Publications by authors named "You-Lin Tain"

235 Publications

Maternal Fructose Intake Exacerbates Cardiac Remodeling in Offspring with Ventricular Pressure Overload.

Nutrients 2021 Sep 18;13(9). Epub 2021 Sep 18.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan.

Recent studies demonstrated that metabolic syndrome and cardiovascular diseases could be elicited by developmental programming, which is regulated by prenatal nutritional and environmental stress. In this study, we utilized a rat model to examine the effect of excessive maternal fructose intake during pregnancy and lactation on cardiac development and progression of pressure overload-induced cardiac hypertrophy in offspring. Transverse aortic constriction (TAC) was performed on 3-month-old male offspring to induce ventricular pressure overload. Four weeks post-TAC, echocardiographic assessment as well as histopathological and biochemical examinations were performed on the myocardium of the offspring. Echocardiographic and gross examinations showed that heart weight, interventricular septal thickness in diastole (IVD; d), and left ventricular posterior wall thickness in diastole (LVPW; d) were elevated in offspring with TAC and further increased by maternal fructose exposure (MFE). However, the left ventricular ejection function was not significantly affected. Myocardial histopathological examination revealed that the indices of fibrosis and oxidative stress were higher in offspring with MFE and TAC than those in animals receiving either treatment. Molecular examinations on the myocardium demonstrated an MFE-induced upregulation of p38-MAPK signaling. Next generation sequence (NGS) analysis indicated a modulation of the expression levels of several cardiac hypertrophy-associated genes, including GPR22, Myh7, Nppa, P2RX4, and Npy by MFE. Subsequent RT-PCR indicated that MFE regulated the expression levels of genes responsive to cardiac hypertrophy (i.e., Myh-7, ANP) and oxidative stress (i.e., GR, GPx, and NQO-1). In conclusion, MFE during pregnancy and lactation modulated myocardial gene expression, increased oxidative stress, and exacerbated ventricular pressure overload-induced cardiac remodeling in rat offspring.
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http://dx.doi.org/10.3390/nu13093267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467570PMC
September 2021

Maternal 3,3-Dimethyl-1-Butanol Therapy Protects Adult Male Rat Offspring against Hypertension Programmed by Perinatal TCDD Exposure.

Nutrients 2021 Aug 30;13(9). Epub 2021 Aug 30.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan.

Maternal exposure to environmental pollutants affects fetal development, which can result in hypertension in adulthood. Gut microbiota-derived metabolite trimethylamine (TMA), trimethylamine-N-oxide (TMAO), and short chain fatty acids (SCFAs) have been associated with hypertension. We tested a hypothesis that maternal 3,3-Dimethyl-1-butanol (DMB, a TMA inhibitor) therapy prevents 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure-induced hypertension in adult offspring relevant to alterations of gut microbiota-derived metabolites, the mediation of aryl hydrocarbon receptor (AHR) signaling, and the renin-angiotensin system (RAS). Pregnant Sprague-Dawley rats were given weekly oral dose of TCDD 200 ng/kg for four doses (T), 1% DMB in drinking water (D), TCDD + DMB (TD), or vehicle (C) in pregnancy and lactation periods. Male progeny ( = 8/group) were sacrificed at the age of 12 weeks. Perinatal TCDD exposure caused hypertension in adult male offspring coinciding with reduced -diversity, increased the to ratio, less abundant beneficial bacteria, impaired SCFA receptors' expression, the activation of AHR signaling, and the aberrant activation of the RAS. Treatment with DMB during pregnancy and lactation rescued hypertension induced by perinatal TCDD exposure. This was accompanied by reshaping gut microbiota, mediating TMA-TMAO metabolic pathway, increasing acetic acid and its receptors, and restoring the AHR and RAS pathway. Our data provide new insights into the therapeutic potential of DMB, a microbiome-based metabolite treatment, for the prevention of hypertension of developmental origins.
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http://dx.doi.org/10.3390/nu13093041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467313PMC
August 2021

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

Antioxidants (Basel) 2021 Aug 30;10(9). Epub 2021 Aug 30.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 83301, Taiwan.

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 ( = 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 , , and . 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.
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http://dx.doi.org/10.3390/antiox10091393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470291PMC
August 2021

Rapid Detection of Gut Microbial Metabolite Trimethylamine N-Oxide for Chronic Kidney Disease Prevention.

Biosensors (Basel) 2021 Sep 14;11(9). Epub 2021 Sep 14.

Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung 804201, Taiwan.

The gut microbiota plays a critical role in chronic kidney disease (CKD) and hypertension. Trimethylamine-N-oxide (TMAO) and trimethylamine (TMA) are gut microbiota-derived metabolites, and both are known uraemic toxins that are implicated in CKD, atherosclerosis, colorectal cancer and cardiovascular risk. Therefore, the detection and quantification of TMAO, which is a metabolite from gut microbes, are important for the diagnosis of diseases such as atherosclerosis, thrombosis and colorectal cancer. In this study, a new "colour-switch" method that is based on the combination of a plasma separation pad/absorption pad and polyallylamine hydrochloride-capped manganese dioxide ([email protected]) nanozyme was developed for the direct quantitative detection of TMAO in whole blood without blood sample pretreatment. As a proof of concept, a limit of quantitation (LOQ) of less than 6.7 μM for TMAO was obtained with a wide linear quantification range from 15.6 to 500 μM through quantitative analysis, thereby suggesting potential clinical applications in blood TMAO monitoring for CKD patients.
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http://dx.doi.org/10.3390/bios11090339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469701PMC
September 2021

Metformin ameliorates maternal high-fat diet-induced maternal dysbiosis and fetal liver apoptosis.

Lipids Health Dis 2021 Sep 8;20(1):100. Epub 2021 Sep 8.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Background: The deleterious effect of maternal high-fat diet (HFD) on the fetal rat liver may cause later development of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effect of maternal HFD-induced maternal hepatic steatosis and dysbiosis on the fetal liver and intestines, and the effect of prenatal metformin in a rat model.

Methods: Sprague-Dawley rats were assigned to three groups (N = 6 in each group). Before mating, the rats were randomly assigned to HFD or normal-chow diet (NCD) group for 7 weeks. After mating, the HFD group rats were continued with high-fat diet during pregnancy and some of the HFD group rats were co-treated with metformin (HFMf) via drinking water during pregnancy. All maternal rats and their fetuses were sacrificed on gestational day 21. The liver and intestinal tissues of both maternal and fetal rats were analyzed. In addition, microbial deoxyribonucleic acid extracted from the maternal fecal samples was analyzed.

Results: HFD resulted in maternal weight gain during pregnancy, intrahepatic lipid accumulation, and change in the serum short-chain fatty acid profile, intestinal tight junctions, and dysbiosis in maternal rats. The effect of HFD on maternal rats was alleviated by prenatal metformin, which also ameliorated inflammation and apoptosis in the fetal liver and intestines.

Conclusions: This study demonstrated the beneficial effects of prenatal metformin on maternal liver steatosis, focusing on the gut-liver axis. In addition, the present study indicates that prenatal metformin could ameliorate maternal HFD-induced inflammation and apoptosis in the fetal liver and intestines. This beneficial effect of in-utero exposure of metformin on fetal liver and intestines has not been reported. This study supports the use of prenatal metformin for pregnant obese women.
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http://dx.doi.org/10.1186/s12944-021-01521-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424801PMC
September 2021

Cardiovascular Disease Risk in Children With Chronic Kidney Disease: Impact of Apolipoprotein C-II and Apolipoprotein C-III.

Front Pediatr 2021 12;9:706323. Epub 2021 Aug 12.

Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

Cardiovascular disease (CVD) is an evolving process that begins in the early stages of chronic kidney disease (CKD) in children. Several surrogate markers, such as ambulatory blood pressure monitoring (ABPM), left ventricular (LV) mass, and arterial stiffness assessment, allow for the early detection of subclinical CVD in pediatric CKD. Four groups of plasma samples ( = 3/group) from congenital anomalies of the kidney and urinary tract (CAKUT), as well as non-CAKUT patients with or without BP abnormalities, were studied to screen differentially expressed proteins using isobaric tags for relative and absolute protein quantification (iTRAQ)-based proteomics. As a result, 20 differentially expressed proteins associated with hypertension in children with CKD were discovered. Among them, apolipoprotein C-II (apoC-II) was found to have the highest abundance among the CKD patients with hypertension. As such, we hypothesized that apoC-II and apolipoprotein C-III (apoC-III) levels were related to BP abnormalities and CVD in children suffering from mild-to-moderate CKD. We examined their associations with surrogate markers of CV risk in 88 pediatric patients with CKD stages G1-G4. Children with CKD stages G2-G4 had a higher plasma apoC-II level than G1 patients (6.35 vs. 5.05 mg/dl, < 0.05). We observed that ABPM abnormalities, LV mass, and arterial stiffness parameters were greater in CKD children who had stages G2-G4 than in those who had stage G1 (all < 0.05). Plasma levels of apoC-II and apoC-III were positively correlated with total cholesterol, triglyceride, and low-density lipoprotein (LDL) (all < 0.001). In multivariate linear regression analyses, apoC-II was correlated with a high LV mass index and an abnormal ABPM profile, and apoC-III was correlated with 24-h hypertension ( = 0.303, = 0.003) and asleep hypertension ( = 0.379, < 0.001). Early evaluations of apoC-II and apoC-III, ABPM, and surrogate markers of CV risk will aid in early preventative interventions to reduce the risk of CV in youths suffering from CKD.
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http://dx.doi.org/10.3389/fped.2021.706323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397580PMC
August 2021

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

Antioxidants (Basel) 2021 Jul 28;10(8). Epub 2021 Jul 28.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan.

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 and the genus 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.
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http://dx.doi.org/10.3390/antiox10081211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388963PMC
July 2021

Fat Mass Index Associated with Blood Pressure Abnormalities in Children with Chronic Kidney Disease.

Children (Basel) 2021 Jul 22;8(8). Epub 2021 Jul 22.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Cardiovascular disease (CVD) risk factors are present early in life in children with chronic kidney disease (CKD), consequently cardiovascular morbidity presents in early adulthood. However, risk factors of CVD have been rarely addressed in children with early stage of CKD. This study included 63 children and adolescents aged 8- to 18 years-old with CKD stage G1-G4. Cardiovascular assessments consisted of 24-h ambulatory blood pressure monitoring (ABPM), arterial stiffness index, and echocardiography. We also applied dual-energy x-ray absorptiometry (DXA) scanning to analyze percentage body fat (PBF), lean body mass index (LBMI), fat mass index (FMI), and the android to gynoid fat ratio (A/G ratio). Up to 63.5% of CKD children had abnormal changes in BP detected by ABPM. CKD children with abnormal ABPM were older, had higher numbers of CKD stage G2 to G4, hyperuricemia, obesity, and higher FMI z-score and A/G ratio compared to individuals with normal ABPM (all < 0.05). Among these factors, only FMI z-score showed an independent association with abnormal ABPM using multivariate logistic regression analysis ( = 0.037). Our data highlight that body fat plays a key role for an abnormal ABPM in CKD children. The assessment of FMI may have clinical utility in discriminating CV risk in children and adolescents with early stages of CKD.
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http://dx.doi.org/10.3390/children8080621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391711PMC
July 2021

Cardiovascular Diseases of Developmental Origins: Preventive Aspects of Gut Microbiota-Targeted Therapy.

Nutrients 2021 Jul 1;13(7). Epub 2021 Jul 1.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Cardiovascular diseases (CVDs) can originate from early life. Accumulating evidence suggests that gut microbiota in early life is linked to CVDs in later life. Gut microbiota-targeted therapy has gained significant importance in recent decades for its health-promoting role in the prevention (rather than just treatment) of CVDs. Thus far, available gut microbiota-based treatment modalities used as reprogramming interventions include probiotics, prebiotics, and postbiotics. The purpose of this review is, first, to highlight current studies that link dysbiotic gut microbiota to the developmental origins of CVD. This is followed by a summary of the connections between the gut microbiota and CVD behind cardiovascular programming, such as short chain fatty acids (SCFAs) and their receptors, trimethylamine-N-oxide (TMAO), uremic toxins, and aryl hydrocarbon receptor (AhR), and the renin-angiotensin system (RAS). This review also presents an overview of how gut microbiota-targeted reprogramming interventions can prevent the developmental origins of CVD from animal studies. Overall, this review reveals that recent advances in gut microbiota-targeted therapy might provide the answers to reduce the global burden of CVDs. Still, additional studies will be needed to put research findings into practice.
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http://dx.doi.org/10.3390/nu13072290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308390PMC
July 2021

Gasotransmitters for the Therapeutic Prevention of Hypertension and Kidney Disease.

Int J Mol Sci 2021 Jul 21;22(15). Epub 2021 Jul 21.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (HS), three major gasotransmitters, are involved in pleiotropic biofunctions. Research on their roles in hypertension and kidney disease has greatly expanded recently. The developing kidney can be programmed by various adverse in utero conditions by so-called renal programming, giving rise to hypertension and kidney disease in adulthood. Accordingly, early gasotransmitter-based interventions may have therapeutic potential to revoke programming processes, subsequently preventing hypertension and kidney disease of developmental origins. In this review, we describe the current knowledge of NO, CO, and HS implicated in pregnancy, including in physiological and pathophysiological processes, highlighting their key roles in hypertension and kidney disease. We summarize current evidence of gasotransmitter-based interventions for prevention of hypertension and kidney disease in animal models. Continued study is required to assess the interplay among the gasotransmitters NO, CO, and HS and renal programming, as well as a greater focus on further clinical translation.
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http://dx.doi.org/10.3390/ijms22157808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345973PMC
July 2021

Resveratrol Butyrate Esters Inhibit Obesity Caused by Perinatal Exposure to Bisphenol A in Female Offspring Rats.

Molecules 2021 Jun 30;26(13). Epub 2021 Jun 30.

Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 824, Taiwan.

Resveratrol butyrate esters (RBE) are derivatives of resveratrol (RSV) and butyric acid and exhibit biological activity similar to that of RSV but with higher bioavailability. The aim of this study was designed as an animal experiment to explore the effects of RBE on the serum biochemistry, and fat deposits in the offspring rats exposed to bisphenol A (BPA), along with the growth and decline of gut microbiota. We constructed an animal model of perinatal Bisphenol A (BPA) exposure to observe the effects of RBE supplementation on obesity, blood lipids, and intestinal microbiota in female offspring rats. Perinatal exposure to BPA led to weight gain, lipid accumulation, high levels of blood lipids, and deterioration of intestinal microbiota in female offspring rats. RBE supplementation reduced the weight gain and lipid accumulation caused by BPA, optimised the levels of blood lipids, significantly reduced the Firmicutes/Bacteroidetes (F/B) ratio, and increased and decreased the abundance of S24-7 and Lactobacillus, respectively. The analysis of faecal short-chain fatty acid (SCFA) levels revealed that BPA exposure increased the faecal concentration of acetate, which could be reduced via RBE supplementation. However, the faecal concentrations of propionate and butyrate were not only significantly lower than that of acetate, but also did not significantly change in response to BPA exposure or RBE supplementation. Hence, RBE can suppress BPA-induced obesity in female offspring rats, and it demonstrates excellent modulatory activity on intestinal microbiota, with potential applications in perinatological research.
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http://dx.doi.org/10.3390/molecules26134010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271435PMC
June 2021

Prenatal Exposure to Di-Ethyl Phthalate (DEP) Is Related to Increasing Neonatal IgE Levels and the Altering of the Immune Polarization of Helper-T Cells.

Int J Environ Res Public Health 2021 06 11;18(12). Epub 2021 Jun 11.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.

Phthalates are substances that are added to plastic products to increase their plasticity. These substances are released easily into the environment and can act as endocrine disruptors. Epidemiological studies in children have showed inconsistent findings regarding the relationship between prenatal or postnatal exposure to phthalates and the risk of allergic disease. Our hypothesis is that prenatal exposure to phthalates may contribute to the development of allergies in children. The objective of this study was to determine the associations between urinary phthalate metabolite concentrations in pregnant women, maternal atopic diathesis, maternal lifestyle, and cord blood IgE. Pregnant mothers and paired newborns (n = 101) were enrolled from an antenatal clinic. The epidemiologic data and the clinical information were collected using standard questionnaires and medical records. The maternal blood and urine samples were collected at 24-28 weeks gestation, and cord blood IgE, IL-12p70, IL-4, and IL-10 levels were determined from the newborns at birth. The link between phthalates and maternal IgE was also assessed. To investigate the effects of phthalates on neonatal immunity, cord blood mononuclear cells (MNCs) were used for cytokine induction in another in vitro experiment. We found that maternal urine monoethyl phthalate (MEP) (a metabolite of di-ethyl phthalate (DEP)) concentrations are positively correlated with the cord blood IgE of the corresponding newborns. The cord blood IL-12p70 levels of mothers with higher maternal urine MEP groups (high DEP exposure) were lower than mothers with low DEP exposure. In vitro experiments demonstrated that DEP could enhance IL-4 production of cord blood MNCs rather than adult MNCs. Prenatal DEP exposure is related to neonatal IgE level and alternation of cytokines relevant to Th1/Th2 polarization. This suggests the existence of a link between prenatal exposure to specific plasticizers and the future development of allergies.
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http://dx.doi.org/10.3390/ijerph18126364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296186PMC
June 2021

Changing trends in dialysis modalities utilization and mortality in children, adolescents and young adults with acute kidney injury, 2010-2017.

Sci Rep 2021 06 4;11(1):11887. Epub 2021 Jun 4.

Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 833, Taiwan.

The aim of the study was to assess trends in the relative use of dialysis modalities in the hospital-based pediatric cohort and to determine risk factors associated with in-hospital morality among pediatric patients receiving dialysis for acute kidney injury (AKI). Patients aged < 20 years who received dialysis between 2010 and 2017 were identified from electronic health records databases of a Taiwan's healthcare delivery system. The annual uses of intermittent hemodialysis (HD), continuous and automated peritoneal dialysis (PD) and continuous kidney replacement therapy (CKRT) were assessed using Cochran-Armitage Tests for trend. Among patients who received their first dialysis as inpatients for AKI, a multivariate logistic regression model was employed to assess mortality risks associated with dialysis modalities, patient demographics, complexity of baseline chronic disease, and healthcare service use during their hospital stays. Kidney dialysis was performed 37.9 per patient per year over the study period. Intermittent hemodialysis (HD) (73.3%) was the most frequently used dialysis modality. In the inpatient setting, the relative annual use of CKRT increased over the study period, while HD use concomitantly declined (P < 0.0001). The overall in-hospital mortality rate after dialysis for AKI was 33.6%, which remained steady over time (P = 0.2411). Patients aged < 2 years [adjusted odds ratio: (aOR) 3.36; 95% confidence interval (CI) 1.34-8.93] and greater vasoactive regimen use (aOR: 17.1; 95% CI: 5.3-55.21) were significantly associated with dialysis-related mortality. Overall treatment modality used for dialysis in pediatric patients increased slowly in the study period, and HD and CRKT modality uses largely evolved in the inpatient setting. Younger ages and use of more vasoactive medication regimens were independently associated with increased early mortality in patients on AKI-dialysis.
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http://dx.doi.org/10.1038/s41598-021-91171-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178371PMC
June 2021

Animal Models for DOHaD Research: Focus on Hypertension of Developmental Origins.

Biomedicines 2021 May 31;9(6). Epub 2021 May 31.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Increasing evidence suggests that fetal programming through environmental exposure during a critical window of early life leads to long-term detrimental outcomes, by so-called developmental origins of health and disease (DOHaD). Hypertension can originate in early life. Animal models are essential for providing convincing evidence of a causal relationship between diverse early-life insults and the developmental programming of hypertension in later life. These insults include nutritional imbalances, maternal illnesses, exposure to environmental chemicals, and medication use. In addition to reviewing the various insults that contribute to hypertension of developmental origins, this review focuses on the benefits of animal models in addressing the underlying mechanisms by which early-life interventions can reprogram disease processes and prevent the development of hypertension. Our understanding of hypertension of developmental origins has been enhanced by each of these animal models, narrowing the knowledge gap between animal models and future clinical translation.
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http://dx.doi.org/10.3390/biomedicines9060623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227380PMC
May 2021

Resveratrol Butyrate Esters Inhibit BPA-Induced Liver Damage in Male Offspring Rats by Modulating Antioxidant Capacity and Gut Microbiota.

Int J Mol Sci 2021 May 17;22(10). Epub 2021 May 17.

Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan.

Resveratrol can affect the physiology or biochemistry of offspring in the maternal-fetal animal model. However, it exhibits low bioavailability in humans and animals. Fifteen-week SD pregnant female rats were orally administered bisphenol A (BPA) and/or resveratrol butyrate ester (RBE), and the male offspring rats (n = 4-8 per group) were evaluated. The results show that RBE treatment (BPA + R30) compared with the BPA group can reduce the damage caused by BPA ( < 0.05). RBE enhanced the expression of selected genes and induced extramedullary hematopoiesis and mononuclear cell infiltration. RBE increased the abundance of and Adlercreutzia in the intestines of the male offspring rats, as well as the concentrations of short-chain fatty acids (SCFAs) in the feces. RBE also increased the antioxidant capacity of the liver by inducing Nrf2, promoting the expression of HO-1, SOD, and CAT. It also increased the concentration of intestinal SCFAs, enhancing the barrier formed by intestinal cells, thereby preventing BPA-induced metabolic disruption in the male offspring rats, and reduced liver inflammation. This study identified a potential mechanism underlying the protective effects of RBE against the liver damage caused by BPA exposure during the peri-pregnancy period, and the influence of the gut microbiota on the gut-liver axis in the offspring.
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http://dx.doi.org/10.3390/ijms22105273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156118PMC
May 2021

Clinical characteristics, triggering etiologies, and response of plasmapheresis in thrombotic microangiopathy in Taiwan.

Medicine (Baltimore) 2021 May;100(20):e25986

Clinical Immunological Center, Children's Hospital, China Medical University, Taichung, Taiwan.

Abstract: Thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse in clinical presentations and etiologies. However, there are still a limited number of large cohort studies focusing on the underlying causes, outcomes, and response to plasmapheresis.A retrospective study was designed to understand trigger etiologies, organ dysfunctions, clinical outcomes, and efficacy of plasmapheresis in patients with TMA. The whole population of Taiwan was set up into 2 cohorts: 875 patients with TMA in the 2006 cohort (2006-2010) and 1352 patients with TMA in the 2011 cohort (2011-2015). One hundred ninety-five patients in the 2006 cohort and 272 patients in the 2011 cohort were under plasmapheresis treatment.The common underlying etiologies were pregnancy, followed by systemic lupus erythematosus, rheumatoid arthritis, transplantation and drugs, which were significantly higher than the control group. Stroke, seizure, arterial thrombosis, vascular stenosis, hypertension, myocardial infarction, and pancreatitis were the main clinical signs and extra-renal involvements. In the multivariate regression analysis, stroke, arterial thrombosis, peripheral arterial disease, and uremia were significantly higher compared with the control group. The mortality rate in TMA under plasmapheresis was significantly higher than all TMA cases (39.33% vs 15.39% in the 2006 cohort and 39.27% vs 15.06% in the 2011 cohort).This study indicated the spectrum of underlying causes, extra-renal characteristics, and the response to plasmapheresis of patients with TMA in Taiwan. Of note, the poor clinical outcomes of plasmapheresis in patients with TMA might highlight the masked underlying etiology or worse disease condition that should be noticed.
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http://dx.doi.org/10.1097/MD.0000000000025986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137071PMC
May 2021

Preventive Aspects of Early Resveratrol Supplementation in Cardiovascular and Kidney Disease of Developmental Origins.

Int J Mol Sci 2021 Apr 19;22(8). Epub 2021 Apr 19.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

The increase in the incidence of cardiovascular diseases (CVDs) and kidney disease has stimulated research for strategies that could prevent, rather than just treat, both interconnected disorders. Resveratrol, a polyphenolic compound with pleiotropic biofunctions, has shown health benefits. Emerging epidemiological data supports that early life environmental insults are regarded as increased risks of developing CVDs and kidney disease in adulthood. Conversely, both disorders could be reversed or postponed by shifting interventions from adulthood to earlier stage by so-called reprogramming. The purpose of this review is first to highlight current epidemiological studies linking cardiovascular and renal programming to resulting CVD and kidney disease of developmental origins. This will be followed by a summary of how resveratrol could exert a positive influence on CVDs and kidney disease. This review also presents an overview of the evidence documenting resveratrol as a reprogramming agent to protect against CVD and kidney disease of developmental origins from animal studies and to outline the advances in understanding the underlying molecular mechanisms. Overall, this review reveals the need for future research to further clarify the reprogramming effects of resveratrol before clinical translation.
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http://dx.doi.org/10.3390/ijms22084210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072983PMC
April 2021

Tadalafil ameliorates bladder overactivity by restoring insulin-activated detrusor relaxation via the bladder mucosal IRS/PI3K/AKT/eNOS pathway in fructose-fed rats.

Sci Rep 2021 04 15;11(1):8202. Epub 2021 Apr 15.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Rd., Niao Song Qu, Kaohsiung, Taiwan, Republic of China.

The pathophysiologies of metabolic syndrome (MS) and overactive bladder (OAB) might overlap. Using fructose-fed rats (FFRs) as a rodent model of MS we investigated the effects of tadalafil (a phosphodiesterase type 5 inhibitor) on the dysregulated insulin signalling in the bladder mucosa and bladder overactivity. Micturition behaviour was evaluated. Concentration-response curves on detrusor relaxation to insulin stimulation were examined. Expression and phosphorylation of proteins in the insulin signalling pathway were evaluated by Western blotting. Levels of detrusor cGMP and urinary nitrite and nitrate (NOx) were measured. We observed FFRs exhibited metabolic traits of MS, bladder overactivity, and impaired insulin-activated detrusor relaxation in organ bath study. A high-fructose diet also impeded insulin signalling, reflected by overexpression of IRS1/pIRS1 and pIRS2 and downregulation of PI3K/pPI3K, AKT/pAKT, and eNOS/peNOS in the bladder mucosa, alongside decreased urinary NOx and detrusor cGMP levels. Tadalafil treatment restored the reduced level of mucosal peNOS, urinary NOx, and detrusor cGMP, improved the insulin-activated detrusor relaxation, and ameliorated bladder overactivity in FFRs. These results suggest tadalafil may ameliorate MS-associated bladder overactivity by restoring insulin-activated detrusor relaxation via molecular mechanisms that are associated with preservation of IR/IRS/PI3K/AKT/eNOS pathway in the bladder mucosa and cGMP production in the bladder detrusor.
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http://dx.doi.org/10.1038/s41598-021-87505-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050041PMC
April 2021

Synthesis of Short-Chain-Fatty-Acid Resveratrol Esters and Their Antioxidant Properties.

Antioxidants (Basel) 2021 Mar 10;10(3). Epub 2021 Mar 10.

Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan.

To expand the applications and enhance the stability and bioactivity of resveratrol (RE), and to simultaneously include the potential health benefits of short chain fatty acids (SCFA) esters of RE were prepared by Steglich reactions with acetic, propionic, and butyric acids, respectively. RE and the esterified RE-SCFA products (including RAE, RPE, and RBE) were analyzed using nuclear magnetic resonance (NMR), Fourier-transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), differential thermal analysis (DTA), and liquid chromatography-mass spectrometry (LC-MS). The FTIR and C NMR spectra of the esterified products included ester-characteristic peaks at 1751 cm and 171 ppm, respectively. Moreover, the peaks in the range of 1700 to 1600 cm in the FTIR spectra of the esterified products indicated that the esterification of RE-SCFA was successful. The TGA results revealed that the RE-SCFA esters decomposed at lower temperatures than RE. The peaks in the LC-MS profiles of the esterified products indicated the formation of mono- and diesters, and the calculated monoester synthesis rates ranged between 45.81 and 49.64%. The RE esters inhibited the Cu-induced low-density lipoprotein oxidation reaction, exhibited antioxidant activity in bulk oil, and effectively inhibited the hydroxyl radical-induced DNA scission. Moreover, the RE-SCFA esters had better hydrogen peroxide scavenging activity than RE. Our results are the first in the literature to successfully including short chain fatty acids in the esters of resveratrol, and the products could be used as a functional food ingredient in processed foods or can be used as dietary supplements to promote health.
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http://dx.doi.org/10.3390/antiox10030420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001046PMC
March 2021

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

Int J Mol Sci 2021 Mar 6;22(5). Epub 2021 Mar 6.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

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 ( = 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 , , and . 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.
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http://dx.doi.org/10.3390/ijms22052674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961901PMC
March 2021

Maternal resveratrol therapy protected adult rat offspring against hypertension programmed by combined exposures to asymmetric dimethylarginine and trimethylamine-N-oxide.

J Nutr Biochem 2021 07 30;93:108630. Epub 2021 Mar 30.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. Electronic address:

Resveratrol, a phytochemical, has shown antioxidant properties and potential benefits in hypertension. Asymmetric dimethylarginine (ADMA)-related nitric oxide deficiency and gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) have been linked to hypertension. We aimed to test whether maternal resveratrol therapy would protect adult offspring against hypertension programmed by prenatal exposure to ADMA and TMAO. Pregnant Sprague-Dawley rats received ADMA 10 mg/kg/day (A), TMAO 0.65 mg/hr (T), ADMA+TMAO (AT), or vesicle (CV). One group of ADMA+TMAO-exposed rats received 50 mg/L of resveratrol in drinking water during pregnancy and lactation periods (ATR). Male offspring (n = 8/group) were assigned to five groups: CV, A, T, AT, and ATR. Rats were killed at 12 weeks of age. ADMA exposure caused the elevation of blood pressure in 12-week-old male offspring, which was exacerbated by TMAO exposure. Treatment with resveratrol rescued hypertension programmed by combined ADMA and TMAO exposure. This was accompanied by alterations in the compositions of gut microbiota and increased fecal butyrate levels. Both the abundance of the butyrate-producing genera Lachnospiraceae and Ruminococcaceae were augmented by resveratrol. Meanwhile, resveratrol therapy significantly increased the abundance of the Cyanobiaceae and Erysipelotrichaceae families. Moreover, the protective effects of resveratrol were related to the mediation of the renin-angiotensin system . Our data provide new insights into the protective mechanisms of resveratrol against hypertension programmed by ADMA and TMAO, including regulation of gut microbiota and their metabolites, the renin-angiotensin system, and nitric oxide pathway. Resveratrol might be a potential reprogramming strategy to protect against the hypertension of developmental origins.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108630DOI Listing
July 2021

Targeting the Renin-Angiotensin-Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins.

Int J Mol Sci 2021 Feb 25;22(5). Epub 2021 Feb 25.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.
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http://dx.doi.org/10.3390/ijms22052298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956566PMC
February 2021

The Association Between Changes in Plasma Short-Chain Fatty Acid Concentrations and Hypertension in Children With Chronic Kidney Disease.

Front Pediatr 2020 4;8:613641. Epub 2021 Feb 4.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung, Taiwan.

Some children with chronic kidney disease (CKD) develop hypertension faster than others. This may be attributable to endothelial dysfunction, among other reasons. Short-chain fatty acids (SCFAs), that is, acetate, butyrate, and propionate, are known for reducing cardiovascular risks preserving endothelial function. This study aimed to investigate the association between changes in plasma SCFA concentrations and in cardiovascular and endothelial parameters in children with CKD. In total, 105 children and adolescents who met the CKD criteria were enrolled in this study, and 65 patients aged >6 years were divided into two groups based on the ambulatory BP measurements. The parameters of plasma SCFAs, endothelial function and morphology, and echocardiography were examined at the index visit and followed up after 1 year. We observed that 27.69% of 65 patients developed hypertension during the study period. Plasma acetate increased by 22.75 μM in the stable group ( < 0.001), whereas there was no change in the worsened BP group. The index higher plasma butyrate was positively correlated with worsened BP (adjusted odd ratio, 1.381; = 0.013). At the follow-up, plasma butyrate decreased by 2.12 and 4.41 μM in the stable and worsened BP groups, respectively ( < 0.001). In 105 subjects, higher index plasma propionate was positively correlated with decreasing ejection fraction (adjusted odd ratio, 1.281; = 0.046). Plasma acetate seemed to play a role in preventing hypertension in children with CKD. However, the index plasma propionate and butyrate concentrations seemed to imply the development of cardiovascular problems in our 1-year study.
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http://dx.doi.org/10.3389/fped.2020.613641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890123PMC
February 2021

Preventing Developmental Origins of Cardiovascular Disease: Hydrogen Sulfide as a Potential Target?

Antioxidants (Basel) 2021 Feb 5;10(2). Epub 2021 Feb 5.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

The cardiovascular system can be programmed by a diversity of early-life insults, leading to cardiovascular disease (CVD) in adulthood. This notion is now termed developmental origins of health and disease (DOHaD). Emerging evidence indicates hydrogen sulfide (HS), a crucial regulator of cardiovascular homeostasis, plays a pathogenetic role in CVD of developmental origins. Conversely, early HS-based interventions have proved beneficial in preventing adult-onset CVD in animal studies via reversing programming processes by so-called reprogramming. The focus of this review will first summarize the current knowledge on HS implicated in cardiovascular programming. This will be followed by supporting evidence for the links between HS signaling and underlying mechanisms of cardiovascular programming, such as oxidative stress, nitric oxide deficiency, dysregulated nutrient-sensing signals, activation of the renin-angiotensin system, and gut microbiota dysbiosis. It will also provide an overview from animal models regarding how HS-based reprogramming interventions, such as precursors of HS and HS donors, may prevent CVD of developmental origins. A better understanding of cardiovascular programming and recent advances in HS-based interventions might provide the answers to bring down the global burden of CVD.
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http://dx.doi.org/10.3390/antiox10020247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914659PMC
February 2021

Maternal Garlic Oil Supplementation Prevents High-Fat Diet-Induced Hypertension in Adult Rat Offspring: Implications of H2S-Generating Pathway in the Gut and Kidneys.

Mol Nutr Food Res 2021 06 5;65(11):e2001116. Epub 2021 May 5.

Department of Pediatrics, College of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, Kaohsiung, Taiwan.

Scope: Perinatal high-fat (HF) diet induces hypertension in adult offspring. Garlic, a naturally dietary source of Hydrogen sulfide (H S) donor, has been shown benefits in hypertension. The article examines whether maternal garlic oil supplementation can prevent hypertension induced by HF diet and elucidate its protective effects.

Methods And Results: Pregnant rats are given either a normal diet or HF diet. Rat dams are given garlic oil or vehicle daily by oral gavage at 100 mg kg day during pregnancy and lactation. Male offspring are sacrificed at 16 weeks of age. Garlic oil supplementation during pregnancy and lactation protected against hypertension induced by HF diet in adult male offspring. The beneficial effects of garlic oil are associated with increased renal mRNA expression and activity of H S-generating enzymes, increased NO bioavailability, increased plasma short chain fatty acid levels, and alterations of gut microbiota composition. Garlic oil supplementation increases abundance of genus Lactobacillus, but decreases genera Turicibacter and Staphylococcus.

Conclusion: The data reveals associations between H S-generating pathway in the gut and kidneys, NO system, gut microbiota, and microbiota-derived metabolites in hypertension induced by HF intake and provide insight to garlic oil as a hypertension reprogramming strategy for further translational research.
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http://dx.doi.org/10.1002/mnfr.202001116DOI Listing
June 2021

Developmental Origins of Kidney Disease: Why Oxidative Stress Matters?

Antioxidants (Basel) 2020 Dec 30;10(1). Epub 2020 Dec 30.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

The "developmental origins of health and disease" theory indicates that many adult-onset diseases can originate in the earliest stages of life. The developing kidney has emerged as being particularly vulnerable to adverse in utero conditions leading to morphological and functional changes, namely renal programming. Emerging evidence indicates oxidative stress, an imbalance between reactive oxygen/nitrogen species (ROS/RNS) and antioxidant systems, plays a pathogenetic role in the developmental programming of kidney disease. Conversely, perinatal use of antioxidants has been implemented to reverse programming processes and prevent adult-onset diseases. We have termed this reprogramming. The focus of this review is twofold: (1) To summarize the current knowledge on oxidative stress implicated in renal programming and kidney disease of developmental origins; and (2) to provide an overview of reprogramming effects of perinatal antioxidant therapy on renal programming and how this may prevent adult-onset kidney disease. Although early-life oxidative stress is implicated in mediating renal programming and adverse offspring renal outcomes, and animal models provide promising results to allow perinatal antioxidants applied as potential reprogramming interventions, it is still awaiting clinical translation. This presents exciting new challenges and areas for future research.
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http://dx.doi.org/10.3390/antiox10010033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823649PMC
December 2020

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

Biomedicines 2020 Dec 4;8(12). Epub 2020 Dec 4.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

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 to ratio, and increased the abundance of the genera and . 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.
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http://dx.doi.org/10.3390/biomedicines8120567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761974PMC
December 2020

Developmental Programming and Reprogramming of Hypertension and Kidney Disease: Impact of Tryptophan Metabolism.

Int J Mol Sci 2020 Nov 18;21(22). Epub 2020 Nov 18.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

The concept that hypertension and chronic kidney disease (CKD) originate in early life has emerged recently. During pregnancy, tryptophan is crucial for maternal protein synthesis and fetal development. On one hand, impaired tryptophan metabolic pathway in pregnancy impacts fetal programming, resulting in the developmental programming of hypertension and kidney disease in adult offspring. On the other hand, tryptophan-related interventions might serve as reprogramming strategies to prevent a disease from occurring. In the present review, we aim to summarize (1) the three major tryptophan metabolic pathways, (2) the impact of tryptophan metabolism in pregnancy, (3) the interplay occurring between tryptophan metabolites and gut microbiota on the production of uremic toxins, (4) the role of tryptophan-derived metabolites-induced hypertension and CKD of developmental origin, (5) the therapeutic options in pregnancy that could aid in reprogramming adverse effects to protect offspring against hypertension and CKD, and (6) possible mechanisms linking tryptophan metabolism to developmental programming of hypertension and kidney disease.
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http://dx.doi.org/10.3390/ijms21228705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698939PMC
November 2020

Early Origins of Hypertension: Should Prevention Start Before Birth Using Natural Antioxidants?

Antioxidants (Basel) 2020 Oct 23;9(11). Epub 2020 Oct 23.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Hypertension may originate in early life. Reactive oxygen species (ROS) generated due to the exposure of adverse in utero conditions causes developmental programming of hypertension. These excessive ROS can be antagonized by molecules which are antioxidants. Prenatal use of natural antioxidants may reverse programming processes and prevent hypertension of developmental origin. In the current review, firstly we document data on the impact of oxidative stress in hypertension of developmental origin. This will be followed by effective natural antioxidants uses starting before birth to prevent hypertension of developmental origin in animal models. It will also discuss evidence for the common mechanisms underlying developmental hypertension and beneficial effects of natural antioxidant interventions used as reprogramming strategies. A better understanding of the reprogramming effects of natural antioxidants and their interactions with common mechanisms underlying developmental hypertension is essential. Therefore, pregnant mothers and their children can benefit from natural antioxidant supplementation during pregnancy in order to reduce their risk for hypertension later in life.
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http://dx.doi.org/10.3390/antiox9111034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690716PMC
October 2020

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

Int J Mol Sci 2020 Sep 30;21(19). Epub 2020 Sep 30.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan.

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 ( = 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.
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http://dx.doi.org/10.3390/ijms21197237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583952PMC
September 2020
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