Placebo-controlled randomized clinical trial of fish oil's impact on fatigue, quality of life, and disease activity in Systemic Lupus Erythematosus.

INTRODUCTION: A recent metabolomic screen of sera from patients with Systemic Lupus Erythematosus (SLE) found reduction of antioxidants and substrates for energy generation. These metabolic alterations may underlie one of the most common features of SLE--fatigue. The metabolomic studies also noted reduced omega-3 fatty acids, which are powerful anti- oxidants. This deficiency may be causally related to oxidative stress, inflammation, disease activity, and fatigue in SLE. Supplementation of omega-3 fatty acids using fish oil in SLE has been shown to reduce oxidative stress in other studies. The objective of this study is to evaluate the effect of fish oil supplementation on clinical measures of fatigue, quality of life, and disease activity as part of a randomized clinical trial. METHODS: Fifty SLE patients recruited in outpatient clinics were randomized 1:1 to fish oil supplementation or olive oil placebo, and blinded to their treatment group. At baseline and after 6 months of treatment, RAND Short Form-36 (RAND SF-36), Fatigue Severity Scale (FSS), SLE Disease Activity Index (SLEDAI), and Physician Global Assessment (PGA) were completed; serum was also collected for soluble mediator analysis. RESULTS: Thirty-two patients completed the study. PGA improved significantly in the fish oil group compared with the placebo group (p = 0.015). The RAND SF-36 Energy/fatigue and Emotional well-being scores demonstrated improvement trends (p = 0.092 and 0.070). No clear difference was seen in FSS and SLEDAI (p = 0.350 and p = 0.417). Erythrocyte sedimentation rate and serum IL-12 were reduced (p = 0.008 and p = 0.058); while serum IL-13 was increased by fish oil supplementation (p = 0.033). CONCLUSIONS: In this randomized, placebo-controlled 6-month trial, SLE patients randomized to fish oil supplementation demonstrated improvement in their PGA, RAND SF-36, and some circulating inflammatory markers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02021513 (registered 13 December 2013).

Nutritional Approach for Relief of Joint Discomfort: A 12-week, Open-case Series and Illustrative Case Report.

CONTEXT: Tetrahydro iso-α acids (THIAAs), derived from Humulus lupulus (hops), have demonstrated anti-inflammatory effects in vitro and in an animal model of rheumatoid arthritis (RA). Undenatured type 2 collagen has been found to be effective in clinical studies in RA and osteoarthritis (OA). OBJECTIVE: The study intended to evaluate the efficacy and safety of a proprietary tablet containing 150 mg of n-enriched THIAA (nTHIAA) and 10 mg of undenatured type 2 collagen (UC-II) (containing 25% UC-II) in patients with arthritis. DESIGN: The study was an open-label case series. This article also includes a case history for 1 participant. SETTING: The study was conducted at the Functional Medicine Research Center (FMRC) in Gig Harbor, WA, USA, from February 2013-June 2013. PARTICIPANTS: Participants were 17 adults, 12 women, and 5 men aged 39-69 y, who had chronic joint pain involving various joints, 13 with probable OA and 4 with possible RA. INTERVENTION: Participants took 2 tablets of nTHIAA + UC-II 2 ×/d with meals for 12 wk. OUTCOME MEASURES: Participants completed arthritis-related and quality-of-life questionnaires, at weeks 2, 4, 8, and 12: (1) the visual analog scale for pain (VAS-P); (2) the medical symptoms questionnaire (MSQ), with the analysis particularly focusing on the joint/muscle subscale and total scores; (3) the health and wellness outcome questionnaire (MOS-SF36), with the analysis particularly focusing on the physical and mental subscales; (4) the arthritis impact questionnaire (AIQ), with the analysis particularly focusing on the arthritis symptoms and daily living subscales; (5) the health assessment questionnaire (HAQ-DI) with the analysis particularly focusing on question 26 (Q26), which indicates overall pain during the week prior to the survey; and (6) the arthritis impact measurement scales 2 (AIMS2). At 12 wk, participants also completed the visual analog scale for efficacy (VAS-E). RESULTS: All participants completed the 12-wk evaluation, and all reported improvements in pain. Significant improvements in scores on the questionnaires were observed as early as 2 wk. For example, the total score on the MSQ was significantly decreased from a mean of 20.76 ± 2.90 (SE) at baseline to 12.24 ± 2.81 after 2 wk (P < .001). At 12 wk, the participants rated the supplement's efficacy at 7.6 ± 0.6 of 10. At baseline, 13 of the 17 participants were using analgesics for joint pain, compared with only 4 participants at 12 wk. Two of those 4 had reduced their analgesic dosages. The studied supplement was well tolerated, and no serious side effects occurred. CONCLUSIONS: The supplement containing nTHIAA and UC-II is safe and efficacious in participants with chronic joint pain.

A Phytochemical-rich Multivitamin-multimineral Supplement Is Bioavailable and Reduces Serum Oxidized Low-density Lipoprotein, Myeloperoxidase, and Plasminogen Activator Inhibitor-1 in a Four-week Pilot trial of Healthy Individuals.

BACKGROUND: A multivitamin-multimineral supplement combined with a diverse blend of bioactive phytochemicals may provide additional antioxidant capacity and anti-inflammatory property for overall health. This convenient feature may be useful for individuals who want to increase their intake of phytochemicals. METHODS: We conducted a pilot study in 15 healthy individuals (8 women and 7 men, mean age 41.7±14.9 years, mean body mass index 28.0±5.6) to investigate the effects of this novel formulation on biomarkers associated with oxidative stress and inflammation. After a 2-week diet that limited intake of fruits and vegetables to 2 servings/day, participants continued with the same restricted diet but began consuming 2 tablets of the study product for the subsequent 4 weeks. Fasting blood samples collected at Week 2 and Week 6 were analyzed and compared using paired t-tests for levels of carotenoids, folate, vitamin B12, homocysteine, oxidized low-density lipoprotein cholesterol (oxLDL), high-sensitivity C-reactive protein (hs-CRP), F2-isoprostane, plasminogen activator inhibitor-1 (PAI-1), and myeloperoxidase. Noninvasive peripheral arterial tonometry (EndoPAT) was also measured. RESULTS: After 4 weeks of supplementation, plasma levels of carotenoids, folate, and vitamin B12, but not homocysteine, were significantly increased (P<.05). Serum levels of oxLDL, PAI-1 and myeloperoxidase were significantly reduced (P<.05), but F2-isoprostane, hs-CRP, and EndoPAT measures were unchanged compared with baseline. The study product was well tolerated. CONCLUSIONS: This nutritional supplement is bioavailable as indicated by the significant increase in plasma carotenoids, vitamin B12, and folate levels and may provide health benefits by significantly reducing serum levels of oxLDL, myeloperoxidase, and PAI-1 in healthy individuals.

Racial Differences in Blood Lipids Lead to Underestimation of Cardiovascular Risk in Black Women in a Nested observational Study.

BACKGROUND: During screening for enrollment in a clinical trial, we noticed potential racial disparities in metabolic syndrome variables in women who responded to our study advertisement. We designed a nested observational study to investigate whether metabolic syndrome variables differed between non-Hispanic blacks and non-Hispanic whites. METHODS: The cohort comprised of women who have met the preliminary clinical trial criteria (body mass index [BMI] 25-45, age 20-75 years, and no use of lipid-lowering medications or supplements). These women, including 116 blacks and 138 whites, provided fasting blood samples for analysis of serum lipid profile. RESULTS: Blacks had lower mean triglycerides (81.1 ± 3.3 mg/dL vs 140.6 ± 5.9 mg/dL; P < .0001), total cholesterol (176.1 ± 3.6 mg/dL vs 201.6 ± 3.3 mg/dL; P < .0001), and low-density lipoprotein (111.7 ± 3.3 mg/dL vs 128.2 ± 2.9 mg/dL; P < .001) and higher mean BMI (37.2 ± 0.5 vs 35.2 ± 0.5; P < .01) and diastolic blood pressure (82.4 ± 0.8 mmHg vs 79.4 ± 0.7 mmHg; P < .01) than whites. Only 7% of blacks, compared with 41% of whites, had triglycerides ≥150 mg/dL; as a result, fewer black women met metabolic syndrome criteria than white women. Additionally, in women with waist circumference ≥88 cm (N = 215), high-density lipoprotein was higher in blacks than in whites (48.3 ± 1.5 mg/dL vs 44.2 ±1.3 mg/dL; P < .05). CONCLUSIONS: Due to racial differences in blood lipids, current metabolic syndrome criteria may result in underestimation of cardiovascular risk in blacks.

A Mediterranean-style, low-glycemic-load diet decreases atherogenic lipoproteins and reduces lipoprotein (a) and oxidized low-density lipoprotein in women with metabolic syndrome.

The objective was to assess the impact of a Mediterranean-style, low-glycemic-load diet (control group, n = 41) and the same diet plus a medical food (MF) containing phytosterols, soy protein, and extracts from hops and Acacia (MF group, n = 42) on lipoprotein atherogenicity in women with metabolic syndrome. Plasma lipids, apolipoproteins (apos), lipoprotein subfractions and particle size, low-density lipoprotein (LDL) oxidation, and lipoprotein (a) were measured at baseline, week 8, and week 12 of the intervention. Three-day dietary records were collected at the same time points to assess compliance. Compared with baseline, women decreased energy intake from carbohydrate (P < .001) and fat (P < .001), whereas they increased energy intake from protein (P < .001). A significant increase in energy from monounsaturated fatty acids was also observed as well as increases in eicosapentaenoic acid and docosahexaenoic acid, whereas trans-fatty acid intake was reduced (P < .00001). The atherogenic lipoproteins, large very low-density lipoprotein (P < .0001) and small LDL (P < .0001), were reduced, whereas the ratio of large high-density lipoprotein to smaller high-density lipoprotein particles was increased (P < .0001). Apolipoprotein B was reduced for all women (P < .0001), with a greater reduction in the MF group (P < .025). Oxidized LDL (P < .05) and lipoprotein (a) (P < .001) were reduced in both groups at the end of the intervention. Consumption of a Mediterranean-style diet reduces the risk for cardiovascular disease by decreasing atherogenic lipoproteins, oxidized LDL, and apo B. Inclusion of an MF may have an additional effect in reducing apo B.

A Mediterranean-style low-glycemic-load diet increases plasma carotenoids and decreases LDL oxidation in women with metabolic syndrome.

Thirty-five women with metabolic syndrome and high plasma low-density lipoprotein (LDL) cholesterol (≥100 mg/dl) participated in a dietary intervention consisting of a Mediterranean-style low-glycemic-load diet for 12 weeks. Participants were randomly allocated to consume diet only (n=15) or diet plus a medical food containing soy protein and plant sterols (n=20). Plasma concentrations of carotenoids, lipoprotein subfractions and oxidized LDL (OxLDL) were measured. Independent of treatment, women had a significant increase in plasma lutein (P<.0001) and ß-carotene (P<.0001), while plasma lycopene was reduced (P<.05) after 12 weeks. Low-density lipoprotein cholesterol was reduced from 138±35 to 114±33 mg/dl (P<.0001). In addition, decreases were observed in the atherogenic subfractions: large very low-density lipoprotein (P<.05), small LDL (P<.00001) and medium high-density lipoprotein (P<.05). Oxidized LDL was significantly reduced by 12% in both groups (P<.01). Changes in OxLDL were inversely correlated with plasma lutein (r=-.478, P<.0001). The data indicate that women complied with the dietary regimen by increasing fruits and vegetable intake. Decreased consumption of high-glycemic foods frequently co-consumed with lycopene-rich tomato sauce such as pasta and pizza may be responsible for the lowering of this carotenoid in plasma after 12 weeks. These results also suggest that plasma lutein concentrations may protect against oxidative stress by reducing the concentrations of OxLDL.

A Mediterranean-style, low-glycemic-load diet reduces the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in mononuclear cells and plasma insulin in women with metabolic syndrome.

We evaluated changes in low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase gene expression in women with metabolic syndrome and elevated plasma LDL cholesterol (LDL-C). We hypothesized that expression of these 2 genes would be modulated by our dietary intervention. Twenty-five women were instructed to follow a Mediterranean-style low-glycemic-load diet for 12 weeks. Quantitative real-time polymerase chain reaction was used to measure messenger RNA (mRNA) abundance of the LDL receptor and HMG-CoA reductase in mononuclear cells, which were used as a proxy of liver expression of these 2 genes. All women experienced favorable impacts on metabolic syndrome variables, with decreases in waist circumference (P < .001), plasma triglycerides (P < .05), and systolic blood pressure (P < .05) compared with baseline. Furthermore, participants had reductions in LDL-C (P < .01), plasma insulin (P < .001), and homeostatic model assessment score for insulin resistance (P < .001) over time. In addition, significant decreases were found in plasma tumor necrosis factor α (P < .01), which might have contributed to the improvements observed in insulin resistance. Although no changes in LDL-receptor mRNA levels were observed, HMG-CoA-reductase gene expression was reduced (P < .001) after 12 weeks. The reductions in plasma insulin correlated with changes in HMG-CoA-reductase mRNA levels (r = 0.45, P < .01). In conclusion, the observed reductions in plasma insulin may have affected the expression of a key regulatory gene of cholesterol synthesis, HMG-CoA reductase. The decreased HMG-CoA-reductase expression may be related to lower secretion of very low density lipoprotein (VLDL)-cholesterol, which, in turn, would account for the reductions in LDL-C.

A program consisting of a phytonutrient-rich medical food and an elimination diet ameliorated fibromyalgia symptoms and promoted toxic-element detoxification in a pilot trial.

BACKGROUND: An effective treatment for fibromyalgia (FM) has yet to become available. OBJECTIVE: To assess the efficacy ofa lifestyle program consisting of a modified elimination diet and a supplemental medical food on clinical symptoms of FM assessed by the Fibromyalgia Impact Questionnaire (FIQ), FibroQuest Symptoms Survey (FibroQuest), Medical Symptoms Questionnaire (MSQ), metallothionein mRNA expression, and urinary toxic element excretion. METHODS: Eight women (aged 48-74 years) were enrolled in an 8-week pilot trial employing a sequential design. During the initial 4-week Program A (control), participants consumed a modified US Department of Agriculture food pyramid diet and a rice protein powder supplement that provided basic macronutrient support. During the second 4-week Program B (intervention), participants consumed a modified elimination diet and a phytonutrient-rich medical food. RESULTS: Compared to baseline, both programs showed trends toward lower mean FIQ total score, MSQ total score, and FibroQuest total score, FIQ stiffness score, and FibroQuest headaches score. Compared to Program A, Program B resulted in a significant decrease (P< .05) in the FIQpain score and stiffness score. Participants also had better pain tolerance at five tender points during Program B than during Program A. Higher metallothionein mRNA expression was observed during Program B. An increase in creatinine-adjusted mercury excretion and suggestive increase in creatinine-adjusted arsenic excretion were noted when Program B was compared to baseline. Urinary mercury/arsenic concentrations were inversely associated with FIQand FibroQuest scores. CONCLUSIONS: Program B was shown to be a safe and efficacious botanically derived medical food treatment program for the amelioration of FM symptoms.

Nutritional supplementation of hop rho iso-alpha acids, berberine, vitamin D3, and vitamin K1 produces a favorable bone biomarker profile supporting healthy bone metabolism in postmenopausal women with metabolic syndrome.

Metabolic syndrome poses additional risk for postmenopausal women who are already at risk for osteoporosis. We hypothesized that a nutritional supplement containing anti-inflammatory phytochemicals and essential bone nutrients would produce a favorable bone biomarker profile in postmenopausal women with metabolic syndrome. In this 14-week, randomized trial, 51 women were instructed to consume a modified Mediterranean-style, low-glycemic-load diet and to engage in aerobic exercise. Those in the intervention arm (n = 25) additionally received 200 mg hop rho iso-alpha acids, 100 mg berberine sulfate trihydrate, 500 IU vitamin D3, and 500 µg vitamin K1 twice daily. Forty-five women completed the study. Baseline nutrient intake did not differ between arms. Compared with baseline, the intervention arm exhibited an approximate 25% mean decrease (P < .001) in serum osteocalcin (indicative of bone turnover), whereas the placebo arm exhibited a 21% increase (P = .003). Serum 25-hydroxyvitamin D increased 23% (P = .001) in the intervention arm and decreased 12% (P = .03) in the placebo arm. The between-arm differences for osteocalcin and 25-hydroxyvitamin D were statistically significant. Serum insulin-like growth factor I was statistically increased in both arms, but the between-arm differences were not statistically significant. Subanalysis showed that among those in the highest tertile of baseline insulin-like growth factor I, the intervention arm exhibited a significant increase in amino-terminal propeptide of type I collagen, whereas the placebo arm showed a significant decrease at 14 weeks. Treatment with rho iso-alpha acids, berberine, vitamin D3, and vitamin K1 produced a more favorable bone biomarker profile indicative of healthy bone metabolism in postmenopausal women with metabolic syndrome.

A Mediterranean-style low-glycemic-load diet improves variables of metabolic syndrome in women, and addition of a phytochemical-rich medical food enhances benefits on lipoprotein metabolism.

BACKGROUND: The high prevalence of metabolic syndrome (MetS) has highlighted the need for effective dietary interventions to combat this growing problem. OBJECTIVE: To assess the impact of a Mediterranean-style low-glycemic-load diet (control arm, n = 44) or the same diet plus a medical food containing phytosterols, soy protein, and extracts from hops and acacia (intervention arm, n = 45) on cardiometabolic risk variables in women with MetS. METHODS: In this 12-week, 2-arm randomized trial, baseline, week 8 and 12, fasting blood samples were drawn to measure plasma lipids, apolipoproteins, and homocysteine. Dietary records were also collected and analyzed. RESULTS: There were decreases in fat and sugar intake (P < .001 for both) and increases in docosahexaenoic acid and eicosapentaenoic acid intake (P < .001 for both) over time, consistent with the prescribed diet. Regarding MetS variables, there were decreases in waist circumference, systolic and diastolic blood pressure, and plasma triglycerides in all subjects (P < .001 for all) with no differences between arms. Plasma low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein (apo) B, and apo B/apo A1 were reduced over time but to a greater extent in the intervention arm (P < .05 for all), indicating the medical food had a greater effect in altering lipoprotein metabolism. Further, medical food intake was associated with reduced plasma homocysteine (P < .01) compared to the control arm. CONCLUSION: A Mediterranean-style low-glycemic-load diet effectively reduces the variables of MetS. Addition of the medical food results in a less atherogenic lipoprotein profile and lower plasma homocysteine.

Waist circumference is positively correlated with markers of inflammation and negatively with adiponectin in women with metabolic syndrome.

The purpose of this study was to correlate biomarkers of metabolic syndrome (MetS), with markers of inflammation and macronutrient intake in 89 women (25-72 years) with MetS. We hypothesized that waist circumference (WC) would have the stronger correlations with inflammatory parameters and would correlate with carbohydrate intake. Values for WC (108.7 ± 11.1 cm) and plasma triglycerides (202.7 ± 52.1 mg/dL) were elevated, whereas plasma glucose levels varied from 66 to 179 mg/dL, with 42% of women having insulin resistance. Plasma levels of interleukin 6 (0.2-15.9 mg/L), tumor necrosis factor α (1.47-12.3 mg/L), and high-sensitivity C-reactive protein (0.06-3.08 mg/dL) varied widely, with most women being above values considered normal. Subjects had high intake of total sugar (92.3 ± 56.4 g/d), high glycemic index (59.8 ± 6.5), and glycemic load (127.2 ± 56.1), whereas dietary fiber (17.1 ± 9.1 g/d) was below recommended intake. Waist circumference was positively correlated with insulin (r = 0.275, P < .01) and with the inflammatory markers interleukin 6 (r = 0.307, P < .01) and tumor necrosis factor α (r = 0.228, P < .05) and negatively correlated with plasma adiponectin (r = -0.309, P < .0001). In addition, WC was positively correlated with total carbohydrate, added sugar, and glycemic load (P < .05) but not with fat or protein. These results are consistent with central obesity being a key marker of the inflammatory state, and they also suggest that carbohydrates, particularly those that are digested rapidly, contribute to increased risk of central obesity and development of MetS.

The macrobiotic diet in chronic disease.

The macrobiotic diet is a low-fat, high-fiber, high-complex carbohydrate, mainly vegetarian diet. It is associated with a lifestyle system and a spiritual philosophy of life. Unlike many diets, the composition is not fixed and may be altered depending on a person's health status, among other considerations. Studies indicating lower serum lipid levels and blood pressure in people following a macrobiotic diet than in the general population suggest it to be an effective preventive strategy for cardiovascular disease. Many of its components suggest macrobiotics would be a valuable approach to cancer prevention. On the other hand, it has been the subject of controversy, especially with respect to its use in patients suffering from malignancies. Several remarkable anecdotal case reports have supported a therapeutic effect in patients with advanced cancers. However, to date, the few studies attempted have been inadequate to prove effectiveness and further research is warranted. Concerns include potential delay in conventional treatment for cancer, risks associated with nutrition deficiencies, and social limitations related to the complexities of strict adherence to this diet. Many aspects of currently popular dietary recommendations such as eating locally grown, in-season, fresh, organic foods are legacies of the macrobiotic lifestyle and diet.

Subjects with elevated LDL cholesterol and metabolic syndrome benefit from supplementation with soy protein, phytosterols, hops rho iso-alpha acids, and Acacia nilotica proanthocyanidins.

BACKGROUND: Metabolic syndrome is associated with increased cardiovascular disease (CVD) risk, a risk that is significantly increased when accompanied by elevated low-density lipoprotein cholesterol (LDL-C). Whereas lifestyle therapies are the initial intervention of choice for both of these risk factors, it has not been clearly determined that this approach is efficacious when they occur concomitantly. OBJECTIVE: To evaluate effects of supplementing a lifestyle program with a medical food and nutraceutical in individuals with metabolic syndrome and elevated LDL-C. METHODS: We conducted a subgroup analysis of a 12-week, randomized trial in adults with metabolic syndrome; data from those with LDL-C ≥ 160 mg/dL were analyzed. Control-arm subjects were instructed to consume a modified Mediterranean-style, low-glycemic-load diet (MED, n = 12). Treatment-arm subjects received a phytochemical-enhanced diet (PED, n = 12) consisting of the same low-glycemic-load diet plus a medical food containing soy protein and plant sterols and a nutraceutical containing hops rho iso-alpha acids and acacia proanthocyanidins. All subjects received identical aerobic exercise counseling. RESULTS: At 12 weeks, mean weight loss did not differ between arms. However, the PED arm exhibited greater improvement than the MED arm (P < .05) in total cholesterol, LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), cholesterol/HDL-C, triglyceride/HDL-C, apolipoprotein (apo) B, apo B/apo A-1, homocysteine, total LDL particle number, and large HDL particle number. All individuals in the PED arm but only one third in the MED arm achieved LDL-C levels < 160 mg/dL. CONCLUSION: Individuals at high CVD risk benefit from a soy/phytosterol containing medical food and phytochemical supplemented lifestyle program.

Hop and Acacia Phytochemicals Decreased Lipotoxicity in 3T3-L1 Adipocytes, db/db Mice, and Individuals with Metabolic Syndrome.

The plant-based compounds rho-iso-alpha acids (RIAA) from Humulus lupulus (hops) and proanthocyanidins (PAC) from Acacia nilotica have been shown to modulate insulin signaling in vitro. We investigated their effects on triglyceride (TG) deposition in 3T3-L1 adipocytes, glucose and insulin in obese mouse models, and metabolic syndrome markers in adults with metabolic syndrome. The combination of RIAA and PAC synergistically increased TG content and adiponectin secretion in 3T3-L1 adipocytes under hyperinsulinemic conditions and reduced glucose or insulin in obese mice. In a clinical trial, tablets containing 100 mg RIAA and 500 mg PAC or placebo were administered to metabolic syndrome subjects (3 tablets/day, n = 35; 6 tablets/day, n = 34; or placebo, n = 35) for 12 weeks. Compared to placebo, subjects taking 3 tablets daily showed greater reductions in TG, TG : HDL, fasting insulin, and HOMA scores. The combination of RIAA : PAC at 1 : 5 (wt : wt) favorably modulates dysregulated lipids in insulin resistance and metabolic syndrome.

Low HDL cholesterol is associated with increased atherogenic lipoproteins and insulin resistance in women classified with metabolic syndrome.

Both metabolic syndrome (MetS) and elevated LDL cholesterol (LDL-C) increase the risk for cardiovascular disease (CVD). We hypothesized that low HDL cholesterol (HDL-C) would further increase CVD risk in women having both conditions. To assess this, we recruited 89 women with MetS (25-72 y) and LDL-C ≥ 2.6 mmol/L. To determine whether plasma HDL-C concentrations were associated with dietary components, circulating atherogenic particles, and other risk factors for CVD, we divided the subjects into two groups: high HDL-C (H-HDL) (≥ 1.3 mmol/L, n = 32) and low HDL-C (L-HDL) (< 1.3 mmol/L, n = 57). Plasma lipids, insulin, adiponectin, apolipoproteins, oxidized LDL, Lipoprotein(a), and lipoprotein size and subfractions were measured, and 3-d dietary records were used to assess macronutrient intake. Women with L-HDL had higher sugar intake and glycemic load (P < 0.05), higher plasma insulin (P < 0.01), lower adiponectin (P < 0.05), and higher numbers of atherogenic lipoproteins such as large VLDL (P < 0.01) and small LDL (P < 0.001) than the H-HDL group. Women with L-HDL also had larger VLDL and both smaller LDL and HDL particle diameters (P < 0.001). HDL-C was positively correlated with LDL size (r = 0.691, P < 0.0001) and HDL size (r = 0.606, P < 0.001), and inversely correlated with VLDL size (r = -0.327, P < 0.01). We concluded that L-HDL could be used as a marker for increased numbers of circulating atherogenic lipoproteins as well as increased insulin resistance in women who are already at risk for CVD.

Hop rho iso-alpha acids, berberine, vitamin D3 and vitamin K1 favorably impact biomarkers of bone turnover in postmenopausal women in a 14-week trial.

Osteoporosis is a major health issue facing postmenopausal women. Increased production of pro-inflammatory cytokines resulting from declining estrogen leads to increased bone resorption. Nutrition can have a positive impact on osteoporosis prevention and amelioration. The objective of this study was to investigate the impact of targeted phytochemicals and nutrients essential for bone health on bone turnover markers in healthy postmenopausal women. In this 14-week, single-blinded, 2-arm placebo-controlled pilot study, all women were instructed to consume a modified Mediterranean-style low-glycemic-load diet and to engage in limited aerobic exercise; 17 randomized to the placebo and 16 to the treatment arm (receiving 200 mg hop rho iso-alpha acids, 100 mg berberine sulfate trihydrate, 500 IU vitamin D(3) and 500 microg vitamin K(1), twice daily). Thirty-two women completed the study. Baseline nutrient intake did not differ between arms. At 14 weeks, the treatment arm exhibited an estimated 31% mean reduction (P = 0.02) in serum osteocalcin (a marker of bone turnover), whereas the placebo arm exhibited a 19% increase (P = 0.03) compared to baseline. Serum 25-hydroxyvitamin D (25(OH)D) increased by 13% (P = 0.24) in the treatment arm and decreased by 25% (P < 0.01) in the placebo arm. The between-arm differences for OC and 25(OH)D were statistically significant. Serum IGF-I was increased in both arms, but the increase was more significant in the treatment arm at 14 weeks (P < 0.01). Treatment with hop rho iso-alpha acids, berberine sulfate trihydrate, vitamin D(3) and vitamin K(1) produced a more favorable bone biomarker profile that supports a healthy bone metabolism.

A science-based, clinically tested dietary approach for the metabolic syndrome.

During the last decade, great strides have been made to delineate the importance of diet in the prevention and treatment of the metabolic syndrome. Dietary recommendations have emphasized a low-fat ("antiatherogenic") diet as the first-line therapeutic approach. However, the complex etiology of the metabolic syndrome would seem to necessitate tailored dietary approaches beyond simple macronutrient modification. Current data have revealed varying biological effects of individual macronutrients within the same category, suggesting that adjusting dietary macronutrient percentages without considering their physiological impact may not be adequate. The concepts of glycemic index and glycemic load support the need for differentiation between various types of carbohydrates. Additionally, significant evidence to date indicates that metabolic syndrome biomarkers improve with dietary patterns rich in phytochemical complexity (e.g., Mediterranean diet). Taking these aspects into account, we designed a specific dietary approach consisting of foods found in the popularized Mediterranean diet, modified to include only those items that are low in glycemic load and grains (gluten) and are antiinflammatory. Initially based on scientific literature, this food plan has since been tested and adapted in our clinic over the past decade. This paper describes the rationale of the dietary program and provides an overview of data on its efficacy in individuals with metabolic syndrome.

Enhancement of a modified Mediterranean-style, low glycemic load diet with specific phytochemicals improves cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia in a randomized trial.

BACKGROUND: As the worldwide dietary pattern becomes more westernized, the metabolic syndrome is reaching epidemic proportions. Lifestyle modifications including diet and exercise are recommended as first-line intervention for treating metabolic syndrome. Previously, we reported that a modified Mediterranean-style, low glycemic load diet with soy protein and phytosterols had a more favorable impact than the American Heart Association Step 1 diet on cardiovascular disease (CVD) risk factors. Subsequently, we screened for phytochemicals with a history of safe use that were capable of increasing insulin sensitivity through modulation of protein kinases, and identified hops rho iso-alpha acid and acacia proanthocyanidins. The objective of this study was to investigate whether enhancement of a modified Mediterranean-style, low glycemic load diet (MED) with specific phytochemicals (soy protein, phytosterols, rho iso-alpha acids and proanthocyanidins; PED) could improve cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia. METHODS: Forty-nine subjects with metabolic syndrome and hypercholesterolemia, aged 25-80, entered a randomized, 2-arm, 12-week intervention trial; 23 randomized to the MED arm; 26 to the PED arm. Forty-four subjects completed at least 8 weeks [MED (n = 19); PED (n = 25)]. All subjects were instructed to follow the same aerobic exercise program. Three-day diet diaries and 7-day exercise diaries were assessed at each visit. Fasting blood samples were collected at baseline, 8 and 12 weeks for analysis. RESULTS: Both arms experienced equal weight loss (MED: -5.7 kg; PED: -5.9 kg). However, at 12 weeks, the PED arm experienced greater reductions (P < 0.05) in cholesterol, non-HDL cholesterol, triglycerides (TG), cholesterol/HDL and TG/HDL compared with the MED arm. Only the PED arm experienced increased HDL (P < 0.05) and decreased TG/HDL (P < 0.01), and continued reduction in apo B/apo A-I from 8 to 12 weeks. Furthermore, 43% of PED subjects vs. only 22% of MED subjects had net resolution of metabolic syndrome. The Framingham 10-year CVD risk score decreased by 5.6% in the PED arm (P < 0.01) and 2.9% in the MED arm (P < 0.05). CONCLUSION: These results demonstrate that specific phytochemical supplementation increased the effectiveness of the modified Mediterranean-style low glycemic load dietary program on variables associated with metabolic syndrome and CVD.

Safety, efficacy and anti-inflammatory activity of rho iso-alpha-acids from hops.

A defined mixture of rho iso-alpha-acids (RIAA), a modified hop extract, was evaluated for anti-inflammatory efficacy and safety. RIAA inhibited LPS-stimulated PGE(2) formation with >200-fold selectivity of COX-2 (IC(50)=1.3 microg/ml) over COX-1 (IC(50)>289 microg/ml). This occurred only when RIAA was added prior to, but not post, LPS stimulation. Consistent with this observation, RIAA produced no physiologically relevant, direct inhibition of COX-1 or COX-2 peroxidase activity. This suggests that RIAA inhibits inducible but not constitutive COX-2. In support, we found RIAA showed minimal PGE(2) inhibition (IC(50)=21mug/ml) relative to celecoxib (IC(50)=0.024 microg/ml), aspirin (IC(50)=0.52 microg/ml) or ibuprofen (IC(50)=0.57 microg/ml) in the AGS gastric mucosal model, where COX-1 and -2 are expressed constitutively. Taken together these results predict RIAA may have lower potential for gastrointestinal and cardiovascular toxicity observed with COX enzyme inhibitors. Following confirmation of bioavailable RIAA administered orally, gastrointestinal safety was assessed using the fecal calprotectin biomarker in a 14-day human clinical study; RIAA (900 mg/day) produced no change compared to naproxen (1000 mg/day), which increased fecal calprotectin 200%. Cardiovascular safety was addressed by PGI-M measurements where RIAA (1000 mg) did not reduce PGI-M or affect the urinary PGI-M/TXB(2) ratio. Drug interaction potential was evaluated against six major CYPs; of relevance, RIAA inhibited CYP2C9. Toxicity was assessed in a 21-day oral, mouse subchronic toxicity study where no dose dependent histopathological effects were noted. Clinically, RIAA (1000 mg/day) produced a 54% reduction in WOMAC Global scores in a 6-week, open-label trial of human subjects exhibiting knee osteoarthritis.

Clinical safety and efficacy of NG440: a novel combination of rho iso-alpha acids from hops, rosemary, and oleanolic acid for inflammatory conditions.

In this report, we examine the clinical safety and efficacy of NG440, a phytochemical-based antiinflammatory formula consisting of a combination of rho iso-alpha acids from hops, rosemary, and oleanolic acid. In a previous study, we demonstrated that NG440 significantly decreased pain by 50% in patients with osteoarthritis. Consistent with these data, results from a multicentre trial indicate that NG440 reduced pain scores in patients with joint discomfort, as measured by VAS (visual analog scale) methodology. As demonstrated in an ex vivo clinical study, these effects on pain relief may be due to reduced inflammatory cytokine production including lower prostaglandin E2 formation. Finally, strong data exist to suggest that NG440 is a safe formula for human consumption. Animal toxicity data revealed no adverse effects of NG440 at dosages < or =250 mg.kg-1.day-1 for 21 days. Furthermore, human trial data suggest that NG440 does not negatively impact cardiovascular and gastrointestinal markers normally affected by selective COX-2 enzyme inhibitors, including platelet function, blood pressure, blood cell count, or fecal calprotectin, a measure of gastrointestinal injury. In conclusion, NG440 may serve as a safe and efficacious alternative in some areas where specific COX-2 inhibitors have been traditionally used.