Few studies have examined associations between plasma choline metabolites and risk of colorectal cancer (CRC). Therefore, we investigated associations between plasma biomarkers of choline metabolism [choline, betaine, dimethylglycine and trimethylamine N-oxide (TMAO)] and CRC risk among postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. We selected 835 matched case-control pairs, and cases were further stratified by tumor site (proximal, distal, or rectal) and stage (local/regional or metastatic). CRC was assessed by self-report and confirmed by medical records over the mean 5.2y of follow-up. Baseline plasma choline metabolites were measured by liquid chromatography-tandem mass spectrometry. In multivariable-adjusted conditional logistic regression models, plasma choline tended to be positively associated with rectal cancer risk [OR (95% CI)highest vs. lowest quartile=2.44 (0.93-6.40);P-trend=0.08], while plasma betaine was inversely associated with CRC overall [0.68 (0.47-0.99);P-trend=0.01] and with local/regional tumors [0.64 (0.42-0.99);P-trend=0.009]. Notably, the plasma betaine:choline ratio was inversely associated with CRC overall [0.56 (0.39-0.82);P-trend=0.004] as well as with proximal [0.66 (0.41-1.06);P-trend=0.049], rectal [0.27 (0.10-0.78);P-trend=0.02] and local/regional [0.50 (0.33-0.76);P-trend=0.001] tumors. Finally, plasma TMAO, an oxidative derivative of choline produced by intestinal bacteria, was positively associated with rectal cancer [3.38 (1.25-9.16);P-trend=0.02] and with overall CRC risk among women with lower (vs. higher) plasma vitamin B12 levels (P-interaction=0.003). Collectively, these data suggest that alterations in choline metabolism, which may arise early in disease development, may be associated with higher risk of CRC. The positive association between plasma TMAO and CRC risk is consistent with an involvement of the gut microbiome in CRC pathogenesis.
Bae, S., et al., Plasma choline metabolites and colorectal cancer risk in the Women's Health Initiative Observational Study. Cancer Res, 2014
Monday, November 3, 2014
Betaine might be applicable to the prevention of inflammation-associated colon carcinogenesis.
In this review, we will summarize the current understanding of modulation of colitis-associated colon tumorigenesis by two natural products, baicalein and betaine, which have anti-inflammatory activities. Baicalein and betaine have been shown to provide various health benefits to organism in many ways. Baicalein is a phenolic flavonoid derived originally from the root of Scutellaria baicalensis Georgi. From ancient times, baicalein has widely been used in oriental medicines as an anti-inflammatory and anti-cancer therapy. Betaine, trimethylglycine, is an essential biochemical molecule of the methionine/homocysteine cycle and is synthesized by conversion of choline. Betaine is an important human nutrient obtained from various foods including sugar beet and lycium. Betaine has provided various health benefits including disease prevention. However, the action mechanisms of their activity remain poorly understood. Recent studies reported the effects of baicalein and betaine on cytotoxicity against colon cancer cells and chemically induced colitis-associated colon tumorigenesis in mice. Administrations of baicalein and betaine containing diets significantly inhibited the incidence of tumors and hyperplasia with down-regulation of inflammation. Therefore, baicalein and betaine might be applicable to the prevention of inflammation-associated colon carcinogenesis.
Kim, D.H., et al., Modulation of Colitis-associated Colon Tumorigenesis by Baicalein and Betaine. J Cancer Prev, 2014. 19(3): p. 153-60
Kim, D.H., et al., Modulation of Colitis-associated Colon Tumorigenesis by Baicalein and Betaine. J Cancer Prev, 2014. 19(3): p. 153-60
Betaine may be a key contributor to reduction of disease risk associated with greater intake of whole grain
Dietary fibre alone does not fully explain the frequent association between greater intake of whole grains and reduced risk of disease in observational studies, and other phytochemicals or food structure may also play an important role. For all the observational evidence for the benefits of a whole-grain-rich diet, we have only limited knowledge of the mechanisms behind this reduction in disease risk, aside from the action of specific cereal fibres on reduction of blood cholesterol and the post-prandial glucose peak. Nutritional metabolomics, the global measurement and interpretation of metabolic profiles, assesses the interaction of food with the endogenous gene-protein cascade and the gut microbiome. This approach allows the generation of new hypotheses which account for systemic effects, rather than just focusing on one or two mechanisms or metabolic pathways. To date, animal and human trials using metabolomics to investigate mechanistic changes to metabolism on eating whole grains and cereal fractions have led to new hypotheses around mechanistic effects of whole grains. These include the role of cereals as a major source of dietary glycine betaine, a possible effect on phospholipid synthesis or metabolism, the role of branched-chain amino acids and improvements in insulin sensitivity, and the possibility that whole grains may have an effect on protein metabolism. These hypotheses help explain some of the observed effects of whole grains, although mechanistic studies using stable isotopes and fully quantitative measures are required to confirm these potential mechanisms.
Ross, A.B., Whole grains beyond fibre: what can metabolomics tell us about mechanisms? Proc Nutr Soc, 2014: p. 1-8
Ross, A.B., Whole grains beyond fibre: what can metabolomics tell us about mechanisms? Proc Nutr Soc, 2014: p. 1-8
Betaine may protect ocular surface epithelia from MMP-mediated disorders in dry eye disease
PURPOSE: Hyperosmolarity has been recognized as a proinflammatory stress in the pathogenesis of dry eye disease. This study investigated the suppressive effect of osmoprotectants (L-carnitine, erythritol, and betaine) on the production and activity of matrix metalloproteinases (MMPs) in primary human corneal epithelial cells (HCECs) exposed to hyperosmotic stress.
METHODS: Primary HCECs were established from fresh donor limbal tissue explants. The cultures in iso-osmolar medium (312 mOsM) were switched to hyperosmotic media with or without prior incubation with different concentrations of L-carnitine, erythritol, or betaine (2, 10, or 20 mM). The mRNA expression of the MMPs was determined with reverse transcription and quantitative real-time PCR (RT-qPCR). Protein production and activity were evaluated with immunofluorescent staining and gelatin zymography.
RESULTS: Hyperosmotic media (400, 450, or 500 mOsM) significantly stimulated mRNA expression of collagenase MMP-13, gelatinases MMP-9 and MMP-2, stromelysin MMP-3, and matrilysin MMP-7, mostly in an osmolarity-dependent fashion. The stimulated mRNA expression and protein production of these MMPs were significantly but differentially suppressed by L-carnitine, erythritol, or betaine, as evaluated with RT-qPCR and immunofluorescent staining. Interestingly, these osmoprotectants not only suppressed production but also inhibited activation of MMP-9 and MMP-2, as evaluated with gelatin zymography.
CONCLUSIONS: Our findings for the first time demonstrate that osmoprotectants, L-carnitine, erythritol, and betaine, suppress the gene expression, protein production, and enzymatic activity of MMPs in HCECs exposed to hyperosmotic stress. L-carnitine appears to have the broadest and strongest suppressive effect on these MMPs. These osmoprotectants may have potential effects in protecting ocular surface epithelia from MMP-mediated disorders in dry eye disease.
Deng, R., et al., Osmoprotectants suppress the production and activity of matrix metalloproteinases induced by hyperosmolarity in primary human corneal epithelial cells. Mol Vis, 2014. 20: p. 1243-52
METHODS: Primary HCECs were established from fresh donor limbal tissue explants. The cultures in iso-osmolar medium (312 mOsM) were switched to hyperosmotic media with or without prior incubation with different concentrations of L-carnitine, erythritol, or betaine (2, 10, or 20 mM). The mRNA expression of the MMPs was determined with reverse transcription and quantitative real-time PCR (RT-qPCR). Protein production and activity were evaluated with immunofluorescent staining and gelatin zymography.
RESULTS: Hyperosmotic media (400, 450, or 500 mOsM) significantly stimulated mRNA expression of collagenase MMP-13, gelatinases MMP-9 and MMP-2, stromelysin MMP-3, and matrilysin MMP-7, mostly in an osmolarity-dependent fashion. The stimulated mRNA expression and protein production of these MMPs were significantly but differentially suppressed by L-carnitine, erythritol, or betaine, as evaluated with RT-qPCR and immunofluorescent staining. Interestingly, these osmoprotectants not only suppressed production but also inhibited activation of MMP-9 and MMP-2, as evaluated with gelatin zymography.
CONCLUSIONS: Our findings for the first time demonstrate that osmoprotectants, L-carnitine, erythritol, and betaine, suppress the gene expression, protein production, and enzymatic activity of MMPs in HCECs exposed to hyperosmotic stress. L-carnitine appears to have the broadest and strongest suppressive effect on these MMPs. These osmoprotectants may have potential effects in protecting ocular surface epithelia from MMP-mediated disorders in dry eye disease.
Deng, R., et al., Osmoprotectants suppress the production and activity of matrix metalloproteinases induced by hyperosmolarity in primary human corneal epithelial cells. Mol Vis, 2014. 20: p. 1243-52
Thursday, October 16, 2014
Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats
SCOPE:: Hypothalamic astrogliosis and inflammation cause neural injury, playing a critical role in metabolic syndrome development. This study investigated whether and how fructose caused hypothalamic astrogliosis and inflammation in vivo and in vitro. The inhibitory effects of betaine on hypothalamic neural injury, astrogliosis and inflammation were explored to address its improvement of fructose-induced metabolic syndrome.
METHODS AND RESULTS:: Rats or astrocytes were exposed to fructose and then treated with betaine. Neural injury, proinflammatory markers, toll-like receptor 4/nuclear factor-kappaB (TLR4/NF-kappaB) pathway and histone deacetylases (HDAC3) expression were evaluated. The reduction of pro-opiomelanocortin (POMC) and melanocortin 4 receptor (Mc4R) neurons in fructose-fed rats were ameliorated by betaine. Moreover, fructose induced astrogliosis and proinflammatory cytokines by increasing TLR4, MyD88 and NF-kappaB expression in rat hypothalamus and astrocytes. HDAC3 over-expression preserved the prolonged inflammation in fructose-stimulated astrocytes by regulating nuclear NF-kappaB-dependent transcription. Betaine suppressed TLR4/NF-kappaB pathway activation and HDAC3 expression, contributing to its inhibition of hypothalamic astrogliosis and inflammation in animal and cell models.
CONCLUSION:: These findings suggest that betaine inhibits fructose-caused astrogliosis and inflammation by the suppression of TLR4/NF-kappaB pathway activation and HDAC3 expression to protect against hypothalamic neural injury, which, at least partly, contributes to the improvement on fructose-induced metabolic syndrome.
Li, J.M., et al., Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats. Mol Nutr Food Res, 2014
METHODS AND RESULTS:: Rats or astrocytes were exposed to fructose and then treated with betaine. Neural injury, proinflammatory markers, toll-like receptor 4/nuclear factor-kappaB (TLR4/NF-kappaB) pathway and histone deacetylases (HDAC3) expression were evaluated. The reduction of pro-opiomelanocortin (POMC) and melanocortin 4 receptor (Mc4R) neurons in fructose-fed rats were ameliorated by betaine. Moreover, fructose induced astrogliosis and proinflammatory cytokines by increasing TLR4, MyD88 and NF-kappaB expression in rat hypothalamus and astrocytes. HDAC3 over-expression preserved the prolonged inflammation in fructose-stimulated astrocytes by regulating nuclear NF-kappaB-dependent transcription. Betaine suppressed TLR4/NF-kappaB pathway activation and HDAC3 expression, contributing to its inhibition of hypothalamic astrogliosis and inflammation in animal and cell models.
CONCLUSION:: These findings suggest that betaine inhibits fructose-caused astrogliosis and inflammation by the suppression of TLR4/NF-kappaB pathway activation and HDAC3 expression to protect against hypothalamic neural injury, which, at least partly, contributes to the improvement on fructose-induced metabolic syndrome.
Li, J.M., et al., Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats. Mol Nutr Food Res, 2014
Higher serum concentrations of betaine is associated with better profiles of body fat and fat distribution in Chinese adults
Objective: Animal studies have suggested that betaine but not choline may improve body composition, but little evidence is available in humans. We examined the associations of serum concentrations of choline and betaine with body composition and fat distribution in adults.
Methods: This community-based study recruited 1996 adults (W/M: 1380/616) aged 40-75 in urban Guangzhou, China. General information and anthropometric measurements were taken, and serum choline and betaine levels were assessed by HPLC-MS between July 2008 and June 2010. After 3.2 years, 1623 of the 1996 participants were measured for fat mass (FM and %FM) over the total body (TB), trunk, limbs, android (A) and gynoid (G) regions. The %FM ratios of the A/G and the trunk and limbs were determined by dual-energy X-ray absorptiometry (DXA).
Results: Univariate analyses showed that higher serum betaine levels were significantly associated with lower values of adiposity indices, except in the case of the %FM at the gynoid area. After adjusting for potential covariates, similar associations were observed. The mean percentage differences between quartiles 4 and 1 of the serum betaine levels were -4.9% (weight), -4.7% (BMI), -2.5% (WC), -7.9% (TB FM) and -3.4% (TB %FM). The mean differences in the FM and %FM were much more pronounced at the trunk (-10.0% and -4.5%) or android areas (-10.7% and -4.7%) than those at the limbs (-0.8% and -2.3%) or gynoid areas (-0.6% and -1.4%). Such favorable associations were stronger in men than in women. No significant associations between serum choline and the adiposity indices were observed, except in the cases of body weight and BMI.
Conclusions: Greater circulating betaine, but not choline, was dose-dependently associated with better body composition and fat distribution due to a lower fat mass in the trunk regions in this population.
Chen, Y.-m., et al., Higher serum concentrations of betaine rather than choline is associated with better profiles of DXA-derived body fat and fat distribution in Chinese adults. Int J Obes, 2014.
Methods: This community-based study recruited 1996 adults (W/M: 1380/616) aged 40-75 in urban Guangzhou, China. General information and anthropometric measurements were taken, and serum choline and betaine levels were assessed by HPLC-MS between July 2008 and June 2010. After 3.2 years, 1623 of the 1996 participants were measured for fat mass (FM and %FM) over the total body (TB), trunk, limbs, android (A) and gynoid (G) regions. The %FM ratios of the A/G and the trunk and limbs were determined by dual-energy X-ray absorptiometry (DXA).
Results: Univariate analyses showed that higher serum betaine levels were significantly associated with lower values of adiposity indices, except in the case of the %FM at the gynoid area. After adjusting for potential covariates, similar associations were observed. The mean percentage differences between quartiles 4 and 1 of the serum betaine levels were -4.9% (weight), -4.7% (BMI), -2.5% (WC), -7.9% (TB FM) and -3.4% (TB %FM). The mean differences in the FM and %FM were much more pronounced at the trunk (-10.0% and -4.5%) or android areas (-10.7% and -4.7%) than those at the limbs (-0.8% and -2.3%) or gynoid areas (-0.6% and -1.4%). Such favorable associations were stronger in men than in women. No significant associations between serum choline and the adiposity indices were observed, except in the cases of body weight and BMI.
Conclusions: Greater circulating betaine, but not choline, was dose-dependently associated with better body composition and fat distribution due to a lower fat mass in the trunk regions in this population.
Chen, Y.-m., et al., Higher serum concentrations of betaine rather than choline is associated with better profiles of DXA-derived body fat and fat distribution in Chinese adults. Int J Obes, 2014.
Carnitine, erythritol and betaine may have efficacy in reducing innate inflammation in dry eye disease.
Purpose: To explore the effects of osmoprotectants on pro-inflammatory mediator production in primary human corneal epithelial cells (HCECs) exposed to hyperosmotic stress.
Methods: HCECs cultured in iso-osmolar medium (312 mOsM) were switched to hyperosmotic media with or without prior incubation with 2-20 mM of l-carnitine, erythritol or betaine for different time periods. The mRNA expression and protein production of pro-inflammatory markers in HCECs were evaluated by RT-qPCR and ELISA.
Results: Hyperosmolar media significantly stimulated the mRNA and protein expression of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, and chemokines, IL-8, CCL2 and CCL20 in HCECs in an osmolarity dependent manner. The stimulated expression of these pro-inflammatory mediators was significantly but differentially suppressed by l-carnitine, erythritol or betaine. l-Carnitine displayed the greatest inhibitory effects and down-regulated 54-77% of the stimulated mRNA levels of TNF-alpha (down from 12.3-5.7 fold), IL-1beta (2.2-0.9 fold), IL-6 (7.3-2.9 fold), IL-8 (4.6-2.0 fold), CCL2 (15.3-3.5 fold) and CCL20 (4.1-1.5 fold) in HCECs exposed to 450 mOsM. The stimulated protein production of TNF-alpha, IL-1beta, IL-6 and IL-8 was also significantly suppressed by l-carnitine, erythritol and betaine. l-carnitine suppressed 49-79% of the stimulated protein levels of TNF-alpha (down from 81.3 to 17.4 pg/ml), IL-1beta (56.9-29.2 pg/ml), IL-6 (12.8-4.6 ng/ml) and IL-8 (21.2-10.9 ng/ml) by HCECs exposed to 450 mOsM. Interestingly, hyperosmolarity stimulated increase in mRNA and protein levels of TNF-alpha, IL-1beta and IL-6 were significantly suppressed by a transient receptor potential vanilloid channel type 1 (TRPV1) activation inhibitor capsazepine.
Conclusions: l-carnitine, erythritol and betaine function as osmoprotectants to suppress inflammatory responses via TRPV1 pathway in HCECs exposed to hyperosmotic stress. Osmoprotectants may have efficacy in reducing innate inflammation in dry eye disease.
Hua, X., et al., Effects of l-Carnitine, Erythritol and Betaine on Pro-inflammatory Markers in Primary Human Corneal Epithelial Cells Exposed to Hyperosmotic Stress. Curr Eye Res, 2014: p. 1-11.
Methods: HCECs cultured in iso-osmolar medium (312 mOsM) were switched to hyperosmotic media with or without prior incubation with 2-20 mM of l-carnitine, erythritol or betaine for different time periods. The mRNA expression and protein production of pro-inflammatory markers in HCECs were evaluated by RT-qPCR and ELISA.
Results: Hyperosmolar media significantly stimulated the mRNA and protein expression of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, and chemokines, IL-8, CCL2 and CCL20 in HCECs in an osmolarity dependent manner. The stimulated expression of these pro-inflammatory mediators was significantly but differentially suppressed by l-carnitine, erythritol or betaine. l-Carnitine displayed the greatest inhibitory effects and down-regulated 54-77% of the stimulated mRNA levels of TNF-alpha (down from 12.3-5.7 fold), IL-1beta (2.2-0.9 fold), IL-6 (7.3-2.9 fold), IL-8 (4.6-2.0 fold), CCL2 (15.3-3.5 fold) and CCL20 (4.1-1.5 fold) in HCECs exposed to 450 mOsM. The stimulated protein production of TNF-alpha, IL-1beta, IL-6 and IL-8 was also significantly suppressed by l-carnitine, erythritol and betaine. l-carnitine suppressed 49-79% of the stimulated protein levels of TNF-alpha (down from 81.3 to 17.4 pg/ml), IL-1beta (56.9-29.2 pg/ml), IL-6 (12.8-4.6 ng/ml) and IL-8 (21.2-10.9 ng/ml) by HCECs exposed to 450 mOsM. Interestingly, hyperosmolarity stimulated increase in mRNA and protein levels of TNF-alpha, IL-1beta and IL-6 were significantly suppressed by a transient receptor potential vanilloid channel type 1 (TRPV1) activation inhibitor capsazepine.
Conclusions: l-carnitine, erythritol and betaine function as osmoprotectants to suppress inflammatory responses via TRPV1 pathway in HCECs exposed to hyperosmotic stress. Osmoprotectants may have efficacy in reducing innate inflammation in dry eye disease.
Hua, X., et al., Effects of l-Carnitine, Erythritol and Betaine on Pro-inflammatory Markers in Primary Human Corneal Epithelial Cells Exposed to Hyperosmotic Stress. Curr Eye Res, 2014: p. 1-11.
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