Associations of artificially sweetened beverages, sugar-sweetened beverages, and pure fruit/vegetable juice with visceral adipose tissue mass.

OBJECTIVE: To test the associations of sugar-sweetened beverage, artificially sweetened beverage, and pure fruit/vegetable juice consumption with visceral adipose tissue (VAT) mass at baseline and follow-up and to determine whether BMI and genetic risk of VAT mass modified the associations. METHODS: A total of 203,348 participants from UK Biobank with consumption data on three beverages were included. Participants were categorized into nonconsumers and consumers with >0-1, >1-2 and >2 L/week. A sex-specific prediction model was used to calculate VAT mass. A weighted genetic risk score for high VAT mass was calculated. RESULTS: The participants with a sugar-sweetened beverage and artificially sweetened beverage consumption of >2 L/week had the greatest B values [B (95% CI): 24.02 (16.53, 31.51) and 60.81 (52.08, 69.54) in men, respectively; 10.20 (5.92, 14.48) and 24.72 (20.80, 28.64) in women]. Low and moderate intake of pure fruit/vegetable juices showed a significantly inverse association with VAT mass in men [-10.52 (-15.37, -5.67); -6.46 (-11.27, -1.65)] and women [-6.70 (-8.99, -4.41); -5.93 (-8.33, -3.54)]. Regarding changes in VAT mass, participants who consumed >2 L/week of sugar-sweetened beverages and artificially sweetened beverages had greater changes. BMI but not genetic risk modified the associations between beverage intake and VAT mass, which were strengthened in participants with BMI ≥25 kg/m2 for sugar-sweetened and artificially sweetened beverage consumption. CONCLUSIONS: Higher consumption of sugar-sweetened beverages or artificially sweetened beverages was associated with greater VAT mass regardless of genetic risk. Mild-to-moderate intake of pure fruit/vegetable juices was linked to lower VAT mass.

Associations of Sugar-Sweetened Beverages, Artificially Sweetened Beverages, and Pure Fruit Juice With Nonalcoholic Fatty Liver Disease: Cross-sectional and Longitudinal Study.

OBJECTIVE: We aimed to test the associations of sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), and pure fruit juice (PJ) consumption with the risk of nonalcoholic fatty liver disease (NAFLD). METHODS: Data for 136 277 UK Biobank participants who completed the dietary questionnaire and did not have a history of liver disease were included. Logistic regression was used for the cross-sectional setting where NAFLD was defined by a fatty liver index (FLI) ≥60. Cox proportional hazard regression was used for the longitudinal setting where hospitalized NAFLD was defined as hospital admission with Internationl Classification of Diseases-10 codes K76.0 and K75.8. RESULTS: Compared with 0 L/wk for corresponding beverages, multivariate-adjusted odds ratios (95% confidence intervals) for NAFLD in consumption ≤1, 1 to 2, and >2 L/wk were 1.06 (1.02-1.10), 1.24 (1.19-1.29), and 1.42 (1.35-1.49) for SSB; 1.43 (1.37-1.50), 1.73 (1.65-1.82), and 2.37 (2.25-2.50) for ASB, and 0.87 (0.84-0.89), 0.91 (0.88-0.94), and 1.07 (1.02-1.13) for PJ, respectively. Consumption of SSB and ASB were both positively correlated with FLI (P for line < .001). During a median follow-up of 10.2 years, 1043 cases of hospitalized NAFLD were recorded. ASB consumption of 1 to 2 and >2 L/wk was associated with a 22% (0.99-1.50) and 35% (1.11-1.65) increased risk of hospitalized NAFLD, respectively (P for trend = .002). However, the associations of SSB and PJ with the risk of hospitalized NAFLD were not significant. CONCLUSIONS: Consumption of SSB, ASB, and PJ were all related to the risk of NAFLD. Excessive consumption of ASBs was associated with an increased risk of incident hospitalized NAFLD.

Association of soft drinks and 100% fruit juice consumption with risk of cancer: a systematic review and dose-response meta-analysis of prospective cohort studies.

BACKGROUND: Studies of the associations between soft drinks and the risk of cancer showed inconsistent results. No previous published systematic reviews and meta-analysis has investigated a dose-response association between exposure dose and cancer risk or assessed the certainty of currently available evidence. Therefore, we aim to demonstrate the associations and assessed the certainty of the evidence to show our confidence in the associations. METHODS: We searched Embase, PubMed, Web of Science, and the Cochrane Library from inception to Jun 2022, to include relevant prospective cohort studies. We used a restricted cubic spline model to conduct a dose-response meta-analysis and calculated the absolute effect estimates to present the results. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence. RESULTS: Forty-two articles including on 37 cohorts enrolled 4,518,547 participants were included. With low certainty evidence, increased consumption of sugar-sweetened beverages (SSBs) per 250 mL/day was significantly associated with a 17% greater risk of breast cancer, a 10% greater risk of colorectal cancer, a 30% greater risk of biliary tract cancer, and a 10% greater risk of prostate cancer; increased consumption of artificially sweetened beverages (ASBs)re per 250 mL/day was significantly associated with a 16% greater risk of leukemia; increased consumption of 100% fruit juice per 250 mL/day was significantly associated with a 31% greater risk of overall cancer, 22% greater risk of melanoma, 2% greater risk of squamous cell carcinoma, and 29% greater risk of thyroid cancer. The associations with other specific cancer were no significant. We found linear dose-response associations between consumption of SSBs and the risk of breast and kidney cancer, and between consumption of ASBs and 100% fruit juices and the risk of pancreatic cancer. CONCLUSIONS: An increment in consumption of SSBs of 250 mL/day was positively associated with increased risk of breast, colorectal, and biliary tract cancer. Fruit juices consumption was also positively associated with the risk of overall cancer, thyroid cancer, and melanoma. The magnitude of absolute effects, however, was small and mainly based on low or very low certainty of evidence. The association of ASBs consumption with specific cancer risk was uncertain. TRIAL REGISTRATION: PROSPERO: CRD42020152223.

Fructose Intake From Fruit Juice and Sugar-Sweetened Beverages Is Associated With Higher Intrahepatic Lipid Content: The Maastricht Study.

OBJECTIVE: Epidemiological evidence regarding the relationship between fructose intake and intrahepatic lipid (IHL) content is inconclusive. We, therefore, assessed the relationship between different sources of fructose and IHL at the population level. RESEARCH DESIGN AND METHODS: We used cross-sectional data from The Maastricht Study, a population-based cohort study (n = 3,981; mean ± SD age: 60 ± 9 years; 50% women). We assessed the relationship between fructose intake (assessed with a food-frequency questionnaire)-total and derived from fruit, fruit juice, and sugar-sweetened beverages (SSB)-and IHL (quantified with 3T Dixon MRI) with adjustment for age, sex, type 2 diabetes, education, smoking status, physical activity, and intakes of total energy, alcohol, saturated fat, protein, vitamin E, and dietary fiber. RESULTS: Energy-adjusted total fructose intake and energy-adjusted fructose from fruit were not associated with IHL in the fully adjusted models (P = 0.647 and P = 0.767). In contrast, energy-adjusted intake of fructose from fruit juice and SSB was associated with higher IHL in the fully adjusted models (P = 0.019 and P = 0.009). Individuals in the highest tertile of energy-adjusted intake of fructose from fruit juice and SSB had a 1.04-fold (95% CI 0.99; 1.11) and 1.09-fold (95% CI 1.03; 1.16) higher IHL, respectively, in comparison with the lowest tertile in the fully adjusted models. Finally, the association for fructose from fruit juice was stronger in individuals with type 2 diabetes (P for interaction = 0.071). CONCLUSIONS: Fructose from fruit juice and SSB is independently associated with higher IHL. These cross-sectional findings contribute to current knowledge in support of measures to reduce the intake of fructose-containing beverages as a means to prevent nonalcoholic fatty liver disease at the population level.

Association of soft drink and 100% fruit juice consumption with all-cause mortality, cardiovascular diseases mortality, and cancer mortality: A systematic review and dose-response meta-analysis of prospective cohort studies.

Sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and 100% fruit juices are frequently consumed and have been documented that they could lead to serious disease burden. However, inconsistent evidence on the association between SSBs, ASBs, and 100% fruit juices consumption and mortality have been presented. PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and PsycINFO were systematically searched. We conducted a random-effects meta-analysis and dose-response meta-analysis to assess the association and calculated the pooled hazard ratio with 95% confidence interval. And we evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Thirteen studies with 1,539,127 participants proved eligible. An SSB-consumption increase per 250 mL/day was associated with a 4% greater risk of all-cause mortality (5 more per 1000 persons; low certainty) and 8% greater risk of cardiovascular disease mortality (3 more per 1000 persons; low certainty). ASB-consumption increase per 250 mL/day demonstrated a 4% greater risk of all-cause mortality (5 more per 1000 persons; low certainty) and 4% greater risk of cardiovascular disease mortality (2 more per 1000 persons; low certainty). The association of SSBs and ASBs with cancer mortality was not significant, with a very low certainty of evidence. There was evidence of a linear dose-response association between SSB intake and cancer mortality, as well as between ASB intake and all-cause mortality and cancer mortality. We observed a non-linear dose-response association between ASB intake and CVD mortality and SSB intake and all-cause and CVD mortality. Low certainty of evidence demonstrated that per 250 mL/day consumption increase in SSBs and ASBs had a small impact on all-cause and cardiovascular disease mortality but not on cancer mortality. The association of 100% fruit juice consumption with all-cause and cardiovascular disease mortality was uncertain.

Efeitos da ingestão do suco de laranja Pera e suco de laranja Moro na microbiota intestinal e marcadores inflamatórios em indivíduos com obesidade / Effect of Pera and Moro orange juice consumption on the gut microbiota and inflammatory parameters in volunteers with obesity

A obesidade é uma doença complexa que está associada inflamação crônica de baixo grau que contribui para o desenvolvimento de diversos distúrbios metabólicos como a resistência à insulina e estudos recentes sugerem a influência da microbiota intestinal no desenvolvimento e manutenção da doença. Diversos estudos apontam para o benefício da ingestão de frutas e vegetais na prevenção e tratamento de doenças crônicas. O suco de laranja contém diversos compostos bioativos com ações anti-inflamatórias, antioxidantes com efeitos na composição da microbiota intestinal. Deste modo, o objetivo principal deste estudo foi avaliar os efeitos da ingestão do suco de laranja Pera e Moro sobre a composição da microbiota intestinal e de parâmetros inflamatórios em voluntários com obesidade e resistência à insulina. Foi realizado um ensaio clínico crossover com suplementação de suco de laranja (400ml/dia) por 15 dias com um período de washout de 40 dias. As análises de sangue, fezes, urina, composição corporal, consumo alimentar foram realizadas antes e após cada intervenção. A comparação entre os tratamentos foi realizada utilizando equações de estimativas generalizadas e adotou-se um nível de significância de 5%. Em relação à microbiota intestinal, em ambos os tratamentos, os dois filos mais abundantes foram Firmicutes e Actinobateria. Dos gêneros analisados, observou-se maior abundância de Bifidobacterium após a suplementação com o suco de laranja Moro. O suco de laranja Pera promoveu uma diminuição da zonulina e o suco de laranja Moro contribuiu para redução de citocinas inflamatórias, diminuição da pressão arterial e aumento nos níveis de acetato nas fezes. Após a separação dos voluntários por grau de obesidade, observamos que o suco de laranja Moro contribuiu para o aumento na abundância de Akkermansia, Alistipes, Bacteroides e Catenibacterium em indivíduos com obesidade grau 3. Além disso, em ambos os sucos encontramos redução da razão Firmicutes/Bacteroidetes e aumento da excreção de metabólitos de flavonoides após os tratamentos. Diante destes resultados, conclui-se que o suco de laranja Pera apresentou ações positivas sobre a permeabilidade intestinal e o suco de laranja Moro promoveu efeitos mais expressivos na modulação da inflamação associada à obesidade e da microbiota intestinal

Obesity is a complex disease that is associated with low-grade chronic inflammation, and it contributes to the development of several metabolic disorders such as insulin resistance, and recent studies suggest the influence of the intestinal microbiota in the development and maintenance of the disease. Several studies have suggested the benefit of fruits and vegetables consumption in the prevention and treatment of chronic diseases. The orange juice contains some bioactive compounds with anti-inflammatory and antioxidant actions with effects in the composition of the gut microbiota. Thus, the main objective of this study was to evaluate the effects of Pera and Moro orange juice consumption on the composition of the gut microbiota and inflammatory parameters in volunteers with obesity and insulin resistance. A crossover clinical trial was carried out with orange juice supplementation (400ml/day) for 15 days with a washout period of 40 days. Blood, feces, urine, body composition, food consumption were analyzed before and after each intervention. Comparison between treatments was performed using generalized estimating equations and a significance level of 5% was adopted. In relation to gut microbiota, in both treatments, the two most abundant phyla were Firmicutes and Actinobateria. In the analysis of bacterial genera, a greater abundance of Bifidobacterium was observed after supplementation with Moro orange juice. The Pera orange juice reduced zonulin and Moro orange juice contributed to a reduction on inflammatory cytokines, a decrease in blood pressure and an increase in acetate levels in the stool. After separating the volunteers by degree of obesity, we observed that Moro orange juice contributed to the increase in the abundance of Akkermansia, Alistipes, Bacteroides and Catenibacterium in individuals with grade 3 obesity. Furthermore, in both juices we found a reduction in the Firmicutes/Bacteroidetes ratio and increased excretion of flavonoid metabolites after treatments. Therefore, we concluded that Pera orange juice had positive actions on intestinal permeability and Moro orange juice promoted more expressive effects on the modulation of inflammation associated with obesity and on the intestinal microbiota

The Concentration of Organic Acids in Cranberry Juice Modulates the Gut Microbiota in Mice.

A daily consumption of cranberry juice (CJ) is linked to many beneficial health effects due to its richness in polyphenols but could also awake some intestinal discomforts due to its organic acid content and possibly lead to intestinal inflammation. Additionally, the impact of such a juice on the gut microbiota is still unknown. Thus, this study aimed to determine the impacts of a daily consumption of CJ and its successive deacidification on the intestinal inflammation and on the gut microbiota in mice. Four deacidified CJs (DCJs) (deacidification rates of 0, 40, 60, and 80%) were produced by electrodialysis with bipolar membrane (EDBM) and administered to C57BL/6J mice for four weeks, while the diet (CHOW) and the water were ad libitum. Different parameters were measured to determine intestinal inflammation when the gut microbiota was profiled. Treatment with a 0% DCJ did not induce intestinal inflammation but increased the gut microbiota diversity and induced a modulation of its functions in comparison with control (water). The effect of the removal of the organic acid content of CJ on the decrease of intestinal inflammation could not be observed. However, deacidification by EDBM of CJ induced an additional increase, in comparison with a 0% DCJ, in the Lachnospiraceae family which have beneficial effects and functions associated with protection of the intestine: the lower the organic acid content, the more bacteria of the Lachnospiraceae family and functions having a positive impact on the gut microbiota.

Methodology to Quantify and Screen the Demineralization of Teeth by Immersing Them in Acidic Drinks (Orange Juice, Coca-Cola™, and Grape Juice): Evaluation by ICP OES.

Oral health problems may occur as a result of the ingestion of acid drinks. The objective of this in vitro study was to quantify and screen the concentration of potassium (K), phosphorus (P), calcium (Ca), magnesium (Mg), manganese (Mn), zinc (Zn), iron (Fe), copper (Cu), barium (Ba), lead (Pb), arsenic (As), cadmium (Cd), aluminum (Al), cobalt (Co), chromium (Cr), molybdenum (Mo), sodium (Na), nickel (Ni), selenium (Se), and vanadium (V) released from bovine incisors during an erosive challenge at different times of exposure when immersed in Coca-Cola™, orange juice, and grape juice. A total of 240 samples of bovine incisor teeth were used for the erosive challenge and allocated in groups. Digestion of drinks was performed using microwave-assisted digestion. The content in acidic drinks was monitored before and after the erosive challenge at exposure times of 1, 5, and 60 min using inductively coupled plasma optical emission spectrometry (ICP OES). The drinks' pH varied slightly during the erosive challenge but remained below the critical value of pH 5 to cause tooth demineralization. The concentrations of elements released from the bovine incisors during the in vitro erosive challenge depend on exposure times when immersed in acidic beverages. For some elements such as Ca, Mn, Zn, Fe, Cu, Ba, Pb, As, and Cd, quantified in acidic drinks, grape juice had greater erosive potential than Coca-Cola™ and orange juice. Quantification and monitoring of chemical elements in bovine teeth can be performed considering a longer erosive time and other types of acidic drinks. Further analysis using human teeth is still not available and must be conducted. The demineralization of teeth not only occurs in acidic beverages; physical and chemical factors play other roles and should be investigated.

Soft Drink and Juice Consumption and Renal Cell Carcinoma Incidence and Mortality in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991-2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks. RESULTS: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97-1.09), total soft drinks (HR = 1.01; 95% CI, 0.98-1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94-1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96-1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97-1.16; 1.03, 0.98-1.09; 0.97, 0.89-1.07; and 1.06, 0.99-1.14, respectively). CONCLUSIONS: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity. IMPACT: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.

Consumption of Sweet Beverages and Cancer Risk. A Systematic Review and Meta-Analysis of Observational Studies.

The consumption of sweet beverages, including sugar-sweetened beverages (SSB), artificial-sweetened beverages (ASB) and fruit juices (FJ), is associated with the risk of different cardiometabolic diseases. It may also be linked to the development of certain types of tumors. We carried out a systematic review and meta-analysis of observational studies aimed at examining the association between sweet beverage intake and cancer risk. Suitable articles published up to June 2020 were sourced through PubMed, Web of Science and SCOPUS databases. Overall, 64 studies were identified, of which 27 were selected for the meta-analysis. This was performed by analyzing the multivariable-adjusted OR, RR or HR of the highest sweet beverage intake categories compared to the lowest one. Random effects showed significant positive association between SSB intake and breast (RR: 1.14, 95% CI: 1.01-1.30) and prostate cancer risk (RR: 1.18, 95% CI: 1.10-1.27) and also between FJs and prostate cancer risk (RR: 1.03, 95% CI: 1.01-1.05). Although the statistically significant threshold was not reached, there tended to be positive associations for the following: SSBs and colorectal and pancreatic cancer risk; FJs and breast, colorectal and pancreatic cancer risk; and ASBs and pancreatic cancer risk. This study recommends limiting sweet beverage consumption. Furthermore, we propose to establish a homogeneous classification of beverages and investigate them separately, to better understand their role in carcinogenesis.

Acute nephrotoxicity and neurotoxicity associated with concentrated star fruit juice consumption.

Star fruit toxicity has been hugely described in patients with chronic kidney disease, either on conservative or renal replacement therapy. This is a case report of a man, without prior kidney or neurological dysfunction, who appeared to develop nephrotoxicity and neurotoxicity less than 12 hours after drinking concentrated star fruit juice (approximately 20 units of the fruit). He received timely renal replacement therapy and renal function fully recovered after discharge.

Sweetened beverages and risk of frailty among older women in the Nurses' Health Study: A cohort study.

BACKGROUND: Consumption of sugar-sweetened beverages (SSBs) has been consistently associated with a higher risk of obesity, type 2 diabetes, cardiovascular disease, and premature mortality, whereas evidence for artificially sweetened beverages (ASBs) and fruit juices on health is less solid. The aim of this study was to evaluate the consumption of SSBs, ASBs, and fruit juices in association with frailty risk among older women. METHODS AND FINDINGS: We analyzed data from 71,935 women aged ≥60 (average baseline age was 63) participating in the Nurses' Health Study (NHS), an ongoing cohort study initiated in 1976 among female registered nurses in the United States. Consumption of beverages was derived from 6 repeated food frequency questionnaires (FFQs) administered between 1990 and 2010. Frailty was defined as having at least 3 of the following 5 criteria from the FRAIL scale: fatigue, poor strength, reduced aerobic capacity, having ≥5 chronic illnesses, and weight loss ≥5%. The occurrence of frailty was assessed every 4 years from 1992 to 2014. During 22 years of follow-up, we identified 11,559 incident cases of frailty. Consumption of SSBs was associated with higher risk of frailty after adjustment for diet quality, body mass index (BMI), smoking status, and medication use, specifically, the relative risks (RRs) and 95% confidence interval (95% CI) for ≥2 serving/day versus no SSB consumption was 1.32 (1.10, 1.57); p-value <0.001. ASBs were also associated with frailty [RR ≥2 serving/day versus no consumption: 1.28 (1.17, 1.39); p-value <0.001]. Orange juice was associated with lower risk of frailty [RR ≥1 serving/day versus no consumption: 0.82 (0.76, 0.87); p-value <0.001], whereas other juices were associated with a slightly higher risk [RR ≥1 serving/day versus no consumption: 1.15 (1.03, 1.28); p-value <0.001]. A limitation of this study is that, due to self-reporting of diet and frailty, certain misclassification bias cannot be ruled out; also, some residual confounding may persist. CONCLUSIONS: In this study, we observed that consumption of SSBs and ASBs was associated with a higher risk of frailty. However, orange juice intake showed an inverse association with frailty. These results need to be confirmed in further studies using other frailty definitions.

Postdiagnostic Fruit and Vegetable Consumption and Breast Cancer Survival: Prospective Analyses in the Nurses' Health Studies.

Fruits and vegetables contain many bioactive components that may contribute to improved survival after diagnosis of breast cancer, however, evidence to date is insufficient. We prospectively assessed the associations of postdiagnostic fruit and vegetable consumption with breast cancer-specific and all-cause mortality among 8,927 women with stage I-III breast cancer identified during follow-up of the Nurses' Health Study (NHS; 1980-2010) and NHSII (1991-2011), using a validated food frequency questionnaire completed every 4 years after diagnosis. We prospectively documented 2,521 deaths, including 1,070 from breast cancer through follow-up until 2014 in the NHS and 2015 in the NHSII. Total fruit and vegetable and total vegetable consumption was related to lower all-cause [HRQ5vsQ1, 0.82; 95% confidence interval (CI), 0.71-0.94; P trend = 0.004, and HRQ5vsQ1, 0.84; 95% CI, 0.72-0.97; P trend = 0.001, respectively], but not breast cancer-specific mortality. Total fruit consumption was not related to breast cancer-specific or all-cause mortality. Greater intake of green leafy and cruciferous vegetables was associated with lower all-cause mortality. Each 2 servings/week of blueberries was associated with a 25% (HR, 0.75; 95% CI, 0.60-0.94) lower breast cancer-specific and a 17% (HR, 0.83; 95% CI, 0.72-0.96) lower all-cause mortality. In contrast, higher fruit juice consumption was associated with higher breast cancer-specific (HRQ5vsQ1, 1.33; 95% CI, 1.09-1.63; P trend = 0.002) and all-cause mortality (HRQ5vsQ1, 1.19; 95% CI, 1.04-1.36; P trend = 0.003). Apple juice largely accounted for these higher risks and orange juice was not associated with risk. Higher postdiagnostic fruit and vegetable consumption among breast cancer survivors was not associated with breast cancer-specific mortality. However, our findings suggest that higher vegetable consumption, particularly green leafy and cruciferous vegetables, was associated with better overall survival among patients with breast cancer. Higher fruit juice consumption, but not orange juice, was associated with poorer breast cancer-specific and all-cause survival. SIGNIFICANCE: A large-scale study shows that high fruit and vegetable consumption may be associated with better overall survival among breast cancer patients, while high fruit juice consumption may be associated with poorer porgnosis.

Simultaneous Ivabradine Parent-Metabolite PBPK/PD Modelling Using a Bayesian Estimation Method.

Ivabradine and its metabolite both demonstrate heart rate-reducing effect (If current inhibitors) and undergo CYP3A4 metabolism. The purpose of this study was to develop a joint parent-metabolite physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model to predict the PK and PD of ivabradine and its metabolite following intravenous (i.v.) or oral administration (alone or co-administered with CYP3A4 inhibitors). Firstly, a parent-metabolite disposition model was developed and optimised using individual plasma concentration-time data following i.v. administration of ivabradine or metabolite within a Bayesian framework. Secondly, the model was extended and combined with a mechanistic intestinal model to account for oral absorption and drug-drug interactions (DDIs) with CYP3A4 inhibitors (ketoconazole, grapefruit juice). Lastly, a PD model was linked to the PBPK model to relate parent and metabolite PK to heart rate (HR) reduction. The disposition model described successfully parent-metabolite PK following i.v. administration. Following integration of a gut model, the PBPK model adequately predicted plasma concentration profiles and the DDI risk (92% and 85% of predicted AUC+inhibitor/AUCcontrol and Cmax+inhibitor/Cmaxcontrol for ivabradine and metabolite within the prediction limits). Ivabradine-metabolite PBPK model was linked to PD by using the simulated unbound parent-metabolite concentrations in the heart. This approach successfully predicted the effects of both entities on HR (observed vs predicted - 7.7/- 5.9 bpm and - 15.8/- 14.0 bpm, control and ketoconazole group, respectively). This study provides a framework for PBPK/PD modelling of a parent-metabolite and can be scaled to other populations or used for investigation of untested scenarios (e.g. evaluation of DDI risk in special populations).

Effects of Maternal Grape Juice Intake on Unfolded Protein Response in the Mammary Glands of Offspring of High Fat Diet Fed Rat Dams.

Maternal high fat diet (HFD) and obesity during pregnancy increase female offspring's mammary cancer risk in animal studies. We aimed to observe whether the consumption of grape juice during pregnancy can reverse this risk. During pregnancy and lactation, female Wistar rats were fed either a control or HFD and also received grape juice or tap water. At the age of 50 days, female offspring were euthanized, and mammary glands were collected to assess changes in biomarkers of increased mammary cancer risk. Maternal HFD increased the number of terminal end buds in offspring's mammary glands and promoted cell proliferation (ki67). Maternal grape consumption blocked these effects. Apoptosis marker caspase 7, but not caspase 3, was reduced in the HFD offspring. HFD offspring also exhibited a reduction in the indicators of cell cycle regulation (p27, p21) and an ability to maintain DNA integrity (reduced p53). Maternal grape juice did not have any effect on these endpoints in the HFD offspring but reduced caspase 7 and p53 levels in the control offspring, perhaps reflecting reduced cellular stress. Maternal HFD increased oxidative stress marker GPx1 mRNA expression, and grape juice increased the levels of GPx2 in both the control and HFD offspring. HFD increased XBP1/Xbp1s, Atf4 and Atf6 mRNA expression and reduced ATF6 and CHOP protein levels. Maternal grape juice reversed the increase in XBP1/Xbp1s, Atf4 and Atf6 in the HFD offspring. PPAR was downregulated in the HFD group, and grape juice reversed this effect. Grape juice also reduced the levels of HER2 and IRS, both in the control and HFD offspring. In conclusion, maternal grape juice supplementation reversed some of the biomarkers that are indicative of increased breast cancer risk in the HFD offspring.

Association of Major Food Sources of Fructose-Containing Sugars With Incident Metabolic Syndrome: A Systematic Review and Meta-analysis.

Importance: Sugar-sweetened beverages (SSBs) are associated with increased risk of metabolic syndrome (MetS). However, the role of other important food sources of fructose-containing sugars in the development of MetS remains unclear. Objective: To examine the association of major food sources of fructose-containing sugars with incident MetS. Data Sources: MEDLINE, Embase, and Cochrane Library were searched from database inception to March 24, 2020, in addition to manual searches of reference lists from included studies using the following search terms: sugar-sweetened beverages, fruit drink, yogurt, metabolic syndrome, and prospective study. Study Selection: Inclusion criteria included prospective cohort studies of 1 year or longer that investigated the association of important food sources of fructose-containing sugars with incident MetS in participants free of MetS at the start of the study. Data Extraction and Synthesis: Study quality was assessed using the Newcastle-Ottawa Scale. Extreme quantile risk estimates for each food source with MetS incidence were pooled using a random-effects meta-analysis. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). Dose-response analyses were performed using a 1-stage linear mixed-effects model. The certainty of the evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Results were reported according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Main Outcomes and Measures: Pooled risk ratio (RR) of incident MetS (pairwise and dose response). Results: Thirteen prospective cohort studies (49 591 participants [median age, 51 years; range, 6-90 years]; 14 205 with MetS) that assessed 8 fructose-containing foods and MetS were included. An adverse linear dose-response association for SSBs (RR for 355 mL/d, 1.14; 95% CI, 1.05-1.23) and an L-shaped protective dose-response association for yogurt (RR for 85 g/d, 0.66; 95% CI, 0.58-0.76) and fruit (RR for 80 g/d, 0.82; 95% CI, 0.78-0.86) was found. Fruit juices (mixed and 100%) had a U-shaped dose-response association with protection at moderate doses (mixed fruit juice: RR for 125 mL/d, 0.58; 95% CI, 0.42-0.79; 100% fruit juice: RR for 125 mL/d, 0.77; 95% CI, 0.61-0.97). Honey, ice cream, and confectionary had no association with MetS incidence. The certainty of the evidence was moderate for SSBs, yogurt, fruit, mixed fruit juice, and 100% fruit juice and very low for all other food sources. Conclusions and Relevance: The findings of this meta-analysis suggest that the adverse association of SSBs with MetS does not extend to other food sources of fructose-containing sugars, with a protective association for yogurt and fruit throughout the dose range and for 100% fruit juice and mixed fruit juices at moderate doses. Therefore, current policies and guidelines on the need to limit sources of free sugars may need to be reexamined.

Application of Cryopreserved Human Intestinal Mucosa and Cryopreserved Human Enterocytes in the Evaluation of Herb-Drug Interactions: Evaluation of CYP3A Inhibitory Potential of Grapefruit Juice and Commercial Formulations of Twenty-Nine Herbal Supplements.

Commercial formulations of 29 commonly used herbal supplements (HSs) and grapefruit juice were evaluated for drug interaction potential via quantification of their CYP3A inhibitory potential in two in vitro experimental models of human small intestine, cryopreserved human intestinal mucosa (CHIM), and cryopreserved human enterocytes (CHEs). Two CYP3A substrates were used-in the studies with CHIM, CYP3A activity was quantified via liquid chromatography tandem mass spectrometry quantification of midazolam 1'-hydroxylation, whereas in CHE, luciferin-IPA metabolism to luciferin was quantified by luminescence. Upon treatment of CHIM with the estimated lumen concentration of the HS upon each oral administration (manufacturers' recommended dosage dissolved in 200 ml of culture medium), >80% CYP3A inhibition was observed for green tea extract, St. John's wort, valerian root, horehound, and grapefruit juice. Less than 50% inhibition was observed for fenugreek, aloe vera, guarana, soy isoflavone, maca, echinacea, spirulina, evening primrose, milk thistle, cranberry, red yeast rice, rhodiola, ginkgo biloba, turmeric, curcumin, white kidney bean, garlic, cinnamon, saw palmetto berries, panax ginseng, black elderberry, wheat grass juice, flaxseed oil, black cohosh, and ginger root. The results were confirmed in a a dose-response study with HSs obtained from three suppliers for the four inhibitory HSs (green tea extract, horehound, St. John's wort, valerian root) and three representative noninhibitory HSs (black cohosh, black elderberry, echinacea). Similar results were obtained with the inhibitory HSs in CHE. The results illustrate that CHIM and CHE represent physiologically relevant in vitro experimental models for the evaluation of drug interaction potential of herbal supplements. Based on the results, green tea extract, horehound, St. John's wort, and valerian root may cause drug interactions with orally administered drugs that are CYP3A substrates, as was observed for grapefruit juice. SIGNIFICANCE STATEMENT: In vitro evaluation of 29 popular herbal supplements in cryopreserved human intestinal mucosa identified green tea extract, horehound, St. John's wort, and valerian root to have CYP3A inhibitory potential similar to that for grapefruit juice, suggesting their potential to have clinically significant pharmacokinetic interaction with orally administered drugs that are CYP3A substrates. The results suggest that cryopreserved human intestinal mucosa can be used for in vitro evaluation of drug interactions involving enteric drug metabolism.

Beverage Consumption and Longitudinal Changes in Lipoprotein Concentrations and Incident Dyslipidemia in US Adults: The Framingham Heart Study.

Background Limited data are available on the prospective relationship between beverage consumption and plasma lipid and lipoprotein concentrations. Two major sources of sugar in the US diet are sugar-sweetened beverages (SSBs) and 100% fruit juices. Low-calorie sweetened beverages are common replacements. Methods and Results Fasting plasma lipoprotein concentrations were measured in the FOS (Framingham Offspring Study) (1991-2014; N=3146) and Generation Three (2002-2001; N=3584) cohorts. Beverage intakes were estimated from food frequency questionnaires and grouped into 5 intake categories. Mixed-effect linear regression models were used to examine 4-year changes in lipoprotein measures, and Cox proportional hazard models were used to estimate hazard ratios for incident dyslipidemia, adjusting for potential confounding factors. We found that regular (>1 serving per day) versus low (<1 serving per month) SSB consumption was associated with a greater mean decrease in high-density lipoprotein cholesterol (ß±standard error -1.6±0.4 mg/dL; Ptrend<0.0001) and increase in triglyceride (ß±standard error: 4.4±2.2 mg/dL; Ptrend=0.003) concentrations. Long-term regular SSB consumers also had a higher incidence of high triglyceride (hazard ratio, 1.52; 95% CI, 1.03-2.25) compared with low consumers. Although recent regular low-calorie sweetened beverage consumers had a higher incidence of high non-high-density lipoprotein cholesterol (hazard ratio, 1.40; 95% CI, 1.17-1.69) and low-density lipoprotein cholesterol (hazard ratio, 1.27; 95% CI, 1.05-1.53) concentrations compared with low consumers, cumulative average intakes of low-calorie sweetened beverages were not associated with changes in non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol concentrations, or incident dyslipidemias. Conclusions SSB intake was associated with adverse changes in high-density lipoprotein cholesterol and triglyceride concentrations, along with a higher risk of incident dyslipidemia, suggesting that increased SSB consumption may contribute to the development of dyslipidemia.