholdt ◽  
Åse Krogh Rasmussen ◽  
Pernille Agnete Heldager Haderslev ◽  
Bjarne Kromann-Andersen ◽  
Claus Larsen Feltoft
Keyword(s):  
Blood Pressure ◽  
Dose Regimen ◽  
Laparoscopic Adrenalectomy ◽  
Dose Group ◽  
Low Dose ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Intravenous Fluids ◽  
Preoperative Treatment

Abstract Background. Alpha-receptor blockade is the mainstay in preoperative treatment of patients with pheochromocytoma and paraganglioma (PPGL). However, evidence regarding optimal dosage regimen is lacking. This study compares the per- and postoperative hemodynamics in patients pre-treated with a high or low dose of phenoxybenzamine. Methods. 30 consecutive patients with PPGL undergoing laparoscopic adrenalectomy were identified retrospectively. All were pretreated with phenoxybenzamine but at two separate endocrine departments aiming at different blood pressure target. End-dosage of phenoxybenzamine differed significantly between departments with 14 patients receiving a high dose regimen and 16 a low dose regimen. As a control group, we included 42 patients undergoing laparoscopic adrenalectomy for other reasons. Primary purpose was to compare per- and postoperative hemodynamics in the high and low dose groups. Secondly, to compare these endpoints to the control group. Results. Baseline characteristics did not differ between the phenoxybenzamine treated groups. The high dose group had less intra-operative systolic and diastolic blood pressure fluctuation (p = 0.03) and less periods with heart rate above 100 bpm (p = 0.04) as compared to the low dose group. Use of intravenous fluids were similar between the two groups. However, postoperatively, more intravenous fluids were administered in the high dose group. Overall, the control group was more hemodynamic stable as compared to either group treated for PPGL. Conclusions. High dose phenoxybenzamine improves per-operative hemodynamic stability but causes a higher postoperative requirement for intravenous fluids. Overall, PPGL surgery is related to greater hemodynamic instability compared to adrenalectomy for other reasons.

scholarly journals Ovarian profile of Wistar rats treated with Theobroa cacao extract.

2019 ◽  
Vol 8 (2) ◽  
pp. 1570-1576
Author(s):  
Kebe E. Obeten ◽  
Victor A. Fischer ◽  
Ugwuja O. Jennifer ◽  
Akim Bonaventure
Keyword(s):  
Body Weight ◽  
Theobroma Cacao ◽  
Dose Group ◽  
Low Dose ◽  
Research Work ◽  
Wistar Rat ◽  
Female Rats ◽  
Control Group ◽  
High Dose ◽  
Test Substance

The study was aimed at determining the effect of aqueous extract of Theobroma cacao on the histology of the ovary of female albino wistar rat. Twenty-four (24) adult wistar female rats weighting about 100- 160g were used for this research work and were divided into three (3) groups of eight (8) animals each. Group A; control, Group B; low dose and Group C; high dose with eight (8) animals in each group. Control group received vital feed; the low dose group was administered 240mgkg body weight of Theobroma cacao extract and the high dose group was administered 500mgkg body weight of the test substance. Extract was given daily by oral gavage method for twenty-one (21) days. Twenty-four hours after the last administration, all animals in each group were sacrificed under chloroform anesthesia. The ovaries were harvested, weighed and fixed in 10% buffered formalin for histological studies. Results showed that following administration of extract of Theoboma cacao at these doses, an insignificant decrease in organ weight was observed. Histological observation showed few follicles as well as loss of the substance of granulose cell this could possibly suggest decrease in production of sex steroids in the ovary.Keywords: Theobroma Cacao, Ovary, Histology

Olprinone, a Phosphodiesterase III Inhibitor, Reduces Gut Mucosal Injury and Portal Endotoxin Level during Acute Hypoxia in Rabbits

2003 ◽  
Vol 98 (6) ◽  
pp. 1407-1414 ◽  
Author(s):  
Tomoyuki Satoh ◽  
Hiroshi Morisaki ◽  
Kimiaki Ai ◽  
Shizuko Kosugi ◽  
Michiko Yamamoto ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Acute Hypoxia ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Phosphodiesterase Iii Inhibitor ◽  
Gut Mucosa ◽  
Progressive Hypoxia ◽  
Phosphodiesterase Iii

Background Preservation of gut integrity has become a therapeutic goal to obviate bacterial translocation in the critically ill. The authors examined whether olprinone, a phosphodiesterase III inhibitor, protected functional and structural integrity of gut mucosa against acute progressive hypoxia. Methods Thirty-two animals were randomly allocated to a control group (n = 12), a low-dose group (0.2 microg x kg-1 x min-1 olprinone; n = 10), or a high-dose group (0.6 microg x kg-1 x min-1 olprinone; n = 10) after preparatory surgery. Ascending aortic and portal blood flow, intramural pH of the ileum, and portal endotoxin levels were measured at normoxia and through three stages of progressive hypoxia (fraction of inspired oxygen = 0.17, 0.13, and 0.10). Results At normoxia, ascending aortic flow in the high-dose group was approximately 20% higher than in the control and low-dose groups. During progressive hypoxia, both ascending aortic and portal flow in the control group were depressed, whereas olprinone infusion attenuated such alterations and redistributed blood to the splanchnic area in a dose-dependent manner. On the contrary, the reduction of intramural pH of the ileum and the elevation of portal endotoxin levels observed in the control group were significantly minimized in both the low- and high-dose groups to a similar extent during acute hypoxia. Histopathologic alterations of gut mucosa observed in the control group were minimized by olprinone infusion dose-independently, accompanied by reduction of mortality rate of the animals. Conclusions Olprinone slows progression of intestinal mucosal acidosis and gut barrier dysfunction, concurrently with preservation of microscopic structures, through both flow-dependent and -independent mechanisms under acute hypoxia. Such properties of olprinone may serve to protect the host under insult.

scholarly journals Pathological Changes of Copper Ion Poisoning in Mice

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Rundong Zhuang
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Cell Swelling ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Renal Tubules ◽  
Pathological Changes ◽  
Renal Tubular ◽  
Copper Poisoning

In this study, the clinical manifestations of copper poisoning and the pathological changes of tissues and organs were observed by copper sulfate. The experimental mice were randomly divided into four groups: control group (0 mg / kg), low dose group (50 mg / kg), medium dose group (100 mg / kg), high dose group (200 mg / kg), 6 rats in each group, the test period was 2 weeks. The results showed that the mortality rate in the high dose group was higher than that in the middle dose group and the low dose group. Pathological observation of high-dose group showed hepatic steatosis and granular degeneration, hepatocyte showed honeycomb appearance, low dose group and middle dose group hepatocyte enlargement, cytoplasm filled with red stained fine particles; low dose group In the renal tubular degeneration, renal tubular epithelial cell swelling, so that the lumen becomes smaller or narrow, interstitial telangiectasia, congestion. In the middle dose group, there were obvious degeneration of the renal tubules, and there were many red dye protein in the lumen. Part of the renal tubular wall cell structure was destroyed. High dose group of renal tubular epithelial necrosis, disintegration, fall off in the lumen. The results show that copper poisoning mainly damage the liver, kidney and other tissues and organs, eventually leading to morbidity and even death.

Different Dosage of Bortezomib Impacts the Prevention of Acute Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4499-4499
Author(s):  
Jianyu Weng ◽  
Meikun Lü ◽  
Xin Du ◽  
Lin Xu ◽  
Suxia Geng ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Dose Group ◽  
Low Dose ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Dosage Group ◽  
Graft Versus Host ◽  
T Cell Apoptosis

Abstract Abstract 4499 The proteasome inhibitor bortezomib which prevents nuclear factor kappaB (NF-kappaB) activation, blocks T-cell activation, induces T cell and dendritic cells apoptosis, and inhibits dendritic cells mature. Bortezomib has been used successfully in the treatment of graft-versus-host disease (GVHD) and autoimmune diseases in animal models. As recent reports, bortezomib not only could prevent GVHD but also induce severe GVHD which depends on the time of administration. We explored whether the dosage of bortezomib impacts the prevention of aGVHD. For this purpose, different dosage of bortezomib (10ug/kg, 100ug/kg, 800ug/kg) were administrated to recipient C57BL/6 (H2b) mice which were lethally irradiated and given transplants of bone marrow cells and splenocytes from major histocompatibility complex (MHC)-disparate BALB/c (H2d) donors. The median survival time of control group was 31 days (19 to 37), low dosage group (10ug/kg) was 27.5 days (range: 18 to 42), intermediate dosage group(100ug/kg) was 45 days (range: 32 to 67), and high dosage group(800ug/kg) was 33 days (range:22 to 67). The survival time of intermediate dosage group compared with control group and other dosage group increased significantly (P < 0.05). On day +30,all the inter-dose group mice were alive(100%), and the control group, the low-dose group and the high-dose group remained 40%(2/5), 30% (3/10) and 60% (6/10) mice, respectively. On day +60, the inter-dsoe group and the high-dose group remained three and one alive, respectively. Pathologic assessment of skin and liver during aGVHD on day +30 showed less lesions in inter-dose group and high-dose group than low-group and control group. Interestingly, pathology also revealed that significant increases in gastrointestinal lesions occurred following high dose (800ug/kg) bortezomib administration in aGVHD. The results show that intermediate dosage bortezomib could effectively improve the survival time and protect injury from aGVHD. In this study, we detected T cell apoptosis by Annexin-V/PI. The percentages of the apoptosis cells in control group, low-, inter- and high dosage group were 4.00±0.14, 4.65±0.2, 12.13±0.14 and 12.37±0.75, respectively. The result indicated T cell apoptosis induced by bortezomib were more evident in the inter-dose group and high-dose group than low-dose group and control group (P<0.05). Also, the proportion of CD4+CD25+ regulatory T cells were significantly increase in the inter-dose group and high-dose group than other two groups (inter-, high-dose group, and contral group, low- dose group were 30.25±6.32%, 35.25±2.14%, and 21.71±0.52%, 23.15±4.12%, respectively; P<0.05). Otherwise, the level of serum IL-2 decreased and IL-4 increased significantly in intermediate and high dosage group, the low dosage bortezomib didn't affect the leverl of serum IL-2 and IL-4. Intermediate dosage of bortezomib prevents aGVHD without presenting obvious adverse effects. The effect of bortezomib on preventing aGVHD are relevant to T cell apoptosis, regulating IL-2 and IL-4 levels and increasing regulatory T cell level. These results indicated that the prevention effects of proteasome inhibition with bortezomib on aGVHD are critically dependent on the dosage of bortezomib administration. And these results establish the basis for the clinical use of bortezomib in the management of graft-versus-host disease (GVHD). This work was supported by Science and Technology Planning Project of Guangdong Province (2006B36005003,2007A032100003) and Science and Technology Planning Project of Guangzhou (2006Z2-E4071,2008A1-E4011-4,2008A1-E4011-5). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dose–response effects of exercise on insulin among colon cancer survivors

2018 ◽  
Vol 25 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Justin C Brown ◽  
Michael R Rickels ◽  
Andrea B Troxel ◽  
Babette S Zemel ◽  
Nevena Damjanov ◽  
...  
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Colon Cancer ◽  
Cancer Survivors ◽  
Aerobic Exercise ◽  
Dose Group ◽  
Low Dose ◽  
High Dose Group ◽  
Control Group ◽  
High Dose

Physical activity is associated with a lower risk of disease recurrence among colon cancer survivors. The pathways through which physical activity may alter disease outcomes are unknown, but may include changes in metabolic growth factors, such as insulin. Between January 2015 and August 2015, 39 stage I–III colon cancer survivors were randomized to one of the three groups: usual care control, 150 min/week of aerobic exercise (low-dose) and 300 min/week of aerobic exercise (high-dose) for six months. The pre-specified key metabolic growth factor outcome was fasting insulin. Insulin resistance was quantified using the homeostatic model assessment. Mean age was 56.5 ± 10.0 years, 51% had stage III disease, 72% were treated with chemotherapy and the mean time since finishing treatment was 10.9 ± 6.1 months. Over six months, the low-dose group completed 141.5 ± 9.9 min/week of aerobic exercise, and the high-dose group completed 247.2 ± 10.7 min/week of aerobic exercise. Fasting insulin concentrations decreased 7.4 ± 9.4 pmol/L in the control group, 28.0 ± 8.3 pmol/L in the low-dose group and 20.7 ± 9.3 pmol/L in the high-dose group (nonlinearPtrend = 0.042). Insulin resistance decreased 0.11 ± 0.20 in the control group, 0.63 ± 0.17 in the low-dose group and 0.43 ± 0.19 in the high-dose group (nonlinearPtrend = 0.012). Aerobic exercise reduces insulin concentrations and insulin resistance among patients with stage I–III colon cancer. Prescribing 150 min/week of aerobic exercise may be sufficient for reducing insulin concentrations and insulin resistance, which may partially mediate the relationship between physical activity and colon cancer prognosis.

Acetaminophen: Neonatal hepatotoxicity due to late pregnancy exposure

1987 ◽  
Vol 45 ◽  
pp. 718-719
Author(s):  
G.A. Miranda ◽  
M.A. Arroyo ◽  
C.A. Lucio ◽  
M. Mongeotti ◽  
S.S. Poolsawat
Keyword(s):  
Low Dose ◽  
Fetal Liver ◽  
Late Pregnancy ◽  
Toxic Chemicals ◽  
Control Group ◽  
High Dose ◽  
Over The Counter ◽  
Liver And Kidney ◽  
Neonatal Liver ◽  
Childbearing Women

Exposure to drugs and toxic chemicals, during late pregnancy, is a common occurrence in childbearing women. Some studies have reported that more than 90% of pregnant women use at least 1 prescription; of this, 60% used more than one. Another study indicated that 80% of the consumed drugs were not prescribed, and of this figure, 95% were “over-the-counter” drugs. Acetaminophen, the safest of all over-the-counter drugs, has been reported to induce fetal liver necrosis in man and animals and to have abortifacient and embryocidal action in mice. This study examines the degree to which acetaminophen affects the neonatal liver and kidney, when a fatty diet is simultaneously fed to the mother during late pregnancy.Timed Swiss Webster female mice were gavaged during late pregnancy (days 16-19) with fat suspended acetaminophen at a high dose, HD = 84.50 mg/kg, and a low dose, LD = 42.25 mg/kg; a control group received fat alone.

scholarly journals Recombinant Human Thyrotropin-Stimulated Radioiodine Therapy in Patients with Multinodular Goiters: A Meta-Analysis of Randomized Controlled Trials

2020 ◽  
Vol 52 (12) ◽  
pp. 841-849
Author(s):  
Chunmei Xu ◽  
Ping Wang ◽  
Huikai Miao ◽  
Tianyue Xie ◽  
Xiaojun Zhou ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Dose Group ◽  
Low Dose ◽  
Radioiodine Therapy ◽  
Meta Analysis ◽  
High Dose Group ◽  
High Dose ◽  
Fixed Effects Model ◽  
Recombinant Human Thyrotropin

AbstractA potential reduction of goiter volume (GV) of recombinant human thyrotropin (rhTSH) on multinodular goiters (MNG) was previously reported but controversial. Hence we conducted a meta-analysis to estimate the effect of rhTSH-stimulated radioiodine therapy in patients with MNG. PubMed, Cochrane, CNKI, VIP, and Wanfang databases were searched. Mean difference (MD) and odds ratios with 95% confidence intervals (95% CI) were derived by using an inverse variance random-effects model and fixed-effects model, respectively. Six studies (n=237) were involved in the analysis. For 12 months follow up, high dose (>0.1 mg) of rhTSH significantly reduced GV (MD=17.61; 95% CI=12.17 to 23.04; p<0.00001) compared with placebo. No effective pooled results of low dose of rhTSH (<0.1 mg) were applicable for only one study included. For 6 months follow up, the source of heterogeneity was determined by subgroup and sensitivity analysis. High dose group showed vast improvement in GV reduction (MD=16.62; 95% CI=1.34 to 31.90; p=0.03). The reduction of low dose group compared with placebo was inferior to high dose group. No available data were obtained to assess the influence of rhTSH after 36 months follow up for the only included study. Hypothyroidism incidence was higher for rhTSH group. No publication bias was seen. High dose of rhTSH treatment-stimulated radioactive 131I therapy after 6 months and 12 months follow up had a better effect in reducing GV, but with higher incidence of hypothyroidism. Owing to the limited methodological quality, more clinical researches are warranted in the future.

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