Bacillus coagulans TCI711 Supplementation Improved Nonalcoholic Fatty Liver by Modulating Gut Microbiota: A Randomized, Placebo-Controlled, Clinical Trial.

Background: Nonalcoholic fatty liver disease (NAFLD) has become one of the major problems of chronic liver disease worldwide. It not only causes damage to the liver but also engenders chronic hepatitis and cirrhosis. Recent studies have shown that regulating Bacillus coagulans can improve NAFLD. Objectives: This trial explores whether B. coagulans TCI711 (BCT) could ameliorate NAFLD. Methods: A total of 57 patients with NAFLD were recruited through FibroScan liver fibrosis scanner and divided into placebo (n = 28) and BCT-supplemented groups (n = 29). Specifically, 1 BCT probiotic capsule was supplemented daily for 8 wk. Furthermore, the blood, stool, and fatty liver content were then examined. Results: Parameters evaluated for liver and kidney indicators showed no side effects after supplementing BCT. A significant reduction of 8.7% in the fatty liver was achieved by effectively suppressing the grade of fatty liver as revealed by controlled attenuation parameter. BCT also regulated gut microbiota profiles, with significant increases observed in Bifidobacterium, Eubacterium, Ruminococcaceae, and Sellimonas compared with the baseline. Conclusions: BCT may improve NAFLD by regulating gut microbiota, and parameters evaluated for liver and kidney indicate no side effects.

Aspartame Intake Delayed Puberty Onset in Female Offspring Rats and Girls.

SCOPE: The disturbance of the hypothalamic-pituitary-gonadal (HPG) axis, gut microbiota (GM) community, and short-chain fatty acids (SCFAs) is a triggering factor for pubertal onset. The study investigates the effects of the long-term intake of aspartame on puberty and GM in animals and humans. METHODS AND RESULTS: Aspartame-fed female offspring rats result in vaginal opening time prolongation, serum estrogen reduction, and serum luteinizing hormone elevation. , 60 mg kg-1 aspartame treatment decreases the mRNA levels of gonadotropin-releasing hormone (GnRH), Kiss1, and G protein-coupled receptor 54 (GPR54), increases the mRNA level of RFamide-related peptide-3 (RFRP-3), and decreases the expression of GnRH neurons in the hypothalamus. Significant differences in relative bacterial abundance at the genus levels and decreased fecal SCFA levels are noted by 60 mg kg-1 aspartame treatment. Among which, Escherichia-Shigella is negatively correlated with several SCFAs. In girls, high-dose aspartame consumption decreases the risk of precocious puberty. CONCLUSIONS: Aspartame reduces the chance of puberty occurring earlier than usual in female offspring and girls. Particularly, 60 mg kg-1 aspartame-fed female offspring delays pubertal onset through the dysregulation of HPG axis and GM composition by inhibiting the Kiss1/GPR54 system and inducing the RFRP-3. An acceptable dose of aspartame should be recommended during childhood.

Relationship between Aspartame-Induced Cerebral Cortex Injury and Oxidative Stress, Inflammation, Mitochondrial Dysfunction, and Apoptosis in Sprague Dawley Rats.

There are emerging concerns about the potential cerebral cortex injury from aspartame due to the accumulation of the various neurotoxic metabolic components in the central nervous system after long-term dietary exposure. The aim of this study was to evaluate the effect of oral aspartame consumption on cerebral cortex injury in the rat brain, and further evaluate the various underlying molecular mechanisms, with a special focus on oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis pathways. Sprague Dawley rats (nineteen, female) were randomly sub-divided into three groups: (i) normal diet with vehicle: control group (five rats), (ii) low dose of aspartame group (LA): seven rats received 30 mg/kg body weight (bw) daily doses of aspartame, (iii) high dose of aspartame group (HA): seven rats received 60 mg/kg bw daily doses of aspartame. After 8 weeks, the LA and HA groups showed lower expression levels of brain-derived neurotrophic factor (BDNF), antioxidant enzyme activity (SOD2, CAT), antioxidant marker (Nrf2), inflammatory response (IκB), mitochondrial biogenesis (Sirt1, PGC1α, Nrf1, TFAM), mitochondrial DNA (mtDNA) copy number, and apoptosis-related proteins (Bax, Caspase-3) expressions. Aspartame administration also elevated oxidative stress levels (Malondialdehyde, MDA), 8-hydroxy-2-deoxy guanosine (8-OHdG), PGE2 and COX-2 expressions, pro-inflammatory cytokines (TNFα, IL6, IL1ß), antioxidant marker expression (Keap1), inflammatory responses (iNOS, NFκB), and glial fibrillary acidic protein (GFAP) levels in the cerebral cortex of the rats, thereby contributing to the reduced survival of pyramidal cells and astrocyte glial cells of the cerebral cortex. Therefore, these findings imply that aspartame-induced neurotoxicity in rats' cerebral cortex could be regulated through four mechanisms: inflammation, enhanced oxidant stress, decreased mitochondrial biogenesis, and apoptosis pathways.

Mangosteen Pericarp Extract Supplementation Boosts Antioxidant Status via Rebuilding Gut Microbiota to Attenuate Motor Deficit in 6-OHDA-Induced Parkinson's Disease.

Oxidative stress and gut dysbiosis have been known to precede Parkinson's disease (PD). An antioxidant-rich product, mangosteen pericarp (MP), has the ability to counterbalance excessive free radicals and the imbalanced gut microbiota composition, suggesting the MP's capacity to delay PD progression. In this study, we explored the effects of two doses of MP extract in a unilateral 6-hydroxydopamine (6-OHDA)-induced PD rat model. We revealed that the 8-week supplementation of a low dose (LMP) and a high dose of the MP extract (HMP) improved motor function, as observed in decreased contralateral rotation, improved time spent on rod, and higher dopamine binding transporter (DAT) in the substantia nigra pars compacta (SNc). The MP extract, especially the HMP, also increased antioxidant-related gene expressions, restored muscle mitochondrial function, and remodeled fecal microbiota composition, which were followed by reduced reactive oxygen species levels in brain and inflammation in plasma. Importantly, bacterial genera Sutterella, Rothia, and Aggregatibacter, which were negatively correlated with antioxidant gene expressions, decreased in the HMP group. It is imperative to note that in addition to directly acting as an antioxidant to reduce excessive free radicals, MP extract might also increase antioxidant state by rebuilding gut microbiota, thereby enhanced anti-inflammatory capacity and restored mitochondrial function to attenuate motor deficit in 6-OHDA-induced PD-like condition. All in all, MP extract is a potential candidate for auxiliary therapy for PD.

Aspartame Consumption, Mitochondrial Disorder-Induced Impaired Ovarian Function, and Infertility Risk.

Frequent consumption of diet drinks was associated with oocyte dysmorphism, decreased embryo quality, and an adverse effect on pregnancy rate. We investigated the harmful effects of aspartame and potential mechanisms through which it increases infertility risk through clinical observations and in vivo and in vitro studies. Methods: We established a cohort of 840 pregnant women and retrospectively determined their time to conceive. We assessed the estrus cycle, the anti-Mullerian hormone level, ovarian oxidative stress, and ovarian mitochondrial function in an animal study. We also evaluated mitochondria function, mitochondrial biogenesis, and progesterone release with in vitro studies. Aspartame consumption was associated with increased infertility risk in the younger women (Odds ratio: 1.79, 95% confidence interval: 1.00, 3.22). The results of the in vivo study revealed that aspartame disrupted the estrus cycle and reduced the anti-Mullerian hormone level. Aspartame treatment also suppressed antioxidative activities and resulted in higher oxidative stress in the ovaries and granulosa cells. This phenomenon is caused by an aspartame-induced decline in mitochondrial function (maximal respiration, spare respiratory capacity, and ATP production capacity) and triggered mitochondrial biogenesis (assessed by examining the energy depletion signaling-related factors sirtuin-1, phosphorylated adenosine monophosphate-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator-1α, and nuclear respiratory factor 1 expression levels). Aspartame may alter fertility by reserving fewer follicles in the ovary and disrupting steroidogenesis in granulosa cells. Hence, women preparing for pregnancy are suggested to reduce aspartame consumption and avoid oxidative stressors of the ovaries.

Development and Validation of the Chinese Version Non-Nutritive Sweetener Food Frequency Questionnaire with Urinary Biomarker in Children and Adolescents.

OBJECTIVE: The purpose of this study was to develop a validated food frequency questionnaire (FFQ) to evaluate the intake of non-nutritive sweeteners (NNSs) in child and adolescent Asian populations. DESIGN: Intensive and overall market research was performed to create the applicable NNS-FFQ with 13 food categories and 305 items. Six intense sweeteners, including acesulfame potassium, aspartame, sucralose, glycyrrhizin, steviol glycosides and sorbitol, were investigated. The validity and reproducibility of the NNS-FFQ were evaluated. The validity was further assessed by examining the consistency of reported NNS intake compared with urinary biomarkers using Cohen's κ analysis. SETTINGS: This work was considered to be relevant in Asian societies. PARTICIPANTS: One hundred and two children and adolescents recruited from several clinics were invited to participate in this study. RESULTS: High content validity indices and high content validity ratio levels were revealed for each sweetener and food category. Reproducibility among subjects was satisfactory. Significant moderate correlations between estimated steviol glycoside/sucralose consumption and sensitive urinary biomarker levels were demonstrated (κ values were 0.59 and 0.45 for steviol glycosides and sucralose, respectively), indicating that the NNS-FFQ can be used to assess an individual's NNS intake. The dietary intense sweetener consumption pattern evaluated in this measurement was similar to those observed in other Asian countries but differed from those observed in Western populations with respect to types and amounts of NNSs. CONCLUSIONS: This validated NNS-FFQ can be an applicable and useful tool to evaluate NNS intake in future epidemiological and clinical studies.

Maternal Vegetable and Fruit Consumption during Pregnancy and Its Effects on Infant Gut Microbiome.

Maternal nutrition intake during pregnancy may affect the mother-to-child transmission of bacteria, resulting in gut microflora changes in the offspring, with long-term health consequences in later life. Longitudinal human studies are lacking, as only a small amount of studies showing the effect of nutrition intake during pregnancy on the gut microbiome of infants have been performed, and these studies have been mainly conducted on animals. This pilot study explores the effects of high or low fruit and vegetable gestational intake on the infant microbiome. We enrolled pregnant women with a complete 3-day dietary record and received postpartum follow-up. The 16S rRNA gene sequence was used to characterize the infant gut microbiome at 2 months (n = 39). Principal coordinate analysis ordination revealed that the infant gut microbiome clustered differently for high and low maternal fruit and vegetable consumption (p < 0.001). The linear discriminant analysis effect size and feature selection identified 6 and 17 taxa from both the high and low fruit and vegetable consumption groups. Among the 23 abundant taxa, we observed that six maternal intake nutrients were associated with nine taxa (e.g., Erysipelatoclostridium, Isobaculum, Lachnospiraceae, Betaproteobacteria, Burkholderiaceae, Sutterella, Clostridia, Clostridiales, and Lachnoclostridium). The amount of gestational fruit and vegetable consumption is associated with distinct changes in the infant gut microbiome at 2 months of age. Therefore, strategies involving increased fruit and vegetable consumption during pregnancy should be employed for modifying the gut microbiome early in life.

Mangosteen Concentrate Drink Supplementation Promotes Antioxidant Status and Lactate Clearance in Rats after Exercise.

High-strength or long-duration exercise can lead to significant fatigue, oxidative stress, and muscle damage. The purpose of this study was to examine the effect of mangosteen concentrate drink (MCD) supplementation on antioxidant capacity and lactate clearance in rats after running exercise. Forty rats were divided into five groups: N, non-treatment; C, control; or supplemented with MCD, including M1, M5, and M10 (0.9, 4.5, and 9 mL/day) for 6 weeks. The rats were subjected to 30 min running and exhaustive-running tests using a treadmill. The blood lactate; triglyceride; cholesterol and glucose levels; hepatic and muscular malonaldehyde (MDA) levels; and antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT), were analyzed. The results of this study demonstrated that MCD supplementation can increase GPx and CAT activities, alleviate oxidative stress in muscle, and increase lactate clearance, and is thereby beneficial to reduced muscle fatigue after exercise.

Mevalonate Pathway Enzyme HMGCS1 Contributes to Gastric Cancer Progression.

The 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a potential regulatory node in the mevalonate pathway that is frequently dysregulated in tumors. This study found that HMGCS1 expression is upregulated in stomach adenocarcinoma samples of patients and tumorspheres of gastric cancer cells. HMGCS1 elevates the expression levels of the pluripotency genes Oct4 and SOX-2 and contributes to tumorsphere formation ability in gastric cancer cells. HMGCS1 also promotes in vitro cell growth and progression and the in vivo tumor growth and lung metastasis of gastric cancer cells. After blocking the mevalonate pathway by statin and dipyridamole, HMGCS1 exerts nonmetabolic functions in enhancing gastric cancer progression. Furthermore, the level and nuclear translocation of HMGCS1 in gastric cancer cells are induced by serum deprivation. HMGCS1 binds to and activates Oct4 and SOX-2 promoters. HMGCS1 also enhances the integrated stress response (ISR) and interacts with the endoplasmic reticulum (ER) stress transducer protein kinase RNA-like endoplasmic reticulum kinase (PERK). Our results reveal that HMGCS1 contributes to gastric cancer progression in both metabolic and nonmetabolic manners.

Mangosteen pericarp components alleviate progression of prostatic hyperplasia and mitochondrial dysfunction in rats.

Prostatic hyperplasia, characterized by progressive hyperplasia of glandular and stromal tissues, is the most common proliferative abnormality of the prostate in aging men. A high-fat diet (HFD) usually is a major factor inducing oxidative stress, inflammation, and an abnormal state of the prostate. Mangosteen pericarp powder (MPP) has abundant xanthones which can be antioxidant, anti-inflammatory, and antiproliferative agents. Therefore, the purpose of this study was to research whether MPP supplementation can affect the progression of prostatic hyperplasia. Twenty-four male F344 rats were randomly divided into four groups, including a control group (C), prostatic hyperplasia-induced group (P), prostatic hyperplasia-induced with low-dose MPP group (PL), and induced with high-dose MPP group (PH). The P, PL, and PH groups were given weekly intraperitoneal injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) at 25 mg/kg body weight for 10 weeks, and simultaneously fed an HFD for 24 weeks. Our findings first demonstrated that MPP consumption significantly decreased the prostate weight, serum testosterone and dihydrotestosterone concentrations, protein expression of proliferating cell nuclear antigen, and malondialdehyde levels and ameliorated mitochondrial function in prostatic tissues. These results suggest that MPP supplementation could be used to attenuate the progression of prostatic hyperplasia.

Body mass index growth trajectories, early pubertal maturation, and short stature.

BACKGROUND: Childhood body mass index (BMI) trajectory classes are rarely linked to early puberty risk, particularly among Chinese children. We estimated early puberty risk across BMI trajectory classes, investigated factors contributing to pubertal development, and examined differences in final adult height between children exhibiting early and nonearly pubertal maturation across the classes. METHODS: The Taiwan Children Health Study recruited 10-year-old children in 2010 from 14 Taiwanese communities and resurveyed them at age 11, 12, and 18 years. The study comprised 3109 children (50.4% boys) with available data for BMI (age 6-11 years) and pubertal stages (age 11, 12, and 18 years). RESULTS: Classes 1-4 were persistently healthy weight, rapid BMI growth, chronically overweight/obese, and early transient overweight/obese. Children in class 3 exhibited the highest risk of early pubertal maturation. Puberty genetic score, low sleep quality, and high fat-free mass collectively explained 15% of the variance in Tanner stages among class 3 children. Early pubertal maturation was considered to cause short and tall stature in boys and girls, respectively. CONCLUSIONS: Modifying sleep quality and fat-free mass may reduce early puberty risk in children with chronic overweight/obesity. Vigorous physical activity may reduce adiposity and increase the final adult height in the children.

Evaluation of a Technological Image-Based Dietary Assessment Tool for Children during Pubertal Growth: A Pilot Study.

We designed an image-based dietary assessment tool called COFIT, which means "fit together" and pilot-tested it in the Taipei Puberty Longitudinal Study (TPLS). Children aged 6-17 years were invited to use COFIT over three days for recording all instances of eating in addition to maintaining written food records (FR). Spearman's correlation and Bland-Altman analysis were used to compare the intake of macronutrients and micronutrients estimated using the image-based dietary assessment and the FR method. Intra-class correlation coefficients were used to estimate reliability between dietitians. In the final analysis, 23 children (mean age: 10.47 ± 0.47 years) with complete data obtained using two dietary assessment methods were included. Reliability among dietitians was high. Most assessments of macronutrients and micronutrients revealed moderate correlations between the two methods (range: 0.27-0.94); moreover, no significant differences in nutrients assessments were observed between the two methods, except for energy and fat. The average difference in energy intake between the methods was 194 kcal/day. Most limits of agreement were within an acceptable range. The Bland-Altman plots showed robust agreement with minimum bias. The limitation was the small sample size and not dividing the population into children and teenagers since the two groups may have different food consumption habits. Overall, the results showed that the image-based assessment tool is suitable for assessing children's dietary intake of macronutrients and micronutrients during pubertal growth.

Assessing causality between childhood adiposity and early puberty: A bidirectional Mendelian randomization and longitudinal study.

AIMS: Obesity and early puberty have been reported to be mutually causative. We investigated the causal relationship between adiposity and early puberty by performing bidirectional Mendelian randomization (MR) and longitudinal data analyses. METHODS: We used information from the Taiwan Children Health Study (3109 adolescents aged 11-12 years) with 17 body mass index (BMI)- and 10 puberty-related single-nucleotide polymorphisms (SNPs) to produce genetic instrumental variables (IVs). The two-stage least squares (2SLS) method, MR sensitivity analysis, and survival analysis were used to explore and confirm causality. RESULTS: Regression estimates from IVs revealed that significantly increased association of BMI with early puberty was noted (coefficients: 0.13, 0.10, and 0.09; 95% CI: 0.07-0.19, 0.02-0.19, and 0.02-0.16 for all participants, male adolescents, and female adolescents, respectively). Genetic IVs for puberty were not associated with BMI. MR sensitivity and two-sample MR analyses produced similar results. Longitudinal analysis results revealed that prepubertal overweight and obesity could predict early onset of puberty. However, after excluding children with a history of overweight and obesity at the age of 7-12 years, early puberty was not found to trigger new-onset of overweight and obesity at the age of 18 years in either sex. CONCLUSIONS: Higher adiposity may lead to early puberty. However, the causal effects of early puberty on adiposity accumulation were not supported by our data. Targeted interventions to reduce childhood obesity are strongly recommended to prevent obesity-related comorbidities, as well as early puberty onset.

Alteration in iron efflux affects male sex hormone testosterone biosynthesis in a diet-induced obese rat model.

This study was motivated by clinical observations that dysmetabolic iron overload syndrome (DIOS) and an androgen deficiency are common features observed in obese adult men; however, the molecular mechanism underlying the effects of DIOS on androgen deficiency remains to be elucidated. We established a DIOS animal model by feeding Sprague-Dawley rats an iron/fat-enriched diet (50% fat plus 0.25, 1, or 2 g ferric iron per kg diet) for 12 weeks to induce iron dysfunction (indicated by decreased tissue iron efflux) in obese rats. Obese rats fed an iron/fat-enriched diet showed decreased levels of testicular total Testosterone (T) and iron exporter ferroportin but increased levels of testicular iron and hepcidin, and these effects were more evident with a >1 g ferric iron per kg diet. A western blot analysis showed that an iron/fat-enriched diet triggered testicular endoplasmic reticular (ER) stress but decreased mitochondrion biogenesis proteins (PGC1α and TFAM) and T-converting proteins (StAR, CYP11A, and 17ß-HSD). TUNEL staining showed that >1 g ferric iron induced apoptosis mainly in germ cells and Leydig's cells. Uncontrolled testicular iron efflux may cause mitochondrial-ER dysfunction and affect T biosynthesis. Future study targeting the testicular hepcidin-ferroportin axis may offer a therapeutic tool to alleviate testicular iron retention and mitochondrial-ER stress in Leydig's cells.

Birthweight, time-varying adiposity growth and early menarche in girls: A Mendelian randomisation and mediation analysis.

OBJECTIVE: To explore the causal effect of time-varying z-BMI growth on early menarche using Mendelian randomisation (MR); to identify critical adiposity predictors of early menarche; to compare the effects of birthweight and time-varying z-BMI growth as mediators of the path from genes to early menarche using mediation analysis. METHODS: We used data from the Taiwan Children Health Study with 21 obesity-related single-nucleotide polymorphisms (SNPs) to yield genetic (instrumental variable)IVs for adiposity. Children with available data on genotyping, birthweight, adiposity, and menarcheal age were included. RESULTS: In MR analyses, results based on the time-varying z-BMI growth show more statistical power and capture more information of adiposity growth (p=0.01) than those based on single point z-BMI (p=0.02). Among adiposity measures, critical predictors of early menarche are fat free mass (RR=1.33, 95% CI 1.07-1.65) and waist/height ratio (RR=1.27, 95% CI 1.03-1.56). Other potential predictors of early menarche are sum of skinfold (RR=1.24, 95% CI 1.03-1.48) and total body fat (RR=1.20, 95% CI 1.05-1.38). In both one-mediation and multi-mediation analyses, time-varying z-BMI growth in the prepubertal years plays a crucial mediator in the pathway from the genes to early menarche. CONCLUSIONS: This study discovered that greater prepubertal adiposity growth is a crucial mediator in the path from genes to early menarche. For girls with genes positively associated with obesity; and/or of lower birthweight, a strategy to prevent childhood adiposity should be implemented in order to avoid early menarche development.

Effect of Endoplasmic Reticular Stress on Free Hemoglobin Metabolism and Liver Injury.

Elevated soluble (s) CD163 and free hemoglobin (Hb) levels predict fatty liver progression; however, the molecular mechanisms underlying Hb metabolism and liver injury remain undefined. We investigated the effects of endoplasmic reticular (ER) stress on red blood cell (RBC) rheology and free Hb recycling pathways. ER stress was induced in Sprague-Dawley rats by an intraperitoneal injection of tunicamycin (TM) (50, 100, and 200 µg/100 g body weight (BW)) or an intravenous injection of Hb (5 mg/100 g BW). A TM injection increased sCD163 levels, attenuated free Hb uptake, and maintained RBC aggregability. An Hb injection increased serum LVV-hemorphin-7 and total bilirubin levels, but this effect was suppressed by TM. A Western blot analysis showed that ER stress suppressed Hb degradation in the liver through downregulation of globin degradation proteins cathepsin D and glyoxalase-1, as well as heme degradation protein heme oxyganase-1 and keap-1 expression. An ER stress activator also increased the translocation of nuclear factor (NF)-κB (p65) and nuclear factor-erythroid 2-related factor 2 (Nrf2) to nuclei. In conclusion, ER stress triggers ineffective Hb metabolism via altering globin and heme iron degradation pathways. Inability to recycle and metabolize free Hb may underlie the association between iron dysfunction and liver injury.

Curcumin supplementation ameliorated vascular dysfunction and improved antioxidant status in rats fed a high-sucrose, high-fat diet.

Vascular endothelial dysfunction is a potential risk factor for cardiovascular disease. This study evaluated the effect of curcumin on factors associated with vascular dysfunction using rats fed a high-sucrose, high-fat (HSF) diet. The experiment included 2 animal feeding phases. In the first feeding phase, male Sprague-Dawley rats were randomly divided into 2 groups: the control group (n = 8) was fed a standard diet (AIN-93G) and the HSF group (n = 24) was fed an HSF diet for 8 weeks to induce obesity. In the second feeding phase, lasting 4 weeks, the HSF group was randomly divided into 3 subgroups: the O group (n = 8) continued feeding on the HSF diet, the OA group (n = 8) had the HSF diet replaced with AIN-93G, and the OC group (n = 8) was fed the HSF diet supplemented with curcumin (300 mg/kg body weight daily). After 8 weeks, the HSF diet significantly elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), insulin, homeostatic model assessment insulin resistance (HOMA-IR), low-density lipoprotein cholesterol (LDL-C), homocysteine (Hcy), C-reactive protein (CRP), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) but significantly reduced levels of nitric oxide (NO) and high-density lipoprotein cholesterol (HDL-C). After dietary intervention, the OA and OC groups exhibited significantly lower levels of AST, ALT, HOMA-IR, cholesterol, LDL-C, Hcy, CRP, VCAM-1, and ICAM-1 and higher levels of NO and catalase (CAT) activity compared with the O group. Superoxide dismutase, CAT, and glutathione peroxidase activities were increased in the OA group, while CAT levels were enhanced in the OC group. In conclusion, this study showed that curcumin supplementation and diet modification can inhibit HSF diet-induced vascular dysfunction potentially by enhancing NO production and antioxidant enzyme activities, thereby suppressing inflammation and oxidative damage in the vascular endothelium.

Notch1-promoted TRPA1 expression in erythroleukemic cells suppresses erythroid but enhances megakaryocyte differentiation.

The Notch1 pathway plays important roles in modulating erythroid and megakaryocyte differentiation. To screen the Notch1-related genes that regulate differentiation fate of K562 and HEL cells, the expression of transient receptor potential ankyrin 1 (TRPA1) was induced by Notch1 receptor intracellular domain (N1IC), the activated form of Notch1 receptor. N1IC and v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1) bound to TRPA1 promoter region to regulate transcription in K562 cells. Transactivation of TRPA1 promoter by N1IC depended on the methylation status of TRPA1 promoter. N1IC and Ets-1 suppressed the DNA methyltransferase 3B (DNMT3B) level in K562 cells. Inhibition of TRPA1 expression after Notch1 knockdown could be attenuated by nanaomycin A, an inhibitor of DNMT3B, in K562 and HEL cells. Functionally, hemin-induced erythroid differentiation could be suppressed by TRPA1, and the reduction of erythroid differentiation of both cells by N1IC and Ets-1 occurred via TRPA1. However, PMA-induced megakaryocyte differentiation could be enhanced by TRPA1, and the surface markers of megakaryocytes could be elevated by nanaomycin A. Megakaryocyte differentiation could be reduced by Notch1 or Ets-1 knockdown and relieved by TRPA1 overexpression. The results suggest that Notch1 and TRPA1 might be critical modulators that control the fate of erythroid and megakaryocyte differentiation.

Alpha-mangostin from mangosteen (Garcinia mangostana Linn.) pericarp extract reduces high fat-diet induced hepatic steatosis in rats by regulating mitochondria function and apoptosis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is caused by multiple factors including hepatic oxidative stress, lipotoxicity, and mitochondrial dysfunction. Obesity is among the risk factors for NAFLD alongside type 2 diabetes mellitus and hyperlipidemia. α- mangostin (α-MG) extracts from the pericarps of mangosteen (Garcinia mangostana Linn.) may regulate high fat diet-induced hepatic steatosis; however the underlying mechanisms remain unknown. The aim of this study was to investigate the regulatory effect of α-MG on high fat diet-induced hepatic steatosis and the underlying mechanisms related to mitochondrial functionality and apoptosis in vivo and in vitro. METHODS: Sprague Dawley (SD) rats were fed on either AIM 93-M control diet, a high-fat diet (HFD), or high-fat diet supplemented with 25 mg/day mangosteen pericarp extract (MGE) for 11 weeks. Thereafter, the following were determined: body weight change, plasma free fatty acids, liver triglyceride content, antioxidant enzymes (superoxide dismutase, SOD; glutathione, GSH; glutathione peroxidase, GPx; glutathione reductase GRd; catalase, CAT) and mitochondrial complex enzyme activities. In the in vitro study, primary liver cells were treated with 1 mM free fatty acid (FFA) (palmitate: oleate acid = 2:0.25) to induce steatosis. Thereafter, the effects of α-MG (10 µM, 20 µM, 30 µM) on total and mitochondria ROS (tROS, mitoROS), mitochondria bioenergetic functions, and mitochondrial pathway of apoptosis were examined in the FFA-treated primary liver cells. RESULTS: The MGE group showed significantly decreased plasma free fatty acids and hepatic triglycerides (TG) and thiorbarbituric acid reactive substances (TBARS) levels; increased activities of antioxidant enzymes (SOD, GSH, GPx, GRd, CAT); and enhanced NADH-cytochrome c reductase (NCCR) and succinate-cytochrome c reductase (SCCR) activities in the liver tissue compared with HFD group. In the in vitro study, α-MG significantly increased mitochondrial membrane potential, enhanced cellular oxygen consumption rate (OCR), decreased tROS (total ROS) and mitoROS (mitochondrial ROS) levels ; reduced Ca2+ and cytochrome c (cyt c) release from mitochondria, and reduced caspases 9 and 3 activities compared with control group. CONCLUSION: These findings demonstrate α-MG attenuated hepatic steatosis in high fat-diet fed rats potentially through enhanced cellular antioxidant capacity and improved mitochondrial functions as well as suppressed apoptosis of hepatocytes. The findings of study represent a novel nutritional approach on the use of α-MG in the prevention and management of NAFLD.

Notch1 pathway-mediated microRNA-151-5p promotes gastric cancer progression.

Gastric carcinoma is the third leading cause of lethal cancer worldwide. Previous studies showed that Notch1 receptor intracellular domain (N1IC), the activated form of Notch1 receptor, promotes gastric cancer progression. It has been demonstrated that a significant cross-talk interplays between Notch pathways and microRNAs (miRNAs) in controlling tumorigenesis. This study identified an intronic microRNA-151 (miR-151), which consists of two mature miRNAs, miR-151-3p and miR-151-5p, as a Notch1 receptor-induced miRNA in gastric cancer cells. Activation of Notch1 pathway enhanced expressions of miR-151 and its host gene, focal adhesion kinase (FAK), in gastric cancer cells. The levels of miR-151 in gastric cancer samples were higher than those of adjacent non-tumor samples. Activated Notch1 pathway induced CBF1-dependent FAK promoter activity. The ectopic expression of miR-151 promoted growth and progression of SC-M1 gastric cancer cells including cell viability and colony formation, migration, and invasion abilities. Activated Notch1 pathway could augment progression of gastric cancer cells through miR-151-5p and FAK. The mRNA levels of pluripotency genes, Nanog and SOX-2, tumorsphere formation ability, tumor growth, and lung metastasis of SC-M1 cells were elevated by activated Notch1 pathway through miR-151-5p. Furthermore, miR-151-5p could target 3'-untranslated region (3'-UTR) of p53 mRNA and down-regulate p53 level in SC-M1 cells. Mechanistically, Notch1/miR-151-5p axis contributed to progression of SC-M1 cells through down-regulation of p53 which in turn repressed FAK promoter activity. Taken together, these results suggest that Notch1 pathway and miR-151-5p interplay with p53 in a reciprocal regulation loop in controlling gastric carcinogenesis.