Licochalcone L, an undescribed retrochalcone from Glycyrrhiza inflata roots.

Glycyrrhiza inflata Batalin is among the three glycyrrhizin producing Glycyrrhiza species and can be distinguished from other species with regard to its retrochalcone contents. Seven retrochalcones, echinatin and licochalcones A, C, D, E, K, and L were isolated and characterized from the chloroform extract of G. inflata roots. Among the isolates, licochalcone L was found to be previously undescribed. Structure elucidation of these specialised metabolites was achieved through NMR and mass spectroscopic data analyses.

Screen detection is a survival predictor independent of pathological grade in colorectal cancer. A prospective cohort study.

INTRODUCTION: Patients with screened detected colorectal cancer (CRC) have a better survival than patients referred with symptoms. This may be because of cancers being identified in a younger population and at an earlier stage. In this study, we assess whether screened detected CRC has an improved outcome after controlling for key pathological and patient factors known to influence prognosis. METHOD: This is a cohort study of all CRC patients diagnosed in NHS Grampian. Patients aged 51-75 years old between June 2007 and July 2017 were included. Data were obtained from a prospectively maintained regional pathology database and outcomes from ISD records. All-cause mortality rates at 1 and 5 years were examined. A Cox proportional hazards regression model was used to estimate the effect of screening status, age, gender, Duke stage, tumour location, extramural venous invasion (EMVI) status and lymph node ratio (LNR) on overall survival. RESULTS: Of 1618 CRC cases, 449 (27.8%) were screened and 1169 (72.2%) were symptomatic. Screened CRC patients had improved survival compared to non-screened CRC at 1 year (88.9% vs 83.9% p < 0.001) and 5-years (42.5% vs 36.2%; p < 0.001). On multivariable analysis of patients who had no neoadjuvant therapy (n = 1272), screening had better survival (HR 0.57; 95% CI 0.44-0.74; p < 0.001). EMVI (HR 2.22; CI 1.76 to 2.79; p < 0.001) and tumour location were found to affect outcome. CONCLUSION: Patients referred through screening had improved survival compared with symptomatic patients. Further research could be targeted to determine if screened CRC cases are pathologically different to symptomatic cancers or if the screening cohort is inherently more healthy.

Scientific and Regulatory Approach to Botanical Drug Development: A U.S. FDA Perspective.

The United States FDA has received over 800 botanical investigational new drug applications (IND) and pre-IND meeting requests (PIND) in the years preceding 2018. The current data show that indications for submitted INDs cover nearly every review division of the FDA. Despite increasing global interest in the investigation of botanical mixtures as drug products, only two botanical new drug applications (NDA) have been approved in the U.S.: Veregen in 2006 and Fulyzaq (also known as Mytesi) in 2012. Given botanicals' chemical and biological complexity, efforts in characterizing their pharmacology, demonstrating therapeutic efficacy, and ensuring quality consistency remain scientific and regulatory challenges. The FDA published a revised Botanical Drug Development Guidance for Industry document in December 2016 to address developmental considerations for late-phase trials and to provide recommendations intended to facilitate botanical drug development. Herein, we present an analysis of botanical INDs showing their variety of botanical raw materials (e.g., coming from different geographic regions, single vs multiple herbs), the varied levels of previous human experience, and therapeutic areas, as well as provide an overview of experience and challenges in reviewing botanical drugs.

Switching to a fibre-rich and low-fat diet increases colonic folate contents among African Americans.

How dietary patterns impact colonic bacterial biosynthesis of vitamins and utilization by humans is poorly understood. Our aim was to investigate whether a reciprocal dietary switch between rural South Africans (traditionally high fibre, low fat) and African Americans (Western diet of low fibre, high fat) affects colonic folate synthesis. Colonic evacuants were obtained from 20 rural South Africans and 20 African Americans consuming their usual diets at baseline. For 2 weeks thereafter, rural South Africans were provided with a Western diet (protein, 27%; fat, 52%; carbohydrate, 20%; and fibre, 8 g/day) and African Americans were provided with a high fibre, low-fat diet (protein, 16%; fat, 17%; carbohydrate, 63%; and fibre, 43 g/day). Colonic evacuants were again collected. No difference between groups at baseline in the folate content of 3-h evacuants was observed. The high-fibre, low-fat diet consumed by African Americans during the intervention produced a 41% increase in mean total folate content compared with baseline values (p = 0.0037). No change was observed in rural South Africans consuming a Western diet. Mean total folate content of colonic evacuants was higher among African Americans at the end of the dietary switch (3107 ± 1811 µg) compared with rural South Africans (2157 ± 1956 µg) (p = 0.0409). In conclusion, consistent with animal studies, switching from a Western diet to one higher in fibre and lower in fat can be expected to result in greater colonic folate content. Future research should confirm that these observations are not transitory and understand the contribution of transit-time to the findings.

Modeling Demonstrates That Folic Acid Fortification of Whole-Wheat Flour Could Reduce the Prevalence of Folate Inadequacy in Canadian Whole-Wheat Consumers.

BACKGROUND: Mandatory folic acid fortification of white-wheat flour and selected other grain products has reduced the prevalence of neural tube defects in Canada; however, the fortification of whole-wheat flour is not permitted. OBJECTIVE: The objective of this study was to model the impact of adding folic acid to whole-wheat flour on the folate intake distribution of Canadians. METHODS: Twenty-four-hour dietary recall and supplement intake data (n = 35,107) collected in the 2004 Canadian Community Health Survey 2.2 were used to calculate the prevalence of folate inadequacy (POFI) and the proportion of folic acid intakes above the Tolerable Upper Intake Level (UL). In model 1, folic acid was added to whole-wheat flour-containing foods in amounts comparable to those that are mandatory for white-wheat flour-containing foods. In model 2, a 50% overage of folic acid fortification was considered. Models 3 and 4 included assessment of folate intake distributions in adult whole-wheat consumers with or without a fortification overage. SIDE (Software for Intake Distribution Estimation; Department of Statistics and Center for Agricultural and Rural Development, Iowa State University) was used to estimate usual folate intakes. RESULTS: Mean folate intakes increased by ∼ 5% in all sex and age groups when whole-wheat foods were fortified (models 1 and 2; P < 0.0001). Folic acid fortification of whole-wheat flour-containing foods did not change the POFI or percentage of intakes above the UL in the general population, whether in supplement users or nonusers. Among whole-wheat consumers, the POFI was reduced by 10 percentage points after fortification of whole-wheat flour-containing foods (95% CIs did not overlap). The percentage of whole-wheat consumers with intakes above the UL did not change. CONCLUSION: Although folic acid fortification of whole-wheat flour-containing foods is unlikely to change the POFI or proportion of folic acid intakes above the UL in the general Canadian population, this fortification strategy may reduce the POFI in adult whole-wheat consumers.

Diacylglycerol oil reduces body fat but does not alter energy or lipid metabolism in overweight, hypertriglyceridemic women.

Diacylglycerol (DAG) may undergo differential metabolism compared with triacylglycerol (TAG) in humans, possibly resulting in decreased serum TAG concentration and TAG synthesis and increased energy expenditure (EE), thus reducing fat accumulation. Our objective was to examine the efficacy of DAG oil (Enova oil) consumption on serum lipid profiles, hepatic lipogenesis, EE, and body weight and composition compared with a control oil-blend composed of sunflower, safflower, and rapeseed oils at a 1:1:1 ratio. Twenty-six overweight (78.3 +/- 3.6 kg body weight and BMI 30.0 +/- 0.7 kg/m(2)) mildly hypertriglyceridemic (1.81 +/- 0.66 mmol/L) women underwent 2 treatment phases of 28 d separated by a 4-wk washout period using a randomized crossover design. They consumed 40 g/d of either DAG or control oil during treatment phases. The baseline, EE, fat oxidation, body composition, and lipid profiles did not differ between the DAG and control oil intervention periods. Relative to control oil, DAG oil did not alter endpoint postprandial EE, fat oxidation, serum lipid profiles, or hepatic lipogenesis. However, DAG oil consumption reduced (P < 0.05) accumulation of body fat within trunk, android, and gynoid regions at the endpoint compared with control oil, although neither DAG nor control oil altered any of these variables during the 4-wk intervention period compared with their respective baseline levels. We conclude that although DAG oil is not effective in lowing serum lipids over a 4-wk intervention, it may be useful for reducing adiposity.

Low and moderate-fat plant sterol fortified soymilk in modulation of plasma lipids and cholesterol kinetics in subjects with normal to high cholesterol concentrations: report on two randomized crossover studies.

BACKGROUND: Although consumption of various plant sterol (PS)-enriched beverages is effective in lowering plasma cholesterol, the lipid-lowering potential of PS in a soymilk format has not been investigated thoroughly. Therefore, to evaluate the efficacy of PS-enriched soy beverages on plasma lipids and cholesterol kinetics, we conducted two separate 28 d dietary controlled cross-over studies. In study 1, the cholesterol-lowering efficacy of a low-fat (2 g/serving) PS enriched soy beverage was examined in 33 normal cholesterolemic subjects in comparison with 1% dairy milk. In study 2, we investigated the efficacy of a moderate-fat (3.5 g/serving) PS-enriched soy beverage on plasma cholesterol concentrations and cholesterol kinetic responses in 23 hypercholesterolemic subjects compared with 1% dairy milk. Both the low and moderate-fat PS-enriched soymilk varieties provided 1.95 g PS/d. Endpoint plasma variables were analyzed by repeated-measures ANOVA using baseline values as covariates for plasma lipid measurements. RESULTS: In comparison with the 1% dairy milk control, the low-fat soy beverage reduced (P < 0.05) total and LDL-cholesterol by 10 and 13%, respectively. Consumption of the moderate-fat PS-enriched soy beverage reduced (P < 0.05) plasma total and LDL-cholesterol by 12 and 15% respectively. Fasting triglycerides were reduced by 9.4% following consumption of the moderate-fat soy beverage in comparison with the 1% dairy milk. Both low and moderate-fat PS-enriched soy varieties reduced (P < 0.05) LDL:HDL and TC:HDL ratios compared with the 1% dairy milk control. Consumption of the moderate-fat PS-enriched soymilk reduced (P < 0.05) cholesterol absorption by 27%, but did not alter cholesterol synthesis in comparison with 1% dairy milk. CONCLUSION: We conclude that, compared to 1% dairy milk, consumption of low and moderate-fat PS-enriched soy beverages represents an effective dietary strategy to reduce circulating lipid concentrations in normal to hypercholesterolemic individuals by reducing intestinal cholesterol absorption. TRIAL REGISTRATION (CLINICALTRIALS.GOV): NCT00923403 (Study 1), NCT00924391 (Study 2).

Effects of dietary cholesterol and simvastatin on cholesterol synthesis in Smith-Lemli-Opitz syndrome.

Deficient cholesterol and/or excessive 7-dehydrocholesterol (7-DHC) may be responsible for the pathology of Smith-Lemli-Opitz syndrome (SLOS). Both high-cholesterol diets given to ameliorate cholesterol deficiency while decreasing 7-DHC and cholesterol-enriched diets plus simvastatin to further decrease sterol synthesis have been used as potential therapies. However, the effect of dietary cholesterol and simvastatin on cholesterol synthesis in SLOS has not been reported. Twelve subjects with SLOS enrolled in the study: Nine had received a high cholesterol diet (HI) for 3 y and three were studied after 4 wk on a low cholesterol diet (LO). Cholesterol fractional synthesis rate (FSR) was measured after oral administration of deuterium oxide, using gas chromatography isotope ratio mass spectrometry. FSR was lower in HI compared with LO (HI: 1.46 +/- 0.62%/d; LO: 4.77 +/- 0.95%/d; p < 0.001). Three HI subjects were retested after 0.8 y taking simvastatin (HI + ST). Simvastatin tended to reduce FSR and significantly decreased (p < 0.01) plasma 7-DHC compared with cholesterol supplementation alone. The study demonstrates the utility of the deuterium incorporation method to understand the effect of therapeutic interventions in SLOS. The data suggest that dietary cholesterol supplementation reduces cholesterol synthesis in SLOS and further support the rationale for the combined treatment of SLOS with a cholesterol-enriched diet and simvastatin.

Fish-oil esters of plant sterols differ from vegetable-oil sterol esters in triglycerides lowering, carotenoid bioavailability and impact on plasminogen activator inhibitor-1 (PAI-1) concentrations in hypercholesterolemic subjects.

BACKGROUND: Consumption of plant sterol (PS) esters lower low-density lipoprotein (LDL)-cholesterol levels by suppressing intestinal absorption of cholesterol. Commercially available PS are mainly esterified to omega-6 fatty acid (FA), such as sunflower oil (SO) FA. Emerging trends include using other sources such as olive oil (OO) or omega-3 FA from fish oil (FO), known to exert potent hypotriglyceridemic effects. Our objective was to compare the actions of different FA esterified to PS on blood lipids, carotenoid bioavailability as well as inflammatory and coagulation markers. METHODS: Twenty-one moderately overweight, hypercholesterolemic subjects consumed experimental isoenergetic diets enriched with OO (70% of fat), each lasting 28-day and separated by 4-week washout periods, using a randomized crossover design. Diets were supplemented with three PS esters preparations, PS-FO, PS-SO, or PS-OO. All PS treatments contained an equivalent of 1.7 PS g/d, and the PS-FO provided a total of 5.4 g/d FO FA (eicosapentaenoic and docosahexaenoic acids). RESULTS: There were no differences between PS-containing diet effects on total cholesterol, LDL-cholesterol, or high-density lipoprotein (HDL)-cholesterol levels. However, PS-FO consumption resulted in markedly lower (P < 0.0001) fasting and postprandial triglyceride concentrations compared with PS-SO and PS-OO. These treatments affected plasma beta-carotene (P = 0.0169) and retinol (P = 0.0244), but not tocopherol (P = 0.2108) concentrations. Consumption of PS-FO resulted in higher beta-carotene (P = 0.0139) and retinol (P = 0.0425) levels than PS-SO and PS-OO, respectively. Plasma TNF-alpha, IL-6, C-reactive protein, prostate specific antigen, and fibrinogen concentrations were unaffected by the PS-interventions. In contrast, plasminogen activator inhibitor 1 (PAI-1) concentrations were lower (P = 0.0282) in the PS-FO-fed than the PS-SO, but not the PS-OO (P = 0.7487) groups. CONCLUSION: Our findings suggest that, in hypercholesterolemic subjects consuming an OO-based diet, PS-FO results in lowered blood triglyceride and PAI-1 concentrations, and higher fat-soluble vitamin levels in comparison to the vegetable oil FA esters of PS (PS-SO and PS-OO). Thus, PS-FO may offer hyperlipidemic subjects a more comprehensive lipid lowering approach while reducing the potential risk of decreased plasma carotenoid concentrations.

Olive oil containing olive oil fatty acid esters of plant sterols and dietary diacylglycerol reduces low-density lipoprotein cholesterol and decreases the tendency for peroxidation in hypercholesterolaemic subjects.

Plant sterols (PS) and MUFA are well-documented cholesterol lowering agents. We aimed to determine the effect of PS esterified to olive oil fatty acids (PS-OO) on blood lipid profile and lipid peroxidation in hypercholesterolaemic subjects. Twenty-one moderately overweight, hypercholesterolaemic subjects consumed three consecutive treatment diets, each lasting 28 d and separated by 4-week washout periods, using a randomized crossover design. Diets contained 30 % energy as fat, 70 % of which was provided by olive oil (OO), and differed only in the treatment oils: OO, PS esterified to sunflower oil fatty acids (PS-SO), and PS-OO. Both PS-SO and PS-OO treatments provided 1.7 g PS /d. PS-OO and PS-SO consumption resulted in a decrease (P = 0.0483) in LDL-cholesterol (LDL-C) concentrations compared with the OO diet. Although total cholesterol and apo B-100 levels were not significantly affected, PS-SO and, to some extent, PS-OO reduced the total:HDL-cholesterol (HDL-C) ratio (P = 0.0142) and the apo B-100:apo A-I ratio (P = 0.0168) compared with the OO diet. There were no differences across diets in lipoprotein(a) (Lp(a)) and lipid peroxidation levels. However, following consumption of OO and PS-SO, Lp(a) concentrations increased (P = 0.0050 and 0.0421, respectively), while PS-OO treatment did not affect Lp(a) levels. Furthermore, there was a decrease (P = 0.0097) in lipid peroxidation levels with PS-OO treatment during the supplementation phase. Our results suggest that supplementing an OO-rich diet with PS-OO favourably alters the plasma lipid profile and may decrease the susceptibility of LDL-C to lipid peroxidation in hypercholesterolaemic subjects.

Fish-oil esters of plant sterols improve the lipid profile of dyslipidemic subjects more than do fish-oil or sunflower oil esters of plant sterols.

BACKGROUND: Fish-oil fatty acid esters of plant sterols (FO-PS) were shown to have hypotriglyceridemic and hypocholesterolemic properties in animal models. OBJECTIVE: The objective of the study was to evaluate the hypolipidemic effects of FO-PS supplementation in healthy hypercholesterolemic persons fed an olive oil (OO)-based diet. DESIGN: Twenty-one moderately overweight, hyperlipidemic subjects participated in a semi-randomized, single-blind, 4-period crossover study including 4 experimental isoenergetic diets of 4 wk each and 4-wk intervening washout periods. Diets contained 30% of energy as fat, of which 70% was from extra-virgin OO, and differed only in the supplement oil: OO, fish oil, FO-PS, or sunflower oil esters of plant sterols (SU-PS). Both fish oil and FO-PS provided 5.4 g total eicosapentaenoic and docosahexaenoic acids/d. FO-PS, SU-PS, and OO provided the equivalent of 1.7, 1.7, and 0.02 g free plant sterols/d, respectively. RESULTS: Fish oil and FO-PS resulted in fasting and postprandial plasma triacylglycerol concentrations that were markedly lower than those observed with OO and SU-PS (P = 0.0001), but to a different extent. LDL cholesterol was significantly lower after supplementation with FO-PS and SU-PS than at the end of the control OO diet (P = 0.0031 and 0.0407, respectively). HDL cholesterol was not affected. FO-PS and SU-PS resulted in a lower ratio of total to HDL cholesterol and lower apolipoprotein (apo) B concentrations than did OO and fish oil. The ratio of apoB to apoA was significantly lower after SU-PS consumption than after consumption of OO (P = 0.0126) and fish oil (P = 0.0292). FO-PS and SU-PS resulted in similar ratios of apoB to apoA. HDL2 and the ratio of HDL2 to HDL3 were significantly higher at the end of the FO-PS treatment than at the end of the OO (P = 0.0006), fish oil (P = 0.0036), and SU-PS (P = 0.0016) treatments. CONCLUSION: Supplementation of an OO-based diet with FO-PS may reduce cardiovascular disease risk more than does supplementation with fish oil or SU-PS.

Plasma concentrations of plant sterols: physiology and relationship with coronary heart disease.

Recently, it has been questioned whether elevated levels of circulating plant sterols increase the risk of coronary heart disease (CHD). To date, no definitive conclusions regarding such a relationship have been reached, nor have there been any studies summarizing the factors that contribute to the observed elevations in plant sterol concentrations in plasma. Thus, the purpose of this review is to systematically compare the plant sterol levels of subjects from the general population and to describe factors that contribute to the variations observed. The question of whether elevated plasma concentrations of plant sterols are associated with an increased risk of CHD was also assessed. Results indicate that the key factors accounting for variations in circulating plant sterol concentrations include: apolipoprotein E phenotypes, ATP-binding cassette transporter polymorphisms, use of statin drugs, presence of metabolic syndrome, dietary intake of plant sterols, gender, and analytical techniques used in the measurement of plant sterols in the plasma. An analysis of the studies examining the relationship between circulating levels of plant sterols and CHD risk in non-sitosterolemic populations revealed no clear associations. Furthermore, it was shown that the above-mentioned factors play an important role in determining the levels of plant sterols in plasma. Since these factors may act as potential confounders, they must be controlled for before more solid conclusions can be reached.