Nutritional Supplement-5 with a Combination of Proteasome Inhibitors (Resveratrol, Quercetin, δ-Tocotrienol) Modulate Age-Associated Biomarkers and Cardiovascular Lipid Parameters in Human Subjects

Abstract

Background Age-associated altered redox imbalances and dysregulated immune function, contribute to the development of a variety of age associated diseases. Inflammatory markers and lipid profiles are useful prognostic indicators of a variety of age-associated and cardiovascular diseases. We have previously studied the impact of several proteasome inhibitors on several markers of inflammation and lipid profiles in vitro, in vivo, in cell lines, animal models, and in human subjects. The current study represents an extension of this work. Our main hypothesis is that a combination of various naturally-occurring proteasome inhibitors, which inhibits nitric oxide (NO), and C-reactive protein (CRP) mediated inflammation, will have better efficacy in the prevention and treatment of age-associated disorders including cardiovascular disease. Methods Two double blind, randomized, placebo-controlled cross-over trials were conducted to determine the impact of a mixture of NS-5 (resveratrol, pterostilbene, quercetin, δ-tocotrienol, nicotinic acid) on serum NO, CRP, γ-glutamyl-transferase (γ-GT) activity, total antioxidant status (TAS), total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides levels. Healthy seniors (Group-1; n = 32) free-living (A, B; 16/group), and hypercholesterolemic (Group-2; n = 64) subjects on AHA-Step-1-diet were divided into two groups (C, D; 32/group). Baseline levels were established for parameters as mentioned above. Groups A, C were administered 4-capsules/d of NS-5 and groups B, D, placebo (starch) for 6-weeks. Groups were crossed-over, followed by a 2-week wash-out period. Groups A, C were given 4-capsules/d of placebo and groups B, D, 4-capsules/d of NS-5 for 6-weeks. Groups C, D were continued on AHA-Step-1-diet. Results All the subjects completed each phase in both studies without any complaints. There were significant (P < 0.01 – 0.05) decreases in the serum levels of NO (30%, 26%), CRP (29%, 21%), γ-GT activity (14%, 17%), and blood pressure (systolic/diastolic, 3/6%, 3/3%) of Groups A and B, respectively, of free-living healthy seniors without affecting the total, HDL-, LDL-cholesterol or triglycerides compared to their respective baseline values. However, serum levels of NO (36%, 43%), CRP (31%, 48%), γ-GT (17%, 20%), total cholesterol (19%, 15%), LDL-cholesterol (28%, 20%), triglycerides (11%, 18%) of Groups C and D were significantly (P < 0.01-0.05) decreased with NS-5 treatment of hypercholesterolemic subjects compared to baseline values, without affecting the serum HDL-cholesterol levels. The serum levels of total antioxidant status (TAS) were increased (10%, 14%; P < 0.05) in Groups A and B, increased (19%, 24%; P < 0.02), and blood pressure (systolic/diastolic, 5/6%, 3/5%) in Groups C and D with NS-5 treatment, compared to respective baseline values. Conclusions The consumption of NS-5 mixture decreased significantly serum NO, CRP and γ-GT levels, improved TAS and lipid profiles at risk cardiovascular and hold promise for delaying onset of age-associated diseases.

Pharmacokinetics and Bioavailability of Annatto δ-tocotrienol in Healthy Fed Subjects

“…The correlation between plasma levels of several pro-inflammatory and anti-inflammatory cytokines affected by δ-tocotrienol treatment has been reported in our recent publications [4,5,37]. Most of the cytokines (eight out of eleven) were down-regulated in a dosedependent manner by δ-tocotrienol treatment, except adiponectin, tumor growth factor β1 and leptin (Table 6).…”

“…The phenomena of bioconversion of tocotrienols to tocopherols have been discussed in earlier publications [4][5][6]29]. It was reported that failure of large doses of palm TRF and rice bran TRF25 to lower lipid parameters in hypercholesterolemic subjects maybe due to their conversion to tocopherols, because the plasma concentrations of tocopherols were 2-to 4-fold higher than tocotrienols as compared to placebo group.…”

“…Several studies have reported the antioxidant, anti-inflammatory, anticancer, hypocholesterolemic and neuroprotective properties of tocotrienols in different cell lines, animal models, and in humans [1][2][3][4][5][6][7][8]. However, question on the bioavailability of pure tocotrienols remained unanswered.…”

“…Moreover, high doses of tocotrienols may be useful for cancer chemoprevention and treatment. Large doses of δ-tocotrienol up to 3200 mg/d have been used to treat patients suffering from resectable pancreatic cancer [23].The biological properties of tocotrienols have been underestimated despite several studies showing their positive effects on physiological and biological functions [1][2][3][4][5][6][7][8]. The scientific recognition for tocotrienols remains limited as compared to tocopherols due to their low concentrations in most food products.…”

Amino Acid-PEGylated Resveratrol and Its Influence on Solubility and the Controlled Release Behavior

“…[1][2][3] RES has received much attention in recent years because of its various health functions and its potential for use in medicinal applications. 4,5) Many studies have demonstrated that RES has significant pharmacological activity 6) and potential to be a chemopreventive and therapeutic agent for cancers, [7][8][9] Alzheimer's disease, 10) cardiovascular disease, 11) hyperlipidemia, 12) ischemia disease and other diseases. 13) Recently, RES has seen widespread use as a food ingredient and nutraceutical supplement in bread, cake and beverage products.…”