Maternal Melatonin Therapy Attenuates Methyl-Donor Diet-Induced Programmed Hypertension in Male Adult Rat Offspring

Although pregnant women are advised to consume methyl-donor food, some reports suggest an adverse outcome. We investigated whether maternal melatonin therapy can prevent hypertension induced by a high methyl-donor diet. Female Sprague-Dawley rats received either a normal diet, a methyl-deficient diet (L-MD), or a high methyl-donor diet (H-MD) during gestation and lactation. Male offspring were assigned to four groups (n = 7–8/group): control, L-MD, H-MD, and H-MD rats were given melatonin (100 mg/L) with their drinking water throughout the period of pregnancy and lactation (H-MD+M). At 12 weeks of age, male offspring exposed to a L-MD or a H-MD diet developed programmed hypertension. Maternal melatonin therapy attenuated high methyl-donor diet-induced programmed hypertension. A maternal L-MD diet and H-MD diet caused respectively 938 and 806 renal transcripts to be modified in adult offspring. The protective effects of melatonin against programmed hypertension relate to reduced oxidative stress, increased urinary NO2− level, and reduced renal expression of sodium transporters. A H-MD or L-MD diet may upset the balance of methylation status, leading to alterations of renal transcriptome and programmed hypertension. A better understanding of reprogramming effects of melatonin might aid in developing a therapeutic strategy for the prevention of hypertension in adult offspring exposed to an excessive maternal methyl-supplemented diet.

Download Full-text

The Interplay between Maternal and Post-Weaning High-Fat Diet and Gut Microbiota in the Developmental Programming of Hypertension

Nutrients ◽

10.3390/nu11091982 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1982 ◽

Cited By ~ 10

Author(s):

Chien-Ning Hsu ◽

Chih-Yao Hou ◽

Chien-Te Lee ◽

Julie Y.H. Chan ◽

You-Lin Tain

Keyword(s):

Gut Microbiota ◽

Short Chain Fatty Acids ◽

Normal Diet ◽

Nutrient Sensing ◽

Male Offspring ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

High Fat ◽

Male Adult ◽

Peroxisome Proliferator Activated Receptor

Excessive intake of saturated fat has been linked to hypertension. Gut microbiota and their metabolites, short-chain fatty acids (SCFAs), are known to be involved in the development of hypertension. We examined whether maternal and post-weaning high-fat (HF) diet-induced hypertension in adult male offspring is related to alterations of gut microbiota, mediation of SCFAs and their receptors, and downregulation of nutrient-sensing signals. Female Sprague–Dawley rats received either a normal diet (ND) or HF diet (D12331, Research Diets) during pregnancy and lactation. Male offspring were put on either the ND or HF diet from weaning to 16 weeks of age, and designated to four groups (maternal diet/post-weaning diet; n = 8/group): ND/ND, HF/ND, ND/HF, and HF/HF. Rats were sacrificed at 16 weeks of age. Combined HF/HF diets induced elevated blood pressure (BP) and increased body weight and kidney damage in male adult offspring. The rise in BP is related to a downregulated AMP-activated protein kinase (AMPK)–peroxisome proliferator-activated receptor co-activator 1α (PGC-1α) pathway. Additionally, HF/HF diets decreased fecal concentrations of propionate and butyrate and decreased G protein-coupled receptor 41 (GPR41), but increased olfactory receptor 78 (Oflr78) expression. Maternal HF diet has differential programming effects on the offspring’s microbiota at 3 and 16 weeks of age. Combined HF/HF diet induced BP elevation was associated with an increased Firmicutes to Bacteroidetes ratio, increased abundance of genus Akkermansia and phylum Verrucomicrobia, and reduced abundance in genus Lactobacillus. Maternal gut microbiota-targeted dietary interventions might be reprogramming strategies to protect against programmed hypertension in children and their mothers on consumption of a fat-rich diet.

Download Full-text

Altered Gut Microbiota and Its Metabolites in Hypertension of Developmental Origins: Exploring Differences between Fructose and Antibiotics Exposure

International Journal of Molecular Sciences ◽

10.3390/ijms22052674 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2674

Author(s):

Chien-Ning Hsu ◽

Julie Y. H. Chan ◽

Kay L. H. Wu ◽

Hong-Ren Yu ◽

Wei-Chia Lee ◽

...

Keyword(s):

Gut Microbiota ◽

Negative Impact ◽

Short Chain Fatty Acids ◽

Normal Diet ◽

Male Offspring ◽

Sprague Dawley ◽

Minocycline Treatment ◽

High Fructose ◽

Induced Hypertension ◽

Pregnancy And Lactation

Gut microbiota-derived metabolites, in particular short chain fatty acids (SCFAs) and their receptors, are linked to hypertension. Fructose and antibiotics are commonly used worldwide, and they have a negative impact on the gut microbiota. Our previous study revealed that maternal high-fructose (HF) diet-induced hypertension in adult offspring is relevant to altered gut microbiome and its metabolites. We, therefore, intended to examine whether minocycline administration during pregnancy and lactation may further affect blood pressure (BP) programmed by maternal HF intake via mediating gut microbiota and SCFAs. Pregnant Sprague-Dawley rats received a normal diet or diet containing 60% fructose throughout pregnancy and lactation periods. Additionally, pregnant dams received minocycline (50 mg/kg/day) via oral gavage or a vehicle during pregnancy and lactation periods. Four groups of male offspring were studied (n = 8 per group): normal diet (ND), high-fructose diet (HF), normal diet + minocycline (NDM), and HF + minocycline (HFM). Male offspring were killed at 12 weeks of age. We observed that the HF diet and minocycline administration, both individually and together, causes the elevation of BP in adult male offspring, while there is no synergistic effect between them. Four groups displayed distinct enterotypes. Minocycline treatment leads to an increase in the F/B ratio, but decreased abundance of genera Lactobacillus, Ruminococcus, and Odoribacter. Additionally, minocycline treatment decreases plasma acetic acid and butyric acid levels. Hypertension programmed by maternal HF diet plus minocycline exposure is related to the increased expression of several SCFA receptors. Moreover, minocycline- and HF-induced hypertension, individually or together, is associated with the aberrant activation of the renin–angiotensin system (RAS). Conclusively, our results provide a new insight into the support of gut microbiota and its metabolite SCAFs in the developmental programming of hypertension and cast new light on the role of RAS in this process, which will help prevent hypertension programmed by maternal high-fructose and antibiotic exposure.

Download Full-text

P1572EFFECTIVENESS OF COENZYME Q10-MICELLE COMPARED WITH COENZYME Q10 ON TACROLIMUS-INDUCED RENAL INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1572 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Sheng Cui ◽

Kang Luo ◽

Yi Quan ◽

Sun Woo Lim ◽

Chul-Woo Yang

Keyword(s):

Oxidative Stress ◽

Coenzyme Q10 ◽

Renal Injury ◽

Apoptotic Cell ◽

Oxidative Stress Marker ◽

Protective Effects ◽

Sprague Dawley ◽

Male Adult ◽

Sprague Dawley Rats ◽

Pathologic Lesions

Abstract Background and Aims We and others have recently demonstrated that Coenzyme Q10 (CoQ10) has protective effects against diabetes mellitus and various types of renal injury. This study investigated whether CoQ10-micelle treatment would affords superior renoprotection compared with CoQ10 in the governing tacrolimus (Tacrolimus)-induced renal injury in the rats. Method Male adult Sprague-dawley Rats were treated daily with Tacrolimus (1.5mg/kg/day, subcutaneous), CoQ10 (20mg/kg/day, oral), and CoQ10-micelle (20 mg/kg/day, oral) for 4 weeks. The effects of CoQ10 orCoQ10-micelle on Tac-induced renal injury were assessed in terms of renal function, histopathology, oxidative stress and apoptotic cell death. Results After 4 weeks of Tacrolimus treatment to rats caused renal dysfunction, typical pathologic lesions, and oxidative stress marker. The serum creatinine was reduced by Tac co-treatment with CoQ10 or CoQ10-micelle groups compared with the Tac and VH group (0.31 ± 0.03 in the VH group vs. 0.43 ± 0.041 in the Tac group vs.0.37 ± 0.031 in the Tac+CoQ10 group 0.30 ± 0.02123 in the Tac+CoQ10-micellegroup; 1P<0.05 vs. VH. 2P<0.05 vs. TAC. . 3P<0.05 vs. TAC+C.) The administration of CoQ10-micelle improved renal immunoreactivity, which was accompanied by reductions in oxidative stress and apoptosis. Assessment of the mitochondrial ultrastructure by electron microscopy revealed that tacrolimus co-treatment with CoQ10-micelle increased the size and number of mitochondria more than co-treatment with CoQ10, compared with that induced by TAC treatment alone. Conclusion These findings suggest that both CoQ10 and CoQ10-micelle effectively attenuates Tac-induced renal injury, and CoQ10-micelle provides more benefits than that of CoQ10.

Download Full-text

Maternal N-Acetylcysteine Therapy Prevents Hypertension in Spontaneously Hypertensive Rat Offspring: Implications of Hydrogen Sulfide-Generating Pathway and Gut Microbiota

Antioxidants ◽

10.3390/antiox9090856 ◽

2020 ◽

Vol 9 (9) ◽

pp. 856 ◽

Cited By ~ 2

Author(s):

Chien-Ning Hsu ◽

Chih-Yao Hou ◽

Guo-Ping Chang-Chien ◽

Sufan Lin ◽

You-Lin Tain

Keyword(s):

Drinking Water ◽

Hydrogen Sulfide ◽

Gut Microbiota ◽

Spontaneously Hypertensive Rat ◽

Later Life ◽

Male Offspring ◽

Protective Effects ◽

Male Adult ◽

Spontaneously Hypertensive ◽

Pregnancy And Lactation

Hypertension can come from early life. N-acetylcysteine (NAC), a hydrogen sulfide (H2S) precursor as well as an antioxidant, has antihypertensive effect. We investigated whether maternal NAC therapy can protect spontaneously hypertensive rats (SHR) male offspring against hypertension. The pregnant rats were assigned to four groups: SHRs without treatment; Wistar Kyoto (WKY) without treatment; SHR+NAC, SHRs received 1% NAC in drinking water throughout pregnancy and lactation; and, WKY+NAC, WKY rats received 1% NAC in drinking water during pregnancy and lactation. Male offspring (n = 8/group) were killed at 12 weeks of age. Maternal NAC therapy prevented the rise in systolic blood pressure (BP) in male SHR offspring at 12 weeks of age. Renal cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulphurtransferase (3MST) protein levels and H2S-releasing activity were increased in the SHR+NAC offspring. Maternal NAC therapy increased fecal H2S and thiosulfate levels in the SHR+NAC group. Additionally, maternal NAC therapy differentially shaped gut microbiota and caused a distinct enterotype in each group. The protective effect of maternal NAC therapy against hypertension in SHR offspring is related to increased phylum Actinobacteria and genera Bifidobacterium and Allobaculum, but decreased phylum Verrucomicrobia, genera Turicibacter, and Akkermansia. Several microbes were identified as microbial markers, including genera Bifidobacterium, Allobaculum, Holdemania, and Turicibacter. Our results indicated that antioxidant therapy by NAC in pregnant SHRs can prevent the developmental programming of hypertension in male adult offspring. Our findings highlight the interrelationships among H2S-generating pathway in the kidneys and gut, gut microbiota, and hypertension. The implications of maternal NAC therapy elicited long-term protective effects on hypertension in later life that still await further clinical translation.

Download Full-text

Whether AICAR in Pregnancy or Lactation Prevents Hypertension Programmed by High Saturated Fat Diet: A Pilot Study

Nutrients ◽

10.3390/nu12020448 ◽

2020 ◽

Vol 12 (2) ◽

pp. 448 ◽

Cited By ~ 1

Author(s):

Wan-Long Tsai ◽

Chien-Ning Hsu ◽

You-Lin Tain

Keyword(s):

Oxidative Stress ◽

Saturated Fat ◽

Nutrient Sensing ◽

Male Offspring ◽

Lactation Period ◽

Sprague Dawley ◽

Male Adult ◽

Ampk Signaling ◽

Pregnancy And Lactation ◽

In Pregnancy

High consumption of saturated fats links to the development of hypertension. AMP-activated protein kinase (AMPK), a nutrient-sensing signal, is involved in the pathogenesis of hypertension. We examined whether early intervention with a direct AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) during pregnancy or lactation can protect adult male offspring against hypertension programmed by high saturated fat consumption via regulation of nutrient sensing signals, nitric oxide (NO) pathway, and oxidative stress. Pregnant Sprague–Dawley rats received regular chow or high saturated fat diet (HFD) throughout pregnancy and lactation. AICAR treatment was introduced by intraperitoneal injection at 50 mg/kg twice a day for 3 weeks throughout the pregnancy period (AICAR/P) or lactation period (AICAR/L). Male offspring (n = 7–8/group) were assigned to five groups: control, HFD, AICAR/P, HFD + AICAR/L, and HFD + AICAR/P. Male offspring were killed at 16 weeks of age. HFD caused hypertension and obesity in male adult offspring, which could be prevented by AICAR therapy used either during pregnancy or lactation. As a result, we demonstrated that HFD downregulated AMPK/SIRT1/PGC-1α pathway in offspring kidneys. In contrast, AICAR therapy in pregnancy and, to a greater extent, in lactation activated AMPK signaling pathway. The beneficial effects of AICAR therapy in pregnancy is related to restoration of NO pathway. While AICAR uses in pregnancy and lactation both diminished oxidative stress induced by HFD. Our results highlighted that pharmacological AMPK activation might be a promising strategy to prevent hypertension programmed by excessive consumption of high-fat food.

Download Full-text

The effects of melatonin on brain nitrosative stress and energy balance in fructose-mediated metabolic syndrome model / Fruktoz-aracılı metabolik sendrom modelinde melatoninin beyinde nitrozatif stres ve enerji dengesi üzerine etkisi

Turkish Journal of Biochemistry ◽

10.1515/tjb-2016-0006 ◽

2016 ◽

Vol 41 (1) ◽

Author(s):

Gonca Ozan ◽

Filiz Sezen Bircan ◽

Turgut Topal ◽

Nurten Türközkan

Keyword(s):

Nitric Oxide ◽

Metabolic Syndrome ◽

Nitrosative Stress ◽

Tap Water ◽

Serum Triglyceride ◽

Experimental Period ◽

Control Group ◽

Protective Effects ◽

Sprague Dawley ◽

Male Adult

AbstractObjective: Metabolic syndrome (MetS), one of the common health problems seen with increasing frequency in today’s modern societies, is also a important risk factor for neurological disorders such as stroke, depression, Alzheimer’s disease. On the other hand, melatonin is a neurohormone, has potent antioxidant and neuroprotective activities. In the present study, we aimed to investigate the possible protective effects of melatonin administration on brain tissue in fructose-mediated MetS model.Methods: Male adult Sprague-Dawley rats were randomly divided into four groups (n=8); control, fructose, melatonin and fructose plus melatonin. MetS was induced by fructose solution 20% in tap water, and melatonin was administered at the dose of 20 mg/kg bw/day by oral gavage. Systolic blood pressures (SBP) were measured by tail-cuff method. After the experimental period of 8 weeks, serum triglyceride, glucose, insulin, and tissue ATP/ADP ratio, nitric oxide (NOx) and 3-nitrotyrosine (3-NT) levels were measured. Also tissue endothelial and inducible nitric oxide synthase (eNOS and iNOS) protein levels were determined.Results: Fructose consumption increased SBP, serum triglyceride, insulin levels and induced insulin resistance significantly compared to control group and MetS model was successfully demonstrated. In comparison with control group, fructose administration did not cause significant changes in tissue ATP/ADP ratio and 3-NT levels. NOx levels did not change significantly among groups, and iNOS-eNOS proteins were not detected in any groups. Interestingly, tissue 3-NT levels were elevated significantly while ATP/ADP ratio was diminished in fructose plus melatonin group compare with both control and fructose groups.Conclusion: These results indicate that high fructose diet for 8 weeks does not influence nitric oxide production, energy metabolism and protein nitration in brain. Nevertheless melatonin acted as a pro-oxidant at that dose when administered with fructose.

Download Full-text

Elateriospermum tapos Supplementation in Dams Ameliorating Obesity Development and Stress Hormone Level among Adult Male Offspring

Proceedings ◽

10.3390/iecn2020-07006 ◽

2020 ◽

Vol 61 (1) ◽

pp. 2

Author(s):

Azrina Zainal Abidin ◽

Santhra Segaran Balan ◽

Kokila Vani Perumal ◽

Nurul Husna Shafie ◽

Maizaton Atmadini Abdullah ◽

...

Keyword(s):

Body Weight ◽

Stress Hormones ◽

Male Offspring ◽

Cafeteria Diet ◽

Control Group ◽

Chow Diet ◽

Adult Offspring ◽

Male Adult ◽

Obesity And Diabetes ◽

Obese Rats

: Maternal obesity is a metabolic disorder described by chronic inflammation and an increase of stress hormones, influencing non-communicable diseases in offspring. Elateriospermum tapos has the potential as an antioxidant and inhibitor of lipids (pancreatic lipase) and carbohydrates (α-amylase and α-glucosidase) which are beneficial to combat obesity and diabetes. This study aimed to investigate the effect of E. tapos supplementation in obese rats prior to pregnancy on the dam and male offspring body weight and the level of stress hormones—adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Thirty female Sprague Dawley rats were used in this study. Six rats were assigned to a normal diet (DND) group fed with a standard chow diet. The remaining rats were fed with a high-fat and cafeteria diet (HFCD) to generate obesity for five weeks. The obese rats were further divided into four groups (n = 6/group); dams negative control group (DNC, normal saline), dams positive control group (DPC, 200 mg/kg body weight of orlistat), dams treatment 1 group (DTX1, 200 mg/kg BW of E. tapos seed) and dams treatment 2 group (DTX2, 200 mg/kg BW of E. tapos shell). The treatment was given for six weeks daily before mating. At weaning, male offspring were designated into six groups according to their dam’s group (n = 6/group) and continued with the cafeteria diet except for the control group. The offspring were culled at 12 weeks of age for blood sample collections. DTX2 and their male adult offspring showed significantly lower body weight compared to DNC and their male offspring. Male offspring from DTX2 also showed significantly low ACTH and CORT levels compared to male offspring from the DNC group and a comparable level with the DND group. E. tapos shell supplementation was effective in reducing the development of obesity and suppressed stress through the regulation of ACTH and CORT release in male adult offspring.

Download Full-text

LINE-1 Hypomethylation in a Choline-Deficiency-Induced Liver Cancer in Rats: Dependence on Feeding Period

Journal of Biomedicine and Biotechnology ◽

10.1155/jbb/2006/17142 ◽

2006 ◽

Vol 2006 ◽

pp. 1-6 ◽

Cited By ~ 25

Author(s):

Kiyoshi Asada ◽

Yashige Kotake ◽

Rumiko Asada ◽

Deborah Saunders ◽

Robert H. Broyles ◽

...

Keyword(s):

Cytosine Methylation ◽

Methylation Status ◽

Repetitive Sequences ◽

Cpg Islands ◽

Surrogate Marker ◽

Surrounding Tissue ◽

Feeding Time ◽

Aberrant Methylation ◽

Deficient Diet ◽

Methyl Donor

Chronic feeding of methyl-donor (methionine, choline, folic acid, and vitamin B12) deficient diet induces hepatocellular carcinoma formation in rats. Previous studies have shown that promoter CpG islands in various cancer-related genes are aberrantly methylated in this model. Moreover, the global genome in methyl-donor-deficient diet fed rats contains a lesser amount of 5-methylcytosine than control livers. It is speculated that more than 90% of all 5-methylcytosines lie within the CpG islands of the transposons, including the long/short interspersed nucleotide elements (LINE and SINE). It is considered that the 5-methylcytosines in LINE-1 limit the ability of retrotransposons to be activated and transcribed; therefore, the extent of hypomethylation of LINE-1 could be a surrogate marker for aberrant methylation in other tumor-related genes as well as genome instability. Additionally, LINE-1 methylation status has been shown to be a good indicator of genome-wide methylation. In this study, we determined cytosine methylation status in the LINE-1 repetitive sequences of rats fed a choline-deficient (CD) diet for various durations and compared these with rats fed a choline-sufficient (CS) diet. The methylation status of LINE-1 was assessed by the combined bisulfite restriction analysis (COBRA) method, where the amount of bisulfite-modified and RsaI-cleaved DNA was quantified using gel electrophoresis. Progressive hypomethylation was observed in LINE-1 of CD livers as a function of feeding time; that is, the amount of cytosine in total cytosine (methylated and unmethylated) increased from 11.1% (1 week) to 19.3% (56 weeks), whereas in the control CS livers, it increased from 9.2% to 12.9%. Hypomethylation in tumor tissues was slightly higher (6%) than the nontumorous surrounding tissue. The present result also indicates that age is a factor influencing the extent of cytosine methylation.

Download Full-text

Perinatal Resveratrol Therapy to Dioxin-Exposed Dams Prevents the Programming of Hypertension in Adult Rat Offspring

Antioxidants ◽

10.3390/antiox10091393 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1393

Author(s):

Chien-Ning Hsu ◽

Chih-Hsing Hung ◽

Chih-Yao Hou ◽

Chi-I. Chang ◽

You-Lin Tain

Keyword(s):

Gut Microbiota ◽

Environmental Chemicals ◽

Male Offspring ◽

Sprague Dawley ◽

T Helper 17 ◽

Renal Inflammation ◽

Beneficial Effects ◽

Adult Rat ◽

Aryl Hydrocarbon ◽

Pregnancy And Lactation

Exposure to environmental chemicals during pregnancy and lactation is a contributing factor in gut microbiota dysbiosis and linked to programming of hypertension. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic dioxin, induces toxic effects by mediating aryl hydrocarbon receptor (AHR). Resveratrol, a potent antioxidant with prebiotic properties, can possess high affinity for AHR and protect against TCDD-activated AHR attack. We examined whether perinatal resveratrol therapy prevents offspring hypertension programmed by maternal TCDD exposure and whether its beneficial effects are related to reshaping gut microbiota and antagonizing AHR-mediated T helper 17 (TH17) cells responses using a maternal TCDD exposure rat model. Pregnant Sprague-Dawley rats were given a weekly oral dose of TCDD 200 ng/kg for four doses (T), 50 mg/L of resveratrol in drinking water (CR), TCDD + resveratrol (TR), or vehicle (C) in pregnancy and lactation periods. Male offspring (n = 7–8/group) were sacrificed at the age of 12 weeks. Perinatal TCDD exposure caused elevated blood pressure in adult male offspring, which resveratrol supplementation prevented. Additionally, the TCDD-induced programming of hypertension is coincided with the activation of AHR signaling, TH17-induced renal inflammation, and alterations of gut microbiota compositions. Conversely, TCDD-mediated induction of AHR signaling and TH17 responses were restored by maternal resveratrol supplementation. Furthermore, maternal resveratrol supplementation prevented the programming of hypertension and was related to increased genera Bacteroides, ASF356, and Lachnoclostridium. Taken together, these results suggest that the interplay between gut microbiota, AHR-mediated TH17 responses, and renal inflammation in the gut and kidneys may play an important role in the action of resveratrol against TCDD-induced programming of hypertension.

Download Full-text