The artificial sweetener erythritol and cardiovascular event risk.

Artificial sweeteners are widely used sugar substitutes, but little is known about their long-term effects on cardiometabolic disease risks. Here we examined the commonly used sugar substitute erythritol and atherothrombotic disease risk. In initial untargeted metabolomics studies in patients undergoing cardiac risk assessment (n = 1,157; discovery cohort, NCT00590200 ), circulating levels of multiple polyol sweeteners, especially erythritol, were associated with incident (3 year) risk for major adverse cardiovascular events (MACE; includes death or nonfatal myocardial infarction or stroke). Subsequent targeted metabolomics analyses in independent US (n = 2,149, NCT00590200 ) and European (n = 833, DRKS00020915 ) validation cohorts of stable patients undergoing elective cardiac evaluation confirmed this association (fourth versus first quartile adjusted hazard ratio (95% confidence interval), 1.80 (1.18-2.77) and 2.21 (1.20-4.07), respectively). At physiological levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo. Finally, in a prospective pilot intervention study ( NCT04731363 ), erythritol ingestion in healthy volunteers (n = 8) induced marked and sustained (>2 d) increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies. Our findings reveal that erythritol is both associated with incident MACE risk and fosters enhanced thrombosis. Studies assessing the long-term safety of erythritol are warranted.

The Nutritional Supplement L-Alpha Glycerylphosphorylcholine Promotes Atherosclerosis.

L-alpha glycerylphosphorylcholine (GPC), a nutritional supplement, has been demonstrated to improve neurological function. However, a new study suggests that GPC supplementation increases incident stroke risk thus its potential adverse effects warrant further investigation. Here we show that GPC promotes atherosclerosis in hyperlipidemic Apoe-/- mice. GPC can be metabolized to trimethylamine N-oxide, a pro-atherogenic agent, suggesting a potential molecular mechanism underlying the observed atherosclerosis progression. GPC supplementation shifted the gut microbial community structure, characterized by increased abundance of Parabacteroides, Ruminococcus, and Bacteroides and decreased abundance of Akkermansia, Lactobacillus, and Roseburia, as determined by 16S rRNA gene sequencing. These data are consistent with a reduction in fecal and cecal short chain fatty acids in GPC-fed mice. Additionally, we found that GPC supplementation led to an increased relative abundance of choline trimethylamine lyase (cutC)-encoding bacteria via qPCR. Interrogation of host inflammatory signaling showed that GPC supplementation increased expression of the proinflammatory effectors CXCL13 and TIMP-1 and activated NF-κB and MAPK signaling pathways in human coronary artery endothelial cells. Finally, targeted and untargeted metabolomic analysis of murine plasma revealed additional metabolites associated with GPC supplementation and atherosclerosis. In summary, our results show GPC promotes atherosclerosis through multiple mechanisms and that caution should be applied when using GPC as a nutritional supplement.

Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression.

OBJECTIVE: Metabolomic studies suggest plasma levels of bile acids (BAs) are elevated amongst subjects with non-alcoholic fatty liver disease (NAFLD) compared to healthy controls. However, it remains unclear whether or not specific BAs are associated with the clinically relevant transition from nonalcoholic fatty liver (i.e. simple steatosis) to non-alcoholic steatohepatitis (NASH), or enhanced progression of hepatic fibrosis, or genetic determinants of NAFLD/NASH. METHODS: Among sequential subjects (n=102) undergoing diagnostic liver biopsy, we examined the associations of a broad panel of BAs with distinct histopathological features of NAFLD, the presence of NASH, and their associations with genetic variants linked to NAFLD and NASH. RESULTS: Plasma BA alterations were observed through the entire spectrum of NAFLD, with several glycine conjugated forms of the BAs demonstrating significant associations with higher grades of inflammation and fibrosis. Plasma 7-Keto-DCA levels showed the strongest associations with advanced stages of hepatic fibrosis [odds ratio(95% confidence interval)], 4.2(1.2-16.4), NASH 24.5(4.1-473), and ballooning 18.7(4.8-91.9). Plasma 7-Keto-LCA levels were associated with NASH 9.4(1.5-185) and ballooning 5.9(1.4-28.8). Genetic variants at several NAFLD/NASH loci were nominally associated with increased levels of 7-Keto- and glycine-conjugated forms of BAs, and the NAFLD risk allele at the TRIB1 locus showed strong tendency toward increased plasma levels of GCA (p=0.02) and GUDCA (p=0.009). CONCLUSIONS: Circulating bile acid levels are associated with histopathological and genetic determinants of the transition from simple hepatic steatosis into NASH. Further studies exploring the potential involvement of bile acid metabolism in the development and/or progression of distinct histopathological features of NASH are warranted.

Relationship of serum leptin with some biochemical, anthropometric parameters and abdominal fat volumes as measured by magnetic resonance imaging.

AIMS: To measure the level of leptin in volunteers and correlate it with several anthropometric, biochemical variables and abdominal fat volumes. METHODS: The level of leptin was investigated in 167 disease-free volunteers. Serum levels of IL-6, adiponectin, and resistin, blood lipid profile (cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) were determined. Waist circumference (WC) was measured using tape and magnetic resonance imaging (MRI) images. RESULTS: All measured anthropometric (BMI, WC measured by tape and MRI) and biochemical variables (adiponectin, resistin, cholesterol, HDL, LDL and TG); and abdominal fats showed a significant (p<0.05) difference between participants with abnormal serum leptin levels and those with normal leptin levels. A higher percentage of participants with abnormal serum leptin were obese males while participants with normal leptin levels were either overweight or normal weight females. A significant (p <0.05) positive correlation was detected between serum leptin concentration and WC, BMI, subcutaneous fat, visceral fat, total abdominal fat, and resistin. A moderate association was found between serum leptin concentration and the inflammatory cytokine IL-6. CONCLUSION: Abnormal serum leptin, was detected in obese male individuals which may be considered as an important indicator for the development of cardiovascular diseases and type 2 diabetes.

Assessment of Abdominal Fat Using High-field Magnetic Resonance Imaging and Anthropometric and Biochemical Parameters.

BACKGROUND: To measure the abdominal subcutaneous fat (SF) and visceral fat (VF) volumes using high-field magnetic resonance imaging (MRI) and to investigate their association with selected anthropometric and biochemical parameters among obese and nonobese apparently healthy participants. METHODS: A cross-sectional study was conducted by recruiting 167 healthy participants. Abdominal scans were acquired at 3T MRI, and the SF and VF were segmented and their volumes were calculated. Selected anthropometric and biochemical measurements were also determined. RESULTS: A significant difference (P < 0.05) was observed between normal body weight and overweight and obese participants for SF and VF, total abdominal fat volumes, leptin, resistin, adiponectin and waist circumference. Waist circumferences were measured by tape and MRI. Findings revealed that MRI-measured fat volumes were different between males and females and had a significant (P < 0.01) strong positive correlation with body mass index, leptin, resistin and WC and had a negative correlation with adiponectin level. MRI-measured fat volumes were found to correlate moderately with interleukin-6 and weakly with cholesterol, serum triglyceride and low-density lipoprotein. Except for cholesterol, all measured biochemical variables and abdominal fat volumes in the current study were significantly associated with body mass index. CONCLUSIONS: All anthropometric and biochemical parameters showed weak-to-strong associations with the MRI-measured fat volumes. Abdominal fat distribution was different between males and females and their correlations with some lipid profiles were found to be sex dependent. These findings revealed that MRI can be used as an alternative tool for obesity assessment.

Association of alanine-valine manganese superoxide dismutase gene polymorphism and microheterogeneity manganese superoxide dismutase activity in breast cancer and benign breast tissue.

PURPOSE: Although the etiology of breast cancer is multifactorial, oxidative stress plays an important role in carcinogenesis. In this study, manganese superoxide dismutase (MnSOD) gene polymorphism and activity were evaluated in benign and breast cancer tissue. METHODS: One hundred and one females were enrolled in this study, 65 who were histopathologically diagnosed with breast cancer and 46 who were benign patients. MnSOD enzyme activity was determined using an indirect competitive inhibition assay and MnSOD gene polymorphism using poly merase chain reaction and agarose gel electrophoresis. RESULTS: MnSOD enzymatic activity (79.83±42.14) was lower in breast cancer tissue compared to benign tumors (236.18±46.37). At the same time, MnSOD enzymatic activity among Ala/Val patients was significantly lower in breast cancer tissue (39.19±7.33) than in Val/Val malignant breast tumors tissue (96.9±22.9). MnSOD enzymatic activity was significantly lower in Val/Val cancer tissue (96.9±22.9) than in benign tissue (255.44±42.7). CONCLUSION: Breast cancer tumors contain less MnSOD than benign breast samples. Patients with Ala/Val polymorphism had reduced MnSOD activity compared to patients with Val/Val breast cancer. Ala/Val gene polymorphism may be a risk factor associated with more advanced breast cancer stage. MnSOD gene polymorphism Ala/Val may be a risk factor associated with more advanced breast cancer stage, and reduction of MnSOD activity may be a mechanism of the progression of benign to malignant tumors. Further investigations are needed to evaluate the role of MnSOD in breast cancer progression.

Relationships among serum CA15-3 tumor marker, TNM staging, and estrogen and progesterone receptor expression in benign and malignant breast lesions.

Serum tumor marker CA15-3 is widely used in follow-up for assessment of breast cancer prognosis. The aim of this study was to evaluate levels among healthy females and patients, to assess differences with tumor stage and grade, and to determine the relationship with estrogen and progesterone receptor expression. One hundred and thirty six Jordanian females were enrolled in this study: Forty-five were healthy females; seventy-two were diagnosed with breast cancer and nineteen diagnosed with benign breast lesions. Elevated serum CA15-3 level was significantly observed among breast cancer patients (37.95±6.65) compared to both healthy (14.97±0.8) and benign females (12.30±1.55), but no significant association was detected between serum CA15-3 level and age of cancer onset, menarche age, menopause age, parity and BMI. Decreased CA15-3 level was significantly associated with hormone therapy and oral contraceptive consumption among breast cancer patients. Significantly elevated CA15-3 serum levels were found among grade II, III and stage II and III breast cancer females compared to normal healthy females. Elevated CA15-3 serum levels were also found among ER+/PR+ (54.242±7.89) and ER+/PR- (37.08±8.22) compared to healthy control females.

Ischemia modified albumin: an oxidative stress marker in ß-thalassemia major.

BACKGROUND: Ischemia modified albumin (IMA) is an altered type of serum albumin that forms under conditions of oxidative stress. This study reports on the levels and clinical significance of IMA in patients with ß-thalassemia major. METHODS: Blood specimens were collected from 166 subjects (101 ß-thalassemia major patients and 65 healthy controls). Serum levels of IMA, ferritin, malondialdehyde (MDA), ferroxidase, transaminases, total protein, and albumin were determined using conventional methods. RESULTS: Serum levels of IMA (ABSU) were significantly higher in patients than in controls (0.725±0.155 vs 0.554±0.154, p=0.000). Similarly, higher levels were also observed for ferritin, MDA, ferroxidase, and transaminases. No significant differences were observed between patients and controls with respect to total protein and albumin. Spearman univariate analysis demonstrated significant correlation between IMA and ferritin, MDA, ferroxidase, and transaminases. Multiple linear regression analysis revealed significant association of IMA with ferritin and ferroxidase after adjusting for the other variables (r=0.343, p=0.002; r=0.228, p=0.029 respectively). MDA however, correlated significantly with ferritin only (r=0.654, p=0.000). CONCLUSION: Our findings suggest that increased levels of IMA in thalassemic patients are likely to be a result of iron-induced oxidative stress and hence its potential significance as a new marker of oxidative stress in such patients.

Association of haptoglobin phenotypes with ceruloplasmin ferroxidase activity in ß-thalassemia major.

BACKGROUND: Haptoglobin (Hp) and ceruloplasmin (CP) are 2 plasma antioxidants playing a role in preventing iron-induced oxidative damage. This study presents data related to Hp phenotypes and ceruloplasmin ferroxidase activity in relation to iron store markers in patients with ß-thalassemia major. METHODS: Blood specimens were collected from 196 subjects (124 ß-thalassemia major patients and 72 healthy controls). Serum levels of iron, total iron binding capacity (TIBC), ferritin, high sensitivity C-reactive protein (hs-CRP), ceruloplasmin, and ferroxidase activity were determined using conventional methods. Haptoglobin phenotypes were determined by polyacrylamide gel electrophoresis. RESULTS: As expected, the mean levels of iron store markers, except TIBC, were significantly higher in patients than in controls. Ceruloplasmin concentrations (mg/dl) and its ferroxidase activity (U/l) were significantly higher in patients than in controls (57.9±18.8 vs 46.9±14.2 and 159.9±47.8 vs 95.3±20.9; p<0.001, for CP and Hp, respectively). As for Hp phenotypes, no significant differences were observed between iron store markers and ferroxidase activity among the control group. In the patients group however, significantly higher concentrations of ceruloplasmin and its ferroxidase activity were observed among patients with Hp2-2 phenotype as compared to patients with the other phenotypes. Additionally, correlations according to Hp phenotypes revealed strong association between ceruloplasmin ferroxidase activity and serum ferritin in patients with Hp 2-2 phenotype and not in the others (r=0.331, p<0.05). CONCLUSION: Thalassemia patients with Hp 2-2 phenotype are under greater iron-driven oxidative stress than patients with other phenotypes.

Skin-lightening practice among women living in Jordan: prevalence, determinants, and user's awareness.

BACKGROUND: The use and misuse of skin-lightening products among women living in Arab communities have not been documented previously. This study investigates the determinants, the prevalence and users awareness associated with the use and misuse of skin-lightening products among women living in Jordan. METHOD: Female customers arriving at selected pharmacy stores were randomly asked to complete a questionnaire. RESULTS: A total of 318 women completed the questionnaire, of which 60.7% reported the use of skin-lightening products. Users included women from different age and economic groups. Main reasons for use were preference of lighter skin tone, the treatment of hyperpigmentary disorders or both. More than a third of the users were not aware of the potential side effects of these products. A significantly larger proportion of skin-lightening product users believed that lighter skin tone plays a role in self-esteem, perception of beauty and youth, marriage and employment opportunities when compared with nonusers. CONCLUSION: Skin lightening is a common practice among women living in Jordan. It is reinforced by the association of lighter skin tone with a number of perceived benefits including perception of beauty, job and marriage opportunity. User's awareness regarding the safety of skin-lightening products and instructions for proper use are important considerations when developing interventions to control the misuse of these products.