Perinatal Use of Citrulline Rescues Hypertension in Adult Male Offspring Born to Pregnant Uremic Rats.

The growing recognition of the association between maternal chronic kidney disease (CKD) and fetal programming highlights the increased vulnerability of hypertension in offspring. Potential mechanisms involve oxidative stress, dysbiosis in gut microbiota, and activation of the renin-angiotensin system (RAS). Our prior investigation showed that the administration of adenine to pregnant rats resulted in the development of CKD, ultimately causing hypertension in their adult offspring. Citrulline, known for enhancing nitric oxide (NO) production and possessing antioxidant and antihypertensive properties, was explored for its potential to reverse high blood pressure (BP) in offspring born to CKD dams. Male rat offspring, both from normal and adenine-induced CKD models, were randomly assigned to four groups (8 animals each): (1) control, (2) CKD, (3) citrulline-treated control rats, and (4) citrulline-treated CKD rats. Citrulline supplementation successfully reversed elevated BP in male progeny born to uremic mothers. The protective effects of perinatal citrulline supplementation were linked to an enhanced NO pathway, decreased expression of renal (pro)renin receptor, and changes in gut microbiota composition. Citrulline supplementation led to a reduction in the abundance of Monoglobus and Streptococcus genera and an increase in Agothobacterium Butyriciproducens. Citrulline's ability to influence taxa associated with hypertension may be linked to its protective effects against maternal CKD-induced offspring hypertension. In conclusion, perinatal citrulline treatment increased NO availability and mitigated elevated BP in rat offspring from uremic mother rats.

CHronic hypERtension and L-citRulline studY (CHERRY): an Early-Phase Randomised Controlled Trial in Pregnancy.

Oral supplementation with L-citrulline, which is sequentially converted to L-arginine then nitric oxide, improves vascular biomarkers and reduces blood pressure in non-pregnant, hypertensive human cohorts and pregnant mice with a pre-eclampsia-like syndrome. This early-phase randomised feasibility trial assessed the acceptability of L-citrulline supplementation to pregnant women with chronic hypertension and its effects on maternal BP and other vascular outcomes. Pregnant women with chronic hypertension were randomised at 12-16 weeks to receive 3-g L-citrulline twice daily (n = 24) or placebo (n = 12) for 8 weeks. Pregnant women reported high acceptability of oral L-citrulline. Treatment increased maternal plasma levels of citrulline, arginine and the arginine:asymmetric dimethylarginine ratio, particularly in women reporting good compliance. L-citrulline had no effect on diastolic BP (L-citrulline: - 1.82 95% CI (- 5.86, 2.22) vs placebo: - 5.00 95% CI (- 12.76, 2.76)), uterine artery Doppler or angiogenic biomarkers. Although there was no effect on BP, retrospectively, this study was underpowered to detect BP changes < 9 mmHg, limiting the conclusions about biological effects. The increase in arginine:asymmetric dimethylarginine ratio was less than in non-pregnant populations, which likely reflects altered pharmacokinetics of pregnancy, and further pharmacokinetic assessment of L-citrulline in pregnancy is advised.Trial Registration EudraCT 2015-005792-25 (2017-12-22) and ISRCTN12695929 (2018-09-20).

Correlations of selenium and selenoprotein P with asymmetric dimethylarginine and lipid profile in patients with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with an increased risk of cardiovascular diseases (CVD). Accumulating evidence has suggested that selenium (Se) is of importance for optimal function of the cardiovascular system. This study aimed to investigate the associations of selenium and selenoprotein P (SePP) with asymmetric dimethylarginine (ADMA) and lipid profile in women with PCOS. METHODS: In this cross-sectional study, 125 females aged 18-45 years diagnosed with PCOS were recruited. An interviewer-administered questionnaire was applied to gather the relevant demographic characteristics, detailed clinical information, and lifestyle habits of participants. Fasting blood samples were obtained to measure biochemical parameters. Serum concentrations of total testosterone, sex hormone-binding globulin (SHBG), ADMA, and lipid profiles as well as anthropometric measurements were assessed across tertiles of serum Se and SePP concentrations. RESULTS: There was a positive correlation between serum Se and SePP concentrations (r = 0.434, p < 0.001). Serum Se level was inversely correlated with ADMA (r = -0.21, p = 0.025) and TG (r = -0.17, p = 0.041) concentrations. There were also inverse correlations between SePP and ADMA (r = -0.34, p < 0.001), TG (r = -0.21, p = 0.019), and oxidized low density lipoprotein (ox-LDL) (r = -0.25, p = 0.007) levels. No significant relationship was found between serum Se and SePP concentrations with total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), apolipoprotein-A1 (Apo-A1), apolipoprotein-B (Apo-B100), total testosterone, SHBG, and free androgen index as well as anthropometric parameters (All p > 0.05). CONCLUSION: The present study found that Se and SePP levels were inversely correlated with ADMA and TG concentrations as well as ox-LDL levels.

Alcohol Drinks Induce Acute Lowering in Circulating l-Arginine in Obese and Type 2 Diabetic Subjects.

Since low serum l-arginine (Arg) and high asymmetric dimethylarginine (ADMA) can predict microvascular complications in type 2 diabetes mellitus (T2DM), we tested whether Arg and ADMA are affected by diet and physical activity in overweight/obese and T2DM subjects. We tested the effects on serum Arg and ADMA of single loads of dextrose, protein, fat, or alcohol (∼300 calories each); one episode of physical exercise; and 12 weeks of standard lifestyle modification (dietary and physical activity counseling). Alcohol drink was followed by ∼30% lowering in Arg. Arg and ADMA increased after a protein load but remained stable after glucose or fat load or 30 min of treadmill walk. Following 12 weeks of lifestyle modification, ADMA declined only in subjects achieving weight loss >5%. In conclusion, alcohol is a previously unrecognized acute suppressor of serum Arg. Lifestyle modification lowers ADMA in subjects who achieve weight loss >5%. Clinical Trial Registration Number: NCT04406402.

Selenium protects against the likelihood of fetal neural tube defects partly via the arginine metabolic pathway.

BACKGROUND AND AIMS: Neural tube defects (NTDs) are severe congenital malformations and have a complex etiology. This study aimed to explore the association between selected essential trace elements (ETEs) and metabolic pathway markers in the serum of women and the likelihood of NTDs. METHODS: The study included 99 mothers of offspring with and 114 mothers of offspring without NTDs. Five ETEs (iron, zinc, selenium [Se], cobalt, and molybdenum) and 106 metabolic pathway markers in maternal serum were quantified. The associations between ETEs and metabolic pathway markers and the chance of NTDs were examined. Mediating effects of the metabolic pathway markers on the association between Se and the likelihood of NTDs were evaluated. RESULTS: Compared to a Se concentration below the median, a concentration above the median was associated with a decreased chance of NTDs with an odds ratio of 0.29 (95% confidence interval: 0.11-0.66). The concentrations of 32 metabolic pathway markers differed between mothers of offspring with and without NTDs; five of these (asymmetric dimethylarginine, ornithine, glutamate, proline, and phenylalanine) were associated with increased chances of NTDs, with adjusted odds ratios of 3.01 (1.31-7.31), 2.79 (1.18-6.86), 2.38 (1.03-5.75), 2.41 (1.05-5.75), and 2.27 (1.09-5.40), respectively, for the higher interquartile of concentration compared to the lower one. Three arginine pathway metabolic markers (i.e., dimethylarginine, ornithine, and proline) mediated the association between Se and the occurrence of NTDs. CONCLUSION: This study suggests an association between Se and a reduced chance of NTDs. The arginine pathway may play a role in mediating this association.

Effect of calcium and vitamin D supplementation on the clinical, hormonal, and metabolic profile in non-obese women with polycystic ovary syndrome.

BACKGROUND: In this study, we investigated the effect of calcium and vitamin D (Ca/Vit D) supplementation on the clinical, hormonal, and metabolic profile of patients with low vitamin D levels. In addition, we investigated the effect of Ca/Vit D supplementation on asymmetric dimethylarginine (ADMA) level in patients with polycystic ovary syndrome (PCOS). METHODS: In total, 75 patients aged 19-35 years, with a normal body mass index and a diagnosis of PCOS and Vit D deficiency/insufficiency, were included in the study. Patients received 50,000 IU of vitamin D3 once a week for 8 weeks. Afterward, 2500 mg calcium carbonate equivalent to 1000 mg calcium ion and 9.68 mg cholecalciferol equivalent to 880 IU vitamin D3 were administered orally as a maintenance treatment once a day. RESULTS: The mean age of the patients was 21.7 ± 3.5. After Ca/Vit D supplementation, Vit D levels significantly increased compared to baseline (8.6 ng/ml) levels. An increase in SHBG levels (p < 0.001), a decrease in total testosterone, FAI (p = 0.042), and ADMA levels (p < 0.001) were observed in the first and third months compared to the onset. Significant improvement compared to baseline was observed in menstrual irregularity and median mFG score. CONCLUSION: Ca/Vit D supplementation can improve PCOS symptoms such as menstrual dysfunction, hirsutism, and hyperandrogenism. It may be effective in reducing the risk of cardiovascular disease in patients with PCOS later in life by decreasing ADMA levels, which is an indicator of endothelial dysfunction.

Melatonin Prevents Chronic Kidney Disease-Induced Hypertension in Young Rat Treated with Adenine: Implications of Gut Microbiota-Derived Metabolites.

Melatonin, a signaling hormone with pleiotropic biofunctions, has shown health benefits. Trimethylamine-N-oxide (TMAO) and asymmetric dimethylarginine (ADMA) are uremic toxins involved in the development of hypertension. TMAO originates from trimethylamine (TMA), a gut microbial product. ADMA is an endogenous nitric oxide (NO) synthase inhibitor. We examined whether melatonin therapy could prevent hypertension and kidney disease by mediating gut microbiota-derived metabolites and the NO pathway using an adenine-induced chronic kidney disease (CKD) young rat model. Six-week-old young Sprague Dawley rats of both sexes were fed a regular diet (C group), a diet supplemented with 0.5% adenine (CKD group), or adenine plus 0.01% melatonin in their drinking water (CKD + M group) for three weeks (N = 8/group). Adenine-fed rats developed renal dysfunction, hypertension, renal hypertrophy and increased uremic toxin levels of TMAO and ADMA. Melatonin therapy prevented hypertension in both sexes and attenuated kidney injury in males. Melatonin reversed the changes to the plasma TMAO-to-TMA ratio induced by CKD in both sexes. Besides, the protective effects of melatonin were associated with restoration of gut microbiota alterations, including increased α-diversity, and enhancement of the abundance of the phylum Proteobacteria and the genus Roseburia in male rats. Melatonin therapy also partially prevented the increases in ADMA in male CKD rats. Melatonin sex-specifically protected young rats against hypertension and kidney injury induced by CKD. The results of this study contribute toward a greater understanding of the interaction between melatonin, gut microbiota-derived metabolites, and the NO pathway that is behind CKD, which will help to prevent CKD-related disorders in children.

[Effect of acupuncture on vascular endothelial function in patients of polycystic ovary syndrome with different glucose tolerance status].

OBJECTIVE: To observe the effect of acupuncture on vascular endothelial function in patients of polycystic ovary syndrome (PCOS) with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). METHODS: A total of 140 patients with PCOS were divided into an IGT group (70 cases, 11 dropped off) and a NGT group (70 cases, 9 cases dropped off). The patients in the two groups were treated with full-cycle acupuncture at Zhongwan (CV 12), Guanyuan (CV 4), Qihai (CV 6), Tianshu (ST 25), etc. once every other day, 3 times a week, for 3 months. Before and after treatment, TCM symptom score, insulin resistance index [including fasting plasma glucose (FPG), 2-hour blood glucose (2hPG), fasting serum insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR)] and vascular endothelial related factors [including asymmetric dimethylarginine (ADMD), endothelin-1 (ET-1), malondialdehyde (MDA), nitric oxide (NO)] were compared between the two groups; in addition, the obese subgroup and non-obese subgroup of the two groups were further compared. RESULTS: Compared before treatment, the TCM symptom scores, ADMD, ET-1 and MDA after treatment were decreased (P<0.05), and NO was increased (P<0.05) in the two groups; FPG, 2hPG, FINS and HOMA-IR after treatment were decreased in the IGT group (P<0.05), the improvement of the above indexes in the IGT group was more significant than that in the NGT group (P<0.05). After treatment, the serum levels of ADMD, ET-1 and MDA were decreased (P<0.05), and NO was increased (P<0.05) in the obese subgroup. In the IGT group, the improvement of serum ADMD, ET-1, MDA and NO in the obese subgroup was more significant than that in the non-obese subgroup (P<0.05). In the NGT group, the improvement of ET-1, MDA and NO in the obese subgroup was more significant than that in the non-obese subgroup (P<0.05). CONCLUSION: Acupuncture could improve vascular endothelial function in PCOS patients, IGT patients have better efficacy than NGT patients, and obese patients have better efficacy than non-obese patients.

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets.

Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-α, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity.

Effect of acupuncture on vascular endothelial function in patients of polycystic ovary syndrome with different glucose tolerance status / 中国针灸

OBJECTIVE@#To observe the effect of acupuncture on vascular endothelial function in patients of polycystic ovary syndrome (PCOS) with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT).@*METHODS@#A total of 140 patients with PCOS were divided into an IGT group (70 cases, 11 dropped off) and a NGT group (70 cases, 9 cases dropped off). The patients in the two groups were treated with full-cycle acupuncture at Zhongwan (CV 12), Guanyuan (CV 4), Qihai (CV 6), Tianshu (ST 25), etc. once every other day, 3 times a week, for 3 months. Before and after treatment, TCM symptom score, insulin resistance index [including fasting plasma glucose (FPG), 2-hour blood glucose (2hPG), fasting serum insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR)] and vascular endothelial related factors [including asymmetric dimethylarginine (ADMD), endothelin-1 (ET-1), malondialdehyde (MDA), nitric oxide (NO)] were compared between the two groups; in addition, the obese subgroup and non-obese subgroup of the two groups were further compared.@*RESULTS@#Compared before treatment, the TCM symptom scores, ADMD, ET-1 and MDA after treatment were decreased (@*CONCLUSION@#Acupuncture could improve vascular endothelial function in PCOS patients, IGT patients have better efficacy than NGT patients, and obese patients have better efficacy than non-obese patients.

Perinatal Resveratrol Therapy Prevents Hypertension Programmed by Maternal Chronic Kidney Disease in Adult Male Offspring: Implications of the Gut Microbiome and Their Metabolites.

The gut microbiota plays a critical role in kidney disease and hypertension; however, whether maternal chronic kidney disease (CKD)-induced offspring hypertension is associated with alterations of the microbiota and microbial metabolites remains elusive. Using rat as an animal model, we conducted a maternal adenine-induced CKD model to examine whether adult male offspring develop hypertension and kidney disease. As resveratrol has antioxidant and prebiotic properties, we also aimed to elucidate whether its use in pregnancy and lactation can benefit hypertension programmed by maternal CKD via mediation of the gut microbiota and oxidative stress. Female Sprague-Dawley rats received regular chow (C) or chow supplemented with 0.5% adenine (CKD) from 3 weeks before pregnancy until lactation. One group of the adenine-induced CKD pregnant rats received resveratrol (R; 50 mg/L) in drinking water during gestation and lactation. Male offspring were divided into three groups: C, CKD, and CKD+R. The microbial metabolites analyzed were short chain fatty acids (SCFAs) in feces and trimethylamine (TMA)/trimethylamine N-oxide (TMAO) in plasma. We found perinatal resveratrol therapy protected against maternal CKD-induced hypertension in adult male offspring. The overall microbial compositions and diversity of bacterial community in the three groups were different. Resveratrol therapy increased α-diversity, decreased the Firmicutes to Bacteroidetes ratio, and increased the abundance of the genera Lactobacillus and Bifidobacterium. Perinatal resveratrol therapy increased plasma TMA levels but decreased the plasma TMAO-to-TMA ratio. Although resveratrol had negligible effect on fecal concentrations of SCFAs, it increased G-protein coupled receptor-41 (GPR41) protein levels in the offspring's kidneys. Additionally, resveratrol therapy increased plasma levels of L-arginine and the L-arginine-to-ADMA ratio (AAR), and decreased oxidative stress. Overall, the protective effects of resveratrol against programmed hypertension are related to gut microbiome remodeling, including an increased abundance of beneficial microbes, mediation of the TMA-TMAO pathway, and alterations of SCFA receptors. Our results highlighted that targeting the microbiome and their metabolites might be potential therapeutic strategies to prevent maternal CKD-induced adverse pregnancy and offspring outcomes.

Physical therapy affects endothelial function in lymphedema patients.

Lymphedema arises due to a malfunction of the lymphatic system and can lead to massive tissue swelling. Complete decongestive therapy (CDT), consisting of manual lymphatic drainage (MLD) and compression bandaging, is aimed at mobilizing fluid and reducing volume in affected extremities. Lymphatic dysfunction has previously been associated with chronic inflammation processes. We investigated plasma ADMA as an indicator of endothelial function/inflammation before-, during- and after-CDT. Also assessed were vascular function parameters such as carotid-femoral pulse wave velocity (PWVcf), flow-mediated dilata-tion (FMD) and retinal microvasculature analysis. 13 patients (3 males and 10 females, 57 ± 8 years old (mean ± SD), 167.2 ± 8.3 cm height, 91.0 ± 23.5 kg weight), with lower limb lymphedema were included. Vascular function parameters were assessed on day 1, 2, 7, 14 and 21 of CDT, pre- and post-MLD. ADMA was significantly lower post-MLD (p=0.0064) and tended to reduce over three weeks of therapy (p=0.0506). PWVcf weakly correlated with FMD (r=0.361, p=0.010). PWVcf, FMD and retinal microvasculature analysis did not show changes due to physical therapy. The novel results from this study indicate that lymphedema does not affect endothelial func-tion and lymphedema patients may therefore not have a higher risk of cardiovas-cular diseases. Our results further suggest that manual lymphatic drainage with or without full CDT could have potentially beneficial effects on endothelial function in lymphedema patients (by reducing ADMA levels), which has not been reported previously.

Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites.

Maternal chronic kidney disease (CKD) during pregnancy causes adverse fetal programming. Nitric oxide (NO) deficiency, gut microbiota dysbiosis, and dysregulated renin-angiotensin system (RAS) during pregnancy are linked to the development of hypertension in adult offspring. We examined whether maternal adenine-induced CKD can program hypertension and kidney disease in adult male offspring. We also aimed to identify potential mechanisms, including alterations of gut microbiota composition, increased trimethylamine-N-oxide (TMAO), reduced NO bioavailability, and dysregulation of the RAS. To construct a maternal CKD model, female Sprague-Dawley rats received regular chow (control group) or chow supplemented with 0.5% adenine (CKD group) for 3 weeks before pregnancy. Mother rats were sacrificed on gestational day 21 to analyze placentas and fetuses. Male offspring (n = 8/group) were sacrificed at 12 weeks of age. Adenine-fed rats developed renal dysfunction, glomerular and tubulointerstitial damage, hypertension, placental abnormalities, and reduced fetal weights. Additionally, maternal adenine-induced CKD caused hypertension and renal hypertrophy in adult male offspring. These adverse pregnancy and offspring outcomes are associated with alterations of gut microbiota composition, increased uremic toxin asymmetric and symmetric dimethylarginine (ADMA and SDMA), increased microbiota-derived uremic toxin TMAO, reduced microbiota-derived metabolite acetate and butyrate levels, and dysregulation of the intrarenal RAS. Our results indicated that adenine-induced maternal CKD could be an appropriate model for studying uremia-related adverse pregnancy and offspring outcomes. Targeting NO pathway, microbiota metabolite TMAO, and the RAS might be potential therapeutic strategies to improve maternal CKD-induced adverse pregnancy and offspring outcomes.

Asymmetric dimethylarginine predicts perioperative cardiovascular complications in patients undergoing medium-to-high risk non-cardiac surgery.

OBJECTIVES: Perioperative cardiovascular events remain an important factor that affects surgery outcome. We assessed if asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, predicts perioperative risk, and if pre-operative supplementation with L-arginine/L-citrulline improves the plasma L-arginine/ADMA ratio. METHODS: In this prospective study, planned thoracic and/or abdominal surgery patients were randomized to receive L-arginine/L-citrulline (5 g/day) or placebo 1 to 5 days before surgery. We measured perioperative plasma ADMA and L-arginine levels. The primary outcome was a 30-day combined cardiovascular endpoint. RESULTS: Among 269 patients, 23 (8.6%) experienced a major adverse cardiovascular event. ADMA and C-reactive protein were significantly associated with the incidence of cardiovascular complications in the multivariable-adjusted analysis. The L-arginine plasma concentration was significantly higher on the day of surgery with L-arginine/L-citrulline supplementation compared with placebo. In patients with high pre-operative ADMA, there was a non-significant trend towards reduced incidence of the primary endpoint with L-arginine/L-citrulline supplementation (six vs. nine events). CONCLUSIONS: ADMA is a predictor of major adverse cardiovascular complications in the perioperative period for patients who are undergoing major abdominal and/or thoracic surgery. Supplementation with L-arginine/L-citrulline increased the L-arginine plasma concentration, enhanced the L-arginine/ADMA ratio, and induced a trend towards fewer perioperative events.

Elevated plasma homocysteine levels are associated with impaired peripheral microvascular vasomotor response.

BACKGROUND: Hyperhomocysteinemia (HHcy) has been proposed as an important cardiovascular risk factor (cRF). However, little is known about the association between plasma homocysteine levels and peripheral microvascular endothelial dysfunction (PMED), which is an integrated index of vascular health. METHODS: This cross-sectional and retrospective cohort study included patients who underwent non-invasive PMED assessment using reactive hyperemia peripheral arterial tonometry (RH-PAT). The association between HHcy and PMED, and its impact on MACE (all-cause mortality and atherosclerotic cardiovascular events) was investigated. RESULTS: A total of 257 patients were enrolled (HHcy > 10.0 µmol/L, N = 51; lower levels of homocysteine [LHcy] ≤ 10 µmol/L, N = 206). Patients with HHcy were older, predominantly males, and with more comorbidities than patients with LHcy (p < 0.05 for all). RH-PAT index was lower in patients with HHcy versus LHcy (p = 0.01). A significant association between HHcy and PMED was observed in older (≥60 years), obese (≥30 kg/m2), present/past smokers and hypertensive patients. HHcy was significantly associated with PMED even after adjusting for other cRF and B-vitamins supplementation. HHcy was associated with an increased risk of MACE with a hazard ratio of 3.65 (95% CI 1.41-9.48, p = 0.01) and an adjusted hazard ratio of 2.44 (95% CI 0.91-6.51, p = 0.08) after adjustment for age (≥60 years). CONCLUSION: HHcy was independently associated with PMED after adjusting for cRF and B-vitamins supplementation. Thus, the link between homocysteine and MACE could be mediated by endothelial dysfunction, and will require further clarification with future studies.

The Effect of Vitamin D on Serum Asymmetric Dimethylarginine in Patients with Mild to Moderate Ulcerative Colitis.

Purpose: In inflammatory bowel disease increased asymmetric dimethylarginine (ADMA) levels could inhibit nitric oxide (NO) synthase. Vitamin D may increase activity and expression of endothelial NO synthase, which could be done through its possible mechanism of decreasing ADMA levels. The aim of this study is to investigate the possible effect of Vitamin D3 on serum ADMA levels in ulcerative colitis (UC) patients. Methods: Ninety mild to moderate UC patients were randomized. Each patient received one single muscular injection of 300,000 IU (7500 µg) Vitamin D3 (Vitamin D group) or 1 ml normal saline (Placebo group). At baseline and 90 days after the intervention measurements were done. Data were analyzed using independent t-test and analysis of covariance. Baseline correlations were assessed by Pearson and Spearman correlation coefficients. Results: Following data analysis of 86 participants (40 in placebo and 46 in vitamin D group), there was no correlation between baseline ADMA with baseline vitamin D, ESR and hs-CRP at baseline (p = 0.77) and at the end of study (p = 0.82). Serum ADMA levels were not statistically different between two groups. Adjustment for baseline ADMA levels and baseline body mass index (BMI) did not change the results. With subgroup analyses based on gender and vitamin D level no statistical differences in ADMA levels between two groups were found. Conclusions: In this study, we found no significant changes in serum ADMA levels 3 months following a high dose vitamin D administration in mild to moderate UC patients. Further studies in vitamin D deficient patients are needed.

Impact of zinc oxide nanoparticles on thioredoxin-interacting protein and asymmetric dimethylarginine as biochemical indicators of cardiovascular disorders in gamma-irradiated rats.

Nanoparticle is a microscopic particle that has been existed in a wide range of biotechnological purposes. Zinc oxide nanoparticles (ZnO-NPs) have fewer environmental hazards and have shown positive impacts in the medical field. This work aimed to observe the effects of low and high doses of ZnO-NPs on heart injury induced by ionizing radiation (IR). Animals were irradiated by 8 Gy of gamma rays and ZnO-NPs (10 and 300 mg/Kg/day) were orally delivered to rats 1 hour after irradiation. Animals were dissected on 15th day postirradiation. Data showed that the oxidative damage resulted from radiation exposure, appeared by marked increments in the malondialdehyde (MDA) content and the level and protein expression of thioredoxin-interacting protein (TXNIP) with a noticeable decline in the level and expression of thioredoxin 1 (Trx-1) and thioredoxin reductase (TrxR), as well as glutathione (GSH) level and the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Moreover, radiation-induced inflammation, manifested by a noticeable elevation in the level of tumor necrotic factor-alpha (TNF-α), interleukin-18 (IL-18), and C-reactive protein (CRP). Additionally, endothelial dysfunction marked with a high level of asymmetric dimethylarginine (ADMA), total nitrite/nitrate (NOx), intercellular adhesion molecule 1 (ICAM-1), homocysteine (Hcy), creatine kinase (CK-MB), cardiac troponin-I (cTn-I), and lactate dehydrogenase (LDH). In addition, a decrease of zinc (Zn) level in the cardiac tissue was recorded. ZnO-NPs treatment (10 mg/kg) mitigated the oxidative stress and inflammation effects on the cardiovascular tissue through the positive modulations in the studied parameters. In contrast, ZnO-NPs treatment (300 mg/kg) induced cardiovascular toxicity of normal rats and elevated the deleterious effects of radiation. In conclusion, ZnO-NPs at a low dose could mitigate the adverse effects on cardiovascular tissue induced by radiation during its applications, while the high dose showed morbidity and mortality in normal and irradiated rats.

Effects of Selenium Supplementation on Asymmetric Dimethylarginine and Cardiometabolic Risk Factors in Patients with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is characterized by various reproductive and cardiometabolic disorders. Asymmetric dimethylarginine (ADMA) is associated with cardiovascular, metabolic, and hormonal status. Selenium, a micronutrient with antioxidant properties, could affect multiple physiological pathways. This study aimed to investigate the effect of selenium supplementation on ADMA, cardiometabolic risk factors, and hormonal status in women with PCOS. In this randomized, double-blind, placebo-controlled clinical trial, 66 women with PCOS, aged 18-45 years, were randomly assigned to receive either 200 µg/day selenium or placebo, for 12 weeks. Circulating concentrations of ADMA, testosterone, sex hormone-binding globulin (SHBG), lipid profiles, and glycemic parameters were assessed at baseline and following supplementation. ADMA concentration decreased significantly compared to baseline values (85.14 ± 75 to 56.4 ± 38.64 ng/l, p = 0.02) in the selenium group. This change was marginally significant compared with the placebo group (28.74 ± 68.63 vs. - 1.77 ± 52.88 ng/l, p = 0.056). Serum testosterone levels declined significantly in the intervention compared to the placebo group (0.01 ± 0.17 vs. - 0.08 ± 0.18 ng/ml, p = 0.038). Pre- to post-Apo-B100/Apo-A1 ratio declined considerably in the intervention group (0.72 ± 0.16 to 0.65 ± 0.16, p = 0.003). No further differences were observed in SHBG, lipid profiles, Apo-A1, Apo-B100, Apo-B100/Apo-A1 ratio, and glycemic control between the two groups at the end of the study. Selenium supplementation for 12 weeks had beneficial effects on reduction of circulating ADMA and total testosterone levels in women with PCOS. No significant improvements were seen in other cardiometabolic risk factors. The effects of selenium supplementation on hormonal, reproductive, and cardiometabolic disorders, considering the potential mediating role of ADMA, should be further investigated.

Blueberry anthocyanin­enriched extract ameliorates transverse aortic constriction­induced myocardial dysfunction via the DDAH1/ADMA/NO signaling pathway in mice.

Blueberry anthocyanin­enriched extract (BAE) has been demonstrated to protect against cardiovascular diseases by activating multiple target genes. The present study investigated the effects of BAE on transverse aortic constriction (TAC)­induced myocardial dysfunction in mice and explored its possible molecular mechanisms. A total of 30 male mice were divided randomly into control, TAC and TAC + BAE groups. Mice in the TAC + BAE groups were administered BAE by oral gavage for 6 consecutive weeks. Myocardial dysfunction was assessed using echocardiogram, histopathology, TUNEL assay, immunofluorescence staining, reverse transcription­quantitative PCR and western blot analysis. The results demonstrated that BAE treatment significantly ameliorated heart weight, left ventricular weight, myocardial dysfunction, left ventricular hypertrophy and fibrosis. In addition, BAE treatment alleviated TAC­induced inflammation, oxidative stress and apoptosis. Notably, BAE treatment markedly reduced asymmetric dimethylarginine (ADMA) concentration and significantly increased dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression and nitric oxide (NO) production. The present data indicated that BAE treatment ameliorated TAC­induced myocardial dysfunction, oxidative stress, inflammatory response and apoptosis via the DDAH1/ADMA/NO signaling pathway.

Impact of Arginine Nutrition and Metabolism during Pregnancy on Offspring Outcomes.

By serving as a precursor for the synthesis of nitric oxide, polyamines, and other molecules with biological importance, arginine plays a key role in pregnancy and fetal development. Arginine supplementation is a potential therapy for treating many human diseases. An impaired arginine metabolic pathway during gestation might produce long-term morphological or functional changes in the offspring, namely, developmental programming to increase vulnerability to developing a variety of non-communicable diseases (NCDs) in later life. In contrast, reprogramming is a strategy that shifts therapeutic interventions from adulthood to early-life, in order to reverse the programming processes, which might counterbalance the rising epidemic of NCDs. This review presented the role of arginine synthesis and metabolism in pregnancy. We also provided evidence for the links between an impaired arginine metabolic pathway and the pathogenesis of compromised pregnancy and fetal programming. This was followed by reprogramming strategies targeting the arginine metabolic pathway, to prevent the developmental programming of NCDs. Despite emerging evidence from experimental studies showing that targeting the arginine metabolic pathway has promise as a reprogramming strategy in pregnancy to prevent NCDs in the offspring, these results need further clinical application.