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 ameliora- tion. 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 exer- cise; 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 D3 and 500 lg vitamin K1, 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 differ- ences 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 D3 and vitamin K1 produced a more favorable bone biomarker profile that supports a healthy bone metabolism.
Obesity is a complex disease resulting from a prolonged positive imbalance between energy intake and energy expenditure with excess fat accumulating in various organs and tissues. META060, a defined hop extract, was analyzed in various cell models of obesity/type‐2 diabetes. META060 stimulated the secretion of GLP‐1 in intestinal L cells (NCI‐H716); stimulated the production of adiponectin in adipocytes (3T3‐L1); activated the phosphorylation of AMPK levels in muscle cells (C2C12); and inhibited nitric oxide levels in both myocytes and macrophages (RAW264.7). META060 was evaluated in a mouse model of high fat diet (HFD) induced obesity. Mice supplemented for 14 weeks with META060 (100 mg/kg body weight) prevented the HFD induced weight gain, and the rate of weight gain was similar to that of the low fat diet group. META060 significantly reduced HFD induced fat accumulation in viscera, subcutaneous tissues and gonads, and exhibited a significant reduction in fasting glucose and insulin. In addition, mice switching to HFD+META060 after 14 weeks of HFD dramatically increased the weight loss within 2 weeks. In oral glucose tolerance test, addition of META060 to HFD for 14 weeks reduced insulin levels. In conclusion, META060 reduced weight gain, fasting plasma insulin and glucose levels, and improved insulin sensitivity in mice fed with high fat diet. Supported by MetaProteomics, LLC.
TNFα induced endothelial activation and vascular inflammation plays a critical role in atherogenesis. We have investigated the effects of Meta060, a modified hop extract, on TNFα activated endothelial inflammation and endothelial‐monocyte interaction. We found that Meta060 or the NF‐κB inhibitor parthenolide inhibited TNFα activated HAEC‐monocyte interactions. Meta060 also inhibited TNFα activated endothelial biomarkers such as MCP‐1, VCAM‐1 and E‐Selectin in HAEC cells. We compared Meta060 with clopidogrel, a known inhibitor of platelet and monocyte activation. Treatment of THP‐1 cells with clopidogrel inhibited the monocyte‐HAEC interactions, but pretreatment of HAEC cells had no effect. These results suggest that clopidogrel inhibited only monocyte mediated interactions. Conversely, Meta060 inhibited both endothelial and monocyte cells independently, resulting in a more effective reduction of adhesion. Meta060 also inhibited a key inflammatory marker, MCP‐1 in THP‐1 cells. We evaluated inhibitory effects of Meta060 on inflammatory kinases in cell free assays. Meta060 dose dependently inhibited several kinases. These kinases mediate multiple signaling pathways, such as PKC, MAPK and NF‐κB. Taken together, this data suggests that Meta060 may be a novel therapeutic to treat inflammation, an important component of atherogenesis (Supported by Metagenics Inc.).
Long chain ω‐3 fatty acids exert anti‐inflammatory and insulin sensitizing effects through the activation of G protein‐coupled receptor 120 (GPR120). GPR120 is expressed in macrophages, intestinal L cells and adipocytes. Activation of GPR120 has been reported to reduce TAB1/TAK1 activation and to inhibit NF‐κB signaling pathway in macrophages. GPR120, through regulation of GLP‐1, plays a major role in glucose homeostasis and insulin sensitivity and may be a novel target for the treatment of type 2 diabetes. Previously, we reported that META060, a modified hop extract, improved arthritic symptoms in a mouse model of collagen induced arthritis. To investigate the effects of META060 on inflammation associated obesity, we examined the activity of META060 at GPR120 in vitro, and the effects of META060 in endocrine cell models. In this study, we identified that META060 activated GPR120 and inhibited inflammation. Moreover, META060 stimulated secretion of GLP‐1 in human intestinal L cells (NCI‐H716) and lipogenesis in adipocytes (3T3‐L1). META060 also was evaluated in a mouse model of high fat diet (HFD) induced obesity and diabetes. Mice supplemented for 14 weeks with META060 (100 mg/kg body weight) exhibited significantly less HFD induced weight gain, reduced fat accumulation in various organs, and improved insulin sensitivity. These data indicate that META060, a novel natural agonist for GPR120, acts as an anti‐inflammatory and improves insulin sensitivity in mice, and may have clinical application for type 2 diabetes. Supported by Metagenics Inc.
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.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.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.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.
Prostaglandin E2 (PGE2) has been implicated in many inflammatory diseases including rheumatoid arthritis, angiogenesis and cancer. Rho-iso-alpha acids (RIAA, modified hop extract from Humulus lupulus) inhibits PGE2 production in lipopolysaccharide (LPS) activated murine macrophage cell line RAW 264.7. Analysis of the mechanism shows that RIAA inhibits PGE2 by inhibiting cyclooxygenase-2 (COX-2) protein expression in RAW 264.7 cells. In vitro and cell-free enzymatic assays reveal that RIAA does not inhibit PGE2 production by inhibiting COX-2 enzymatic activity. RIAA inhibits NF-□B mediated signaling pathway, as evidenced by reductions in I□B□ degradation, NF-□B p50 nuclear translocation and binding, and NF-□B driven promoter activity. Moreover, the dose dependent inhibition of LPS activated murine COX-2 promoter activity by RIAA is attenuated by mutations at two NF-□B binding sites (−401 and −668) on the COX-2 promoter. Inducible nitric oxide synthase (iNOS), a known NF□B dependent gene, was also inhibited by RIAA. It appears that the anti-inflammatory properties of RIAA are independent of ERK-1/2, p38 and JNK signaling pathways. These results demonstrate that RIAA from hop extract inhibit inflammation through multiple mechanisms, including the NF-□B signaling pathway. (Supported by Metagenics Inc.)
Prostaglandin E2 (PGE2) has been implicated in many inflammatory conditions including osteoarthritis, rheumatoid arthritis, angiogenesis and cancer. Previously we showed that RIAA, a modified hop extract, inhibited NFκB driven COX-2 expression and PGE2 formation in LPS stimulated RAW 264.7 macrophages. Consistent with these results, we found RIAA inhibited multiple protein kinases involved in LPS induced inflammation. We coined the term Selective Kinase Response Modulators (SKRM) to describe molecules that cooperatively modulate multiple kinases of a given pathway. Shown here, a close analog of RIAA, THIAA was also a potent PGE2 inhibitor with an IC50 2.5x lower. RIAA and THIAA were analyzed in cell free enzyme assays against select protein kinases. Both analogs inhibited multiple kinases in the MAP kinase and B cell receptor (BCR) inflammatory signal transduction pathways; THIAA showed substantially greater inhibition than RIAA. Combinational experiments revealed that THIAA, like RIAA, synergize with rosemary and oleanolic acid to inhibit PGE2 formation in LPS stimulated RAW 264.7 cells. Replacing RIAA with THIAA in a proprietary formula with rosemary and oleanolic acid also showed better inhibition of COX-2, TNFα and nitric oxide production. These results suggest that THIAA based formulas may have significant therapeutic potential for inflammatory conditions (Supported by MetaProteomics, LLC).
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