RESUMO
An open-label, randomized, exploratory study of 44 healthy overweight subjects with cardio-metabolic syndrome (CMS) risk factors was conducted to assess the safety, tolerability, and efficacy of a proprietary lifestyle modification program without (DIET) and with (PROG) targeted nutraceutical supplementation, including phytosterols, antioxidants, probiotics, fish oil, berberine, and soy, pea, and whey proteins over 13 weeks. Key metrics were recorded at baseline and weeks 9 and 13. For the DIET and PROG groups, compliance was 85% and 86%, respectively, with no adverse events related to the diet or supplements. Twelve subjects discontinued participation before week 9 for reasons unrelated to the study. PROG subjects experienced greater decreases (p < 0.05) than DIET in body mass, fat mass, total cholesterol, LDL cholesterol, TG, cholesterol / HDL ratio, TG/HDL ratio, apolipoprotein B / apolipoprotein A1 ratio, and hs-CRP. The Framingham 10-year cardiovascular disease risk score decreased by 40% (p < 0.01) in the PROG arm versus no change for the DIET arm. As a pilot study, it was not possible to state whether the observed effects were the result of nutraceutical supplementation alone or the result of additive or synergistic interactions among diet, lifestyle modifications, and nutraceutical supplementation. Moreover, individuals with CMS risk factors following a lifestyle modification program received additional health benefits from targeted nutraceutical supplementation.
Assuntos
Peso Corporal/efeitos dos fármacos , Proteínas Alimentares/farmacologia , Suplementos Nutricionais , Carga Glicêmica , Estilo de Vida , Adulto , Apolipoproteínas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Segurança , Fatores de Tempo , Circunferência da Cintura/efeitos dos fármacosRESUMO
We examined the clinical safety and efficacy of F105 in 11 subjects with moderate dyslipidemia. F105 is a combination of bergamot fruit extract (Citrus bergamia, BFE) and 9 phytoextracts selected for their ability to improve the antioxidant and anti-inflammatory activity of BFE. In vitro F105 exhibited a synergistic inhibition of oxygen radical absorbing capacity, peroxynitrite formation, and myeloperoxidase activity. Following 12 weeks of F105 daily, no treatment-related adverse events or changes in body mass were seen. Statistically significant changes were noted in total cholesterol (-7.3%), LDL-cholesterol (-10%), non-HDL cholesterol (-7.1%), cholesterol/HDL (-26%), and apolipoprotein B (-2.8%). A post hoc analysis of 8 subjects with HbA1c > 5.4 and HOMA-IR score > 2 or elevated triglycerides revealed additional statistically significant changes in addition to those previously observed in all subjects including triglycerides (-27%), oxLDL (-19%), LDL/HDL (-25%), triglycerides/HDL (-27%), oxLDL/HDL (-25%), and PAI-1 (-37%). A follow-up case report of a 70-year-old female patient, nonresponsive to statin therapy and placed on F105 daily, demonstrated improved cardiometabolic variables over 12 weeks similar to the subgroup. In summary, F105 was clinically well-tolerated and effective for ameliorating dyslipidemia in subjects with moderate cardiometabolic risk factors, particularly in the individuals with HbA1c > 5.4%.
Assuntos
Antioxidantes/uso terapêutico , Citrus , Dislipidemias/tratamento farmacológico , Doenças Metabólicas/prevenção & controle , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Adulto , Idoso , Antioxidantes/química , Antioxidantes/isolamento & purificação , Composição de Medicamentos , Sinergismo Farmacológico , Dislipidemias/diagnóstico , Dislipidemias/metabolismo , Feminino , Humanos , Masculino , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Projetos Piloto , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Fatores de RiscoRESUMO
Commercially available hops (Humulus lupulus L.) bitter acid extracts contain a mixture of three major congeners (co-, n-, and ad-) in addition to cis/trans diastereomers for each congener. Individual isomerized α-acids were obtained by the consecutive application of two separate countercurrent chromatography methods. First, individual isomerized α-acid congeners as a mixture of cis/trans diastereomers were obtained using a solvent system consisting of hexane and aqueous buffer. The second purification, capable of separating cis/trans diastereomers, was accomplished using a quaternary solvent system; an alternative procedure using ß-cyclodextrin followed by countercurrent chromatography was also investigated. The NaBH(4) reduction of the purified isomerized α-acid compounds followed by countercurrent chromatography purification resulted in individual ρ iso α-acids (>95%). Similarly, catalytic hydrogenation of the purified isomerized α-acid compounds followed by countercurrent chromatography purification produced individual tetrahydro isomerized α-acids (>95%). Reported herein is a widely applicable approach that focuses on three critical variables--solvent system composition, pH, and buffer-to-sample ratio--that enable the efficient purification of individual bitter acids (≥95%) from commercially available hops extracts.
Assuntos
Ácidos/isolamento & purificação , Distribuição Contracorrente/métodos , Humulus/química , Extratos Vegetais/isolamento & purificação , Ácidos/química , Isomerismo , Extratos Vegetais/químicaRESUMO
OBJECTIVE: The multikinase inhibitor META060 has been shown to inhibit NF-kappaB activation and expression of markers of inflammation. This study was undertaken to investigate the effect of META060 on biomarkers associated with bone and cartilage degradation in vitro and its antiinflammatory efficacy in vivo in both acute and chronic inflammation models. METHODS: Glycogen synthase kinase 3beta (GSK3beta)-dependent beta-catenin phosphorylation was evaluated in RAW 264.7 macrophages to assess kinase inhibition. The inhibition of osteoclastogenesis and tartrate-resistant acid phosphatase (TRAP) activity was evaluated in RANKL-treated RAW 264.7 cells. The inhibition of interleukin-1beta (IL-1beta)-mediated markers of inflammation was analyzed in human rheumatoid arthritis synovial fibroblasts (RASFs). Mice with carrageenan-induced acute inflammation and collagen-induced arthritis (CIA) were used to assess efficacy. RESULTS: META060 inhibited the activity of kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], phosphatidylinositol 3-kinase [PI 3-kinase], and GSK3) associated with RA and inhibited beta-catenin phosphorylation. META060 inhibited osteoclastogenesis, as indicated by decreased transformation of RAW 264.7 cells to osteoclasts and reduced TRAP activity, and inhibited IL-1beta-activated prostaglandin E(2), matrix metalloproteinase 3, IL-6, IL-8, and monocyte chemotactic protein 1 in RASFs. In mice with acute inflammation, oral administration of META060 reduced paw swelling similar to the effect of aspirin. In mice with CIA, META060 significantly reduced the arthritis index and decreased bone, joint, and cartilage degradation. Serum IL-6 concentrations in these mice were inhibited in a dose-dependent manner. CONCLUSION: Our findings indicate that META060 reduces swelling in a model of acute inflammation and inhibits bone and cartilage destruction in a model of chronic inflammation. Its efficacy is associated with the inhibition of multiple protein kinases, including Syk, Btk, PI 3-kinase, and GSK3. These results warrant further clinical testing of META060 for its therapeutic potential in the treatment of inflammatory diseases.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Osso e Ossos/efeitos dos fármacos , Cartilagem/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ciclopentanos/farmacologia , Inflamação/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Western Blotting , Osso e Ossos/metabolismo , Cartilagem/metabolismo , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Inflamação/metabolismo , Interleucina-6/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Ligante RANK/metabolismoRESUMO
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.
Assuntos
Dieta/métodos , Fibras na Dieta/administração & dosagem , Fibromialgia/dietoterapia , Micronutrientes/administração & dosagem , Dor/prevenção & controle , Extratos Vegetais/administração & dosagem , Idoso , Assistência Ambulatorial/métodos , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Feminino , Fibromialgia/complicações , Fibromialgia/prevenção & controle , Humanos , Pessoa de Meia-Idade , Dor/etiologia , Medição da Dor , Projetos Piloto , Resultado do Tratamento , Saúde da MulherRESUMO
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.
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Remodelação Óssea , Suplementos Nutricionais , Pós-Menopausa , 25-Hidroxivitamina D 2/sangue , Berberina/administração & dosagem , Biomarcadores/sangue , Biomarcadores/urina , Calcifediol/sangue , Colecalciferol/administração & dosagem , Feminino , Humanos , Humulus/química , Fator de Crescimento Insulin-Like I/análise , Pessoa de Meia-Idade , Osteocalcina/sangue , Osteoporose Pós-Menopausa/prevenção & controle , Fitoterapia , Projetos Piloto , Extratos Vegetais/administração & dosagem , Método Simples-Cego , Vitamina K 1/administração & dosagemRESUMO
Among the comorbidities of high body mass index, cardiovascular disease continued to be the leading cause of death and disability globally in 2015, while type 2 diabetes remained second. The primary objectives of this observational study were to confirm the safety, tolerability, and efficacy of our calorie-restricted Mediterranean diet with targeted dietary supplementation (PROG1) using globally recognized dietary supplementation. Fifty healthy overweight and obese subjects with cardiometabolic risk factors were assigned a modified Mediterranean diet, including protein shakes and targeted supplementation (PROG2), providing â¼68-76% of subject estimated calorie requirements. Salivary nitrite was assessed weekly and key cardiometabolic metrics were recorded at baseline and weeks 9 and 13. PROG2 was well tolerated with 86% compliance. The most common adverse effects were bloating, flatulence, and constipation, which were self-limiting. Subjects exhibited decreases (P < .01) from baseline of 12% in body weight, 18% in body fat, and 8.8% in waist circumference. Total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) were reduced (P < .01), respectively, 19%, 22%, and 40%. Lipid ratios of TC/high-density lipoprotein (HDL), TG/HDL, and oxidized LDL (oxLDL)/HDL were decreased 15% (P < .01), 35% (P < .01), and 13% (P < .05), respectively. Inflammation biomarkers, oxLDL and high-sensitivity C-reactive protein, were reduced 17% (P < .01) and 30% (P < .05), respectively. Reductions of 9.0% for systolic (P < .01) and 12% (P < .01) for diastolic blood pressure were noted. In concert, the nitrogen dioxide salivary biomarker for nitric oxide was increased relative to baseline. PROG2 produced a dramatic 50% reduction in subjects meeting cardiometabolic syndrome criteria and a 38% decrease in Framingham 10-year cardiovascular risk. These results confirmed our previous findings that the addition of targeted nutraceutical supplementation to a calorie-restricted Mediterranean diet with lifestyle modifications improves multiple longevity risk factors more effectively than diet and lifestyle modification alone.
Assuntos
Dieta Mediterrânea , Miocárdio/metabolismo , Sobrepeso/dietoterapia , Extratos Vegetais/administração & dosagem , Probióticos/administração & dosagem , Adulto , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Colesterol/metabolismo , Suplementos Nutricionais/análise , Feminino , Índice Glicêmico , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Estilo de Vida , Longevidade/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Sobrepeso/tratamento farmacológico , Sobrepeso/fisiopatologia , Sobrepeso/psicologia , Triglicerídeos/metabolismoRESUMO
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.
Assuntos
Alcanos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Ciclopentanos/uso terapêutico , Humulus/química , Osteoartrite/prevenção & controle , Extratos Vegetais/uso terapêutico , Adulto , Idoso , Alcanos/efeitos adversos , Alcanos/farmacocinética , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacocinética , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Cromatografia Líquida , Inibidores de Ciclo-Oxigenase/efeitos adversos , Inibidores de Ciclo-Oxigenase/farmacocinética , Inibidores de Ciclo-Oxigenase/uso terapêutico , Ciclopentanos/efeitos adversos , Ciclopentanos/farmacocinética , Fezes/química , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Complexo Antígeno L1 Leucocitário/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Espectrometria de Massas , Camundongos , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Osteoartrite/patologia , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacocinética , Prostaglandinas/urina , Resultado do TratamentoRESUMO
OBJECTIVES: Cardiovascular disease (CVD) is the leading cause of death in women. Hyperlipidemia is a major risk factor for CVD, but research suggests that metabolic syndrome and type 2 diabetes are also key factors in CVD in postmenopausal women. Most dietary programs, however, focus only on hyperlipidemia and not on insulin resistance associated with diabetes and metabolic syndrome. This 12-wk trial compared the effects of a dietary program combining a low glycemic index diet with a functional food delivering 30 g of soy protein and 4 g of phytosterols per day (LGID) with a standard dietary program (American Heart Association Step 1 diet; AHAD) in postmenopausal women. METHODS: Fifty-nine postmenopausal women (average age 54.6 y, range 44-65 y) with a body mass index of 27 to 39 kg/m2 were randomly assigned to the LGID or the AHAD program for 12 wk. Total caloric intake and exercise were matched in each arm. RESULTS: Twenty-seven women completed the LGID program, and 26 completed the AHAD program. The participants on the LGID program showed statistically significant decreases in total cholesterol (15.8%, P = 0.0036 between-group comparison), low-density lipoprotein cholesterol (14.8%, P = 0.004 between-group comparison), and triacylglycerol (44.8%, P = 0.006 between-group comparison). In addition, significant improvements were observed in ratios of total to high-density lipoprotein cholesterol and of triacylglycerol to high-density lipoprotein cholesterol, blood pressure, and Framingham risk assessment for coronary heart disease compared with the AHAD program. CONCLUSIONS: A significantly greater improvement was observed in CVD risk factors in postmenopausal women on the LGID program (incorporating 30 g of soy protein and 4 g of phytosterols per day) than with a standard therapy.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Dieta com Restrição de Gorduras , Índice Glicêmico , Fitosteróis/administração & dosagem , Pós-Menopausa , Proteínas de Soja/administração & dosagem , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Colesterol/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Prevenção Primária , Fatores de Risco , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
A ribosomal DNA (rDNA) binding activity was previously characterized in fission yeast that recognized the upstream ribosomal RNA (rRNA) gene promoter in a sequence specific manner and which stimulated rRNA synthesis. It was found to share characteristics with Saccharomyces cerevisiae's Upstream Activating Factor (UAF), an RNA polymerase I (pol I) specific transcription stimulatory factor. Putative fission yeast homologs of the S.cerevisiae UAF subunits, Rrn5p and Rrn10p, were identified. The Schizosaccharomyces pombe rDNA binding activity/transcriptional stimulatory activity was found to co-fractionate with both SpRrn5h and SpRrn10h. Analysis of polypeptides interacting with SpRrn10h uncovered a 27 kDa polypeptide (Spp27) homologous to a SWI/SNF component (now known to be homologous to Uaf30p). The contributions of the S.pombe and S.cerevisiae upstream rDNA promoter domains were assessed in cross-species transcriptional assays. Furthermore, comparative genomic analysis revealed putative Rrn5p, Rrn10p, Rrn9p and p27 homologs in multiple non-vertebrates. The S.pombe rDNA binding activity is proposed to be an RNA pol I specific SWI/SNF type factor.
Assuntos
Proteínas de Transporte/metabolismo , DNA Ribossômico/metabolismo , Proteínas de Saccharomyces cerevisiae , Schizosaccharomyces/genética , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Transporte/genética , Proteínas de Transporte/isolamento & purificação , Proteínas de Ciclo Celular , Fracionamento Celular , Proteínas Cromossômicas não Histona , DNA Ribossômico/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Dados de Sequência Molecular , Ligação Proteica , Saccharomyces cerevisiae/genética , Proteínas de Schizosaccharomyces pombe , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Técnicas do Sistema de Duplo-HíbridoRESUMO
BACKGROUND: As they reach menopause, a majority of women living in Westernized countries experience climacteric symptoms. Hormone replacement therapy (HRT) has been used to remediate these symptoms. Recent studies, however, have suggested that HRT may increase the risk of developing breast cancer and cardiovascular disease (CVD). Therefore, many women are looking for alternative treatment options. PURPOSE: This trial was a pilot study to assess the effect of a nutritional supplement containing isoflavones from kudzu and red clover, along with other targeted nutrients on menopausal symptoms and markers of breast cancer and CVD risk. Twenty-five menopausal women suffering from severe hot flushes and night sweats completed a 12-week intervention using this combination isoflavone nutritional supplement. RESULTS: We observed a 46% decrease in reported hot flushes, from an average of 9.7 to 5.2 per day. Quality of life, as assessed by the standardized Greene Questionnaire, showed similar improvement. Two markers of CVD risk, the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol and homocysteine, showed modest improvement. A proposed marker of breast cancer risk, the ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone, also showed a statistically significant improvement. CONCLUSIONS: The results of this pilot trial suggests that this combination isoflavone nutritional supplement may significantly relieve the most troubling symptoms of menopause, as well as confer some chemopreventive and cardioprotective benefits.
Assuntos
Suplementos Nutricionais , Fogachos/tratamento farmacológico , Isoflavonas/administração & dosagem , Menopausa/efeitos dos fármacos , Fitoestrógenos/administração & dosagem , Trifolium , Adulto , Neoplasias da Mama/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Comportamento Alimentar , Feminino , Fogachos/prevenção & controle , Humanos , Pessoa de Meia-Idade , Fitoterapia , Projetos Piloto , Extratos Vegetais/administração & dosagem , Qualidade de Vida , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
Production of eukaryotic ribosomal RNAs (rRNAs) entails sequence-specific recognition of regulatory sequences in the rRNA gene promoter. A putative subunit of the Schizosaccharomyces pombe essential transcription initiation factor for rRNA synthesis has been identified that shares homology with both murine TAF(I)68 and Saccharomyces cerevisiae Rrn7p, subunits of their species' transcription initiation factor. Affinity purified putative SpRrn7h and associated factors, including a putative Rrn11p homolog, SpRrn11h, bear RNA polymerase I transcription initiation factor activity, and recombinant SpRrn7h associates with S. pombe core rDNA promoter sequences. In the first widespread search for putative homologs of SpRrn7h/murine TAF(I)68, and SpRrn11h/murine TAF(I)48, multiple ones were identified across eukaryotes. Analysis of residues conserved between the fission yeast and murine essential initiation factor subunits aided in these identifications. Sequences in the core rRNA gene promoter contributing to transcriptional activation were investigated, including a perfect TATAAA element located at -35.
Assuntos
Proteínas Fúngicas/genética , Proteínas Pol1 do Complexo de Iniciação de Transcrição , Proteínas de Saccharomyces cerevisiae , Schizosaccharomyces/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , DNA Fúngico/genética , DNA Ribossômico/genética , DNA Ribossômico/metabolismo , Proteínas Fúngicas/metabolismo , Genes de RNAr/genética , Mamíferos/genética , Dados de Sequência Molecular , Mutação , Testes de Precipitina , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas de Schizosaccharomyces pombe , Deleção de Sequência , Homologia de Sequência de Aminoácidos , TATA Box/genética , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição , Transcrição Gênica , Técnicas do Sistema de Duplo-HíbridoRESUMO
OBJECTIVE: We investigated whether a reduced iso-α acid derived from an extract of Humulus lupulus L., META060, had an effect on weight gain, body composition, and metabolism in a high-fat-diet (HFD) fed mouse model. METHODS: Weight gain was monitored for up to 20 wk in mice receiving a low-fat diet, an HFD, or an HFD supplemented with META060 or rosiglitazone. Body composition was determined using dual-energy x-ray absorptiometric analysis. Indirect calorimetric measurements were performed to investigate the energy balance in the mice, and oral glucose tolerance tests were administered to examine the effect of META060 on the glycemic response. RESULTS: The HFD-fed mice administered META060 for 14 wk had a significantly lower mean weight than HFD-fed mice (30.58 ± 0.5 versus 37.88 ± 0.7 g, P < 0.05). Indirect calorimetric measurements showed an increased metabolic flexibility in mice supplemented with META060. In addition, glucose tolerance was improved, comparable to the effects of rosiglitazone treatment. CONCLUSIONS: META060 has potential therapeutic value for managing obesity and insulin resistance, and further research into the mechanism of action is warranted.
Assuntos
Humulus , Resistência à Insulina , Obesidade/prevenção & controle , Animais , Composição Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Teste de Tolerância a Glucose , Humulus/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Rosiglitazona , Tiazolidinedionas/farmacologiaRESUMO
Niacin favorably modifies cardiovascular risk factors but is associated with flushing and shows limited benefit in improving endothelial function. We investigated whether combining anti-inflammatory tetrahydro-iso-alpha acids (THIAA) from hops with niacin would improve endothelial function. We hypothesized that the THIAA+niacin combination would demonstrate benefits not seen with niacin alone. In an in vitro model, a THIAA+niacin mixture inhibited several TNF-α-induced cytokines in human aortic endothelial cells and in human monocytic cells and was significantly more efficacious than niacin alone. Subsequently, the effect of 125 mg THIAA and 500 mg niacin on endothelial-regulated flow-mediated vasodilation (FMD) was explored in a pilot study of 11 dyslipidemic volunteers. The 12-week treatment (2 tablets/day) resulted in a clinically relevant FMD increase compared to a trend toward an FMD decrease with placebo; the between-arm difference was statistically significant. THIAA+niacin treatment also improved total cholesterol, low-density lipoprotein cholesterol, and uric acid. No significant improvement in these parameters was observed with placebo. High-sensitivity C-reactive protein was significantly increased only in the placebo arm. Nutritional support with a THIAA+niacin combination may provide benefits for endothelial function in those with dyslipidemia.
La niacina modifica favorablemente los factores de riesgo cardiovascular pero se asocia con la rubefacción y presenta un beneficio escaso en la mejora de la función endotelial. Investigamos si la combinación de ácidos tetrahidro-iso-alfa (tetrahydro-iso-alpha acids, THIAA) de lúpulo antiinflamatorios con niacina mejoraría la función endotelial. Planteamos la hipótesis de que la combinación THIAA-niacina revelaría beneficios no observados con la monoterapia de niacina. En un modelo in vitro, una mezcla de THIAA-niacina inhibió varias citocinas inducidas por el TNF-α en células endoteliales aórticas humanas y en monocitos THP-1; asimismo, esta combinación resultó significativamente más eficaz que la monoterapia de niacina. Posteriormente, en un estudio preliminar de 11 voluntarios con dislipidemia, se estudió el efecto de 125 mg de THIAA y 500 mg de niacina sobre la vasodilatación regulada por el endotelio en respuesta al flujo (VRF). El tratamiento de 12 semanas (2 comprimidos/día) provocó un aumento clínicamente relevante de la VRF, en comparación con la tendencia a la disminución de la VRF observada con el placebo; la diferencia entre grupos fue estadísticamente significativa. Asimismo, el tratamiento con THIAA-niacina mejoró los niveles de colesterol total, de colesterol unido a lipoproteínas de baja densidad y de ácido úrico. No se observaron mejoras significativas de estos parámetros con el placebo. Se detectó un aumento significativo de proteína C reactiva únicamente en el grupo que recibió el placebo. Es posible que los complementos nutricionales y la combinación de THIAA-niacina proporcionen efectos beneficiosos sobre la función endotelial en pacientes con dislipidemia.
RESUMO
BACKGROUND: Cytokine-induced monocyte-endothelial interaction and vascular inflammation play a critical role in atherogenesis. A modified hop extract, META060, was identified as an inhibitor of inflammatory mediators in human rheumatoid arthritis synovial fibroblasts. OBJECTIVE: To determine how META060 may impact the initial stages of atherosclerosis, we investigated the effects of META060 in endothelial and monocyte cell models. METHODS: and results: TNF-α (10 ng/mL)-activated human monocytic THP-1 cells adhered to human aortic endothelial cells (HAECs); pre-treatment of cells with META060 (10 µg/mL) significantly inhibited cell adhesion. META060 (1-20 µg/mL) inhibited TNF-α-induced expression of inflammatory mediators including IL-1ß, MCP-1 and RANTES in HAECs and THP-1 cells. TNF-α- or LPS-mediated MMP-9 protein levels (measured by an immunoassay) and enzyme activity (determined by zymography) were inhibited by META060 in a dose-dependent manner. Data from transcription factor screening assays showed that META060 selectively inhibited NF-κB and AP-1 in THP-1 cells, suggesting that META060 regulated inflammatory markers through gene regulation. CONCLUSION: META060 inhibited monocyte-endothelial cell interactions and suppressed multiple biomarkers of inflammation in both a monocytic cell line and an endothelial cell line. MMP-9 expression and activity also were inhibited. These effects resulted in part from META060's inhibition of transcription factors NF-κB and AP-1. META060 may have beneficial effects for prevention or treatment of cardiovascular diseases by ameliorating inflammation and plaque destabilization, which are hallmarks of atherosclerosis.
Assuntos
Anti-Inflamatórios/farmacologia , Comunicação Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Humulus , Mediadores da Inflamação/antagonistas & inibidores , Inibidores de Metaloproteinases de Matriz , Monócitos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/farmacologia , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Anti-Inflamatórios/isolamento & purificação , Aterosclerose/enzimologia , Aterosclerose/imunologia , Aterosclerose/prevenção & controle , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Regulação para Baixo , Células Endoteliais/enzimologia , Células Endoteliais/imunologia , Humanos , Humulus/química , Inflamação/enzimologia , Inflamação/imunologia , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Monócitos/enzimologia , Monócitos/imunologia , NF-kappa B/metabolismo , Extratos Vegetais/isolamento & purificação , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
Rho iso-alpha acids-rich extract (RIAA) from Humulus lupulus (hops) and proanthocyanidins-rich extracts (PAC) from Acacia nilotica exert anti-inflammatory and anti-diabetic activity in vitro and in vivo. We hypothesized that a combination of these two extracts would exert enhanced effects in vitro on inflammatory markers and insulin signaling, and on nonfasting glucose and insulin in db/db mice. Over 49 tested combinations, RIAA:PAC at 5:1 (6.25 µg/mL) exhibited the greatest reductions in TNFα-stimulated lipolysis and IL-6 release in 3T3-L1 adipocytes, comparable to 5 µg/mL troglitazone. Pretreatment of 3T3-L1 adipocytes with this combination (5 µg/mL) also led to a 3-fold increase in insulin-stimulated glucose uptake that was comparable to 5 µg/mL pioglitazone or 901 µg/mL aspirin. Finally, db/db mice fed with RIAA:PAC at 5:1 (100 mg/kg) for 7 days resulted in 22% decrease in nonfasting glucose and 19% decrease in insulin that was comparable to 0.5 mg/kg rosiglitazone and better than 100 mg/kg metformin. RIAA:PAC mixture may have the potential to be an alternative when conventional therapy is undesirable or ineffective, and future research exploring its long-term clinical application is warranted.
RESUMO
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.
Assuntos
Osso e Ossos/efeitos dos fármacos , Suplementos Nutricionais , Síndrome Metabólica/complicações , Osteoporose Pós-Menopausa/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , Vitaminas/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Berberina/farmacologia , Berberina/uso terapêutico , Biomarcadores/sangue , Osso e Ossos/metabolismo , Colecalciferol/farmacologia , Colecalciferol/uso terapêutico , Colágeno Tipo I/sangue , Feminino , Humanos , Humulus , Fator de Crescimento Insulin-Like I/metabolismo , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Osteocalcina/sangue , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/etiologia , Extratos Vegetais/farmacologia , Método Simples-Cego , Vitamina D/análogos & derivados , Vitamina D/sangue , Vitamina K 1/farmacologia , Vitamina K 1/uso terapêutico , Vitaminas/farmacologiaRESUMO
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.
RESUMO
Numerous botanicals are purported to improve glucose metabolism and diabetic risk factors with varying degrees of supportive evidence. We investigated 203 commercially available botanical products representing 90 unique botanical species for effects on lipogenic activity in differentiating 3T3-L1 adipocytes. Anti-inflammatory activity of 21 of these products was further assessed in tumor necrosis factor alpha (TNFalpha)-stimulated, mature 3T3-L1 adipocytes. From these results, rho-isoalpha acids, Acacia nilotica bark, fennel, and wasabi were tested in the db/db mouse model. Fifty-nine percent of the 90 unique botanicals increased adipogenesis as did the standard troglitazone relative to the solvent controls. Botanical species with the greatest percentage of positive products were Centella asiatica, Panax quinquefolius, and Phyllanthus amarus at 100%, Vitis vinifera at 80%, Humulus lupulus at 71%, Aloe barbadensis at 66%, and Momordica charantia, Phaseolus vulgaris, and Punica granatum at 60%. All 21 subset samples inhibited TNFalpha-stimulated free fatty acid release and attenuated TNFalpha inhibition of adiponectin secretion. Both rho-isoalpha acids and A. nilotica reduced nonfasting glucose in the db/db mouse model, whereas A. nilotica also decreased nonfasting insulin levels. A post hoc analysis of the screening results indicated that the positive predictive value of the lipogenesis assay alone was 72%, while adding the criterion of a positive response in the anti-inflammatory assays increased this figure to 82%. Moreover, this large-scale evaluation demonstrates that antidiabetic, in vitro efficacy of botanicals is more a function of manufacturing or quality control differences than the presence of marker compounds and further underscores the need to develop functional as well as analytical bases for standardization of dietary supplements.
Assuntos
Adipócitos/efeitos dos fármacos , Diabetes Mellitus/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Extratos Vegetais/farmacologia , Plantas/química , Células 3T3-L1 , Adipócitos/imunologia , Adipócitos/fisiologia , Adipogenia/efeitos dos fármacos , Animais , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Obesos , Extratos Vegetais/administração & dosagem , Fator de Necrose Tumoral alfa/imunologiaRESUMO
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.