Increased Glycine-conjugated and Unconjugated Bile Acid Levels Associated with Aggravation of Nonalcoholic Steatohepatitis and Cardiovascular Disease in SHRSP5/Dmcr Rat.

The SHRSP5/Dmcr is a useful animal model for the development of nonalcoholic steatohepatitis (NASH) pathology when fed a high-fat, high-cholesterol diet, and further drug interventions can lead to concomitant cardiovascular disease. While SHRSP5/Dmcr rats have been used for basic research related to NASH, details of their bile acid metabolism in this condition are unknown. In this study, we aimed to clarify the changes in the serum bile acid (BA) fractions associated with NASH and found that glycine-conjugated and unconjugated bile acid increased with worsening NASH and cardiovascular disease while taurine-conjugated BA relatively decreased.

A Meta-Analysis of Randomized Controlled Trials of the Effects of Soy Intake on Inflammatory Markers in Postmenopausal Women.

BACKGROUND: Elevated concentrations of serum inflammatory cytokines, specifically TNF-α and IL-6, as well as C-reactive protein (CRP), are commonly observed after menopause. OBJECTIVES: Because soy isoflavones may have some anti-inflammatory potential, the aim of the present systematic review and meta-analysis of randomized controlled trials (RCTs) was to explore whether soy intake affects serum markers of inflammation in postmenopausal women. METHODS: PubMed, Web of Science, and the Cochrane Library were systematically searched up to August 2020. All RCTs that met the following criteria were included: 1) studies of the effects of soy intake on inflammatory markers; 2) any date of publication; 3) conducted on postmenopausal women; 4) with sufficient quantitative data for meta-analysis. Effect sizes were expressed as weighted mean differences (WMDs) and 95% CIs. A total of 24 RCTs assessing the effects of soy intake on serum concentrations of CRP, TNF-α, and IL-6 were included in the analysis. A random-effects model was used to determine the overall effect. RESULTS: Soy supplementation significantly reduced CRP by 0.11 mg/L in postmenopausal women (95% CI: -0.22, -0.004 mg/L; P = 0.0414), but did not affect IL-6 or TNF-α. Significant reductions in CRP concentration occurred when natural soy products were given (WMD: -0.23 mg/L; 95% CI: -0.29, -0.17 mg/L; P < 0.001). This is equivalent to a ∼9% reduction in CRP concentration from baseline. CONCLUSIONS: Although our meta-analysis found evidence that soy products significantly reduce CRP concentrations in postmenopausal women, the mechanisms by which soy foods and their constituents affect inflammatory biomarkers still need to be clarified.This systematic review was registered at www.crd.york.ac.uk/prospero/ as CRD42020179232.

Analysis of spot urine biomarkers and association with body weight in Japanese elementary schoolchildren.

Childhood obesity is rapidly increasing worldwide and is largely the consequence of adoption of unhealthy diets excessive in calories and salt (NaCl) as well as devoid in pivotal micronutrients such as potassium (K) and magnesium (Mg). Education-based programs aiming to encourage healthy food knowledge and behaviors are crucial at a young age, and for this purpose, convenient ways to assess daily dietary intake are warranted. We therefore attempted to evaluate the dietary intake of Okinawan schoolchildren in Japan by analyzing a series of biomarkers in morning spot urine samples and explore whether these biomarkers correlate with body weight and a series of metabolic parameters. We enrolled 98 third-grade elementary schoolchildren in Okinawa, Japan. Morning spot urine samples were collected and analyzed using high-performance liquid chromatography (HPLC) to assess dietary intake. We found that estimated daily NaCl intake was higher in obese/overweight children as compared to healthy-weight children (p = 0.0001). There was also a significant positive correlation between body mass index (BMI) and NaCl intake (Spearman) (ρ = 0.45, p < 0.0001) and a negative correlation between BMI and Mg/Cr (ρ = -0.27, p = 0.01). Furthermore, Na/K ratio was higher in samples collected on Monday (weekend) as compared to samples collected on Thursday or Friday (weekday) (p < 0.0001). CONCLUSION: Via the use of morning spot urine analyses, our results show that NaCl intake was associated with obesity, and Mg excretion negatively correlated with BMI in Japanese schoolchildren, highlighting the potential role of these micronutrients in maintaining a healthy body weight. WHAT IS KNOWN: •Overweight and obesity are largely due to excessive consumption of calories and positively correlated with salt (NaCl) intake. •Spot urine methods are convenient for assessing the nutritional needs and targeting prevention programs in children. WHAT IS NEW: •Utilizing morning spot urine analyses, estimated NaCl intake is positively correlated and Mg/Cr negatively correlated with BMI in Okinawan schoolchildren. •As estimated via morning spot urine samples, a greater proportion of children likely exceeds the recommended NaCl intake on the weekend as compared to weekday.

Grading of Japanese Diet Intakes by 24-Hour Urine Analysis of Taurine and Soy Isoflavones in Relation to Cardiovascular Risks.

To investigate the association of the Japanese diet with risks for lifestyle-related diseases, the biomarkers of seafood and soybean consumption, taurine (T) and soy isoflavones (I), and others were analyzed in 24-hour urine (24U) samples collected from participants of the Cardiovascular Diseases and Alimentary Comparison (CARDIAC) Study coordinated by the World Health Organization (WHO). The data of T and I normalized for creatinine content in 24U were divided into five quintiles, T1 to T5, and I1 to I5. The total data of the collected samples were divided into 25 groups, which were obtained by 5 (T1-T5) × 5 (I1-I5) according to 24U excretions of T and I corresponding to the intake of seafood and soybeans from the least to the highest, respectively. Since these two nutrients were often consumed together in the Japanese diet, this characteristic was expressed as J1 to J5 based on the amounts of 24U T and I excretions. The risks for lifestyle-related diseases, obesity (body mass index, BMI), and cholesterolemia became lower during the transition from J1 to J5, while HDL cholesterol levels became higher from J1 to J5. On the contrary, urinary salt excretion and the sodium (Na)/potassium (K) ratio became higher from J1 to J5. Systolic blood measure was significantly lower in J3 than in J5. Diastolic blood pressure was also significantly lower in J3 than in J1. In conclusion, the higher the J score, which corresponds to Japanese dietary habits, the lower the BMI and cholesterol levels, as well as mortality rate from coronary heart disease, but the higher the average life expectancy among the Japanese. However, these higher J scorings were associated with high-salt intake and high Na/K ratios; therefore, they contributed to high blood pressure and high mortality rate caused by stroke in Japan. These results indicate that low-salt intake should be recommended to the Japanese who are consuming seafood and soy regularly in order to maintain lower blood pressure and to extend healthy life expectancy with a lower risk of stroke. Moreover, high scorings of the Japanese diet correspond to the high intake of magnesium (Mg) which is rich in seafood including seaweeds and soy. Therefore, low-salt seafood and soy intake is expected to reduce the incidence of the metabolic syndrome, the risk of which is inversely related to T and Mg intake.

Health Effects of Soy Isoflavones and Green Tea Catechins on Cancer and Cardiovascular Diseases Based on Urinary Biomarker Levels.

Plant polyphenols have various health effects. Genistein, which is abundant in soybeans, and epigallocatechin-3-gallate, which is abundant in green tea, are major flavonoids, a subclass group of polyphenols. Several epidemiological studies have shown that these flavonoids have beneficial effects against cancer and cardiovascular diseases. However, other studies did not show such effects. Several confounding factors, including recall bias, are related to these inconsistent findings, and the determination of metabolites in the urine may be useful in reducing the number of confounding factors. Equipment, which can be used by research participants to collect samples from a portion of voided urine within 24 h without the help of medical workers, has been developed for epidemiological investigations. Previous studies, in which flavonoid metabolites in these urine samples were measured, revealed that soy intake was correlated with a reduced risk of certain types of cancer and cardiovascular diseases worldwide. Although soybeans and green tea consumption may have protective effects against cancer and cardiovascular diseases, further clinical studies that consider different confounding factors are required to provide evidence for the actual impact of dietary flavonoids on human diseases, including cancer and cardiovascular diseases. One possible mechanism involved is discussed in relation to the downregulation of reactive oxygen species and the upregulation of 5'-adenosine monophosphate-activated protein kinase elicited by these flavonoids.

Altered Properties of Neurons and Astrocytes and the Effects of Food Components in Stroke-Prone Spontaneously Hypertensive Rats.

ABSTRACT: In stroke-prone spontaneously hypertensive rats (SHRSP), stroke induces neuronal vulnerability and neuronal death, while astrocytes show a weakened support function toward neurons. Moreover, certain food components have been demonstrated to prevent the occurrence of stroke. This review aims to explain the stroke-related properties of SHRSP-derived neurons and astrocytes. In addition, it describes the effects of particular dietary phytochemicals on SHRSP. In this study, we obtained information using PubMed, ScienceDirect, and Web of Science. We searched for the functions of neurons and astrocytes and the molecular mechanism of ischemic stroke induction. We summarized the recent literature on the underlying mechanisms of stroke onset in SHRSP and the alleviating effects of typical food-derived phytochemical components. Neuronal death in SHRSP is induced by hypoxia-reoxygenation, suggesting the involvement of oxidative stress. Furthermore, the production of lactate, l-serine, and glial cell line-derived neurotrophic factor in SHRSP-derived astrocytes was reduced compared with that in control Wistar-Kyoto rats. Vitamin E exerts an inhibitory effect on hypoxia-reoxygenation-induced neuronal death in SHRSP. Curcumin, epigallocatechin gallate, resveratrol, and carotenoids can prevent the development of stroke in SHRSP. In particular, the properties of SHRSP-derived neurons and astrocytes affect stroke-induced neuronal death. This review suggests the potential and therapeutic applications of dietary phytochemicals in reducing stroke risk and lowering blood pressure in SHRSP, respectively, by targeting various processes, including oxidative stress, apoptosis, and inflammation. Thus, future research on SHRSP brain cells with a genetic predisposition to stroke can consider using these food ingredients to develop approaches for stroke prevention.

Potential Effects of Soy Isoflavones on the Prevention of Metabolic Syndrome.

Isoflavones are polyphenols primarily contained in soybean. As phytoestrogens, isoflavones exert beneficial effects on various chronic diseases. Metabolic syndrome increases the risk of death due to arteriosclerosis in individuals with various pathological conditions, including obesity, hypertension, hyperglycemia, and dyslipidemia. Although the health benefits of soybean-derived isoflavones are widely known, their beneficial effects on the pathogenesis of metabolic syndrome are incompletely understood. This review aims to describe the association between soybean-derived isoflavone intake and the risk of metabolic syndrome development. We reviewed studies on soy isoflavones, particularly daidzein and genistein, and metabolic syndrome, using PubMed, ScienceDirect, and Web of Science. We describe the pathological characteristics of metabolic syndrome, including those contributing to multiple pathological conditions. Furthermore, we summarize the effects of soybean-derived daidzein and genistein on metabolic syndrome reported in human epidemiological studies and experiments using in vitro and in vivo models. In particular, we emphasize the role of soy isoflavones in metabolic syndrome-induced cardiovascular diseases. In conclusion, this review focuses on the potential of soy isoflavones to prevent metabolic syndrome by influencing the onset of hypertension, hyperglycemia, dyslipidemia, and arteriosclerosis and discusses the anti-inflammatory effects of isoflavones.

Bile acids aggravate nonalcoholic steatohepatitis and cardiovascular disease in SHRSP5/Dmcr rat model.

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is linked to an increased risk of cardiovascular disease, regardless of the risk factors in metabolic syndrome. However, the intermediary factors between NASH and cardiovascular disease are still unknown. A previous study revealed that serum and hepatic bile acid (BA) levels are increased in some NASH patients. We aimed to examine whether NASH and cardiovascular disease were aggravated by BA using an animal model. METHOD AND RESULTS: From 10 to 18 weeks of age, SHRSP5/Dmcr rats divided into 3 groups were fed 3 types of high-fat and high-cholesterol (HFC) diets which were changed in the cholic acid (CA) concentration (0%, 2%, or 4%). The nitro oxide synthase inhibition (L-NAME) was administered intraperitoneally from 16 to 18 weeks of age. The 4% CA groups showed the worst LV dysfunction and myocardial fibrosis, and demonstrated severe hepatic fibrosis and lipid depositions. In addition, a large amount of lipid accumulation was observed in the aortas of the 4% CA group, and NFκB and VCAM-1 gene expression levels were increased. These findings were not seen in the 0% CA group. CONCLUSION: In the SHRSP5/Dmcr rat model, NASH and cardiovascular disease were aggravated with increasing BAs concentrations in an HFC diet.

Inhibition of Endothelial Dysfunction by Dietary Flavonoids and Preventive Effects Against Cardiovascular Disease.

Cardiovascular disease (CVD), such as stroke, ischemic heart disease, and heart failure, accounts for many deaths, and its increasing incidence is a worldwide concern. Accumulating evidence suggests that the elevated risk of CVD caused by dysfunction of vascular endothelial cells and resultant arteriosclerosis can be mitigated by increased consumption of fruits and vegetables. These foods contain phytochemicals such as polyphenols and carotenoids, as well as dietary fiber. Flavonoids of the polyphenol class are found in vegetables, fruits, grains, bark, roots, stems, flowers, tea, and wine. Several studies have indicated that flavonoids reduce CVD mortality by inhibiting endothelial dysfunction. Flavonoids have a common carbon skeleton and are classified as flavonols, flavones, flavanols, flavanones, anthocyanidins, and isoflavones. In this review, we discuss recent progress in identifying the mechanisms by which dietary flavonoids improve vascular endothelial cell function. Furthermore, we describe the beneficial role that these flavonoids may play in preventing CVD caused by endothelial dysfunction-related atherosclerosis.

Non-alcoholic steatohepatitis aggravates nitric oxide synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rat model.

Non-alcoholic steatohepatitis (NASH) is linked to increased cardiovascular risk, independent of the broad spectrum of metabolic syndrome risk factors. Stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr) fed a high-fat and high-cholesterol (HFC) diet developed hepatic lesions similar to those in human NASH pathology. These rats simultaneously developed lipid deposits in the mesenteric arteries, cardiac fibrosis, endothelial dysfunction and left ventricle (LV) diastolic dysfunction. However, the intermediary factors between NASH and cardiovascular disease are still unknown. We investigated whether NASH aggravates nitric oxide (NO) synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rats. Wistar Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 and fed the stroke-prone (SP) or HFC diets for 8 weeks. To induce NO synthase inhibition, Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME) mixed with drinking water was administered in the final 2 weeks. The NASH+L-NAME group demonstrated the following characteristics related to arteriosclerosis and myocardial ischaemia: (a) LV systolic dysfunction with asynergy, (b) replacement fibrosis caused by the shedding of cardiomyocytes and (c) arterial lipid deposition and coronary occlusion secondary to endothelial dysfunction. These characteristics were not observed in the NASH or non-NASH+L-NAME groups. The SHRSP5/Dmcr rat model demonstrates that NASH significantly aggravates cardiovascular risk.

The effects of fermented milk containing Lactococcus lactis subsp. cremoris FC on defaecation in healthy young Japanese women: a double-blind, placebo-controlled study.

The objective of this double-blind, placebo-controlled study was to elucidate the effects of fermented milk containing Lactococcus lactis subsp. cremoris FC (FC) on defaecation in healthy young women. We included 31 women (18-31 years old) who were randomly selected into two groups. Subjects in the test group consumed fermented milk containing FC, while subjects in the placebo group consumed non-fermented gelled milk. In the test group, defaecation frequency (both in days and times per week) and stool volume significantly increased during the consumption of fermented milk containing FC compared with before consumption. These effects were also observed in subjects with mild constipation. Furthermore, in subjects with mild constipation, stool ammonia concentration was significantly lower in the test group than that in the placebo group after 4 weeks. These results suggest that fermented milk containing FC is beneficial for improving defaecation and faecal properties.

Taurine Intake with Magnesium Reduces Cardiometabolic Risks.

WHO-CARDIAC (Cardiovascular Diseases and Alimentary Comparison) Study revealed the quintile analyses of 24-h urinary (24 U) taurine (T) and magnesium (Mg) excretions were inversely related with cardiometabolic risks (CMR) such as obesity, hypertension and hypercholesterolemia in 50 population samples in the world. To exclude the influence of ethnicity in the study, 24 U T and Mg excretions were analyzed for the association with CMR in one ethnicity, Japanese population.24 U T/creatinine (C) ratios were divided into 5 quintiles and the ratios of Japanese to the total of each quintile were analyzed from CARDIAC Study samples. The highest 24 U T quintile consisted of 60% Japanese, indicating high seafood consumption in Japanese.Over 600 Japanese aged 30-79 were invited to a health examination for blood pressure measurement and for fasting blood and 24 U samplings. Tertile analysis of 24 U T/C ratios in relation to CMR indicated the third tertile had significantly higher HDL cholesterol, 24 U potassium (K) and 24 U salt than the first (lowest) tertile. Tertile analysis of 24 U Mg/C ratios indicated the third tertile had significantly lower body mass index and significantly higher folic acid, 24 U isoflavones, K and salt than the first tertile after age and gender adjustment. The third tertile of both T/C and Mg/C had significantly lower body mass index, LDL/HDL and Na/K ratios, and significantly higher HDL cholesterol and folic acid than the first tertile, indicating seafood eaters taking Mg rich diets had lower risks of obesity, atherosclerosis, hypertension and higher folic acid, beneficial for healthy longevity.

Mediating effects of nocturnal blood pressure and morning surge on the contributions of arterial stiffness and sodium intake to morning blood pressure: A path analysis.

BACKGROUND: The aim of this study was to evaluate the mediating effects of nocturnal blood pressure (BP) and morning surge on the contribution of arterial stiffness and sodium intake to morning BP in a middle-aged general population. METHODS: The study included 124 subjects aged 30-59 years, from rural Yeoju County, Gyeonggi Province, South Korea. Ambulatory BP monitoring, 24 h urinary sodium excretion (24 h UNa) and brachial-ankle pulse wave velocity (baPWV) measurements were performed in all subjects. RESULTS: The mean ± SD age was 48.1 ± 8.2 years and the proportion of male subjects was 41.1%. After adjusting for covariates, morning systolic blood pressure (SBP) was significantly correlated with morning surge [coefficient = 0.761, 95% confidence interval (CI) 0.651-0.872, p < 0.001], nocturnal SBP (coefficient = 0.576, 95% CI 0.454-0.698, p < 0.001) and baPWV (coefficient = 3.550, 95% CI 1.447-5.653, p = 0.001). Path analysis modeling revealed that baPWV had significant direct (0.035, p = 0.013) and indirect effects (0.042, p = 0.012) on morning SBP. The indirect effect mediated by nocturnal SBP was statistically significant (0.054, p = 0.005), but the indirect effect mediated by the morning surge was not significant. The 24 h UNa had no significant direct or indirect effects on morning SBP. CONCLUSION: baPWV had significant direct and indirect effects on morning SBP. The indirect effect was mediated by nocturnal SBP, but not by morning surge. The 24 h UNa had neither significant direct nor indirect effects on morning SBP.

A possible role of chenodeoxycholic acid and glycine-conjugated bile acids in fibrotic steatohepatitis in a dietary rat model.

BACKGROUND AND AIMS: Our previous study indicated that hepatic bile acids (BAs) may have deposited and stimulated the pathogenesis of a high fat-cholesterol (HFC) diet-induced fibrotic steatohepatitis in stroke-prone spontaneously hypertensive 5/Dmcr rats, based on dysregulated BA homeostasis pathways. We aimed to further characterize BA profiles in liver and evaluate their relationships to liver injury using this model. METHODS: Hepatic 21 BA levels were determined by ultra-performance liquid chromatography-tandem mass spectrometry, and their correlations with macrovesicular steatosis score, serum alanine aminotransferase (ALT) level and quantified fibrotic area were assessed using Spearman and Pearson correlations. RESULTS: Compared to control, BAs highly accumulated in HFC-fed rat liver at 2 weeks: cholic acid (CA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) were major species, thereafter, levels of CA and DCA declined, but CDCA species persistently increased, which induced a decrease in total CA/total CDCA ratio at 8 and 14 weeks. CDCA species positively, while total CA/total CDCA negatively, correlated with macrovesicular steatosis score, serum ALT and quantified fibrotic area. Unlike control, total ursodeoxycholic acid was minor in HFC-fed rat liver, and inversely correlated to aforementioned indicators of liver injury; total glyco-BAs, rather than tauro-BAs, were predominant in HFC-fed rat liver, and positively correlated with macrovesicular steatosis score. Moreover, its ratio to total tauro-BAs positively correlated with each parameter of liver injury, while inverse associations were detected for total tauro-BAs. CONCLUSIONS: Hepatic BA accumulation may potentiate liver disease. CDCA and glyco-BAs play a more important role in the pathogenesis of fibrotic steatohepatitis.

Effects of dietary seaweed on obesity-related metabolic status: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Seaweed is a promising source of anti-obesity agents, including polysaccharides, proteins, polyphenols, carotenoids, and n-3 long-chain polyunsaturated fatty acids. The anti-obesity effects of such compounds may be due to several mechanisms, including inhibition of lipid absorption and metabolism, effect on satiety, and inhibition of adipocyte differentiation. OBJECTIVE: The aim of this study was to assess the evidence from human randomized controlled trials for the effects of seaweed on body-weight status as well as lipid and nonlipid parameters in adults with overweight and obesity. DATA SOURCES: Four databases-Medline, Scopus, Web of Science, and Cochrane Library-were searched from December 2022 to June 2023 using the following key words: Seaweed OR fucoxanthin OR alginates OR fucoidans OR phlorotannin's OR macroalgae OR marine algae AND obesity OR overweight OR BMI OR body mass index. DATA EXTRACTION: Eleven interventional studies (10 parallel and 1 crossover) were extracted. DATA ANALYSIS: Meta-analysis showed a significant effect, favoring the intervention group for BMI (body mass index) (standardized mean difference [SMD]: -0.40; 95% CI: -0.65 to -0.16 kg/m2; P = 0.0013) and percentage of fat mass (SMD: -1.48; 95% CI: -2.66% to -0.30%, P = 0.0138). The results were seen when refined or extracted brown seaweed (BMI) or only refined brown seaweed (% fat mass) were administered to participants for at least 8 weeks. Moreover, a significant overall effect of seaweed supplementation on total cholesterol (SMD: -7.72; 95% CI: -12.49 to -2.95 mg/dL; P = 0.0015) and low-density-lipoprotein cholesterol (SMD: -7.33; 95% CI: -11.64 to -3.02 mg/dL; P < 0.001) was noted. Any significant effects of seaweed on glucose metabolism were not shown. CONCLUSION: Edible seaweed supplementation shows potential for managing obesity and disorders of the blood lipid profile when administered to participants for at least 8 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022378484 (www.crd.york.ac.uk/PROSPERO).

Supplementation of elderly Japanese men and women with fucoidan from seaweed increases immune responses to seasonal influenza vaccination.

The elderly are known to have an inadequate immune response to influenza vaccine. Mekabu fucoidan (MF), a sulfated polysaccharide extracted from seaweed, was previously shown to have an immunomodulatory effect. We therefore investigated antibody production after influenza vaccination in elderly Japanese men and women with and without oral MF intake. A randomized, placebo-controlled, double-blind study was conducted with 70 volunteers >60 y of age. They were randomly assigned to 1 of 2 groups, consuming either MF (300 mg/d) or placebo for 4 wk, and then given a trivalent seasonal influenza vaccine. Serum was sampled at 5 and 20 wk after vaccination to measure the hemagglutination inhibition titer and natural killer cell activity. The MF group had higher antibody titers against all 3 strains contained in the seasonal influenza virus vaccine than the placebo group. Titers against the B/Brisbane/60/2008 (B) strain increased substantially more in the MF group than in the placebo group over the product consumption period. The immune response against B antigen met the European Union Licensure criteria regarding the geometric mean titer ratio in the MF group (2.4), but not in the placebo group (1.7). In the MF group, natural killer cell activity tended to increase from baseline 9 wk after MF intake (P = 0.08). However, in the placebo group no substantial increase was noted at 9 wk, and the activity decreased substantially from 9 to 24 wk. In the immunocompromised elderly, MF intake increased antibody production after vaccination, possibly preventing influenza epidemics.

Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats.

BACKGROUND AND AIMS: Cholesterol over-intake is involved in the onset of nonalcoholic steatohepatitis (NASH), and hepatocellular bile acid (BA) accumulation correlates with liver injuries. However, how dietary cholesterol influences cholesterol and BA kinetics in NASH liver remains ambiguous and needs to be clarified. METHODS: Molecular markers involved in cholesterol and BA kinetics were investigated at protein and mRNA levels in an already-established stroke-prone spontaneously hypertensive 5/Dmcr rat model with fibrotic steatohepatitis, by feeding a high fat-cholesterol (HFC) diet. RESULTS: Unlike the control diet, the HFC diet deposited cholesterol greatly in rat livers, where 3-hydroxy-3-methylglutaryl CoA reductase, low-density lipoprotein (LDL) receptor and LDL receptor-related protein-1 were expectedly downregulated, especially at 8 and 14 weeks, suggesting that cholesterol synthesis and uptake in response to cholesterol accumulation may not be disorganized. The HFC diet did not upregulate liver X receptor-α, conversely, it enhanced classic BA synthesis by upregulating cholesterol 7α-hydroxylase but downregulating sterol 12α-hydroxylase, and influenced alternative synthesis by downregulating sterol 27-hydroxylase but upregulating oxysterol 7α-hydroxylase, mainly at 8 and 14 weeks, indicating that there were different productions of primary BA species. Unexpectedly, no feedback inhibition of BA synthesis by farnesoid X receptor occurred. Additionally, the HFC diet impaired BA detoxification by UDP-glucuronosyltransferase and sulfotransferase 2A1, and decreased excretion by bile salt export pump at 8 and 14 weeks, although it induced compensatory export by multidrug resistance-associated protein-3. The disturbed BA detoxification may correlate with suppressed pregnane X receptor and constitutive androstane receptor. CONCLUSIONS: The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.

Serial changes in adipocytokines and cardiac function in a rat model of the metabolic syndrome.

Obesity is associated with high chronic cardiac workload due to the need to supply more blood to peripheral tissue, and frequently leads to left ventricular (LV) dysfunction. The present study examined serial changes in cardiac function in the SHR/NDmcr-cp (SHR/cp) strain, an experimental model of obesity plus hypertension and metabolic syndrome. Transthoracic echocardiography was used to define cardiac dimensions and function in male spontaneously hypertensive rats (SHR/lean), SHR/cp and Wistar-Kyoto rats. We also assessed age-related changes in plasma and LV adipocytokine levels in this model. Although there were no significant differences in LV end-diastolic diameter and end-systolic diameter among the three rat strains until 24 weeks of age, these parameters were significantly higher and LV fractional shortening (%FS) was significantly lower in SHR/cp compared with SHR/lean at 32 weeks of age. At the same age, pronounced interstitial fibrosis and infiltration of macrophages and T lymphocytes into the LV was noted in SHR/cp relative to the other strains. In the myocardium, adiponectin levels were significantly lower and resistin levels and the expression of proinflammatory cytokines (tumour necrosis factor-α and interleukin-6) were significantly higher in SHR/cp than SHR/lean at 32 weeks of age. Using echocardiography, we demonstrated reduced systolic function in 32-week-old SHR/cp. Changes in myocardial cytokine concentrations could be involved in worsening of cardiac function in our animal model of metabolic syndrome.

Caffeic acid phenethyl ester suppresses oxidative stress in 3T3-L1 adipocytes.

The generation of oxidative stress, characterized by enhanced reactive oxygen species (ROS) formation, has been found in obesity. ROS production was increased during the differentiation of 3T3-L1 cells into adipocytes. We previously reported that caffeic acid phenethyl ester (CAPE) suppresses 3T3-L1 differentiation to adipocytes through the inhibition of peroxisome proliferator-activated receptor γ. In this study, the preventive effect of CAPE on oxidative stress in 3T3-L1 cells was observed. The results were as follows: (1) ROS production during 3T3-L1 cell differentiation to adipocytes was significantly (p < 0.05) suppressed by CAPE treatment in a concentration-dependent manner, (2) with CAPE treatment, the extracellular superoxide dismutase mRNA expression level significantly increased, but the NOX4 mRNA expression level did not change, and (3) CAPE treatment significantly increased superoxide dismutase (SOD) activity in 3T3-L1 cells. From these results, we suggest that the increased oxidative stress in 3T3-L1 differentiation to adipocytes is attenuated by CAPE treatment. This attenuation may be partly caused by increased SOD production.

Relationship between Regional Distribution of Centenarians and Drinking Water Hardness in the Amami Islands, Kagoshima Prefecture, Japan.

People who drink naturally hardened water may experience longevity-enhancing effects. In this study, we investigated water hardness and longevity from both geological and epidemiological perspectives in Japan's Amami islands, where drinking water is drawn from coralline or non-coralline bedrock. We investigated drinking water hardness, limestone bedrock occupancy, and the centenarian rate (number per 10,000 population) by municipality across four adjacent islands (Amami-Oshima (non-coralline), Tokunoshima, Okinoerabu, and Yoron (predominantly coralline)). Limestone was strongly correlated with water hardness (r = 0.99; p < 0.01), occupying more than 80% of the bedrock where the water was the hardest (Tokunoshima's Isen municipality: 86.5%; Yoron: 82.9%) and being scarcely detectable in Amami-Oshima (0.0 to 0.2%), where the water was the least hard. The centenarian rate was also strongly correlated with water hardness (r = 0.84, p < 0.01), with the highest figures in Yoron (29.7) and Isen (29.2), and the lowest in Amami-Oshima (0.0 to 12.2). Therefore, we hypothesize a potentially beneficial effect of hard water on longevity when that water is drawn from coralline limestone. Water hardness is determined by the water content of calcium and magnesium and may plausibly influence life expectancy through a preventative effect against cardiovascular disease. Our findings are of interest to current debates about future global access to drinking water and its quality.