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    • 专利摘要:
    THERAPEUTIC USE OF CHARDONNAY SEED PRODUCTS. The present description refers to the health benefits of Chardonnay seed products.
    公开号:BR112014026926B1
    申请号:R112014026926-2
    申请日:2013-04-29
    公开日:2021-03-09
    发明作者:Torey James Arvik；Rebecca Susan Lipson；Wallace H. Yokoyama
    申请人:Sonomaceuticals, Llc；THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by THE SECRETARY OF AGRICULTURE；
    IPC主号:
    专利说明:

    1. BACKGROUND OF THE INVENTION 1.1 Metabolic conditions
    [0001] Obesity is a well-known risk factor for the development of many very common diseases, such as atherosclerosis, hypertension, type 2 diabetes ((non-insulin dependent diabetes mellitus (DMNDI)), dyslipidemia, coronary heart disease, osteoarthritis and various malignancies.It also causes considerable problems by reducing motility and decreasing quality of life.The incidence of obesity and, through it, also of these diseases, is increasing throughout the industrialized world.
    [0002] The term obesity implies an excess of adipose tissue. In this context, obesity is best viewed as any degree of excess adiposity that confers a health risk. The cutoff point between normal and obese individuals can only be approximated, but the risk to health transmitted by obesity is probably a continuity with the increase in adiposity.
    [0003] Even mild obesity increases the risk of premature death and diseases such as diabetes, dyslipidemia, hypertension, atherosclerosis, gallbladder disease and certain types of cancer. In the western industrialized world, the prevalence of obesity has increased significantly in recent decades. Due to the high prevalence of obesity and its health consequences, its prevention and treatment must be a high public health priority.
    [0004] When energy consumption exceeds expenditure, excess calories are stored predominantly in the adipose tissue, and if this net positive balance is prolonged, it results in obesity, that is, there are two components to the weight balance, and one abnormality on both sides (consumption or expenditure) can lead to obesity. This process can be neutralized by increasing energy expenditure (for example, through exercise) or by decreasing energy consumption (for example, through diet). Except for exercise, diet and food restriction, which is not feasible for a large number of individuals, no convincing treatment to reduce body weight in an effective and acceptable way exists today.
    [0005] A possible way to increase energy expenditure is by increasing the metabolic rate. The agents that act by increasing the metabolic rate can, therefore, be useful to treat obesity, but also for the treatment of other conditions, such as atherosclerosis, hypertension, diabetes, especially type 2 diabetes (non-insulin dependent diabetes mellitus (NIDDM) )), dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer, such as endometrial, breast, prostate and colon cancer and the risk of premature death.
    [0006] Thus, it would be desirable to identify agents that can increase energy expenditure. Preferably, such agents would be natural agents that avoid the adverse effects associated with pharmaceutical compounds. 1.2 Intestine Biome
    [0007] The infant intestine is sterile before birth. After birth, the intestine is rapidly colonized by environmental bacteria until a dense biome of the intestine is established. Infants born by normal birth acquire bacteria that colonize the intestine of their mother's vaginal and fecal flora. In contrast, infants who are born by caesarean section are not exposed to their mother's vaginal and fecal flora during delivery and thus develop an intestine biome that is different in the composition of the intestine biome of normally-born infants. These differences in the composition of the gut biome persist in the months immediately after birth. Likewise, differences in the composition of the gut biome have been observed between infants who are breastfed and those who are fed formulas.
    [0008] The adult human intestine has about 1013 (10,000,000,000,000) individual residents (Backhead, F., et al. (2004) PNAS Volume 101; no 44 pp 15718-152323) and there are three consistent enterotypes established across from many human cultural backgrounds (Arumugam, M. et al., (2011) Nature Vol. 473 pp. 174-180). The gut biome is influenced by plant-based polyphenols in the diet, and it is believed that microorganisms convert them to be bioavailable for the human host (Rastmanesh, R. (2011), Chemico-Biol. Interact. Vol. 189 pp.1- 8; Moco, S., FJ Martin, and S. Rezzi (2012) J. Proteome Res Volume 11, pp 4781-4790). Acting as an organ, the gut biome is also responsible for the conversion and production of essential vitamins, such as cholecalciferol (vitamin D25), biotin (vitamin H), riboflavin (vitamin B2), pantothenate (vitamin B5), ascorbate (vitamin C ), thiamine (vitamin B1) and folate (vitamin B9); particularly in two (Bacteroides and Prevotella) of the three enterotypes (Bacteroides, Ruminococcus, and Prevotella) discovered. Some polyphenols have been described as vitamins in their own right by Dr. Norman Hollenberg, professor of medicine at Harvard Medical School. However, modern diets, particularly Western diets, comprise large amounts of processed foods, and can promote a composition of the gut biome that fails to convert or produce adequate or ideal amounts of these essential vitamins.
    [0009] Thus, it would be desirable to identify agents that can “fill nutritional gaps” caused by the consumption of traditionally processed foods and modulate the human gut biome to achieve improved health. Preferably, such agents would be natural agents that prevent the side effects associated with pharmaceutical compounds. 2. SUMMARY OF THE INVENTION
    [0010] The present description refers to the health benefits of Chardonnay seed products.
    [0011] In certain respects, the present description relates to a method for increasing lipid metabolism in a mammal by administering to the mammal an effective amount of Chardonnay seed product to increase lipid metabolism in mammals.
    [0012] In certain respects, the present description relates to a method of increasing the metabolic rate in a mammal by administering an amount of Chardonnay seed product effective to increase the mammal's metabolic rate.
    [0013] The present invention also relates to a method for treating or preventing obesity, cardiovascular disease, dyslipidemia, dyslipoproteinemia or a disorder of glucose metabolism in a mammal by administering to a mammal a quantity of product of Chardonnay seed effective to treat or prevent obesity in the mammal.
    [0014] The present description further relates to a method of treating or preventing cardiovascular disease in a mammal by administering to a mammal an amount of Chardonnay seed product effective to treat or prevent said cardiovascular disease. In certain aspects, cardiovascular disease is arteriosclerosis, atherosclerosis, stroke, ischemia, endothelial dysfunction, peripheral vascular disease, coronary heart disease, myocardial infarction, cerebral infarction or restenosis.
    The present invention further relates to a method of treating or preventing dyslipidemia in a mammal by administering to a mammal an amount of Chardonnay seed product effective to treat or prevent dyslipidemia. In some ways, dyslipidemia is hyperlipidemia or low blood levels of high-density lipoprotein (HDL) cholesterol. In certain aspects, hyperlipidemia is selected from familial hypercholesterolemia, familial combined hyperlipidemia, reduced or deficient levels of lipase lipoprotein, hypertriglyceridemia, hypercholesterolemia, elevated blood levels of ketone bodies, elevated blood levels of Lp (a) cholesterol, levels high blood levels of low density lipoprotein cholesterol (LDL), high blood levels of very low density lipoprotein cholesterol (VLDL), and high blood levels of unesterified fatty acids.
    [0016] The present invention also relates to a method of treating or preventing dyslipoproteinemia in a mammal by administering to a mammal an amount of Chardonnay seed product effective to treat or prevent said dyslipoproteinemia. In certain respects, dyslipoproteinemia is elevated blood levels of LDL, elevated blood levels of apolipoprotein B (apo B), elevated blood levels of Lp (a), elevated blood levels of apo (a), elevated blood levels of VLDL, elevated blood levels low blood levels of HDL, deficient or reduced lipoprotein lipase levels or activity, hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's Disease, or familial combined hyperlipidemia.
    [0017] The present invention further relates to a method for treating or preventing a disorder of glucose metabolism in a mammal by administering to a mammal an amount of Chardonnay seed product effective to treat or prevent said disorder glucose metabolism. In some ways, glucose metabolism disorder is impaired glucose tolerance, insulin resistance, breast-related insulin resistance, colon or prostate cancer, diabetes, pancreatitis, hypertension, polycystic ovarian disease, high insulin levels in the blood or high blood glucose levels. In some respects, diabetes is non-insulin-dependent diabetes mellitus (DMNDI), insulin-dependent diabetes mellitus (DMDI), gestational diabetes mellitus (DMG), or diabetes beginning at a young age (MODY).
    [0018] The description further relates to a method of treating or preventing metabolic syndrome in a mammal by administering to a mammal an amount of Chardonnay seed product effective to treat or prevent metabolic syndrome in the mammal.
    [0019] In certain respects, an amount that is administered is effective in modulating the expression of one or more genes involved in fat, cholesterol, and / or bile metabolism. In specific embodiments, the amount is effective to increase the expression of ACOX1 in the liver tissue, to increase the expression of CYP51 in the liver tissue, to increase the expression of CYP7al in the liver tissue, to decrease the expression of SCD1 in the liver tissue, and / or to decrease the expression of ABCG5 in liver tissue, for example, at least 10%, at least 20%, at least 50%, or at least 100%.
    [0020] The present invention further relates to a method of increasing the amount of Clostridium bacteria in a mammal's intestine by administering to a mammal an amount of Chardonnay seed product effective to increase the amount of Clostridium bacteria in the intestine of the mammal. mammal.
    [0021] The present invention further relates to a method of decreasing the amount of Enterobacteriaceae bacteria in a mammal's intestine by administering to a mammal an amount of Chardonnay seed product effective in decreasing the amount of Enterobacteriaceae bacteria in the intestine of the mammal.
    [0022] The present invention also relates to a method of increasing the amount of bacteria of the group Bacteroides fragilis in the gut of a mammal by administering to a mammal an amount of Chardonnay seed product effective to increase the amount of bacteria in the mammal. Bacteroides fragilis group in the intestine of the mammal.
    [0023] The present invention further relates to a method of treating or preventing lactic acidosis in a mammal by administering to a mammal an amount of Chardonnay seed product effective to treat or prevent lactic acidosis.
    [0024] In certain methods, a second grape seed or grape skin product that is not a Chardonnay seed product is administered to the mammal. In certain respects, the combination of Chardonnay seed product and second grape seed or grape skin product provides a therapeutic effect or health benefit that is greater than the effect of administering only the Chardonnay seed product .
    [0025] In certain respects, the Chardonnay seed product is prepared from seeds that have an epicatechin content of at least 600 mg of epicatechin per 100 g of seeds, or an epicatechin content of at least 700 mg of epicatechin per 100 g of seeds. In specific embodiments, the epicatechin content ranges from 600 to 800 mg / 100 g of seeds or from 650 to 800 mg / 100 g of seeds.
    [0026] In certain embodiments, the Chardonnay seed product is incorporated into a food or drink product.
    [0027] In certain embodiments, the Chardonnay seed product is Chardonnay seed flour. In certain embodiments, the Chardonnay seed product is Chardonnay seed extract. In certain embodiments, the Chardonnay seed product is from grapes grown in a type I, II, III or IV climate in the Winkler region.
    [0028] In certain modalities, the mammal is a domestic animal, for example, a cat or a dog. In other methods, the mammal is a human being. In other modalities, the human being is an infant.
    [0029] The present invention also relates to an infant formula comprising a Chardonnay seed product and methods of using the infant formula to promote the development of the intestinal microbiome in an infant. In certain respects, the infant formula promotes the development of the intestinal microbiota when administered to an infant by modulating the levels of intestinal bacteria. In certain modalities, the infant was born by caesarean section. In certain modalities, the infant is fed by formula. 3. BRIEF DESCRIPTION OF THE FIGURES
    [0030] FIGURE 1: protein, fat, ash, carbohydrates and total dietary fiber content of seeds (Sd) and husks (Sk) from Chardonnay (Chr), Cabernet (Cab) and Syrah (Syr).
    [0031] FIGURE 2: Composition of the hamsters diet in Example 1.
    [0032] FIGURE 3: Body weight of diets with seeds per week of the animals of Example 1.
    [0033] FIGURE 4: Body weight of diets with shells per week of the animals of Example 1.
    [0034] FIGURE 5: Weekly feed consumption of the animals in Example 1.
    [0035] FIGURE 6: Total feed consumption of the animals of Example 1.
    [0036] FIGURE 7: Total caloric consumption of the animals in Example 1.
    [0037] FIGURE 8: Plasma levels of lipoprotein cholesterol from animals of Example 1 at the end of four weeks.
    [0038] FIGURE 9: Blood glucose levels of the animals of Example 1 at the end of four weeks.
    [0039] FIGURE 10: Organ weights of the animals of Example 1 at the end of four weeks.
    [0040] FIGURE 11: Epicatechin levels in the seed and skin of different grape varieties.
    [0041] FIGURE 12: Body weight, weight gain and total feed consumption of the animals in the diets of Example 2 comprising 3%, 7% and 10% of Chardonnay seed meal by weight.
    [0042] FIGURE 13: VLDL, LDL, HDL and cholesterol levels of animals in Example 2 fed with Chardonnay seed ethanolic extract (40EtChrSdEx), Chardonnay seed methanolic extract (MeChrSdEx), residue from ethanolic seed extract of Chardonnay (40EtChrSdRes), residue from methanolic extract of Chardonnay seeds (MeChrSdRes), Chardonnay seed flour at 10%, 7% and 3% by weight of the diet (10% ChrSd, 7% ChrSd, and 3% ChrSd, respectively ), 10% White Riesling seed meal by weight of the diet (10% WRSd), and 10% Sauvignon Blanc seed meal by weight of the diet (10% SBSD) at the end of four weeks.
    [0043] FIGURE 14: LDL / HDL cholesterol ratio of animals from Example 2 fed with Chardonnay ethanol extract (40EtChrSdEx), Chardonnay methanol extract (MeChrSdEx), Chardonnay ethanol extract residue (40EtChrSdRes) , Chardonnay seed methanol extract residue (MeChrSdRes), Chardonnay seed flour at 10%, 7% and 3% by weight of the diet (10% ChrSd, 7% ChrSd, and 3% ChrSd, respectively), 10% of White Riesling seed flour by weight of the diet (10% WRSd), and 10% of Sauvignon Blanc seed flour by weight of the diet (10% SBSD) at the end of four weeks.
    [0044] FIGURE 15: Weights of the Liver, Epididymal Adipose (EA), and Retroperitoneal Adipose (AR) of the animals of Example 2 fed with ethanolic extract of Chardonnay seeds (40EtChrSdEx), methanolic extract of Chardonnay seeds (MeChrSdEx), residue of Chardonnay seed ethanolic extract (40EtChrSdRes), Chardonnay seed methanolic extract residue (MeChrSdRes), Chardonnay seed flour at 10%, 7% and 3% by weight of the diet (10% ChrSd, 7% ChrSd, and 3% ChrSd, respectively), 10% White Riesling seed meal by weight of the diet (10% WRSd), and 10% Sauvignon Blanc seed meal by weight of the diet (10% SBSD) at the end of four weeks.
    [0045] FIGURE 16: Expression of the relative adipose gene of Example 3.
    [0046] FIGURE 17: Expression of the relative hepatic gene of Example 3.
    [0047] FIGURE 18: Total plasma lipoprotein cholesterol levels of animals from Example 4 fed diets supplemented with Chardonnay seed flour (CharSdFl), Vitacost® grape seed extract (VC1 and VC7), Mega Natural® BP grape (BP1, BP7), Leucoselect® grape seed extract (L1, L7), catechin (Cat), and epicatechin (EpiCat) at the end of four weeks.
    [0048] FIGURE 19: VLDL, LDL and HDL cholesterol levels of the animals of Example 4 fed diets supplemented with Chardonnay seed flour (CharSdFl), Vitacost® grape seed extract (VC1 and VC7), Mega Natural® BP grape (BP1, BP7), Leucoselect® grape seed extract (L1, L7), catechin (Cat), and epicatechin (EpiCat) at the end of four weeks.
    [0049] FIGURE 20: Total levels of fecal bacteria from the animals of Example 5 fed a control diet, a high fat diet supplemented with Cabernet seed flour (RGF + HF), a high fat diet supplemented with seed meal Chardonnay (WGF + HF), and high-fat control diet (HF).
    [0050] FIGURE 21: Levels of Enterococcus spp. of animals in Example 5 fed a control diet, a high fat diet supplemented with Cabernet seed flour (RGF + HF), a high fat diet supplemented with Chardonnay seed flour (WGF + HF), and a control diet high in fat (HF).
    [0051] FIGURE 22: Levels of Bifidobacterium spp. of animals in Example 5 fed a control diet, a high fat diet supplemented with Cabernet seed flour (RGF + HF), a high fat diet supplemented with Chardonnay seed flour (WGF + HF), and a control diet high in fat (HF).
    [0052] FIGURE 23: Levels of Lactobacillus spp. of animals in Example 5 fed a control diet, a high fat diet supplemented with Cabernet seed flour (RGF + HF), a high fat diet supplemented with Chardonnay seed flour (WGF + HF), and a control diet high in fat (HF).
    [0053] FIGURE 24: Levels of Clostridium bacteria from Group IV of Example 5 animals fed a control diet, a high-fat diet supplemented with Cabernet seed flour (RGF + HF), a high-fat diet supplemented with flour Chardonnay seed (WGF + HF), and high-fat control diet (HF).
    [0054] FIGURE 25: Levels of bacteria from the Bacteroides fragilis group of animals in Example 5 fed a control diet, a diet rich in fat supplemented with Cabernet seed flour (RGF + HF), a diet rich in fat supplemented with flour Chardonnay seed (WGF + HF), and high-fat control diet (HF).
    [0055] FIGURE 26: Enterobacteriaceae levels of animals of Example 5 fed a control diet, a high-fat diet supplemented with Cabernet seed flour (RGF + HF), a high-fat diet supplemented with Chardonnay seed flour ( WGF + HF), and high-fat control diet (HF). 4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Chardonnay Seed Products
    [0056] The present invention relates to Chardonnay seed products and methods of treating or preventing obesity and other conditions using Chardonnay seed products. Preferably, Chardonnay seed products are produced from grapes grown in the climates of the Winkler region types I to IV (Jones et al., 2010, J. Am Enol Vitic 61 (3): 313-326). In some embodiments, Chardonnay seed products are produced from grapes grown in the northern California coastal valleys, for example, the Napa Valley and / or the Sonoma Valley. In another embodiment, the Chardonnay seed products are produced from grapes grown in other warmer vineyards in the interior valley, for example, in the climates of the Winkler region types IV to V. In a preferred embodiment, the seed product de Chardonnay is from grapes in a coastal area.
    [0057] In one embodiment, Chardonnay seed products contain the defatted portion of Chardonnay seed, such as Chardonnay bagasse meal, Chardonnay bagasse flour, Chardonnay seed meal, or, more preferably, Chardonnay seed meal. Chardonnay seed. In some embodiments, the Chardonnay seed product includes the content of defatted Chardonnay seeds that are not extracted by an organic solvent, for example, are not extractable by ethanol and / or methanol. In certain respects, the Chardonnay seed product is prepared from seeds that have an epicatechin content of at least 600 mg of epicatechin per 100 g of seeds or an epicatechin content of at least 700 mg of epicatechin per 100 g of seed. seeds. In specific embodiments, the epicatechin content ranges from 600 to 800 mg / 100 g of seeds or 650 to 800 mg / 100 g of seeds.
    [0058] As used herein, "Chardonnay seed meal" is whole ground seeds and "Chardonnay seed meal" is the seed ground after the oil has been extracted. Chardonnay seed flour can be obtained using "cold pressing", "hot pressing" and solvent extraction processes as are known in the art, to extract oil from the seeds yielding defatted seed flour. The meal or flour can be dried to the desired moisture content, using conventional drying techniques suitable for drying food products.
    [0059] The meal or dry flour is further milled under ambient temperature conditions to form Chardonnay seed powder with free flowing particles. In one embodiment, the free flowing particles can vary from a size not exceeding 841 microns (20 mesh) to a size not exceeding 37 microns (400 mesh). In certain embodiments, the size does not exceed 20 mesh, 40 mesh, 60 mesh, 80 mesh, 100 mesh, 200 mesh, 300 mesh, or 400 mesh.
    [0060] In an exemplary method, Chardonnay seed flour is made by separating and drying Chardonnay grape seeds, for example, from the bagasse produced after Chardonnay grapes are pressed to produce grape juice (for example , to make wine). Grape seeds can be "cold pressed" to degrease them (producing Chardonnay seed oil as a by-product). Grape seed flours are ground from the press cake after the oil has been expelled. In one embodiment, after the production of grape juice, the seed is separated from the skins, cleaned, mechanically degreased, finely ground and sieved to create a 100 mesh (150 micron) fluid powder.
    [0061] Chardonnay seed flour can also be purchased from Apres Vin (Yakima, Washington), Botanical Oil Innovations (Spooner, Wisconsin) or Fruitsmart, Inc. (Grandview, Washington). FruitSmart's Chardonnay seed flour is a fluid 85 mesh powder, but it can still be ground and sieved to produce a flour with a smaller particle size.
    [0062] In one embodiment, bark, stems and leaves (the remainder of the bagasse) are removed from the seeds before pressing. Removing the bark, stems and leaves allows for the ideal pressing of oil.
    [0063] "Chardonnay seed extract" is made by solvent extraction of Chardonnay seeds with a suitable solvent, such as ethanol or methanol. For example, “40EtChrSdEx” is a Chardonnay seed extract made using a 40% ethanol solution as an extraction solvent. The extraction process, in addition to the extract containing the components soluble in solvents, also produces a residue of non-soluble solids. 4.2 Effective quantity
    [0064] In one embodiment of the methods of the invention, the amount of Chardonnay seed meal consumed as a percentage of the daily diet is at least 3%, at least 5%, or at least 8% by weight. Preferably 5 to 10%, more preferably 7%, and in some embodiments 10% of the daily bulk diet is Chardonnay seed flour.
    [0065] In one embodiment of the methods of the invention, the amount of Chardonnay seed meal consumed as a percentage of the daily diet is at least 3%, at least 5%, or at least 8% of the total calories consumed. Preferably from 5 to 10%, more preferably 7%, and in some embodiments, 10% of the daily diet is from Chardonnay seed flour.
    [0066] In another embodiment, the amount of Chardonnay seed meal consumed daily is at least 10 g, at least 15 g, at least 20 g, at least 25 g, at least 30 g, at least 35 g, at least 40 g, or at least minus 45g. Preferably, 50 g of Chardonnay seed flour is consumed daily.
    [0067] In another embodiment, the amount of Chardonnay seed meal consumed daily is at least 1 tablespoon, at least 2 tablespoons, at least 3 tablespoons, at least 4 tablespoons, or at least 5 tablespoons.
    [0068] In another modality, the amount of Chardonnay seed meal consumed daily in a Chardonnay seed meal ratio: body weight basis is at least 0.2 g / kg, at least 0.5 g / kg, or at least 0.7 g / kg. Preferably at least 1 g of Chardonnay seed meal per kg of body weight is consumed per day.
    [0069] In certain respects, an amount of Chardonnay seed meal that is administered is effective in modulating the expression of one or more genes involved in the metabolism of fat, cholesterol, and / or bile. In specific embodiments, the amount is effective for increasing the expression of ACOX1 in liver tissue, for increasing the expression of CYP51 in liver tissue, for increasing the expression of CYP7al in liver tissue, for decreasing the expression of SCD1 in liver tissue, and / or to decrease the expression of ABCG5 in liver tissue, for example, at least 10%, at least 20%, at least 50%, or at least 100%.
    [0070] Chardonnay seed flour can be replaced with Chardonnay bagasse meal, bagasse meal, bark flour, seed extract, or seed meal in the methods of the invention. The amount of meal meal of Chardonnay meal, meal of meal, bark meal, seed extract, or meal of meal that will have to be consumed daily to achieve the same benefits as a given amount of meal of Chardonnay meal can be readily determined by technicians specialized in the subject. For example, it is expected that an individual will need to consume about three times as much as Chardonnay husk flour to achieve the same benefits as a given amount of Chardonnay seed meal.
    [0071] In certain embodiments, the Chardonnay seed product, for example, Chardonnay seed flour is taken at least twice a week, at least 3 times a week, or every other day. Preferably, the Chardonnay seed product is incorporated into the daily diet.
    [0072] The Chardonnay seed product, for example, the Chardonnay seed flour, can be taken for an amount of time sufficient to treat and / or prevent a condition susceptible to treatment and / or prevention of the Chardonnay seed product, such as as described here. The Chardonnay seed product can be taken for at least one week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least one year, or indefinitely.
    [0073] In certain methods, a second grape seed or grape skin product that is not a Chardonnay seed product is administered to the mammal. In certain respects, the combination of Chardonnay seed product and second grape seed or grape skin product provides a therapeutic effect or health benefit that is greater than the effect of administering only the Chardonnay seed product .
    [0074] In other modalities, the quantity of Chardonnay seed product and the quantity of the second grape seed or grape skin product are selected so that the effect achieved is at least the same as the effect achieved by a given amount of Chardonnay seed product administered alone. 4.3 Chardonnay Seed Compositions
    [0075] Chardonnay seed products can be included in a variety of food products, such as nutritional drinks (for example, nutritional shakes), bakery products (for example, cookies, brownies, cakes, breads, cookies, crackers) , puddings, confectionery (ie sweets), snacks (for example, pretzels), ice cream, frozen and fresh, or un-baked sweets, extruded food products such as bars, including diet or energy bars. The Chardonnay seed product can also be supplied as a nutritional supplement, either in tablet form or in powder form for use as a nutritional food additive.
    [0076] In one embodiment, the Chardonnay seed product can be mixed with other dry food materials for use in the preparation of food products enriched with Chardonnay seed products. Dry food materials include, for example, dry materials that contain starch, dry materials that contain proteins or combinations thereof. Suitable starch-containing materials can be derived from, for example, rice, corn, soy, sunflower, canola, wheat, oats, rye, potatoes, or any combination thereof. Suitable dry materials that contain proteins can be derived from, for example, meat, milk, fish, or any combination thereof. For bakery applications, the Chardonnay seed product used in an amount ranging from 3% to 15% of the dry feed material (for example, white or whole wheat flour). The dry food can optionally also include additional ingredients, such as vitamins, fortifying minerals, salts, colors, flavors, flavor enhancers or sweeteners.
    [0077] Chardonnay seed products can be incorporated into beverages, processed meats, frozen desserts, confectionery, dairy products, gravy compositions, and cereal grain products. Drinks include, for example, smoothies, infant formulas, fruit juice drinks, yogurt drinks, coffee drinks, beer, dry beverage mixes, tea fusion drinks, sports drinks, soy liqueurs, soft drinks, granites and mixtures of cold drinks. Meat products include, for example, ground chicken products, ham products with added water, bologna, hot dogs, franchises, chicken patties, chicken nuggets, meat patties, fish patties, surimi, bacon, beef. lunch, sandwich fillings, cold cuts, meat snacks, meatballs, dried meat, fajitas, pieces of bacon, injected meats, and bratwurst. Confectionery products include, for example, chocolates, mousses, chocolate toppings, yogurt coatings, cocoa, toppings, sweets, energy bars and chocolate bars. Frozen dessert products include, for example, ice cream, malts, shakes, popsicles, sorbets, and frozen pudding products. Dairy products include, for example, yogurt, cheese, ice cream, whipped topping, coffee cream, cream cheese, sour cream, cottage cheese, butter, mayonnaise, milk-based sauces, milk-based salad dressings and rennet cheese. Products derived from cereal grains include, for example, breads, muffins, bagels, pasties, macaroni, cookies, pancakes, waffles, cookies, semolina, chips, tortillas, cakes, cookies, breakfast cereals (including both ready-to-eat cereals) -to-eat and home cooked), pretzels, dry bakery mixes, toast, bread sticks, croutons, fillings, energy bars, donuts, cakes, popcorn, tacos, fried coatings, pasta, bread making, crusts, brownies, pies , truffled soy cakes, crepes, croissants, flour, and polenta. Dressing compositions include salads, nut butter spread (for example, peanut butter spread), marinades, sauces, parsley, jam, cheese sauces, mayonnaise, tartar sauce, soy humus, pastes, fruit syrups and maple syrups. The dressing composition may also include a suspending agent to help maintain uniformity of the composition. Examples of suitable suspending agents include polysaccharides, such as starch, cellulose (for example, microcrystalline cellulose) and carrageenan, and polyuronides, such as pectin. Gelatin is another example of a suspending agent that can also be used in beverage compositions. Examples of additional supplemented food products prepared using premixes according to the invention include tofu, formulated soy essence, powdered protein supplements, mixable juice protein supplements, foaming agents, clouding agents, infant foods, meatballs meatless, meat substitutes, egg products (eg scrambled eggs), soups, stews, broths, alternatives to milk, soy milk products, pepper, spice mixes, starch, soy whiz, salad dressing, edible films, edible sticks, chewing gum, bacon pieces, veggie pieces, pizza crust barriers, soy pie, non-synthetic beans, soy aids, soy cotton candy, fruit pieces, pizza rolls, puree potatoes, spun soy protein fiber, soy roll-ups, extruded snacks, condiments, lotions, chips, gelatin dessert products, vitamin supplements, nutritional bars, cake dry, mixes of bread or muffins, instant dry mixes for microwaves.
    [0078] In a particular aspect, the Chardonnay seed product can be provided as an energy bar (suitable for consumption during physical activity) or a meal replacement bar. The energy bar or meal replacement bar may also contain one or more vitamins, minerals, food supplements, botanical extracts, or plants or herbs or ingredients known in the art or used in energy bars or meal replacement bars, such as a fruit juice or extract, an herb or herb flavoring, natural or artificial flavorings, vitamins, minerals, extracts containing antioxidants, coenzyme Q, omega-3 fatty acids, guarana, caffeine, theobromine, maltodextrin, and proteins. In some modalities, the energy bar or meal replacement bar may have energy levels available in the total carbohydrate / protein / fat of 40/30/30, respectively.
    [0079] Energy bars and meal replacement can be supplemented to improve athletic performance, mental energy or improve cognitive focus and / or nutritional benefit. Exemplary supplements include, but are not limited to, Vinpocetine, Vincamine Ginkgo Biloba, L-Arginine, Acetyl-L-Carnitine, Feverfew, DMAE (dimethylaminoethanol), DMAE bitartrate, P-chlorophenoxyacetate, Complex B Vitamin, Ginseng, 5-HTP ( 5-Hydroxytryptophan), L-Theanine, Androstenedione, L-Glutamine, L-Tyrosine, L-glycine; L-lysine; Whey protein; DHEA (Dehydroepiandrosterone).
    [0080] In another aspect, the Chardonnay seed product can be supplied in or added to a liquid or powdered infant formula. The infant formula can contain a protein source, a fat source, and / or a carbohydrate source. The protein source can be, for example, liquid or dry cow's milk, buttermilk and / or casein, or soy protein. The fat source can be, for example, milk fat and / or one or more vegetable oils. The carbohydrate source can be, for example, lactose, glucose or sucrose. The infant formula can additionally contain one or more vitamins and / or one or more minerals. In one embodiment, the Chardonnay seed product can be added to a commercially available liquid or powdered infant formula.
    [0081] The composition of the Chardonnay seed may also contain an amount of a second grape seed or grape skin product that is not a Chardonnay seed product. In some embodiments, an amount of Chardonnay seed product is replaced in the Chardonnay seed composition with an amount of the second grape seed or grape skin product. The amount of the grape seed or grape skin product that needs to be added to the Chardonnay seed composition to achieve the same benefits as a given amount of Chardonnay seed product can be readily determined by those skilled in the art. 4.4 Therapeutic Uses of Chardonnay Seed Flour Compositions
    [0082] According to the invention, a composition of the invention comprising a Chardonnay seed meal composition is administered to an individual, preferably a human individual, in which an increase in lipid metabolism is useful or desirable. The individual may be in need of treatment or prevention of cardiovascular disease, dyslipidemia, a disorder of glucose metabolism, Alzheimer's disease, Syndrome X, a disorder associated with PPAR, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, a kidney disease, cancer, inflammation, or impotence.
    [0083] In another aspect of the invention, a composition of the invention comprising a Chardonnay seed meal composition is administered to an individual, preferably a human individual, in which modulation of the gut biome is useful or desirable. In one embodiment, the individual may be in need of treatment or prevention of, for example, lactic acidosis, colitis, or colorectal cancer. In one embodiment, the individual is genetically susceptible to colon cancer.
    [0084] In one embodiment, "treatment" or "treating" refers to an improvement in a disease or disorder, or at least a noticeable symptom thereof. In another modality, "treatment" or "treating" refers to an improvement of at least one measurable physical parameter, not necessarily discernible by the individual. In yet another modality, "treatment" or "treating" refers to inhibiting the progression of a disease or disorder, whether physically, for example, stabilization of a noticeable symptom, physiologically, for example, stabilization of a physical parameter, or both . In yet another modality, "treatment" or "treating" refers to delaying the onset of a disease or disorder.
    [0085] In certain embodiments, the compositions of the invention are administered to an individual, preferably a human, as a preventive measure against such diseases. As used herein, "prevention" or "prevent" refers to a reduction in the risk of contracting a given disease or disorder. In a preferred aspect, the compositions of the present invention are administered as a preventive measure to an individual, preferably a human being with a genetic predisposition to cardiovascular disease, dyslipidemia, dyslipoproteinemia, glucose metabolism disorder, Alzheimer's disease , Syndrome X, a disorder associated with PPAR, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, kidney disease, cancer, inflammation, or impotence. Examples of such genetic predispositions include, but are not limited to, the E4 allele of apolipoprotein E, which increases the risk of Alzheimer's Disease; a loss of function or null mutation in the coding region or promoter of the lipoprotein lipase gene (for example, mutations in the coding regions resulting in D9N and N291S substitutions; for a review of genetic mutations in the lipoprotein lipase gene that increase the risk cardiovascular diseases, dyslipidemias and dyslipoproteinemias, see Hayden and Ma, 1992, Mol. Cell Biochem 113: 171-176); and combined familial hyperlipidemia and familial hypercholesterolemia.
    [0086] In another preferred mode of the embodiment, the compositions of the invention are administered as a preventive measure to an individual who has a non-genetic predisposition to cardiovascular disease, dyslipidemia, dyslipoproteinemia, glucose metabolism disorder, Alzheimer's, Syndrome X, a disorder associated with PPAR, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, a kidney disease, cancer, inflammation, or impotence. Examples of such non-genetic predispositions include, but are not limited to, cardiac bypass surgery and percutaneous transluminal coronary angioplasty, which often lead to restenosis, an accelerated form of atherosclerosis; diabetes in women, which often leads to polycystic ovary disease; and cardiovascular disease, which often leads to impotence.
    [0087] In certain modalities, the mammal consumes a diet rich in fat. In one embodiment, a high-fat diet is a diet in which at least 30%, 35%, or 40% of the total daily calories are obtained from fat.
    [0088] In certain embodiments, a second grape-skin grape seed product that is not Chardonnay seed flour is administered to the mammal to provide an effect that is greater than the effect of administering only seed seed flour. Chardonnay. 4.4.1 Dyslipidemias
    [0089] The present invention provides methods for the treatment or prevention of a dyslipidemia comprising administering to a subject a therapeutically effective amount of a Chardonnay seed meal composition.
    [0090] As used herein, the term "dyslipidemia" refers to disorders that lead to or are manifested by aberrant levels of circulating lipids. As the blood lipid levels are very high, the compositions of the invention are administered to an individual to restore normal levels. Normal levels of lipids are reported in medical treaties known to those skilled in the art. For example, recommended blood levels of LDL, HDL, free triglycerides and other parameters related to lipid metabolism can be found on the websites of the American Heart Association and the National Cholesterol Education Program of the National Heart, Lung and Blood Institute. At the present time, the recommended level of HDL cholesterol in the blood is greater than 35 mg / dL; the recommended level of LDL cholesterol in the blood is less than 130 mg / dL; the proportion of recommended LDL: HDL cholesterol in the blood is less than 5: 1, preferably 3.5: 1; and the recommended level of free triglycerides in the blood is less than 200 mg / L.
    [0091] Dyslipidemias that the Chardonnay seed meal compositions of the present invention are useful for preventing or treating include, but are not limited to, hyperlipidemia and low blood levels of high density lipoprotein (HDL) cholesterol. In certain embodiments, hyperlipidemia for the prevention or treatment by the compounds of the present invention is familial hypercholesterolemia; familial combined hyperlipidemia; deficient or reduced lipoprotein lipase levels or activity, including reductions or deficiencies resulting from mutations in the lipoprotein lipase; hypertriglyceridemia; hypercholesterolemia; elevated blood levels of ketone bodies (eg, butyric acid β-OH); high blood levels of Lp (a) cholesterol; high blood levels of low-density lipoprotein (LDL) cholesterol; high blood levels, very low density lipoprotein (VLDL) cholesterol levels, e); high blood levels of non-esterified fatty acids.
    [0092] The present invention further provides methods for altering lipid metabolism in an individual, for example, reduction of LDL in an individual's blood, reduction of free triglycerides in an individual's blood, increasing the ratio of HDL to LDL in the blood of an individual. an individual, and inhibition of the synthesis of saponified and / or non-saponified fatty acids, said methods comprising administering to the individual a composition of Chardonnay seed flour in an effective amount that alters lipid metabolism. 4.4.2 Cardiovascular Diseases
    The present invention provides methods for treating or preventing cardiovascular disease, comprising administering to a subject a therapeutically effective amount of a Chardonnay seed meal composition. As used herein, the term "cardiovascular disease" refers to diseases of the heart and circulatory system. These diseases are often associated with dyslipoproteinemias and / or dyslipidemias. Cardiovascular diseases in which the compositions of the present invention are useful for preventing or treating include, but are not limited to, arteriosclerosis; atherosclerosis; stroke; ischemia; endothelial dysfunctions, namely dysfunctions that affect the elasticity of blood vessels; peripheral vascular disease; coronary heart disease; myocardial infarction; cerebral infarction and restenosis. 4.4.3 Dyslipoproteinemias
    The present invention provides methods for the treatment or prevention of a dyslipoproteinemia comprising administering to a subject a therapeutically effective amount of a Chardonnay seed meal composition.
    [0095] As used herein, the term "dyslipoproteinemias" refers to disorders that lead to or are manifested by aberrant levels of circulating lipoproteins. Insofar as the levels of lipoproteins in the blood are too high, the compositions of the invention are administered to an individual to restore normal levels. On the other hand, insofar as the levels of lipoproteins in the blood are very low, the compositions of the invention are administered to an individual to restore normal levels. Normal levels of lipoproteins are reported in medical treaties known to those skilled in the art.
    [0096] Dyslipoproteinemias which the compositions of the present invention are useful for preventing or treating include, but are not limited to, elevated blood levels of LDL; elevated blood levels of apolipoprotein B (apo B); elevated blood levels of Lp (a); elevated blood levels of apo (a); high blood levels of VLDL; low blood levels of HDL; deficient or reduced lipoprotein lipase levels or activity, including reductions or deficiencies resulting from lipoprotein lipase mutations; hypoalphalipoproteinemia; lipoprotein abnormalities associated with diabetes; lipoprotein abnormalities associated with obesity; lipoprotein abnormalities associated with Alzheimer's disease; and familial combined hyperlipidemia.
    [0097] The present invention further provides methods for reducing the levels of apo C-II in an individual's blood; reduce the levels of apo C-III in an individual's blood; raise levels of proteins associated with HDL, including but not limited to apo A-I, apo A-II, apo A-IV and apo E in an individual's blood; raise apo E levels in an individual's blood, and promote a movement of triglycerides from an individual's blood, said methods comprising administering to the individual a composition of Chardonnay seed flour in an effective amount to cause the said reduction, increase or promotion, respectively. 4.4.4 Glucose Metabolism Disorders
    [0098] The present invention provides methods for treating or preventing a disorder in glucose metabolism, which comprises administering to a subject a therapeutically effective amount of a Chardonnay seed meal composition. As used herein, the term "glucose metabolism disorders" refers to disorders that lead to or are manifested by aberrant glucose storage and / or use. Insofar as evidence of glucose metabolism (i.e., blood insulin, blood glucose) is too high, the compositions of the invention are administered to an individual to restore normal levels. On the other hand, insofar as evidence of glucose metabolism is too low, the compositions of the invention are administered to an individual to restore normal levels. Normal signs of glucose metabolism are reported in medical treaties known to those skilled in the art.
    [0099] Disorders of glucose metabolism which the compositions of the present invention are useful for preventing or treating include, but are not limited to impaired glucose tolerance; insulin resistance; insulin resistance related to breast, colon or prostate cancer; diabetes, including, but not limited to, non-insulin-dependent diabetes mellitus (DMNDI), insulin-dependent diabetes mellitus (DMDI), gestational diabetes mellitus (DMG), or diabetes beginning at a young age (MODY). ; pancreatitis; hypertension; polycystic ovary disease; and high levels of blood insulin and / or glucose.
    [00100] The present invention further provides methods for altering glucose metabolism in an individual, for example, to increase an individual's insulin sensitivity and / or oxygen consumption, said methods comprising administering to the individual a composition of Chardonnay seed flour in an effective amount to alter glucose metabolism. 4.4.5 Modulation of Intestinal Bacteria
    [00101] Human intestine biomes have been classified into three enterotypes according to the species that dominate the bacterial population. These are Bacteroides, Ruminococcus, and Prevotella enterotypes. The Bacteroides enterotype has been verified to produce several vitamins, including C and H, while the Prevotella enterotype has been verified to produce folic acid and vitamin B1.
    [00102] The present invention provides methods for modulating the levels of gut bacteria, which comprises administering to an individual an amount of a Chardonnay seed meal composition effective in modulating the levels of gut bacteria. As used herein, “modulating the levels of bacteria in the gut” refers to (i) a decrease in the amount of total levels of bacteria in the gut, and / or (ii) an increase or decrease in the levels of bacteria in a gut. subset of the total bacteria in the intestine. A subset of the total bacteria in the gut can be a single species, a genus, a family, an order, a class, a phylum, or a combination of more than one of the above.
    [00103] It may be desirable, for example, to modulate levels of gut bacteria levels in infants born by caesarean section, due to the fact that bacterial colonization of the intestine is delayed in children born by cesarean section, compared to infants born by normal birth. Differences in intestinal microbiota can persist for up to six months after birth (Grolund, M. et al, Journal of Pediatric Gastroenterology & Nutrition, (1999), vol. 28 (1): 19-25). For example, infants born by caesarean section are significantly less colonized by bacteria in the Bacteroides fragilis group than infants born vaginally at 6 months of age. Seven days after birth, infants born by caesarean section have higher levels of bacteria Enterobacteriaceae Citrobacter spp. and E. coli as a percentage of total intestinal bacteria compared to infants born by normal delivery (Pandey, P. et al, J. Biosci (2012) vol 37 (6): 989-998). The compositions of Chardonnay seed meal can be used to increase the level of bacteria in the Bacteroides fragilis and Clostridium spp. Group, and to decrease the level of Enterobacteriaceae bacteria in infants born by caesarean section, for example, in order to promote the formation of a biome of the intestine that most closely resembles the intestinal microbiome of infants born by normal birth.
    [00104] Chardonnay seed meal compositions can also be used to treat or prevent lactic acidosis by reducing the amount of lactic acid-producing bacteria, for example, Lactobacillus spp., In the intestine. Chardonnay seed meal compositions can also be used to promote colon health by increasing the level of Clostridium spp. in the intestine. Clostridium bacteria produce butyrate, which is the preferred source of energy in the colon mucosa. Butyrate protects against colitis and colorectal cancer, and is important for the normal development of colon epithelial cells. Shen, J. et al., Applied and Environmental Microbiology, vol.72: 5.232-5.238 (2006).
    [00105] Chardonnay seed meal compositions can also be used to lower levels of Bifidobacterium spp. in the intestine. However, if the level of Bifidobacterium spp. is not desired, but another therapeutic benefit of administering Chardonnay seed meal is desired, a probiotic supplement containing one or more species of Bifidobacterium can be administered to the individual to increase the levels of Bifidobacterium species in the individual's gastrointestinal tract. Examples of Bifidobacterium species that can be administered in a probiotic supplement include Bifidobacterium bifidum, Bifidobacterium breve, and Bifidobacterium longum. The probiotic supplement can include additional bacterial species, for example, one or more of Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus salivarious, Lactobacillus casei, Lactobacilus paracasei, Lactobacillus rhamnosus, and Streptococcus thermophilus.
    [00106] In one embodiment, the individual is identified as having an enterotype that is Bacteroides, Ruminococcus, or Prevotella. In one embodiment, the individual has a Bacteroides enterotype. In one embodiment, the individual has a Ruminococcus enterotype. In one embodiment, the individual has a Prevotella enterotype. 4.5 Therapeutic Uses of Chardonnay Seed Extract Compositions
    [00107] According to the invention, a composition of the invention comprising a Chardonnay seed extract composition is administered to an individual, preferably a human individual, for each of the therapeutic uses described in Section 4.4. Chardonnay seed extract has similar biological effects as Chardonnay seed flour (data not shown). In order to achieve a benefit that compared to the benefit obtained by using an amount of Chardonnay seed flour, the amount of Chardonnay seed extract administered should be an amount that provides 2 to 5 times above the levels of catechins the amount of Chardonnay seed meal. Specific amounts of Chardonnay seed extract, which will have to be consumed daily to achieve the same benefits as a given amount of Chardonnay seed flour, can be readily determined by those skilled in the art. 5. EXAMPLE 1: COMPARISON OF CHARDONNAY HEALTH BENEFITS PRODUCTS FROM SAUVIGNON BLANC AND WHITE RIESLING 5.1 Materials and Methods 5.1.1 Hamsters and diets
    [00108] Syrian golden male hamsters (-80 g, LVG strain, Charles River) were acclimatized and received water and a 5001 rodent diet ad libitum (LabDiet, PMI International; protein, 239 g / kg; fat, 50 g / kg ; non-nitrogen substances, 487 g / kg; crude fiber, 51 g / kg; ash, 70 g / kg, energy, 17 MJ kg; and sufficient amounts of vitamins and minerals for healthy maintenance) for one week, before beginning of experimental diets. Hamsters were weighed and randomly distributed in two groups of 15 hamsters each, and were fed diets high in fat ad libitum containing either 10% (by weight) of grape seed flour or Chardonnay, Cabernet or grape husk flour. Syrah or control (diets) for 4 weeks. Grapes from which the flours were produced were grown in the valleys of the northern California coast. The flour compositions are shown in Figure 1. The treatments consisted of 18% energy as protein, 43% as carbohydrates, and 39% fat supplemented with 0.1% cholesterol (Figure 2). GenOil refers to a commercially available grape seed oil from an unspecified grape variety. Body weights were recorded weekly and food intake was monitored twice a week. The study was approved by the Animal Care and Use Committee, Western Regional Research Center, USDA, Albany, CA. 5.1.2 Plasma and Fabric Collection
    [00109] The hamsters were fasted for 12 hours and anesthetized with isoflurane (Phoenix Pharmaceutical). The blood was collected by cardiac puncture with syringes previously washed with a solution of potassium EDTA (15% by weight: v) and the plasma was separated after centrifugation at 2000 xg for 30 minutes at 4 ° C. The livers were removed, weighed, and immediately frozen in liquid nitrogen for analysis. 5.1.3 Plasma Biomarker Analysis
    [00110] Cholesterol in plasma lipoproteins was determined by size exclusion chromatography as previously described (German et al, 1996. Res Nutr. 1996; 16: 1239-1249). Plasma triglycerides, total cholesterol, free cholesterol, and glucose were determined by enzymatic colorimetric assays using a Roche Diagnostics / Hitachi 914 Clinical Analyzer with assay kits (Roche Diagnostics and Wako Chemicals). The plasma concentrations of adiponectin (B-bridge International) and insulin (Mercodia) from feed-deprived hamsters were determined using adiponectin and insulin immunoassay kits from ultra-sensitive mice, as previously described (Hung et al, 2009, J. Diabetes 1: 194-206). Blood glucose concentrations in feed-deprived rats were measured in tail vein samples using a OneTouch Ultrameter (LifeScan). 5.1.4 Liver Lipid Analysis
    [00111] Ground and freeze-dried liver samples were extracted using an accelerated solvent extractor (Dionex), at 100 ° C; 13.8 MPa with 75/25 hexane / 2-propanol. The sample extract was analyzed on a Roche Diagnostic / Hitachi 914 Clinical Analyzer (Roche Diagnostics) to determine liver triglycerides, total cholesterol and free cholesterol, using the kits described above. 5.1.5 Analysis of Fecal Bile Acids and Sterol
    [00112] Faeces were collected for 3 consecutive days, just before when the hamsters were euthanized and were lyophilized, ground, and stored at -20 ° C. Bile acids and sterols were determined by HPLC as previously described (Hong et al, 2007, J Agric Food Chem. 55: 9750-7). 5.1.6 Statistical Analysis
    [00113] All data are expressed as mean ± SE. Differences between control and different diet groups were determined by Student 2-tailed t-tests. When the variations in each group were uneven, the significance of the differences was determined using the Welch test. Pearson's correlation coefficients were calculated to investigate plasma total cholesterol ratios, plasma adiponectin concentrations, hepatic cholesterol, and triglyceride concentrations with the expression of liver genes (JMP 7 statistical program, SAS Institute). Significance was defined at P <0.05. 5.2 Results
    [00114] Animals fed with Chardonnay seed meal had significantly decreased weight compared to animals fed with the other diets (Figures 3-4). The animals fed the Chardonnay seed meal diet had an average weight of about 97 grams, after four weeks. The animals fed the control diet had an average weight of about 110 grams after four weeks.
    [00115] Although treatment animals with Chardonnay seed meal weighed less than control animals, treatment animals with Chardonnay seed meal ate more (Figure 5), both in terms of volume (Figure 6) and of calories (Figure 7).
    [00116] Animals fed the Chardonnary seed meal diet showed the greatest decrease in VLDL (66%) and LDL (50%) cholesterol (Figure 8). Blood glucose showed a slight reduction (Figure 9).
    [00117] Chardonnay seed flour reduced the weight of the liver and epididymal adipose tissue (EA) by 30% and 20% by weight, respectively (Figure 10).
    [00118] These data show that Chardonnay seed flour was the obvious highlight among the tested grape products. Chardonnay husk flour showed a similar trend, but not as great a benefit as Chardonnay seed flour. 6. EXAMPLE 2: COMPARISON OF CHARDONNAY HEALTH BENEFITS, SAUVIGNON BLANC PRODUCTS AND WHITE RIESLING 6.1 Materials and Methods 6.1.1 Hamsters and diets
    [00119] Syrian golden male hamsters (-80 g, LVG strain, Charles River) were acclimatized and received water and a 5001 ad libitum rodent diet (LabDiet, PMI International; protein, 239 g / kg; fat, 50 g / kg ; non-nitrogen substances, 487 g / kg; crude fiber, 51 g / kg; ash, 70 g / kg, energy, 17 MJ kg; and sufficient amounts of vitamins and minerals for healthy maintenance) for one week, before beginning of experimental diets. Hamsters were weighed and randomly distributed into 10 groups of 10 hamsters each, and were fed diets high in fat ad libitum containing Chardonnay ethanolic seed extract, Chardonnay methanolic extract, ethanolic residue extracted from Chardonnay seed, methanolic extracted residue of Chardonnay seed, 10% (by weight) of Chardonnay seed flour, 10% (by weight) of Sauvignon Blanc seed flour, 10% (by weight) of White Riesling seed flour, 7% (by weight) ) of Chardonnay seed flour, 3% (by weight) of Chardonnay seed flour, or a control diet for 4 weeks. Grapes from which the flours were produced were grown in the valleys of the northern California coast. Ethanol extracts and extracted residues were prepared by a “tea extraction method” that comprises the following steps: (1) solvent (1625 ml of 40% ethanol in distilled water) was added to 325 g of Chardonnay seed flour and stirred at 80 ° C for two hours; (2) the mixture from step (1) was then filtered through Whatman 1 filter paper; (3), then the ethanol was removed from the filtrate from step (2) on a rotovac; (4) the solution from step (3) and the filter cake from step (2) were frozen and lyophilized to produce ethanolic extract from Chardonnay seeds and ethanol residue extracted from Chardonnay seeds, respectively. Similar procedures were used to produce methanolic extract from Chardonnay seeds and waste extracted from Chardonnay seeds, respectively.
    [00120] The treatments consisted of 18% energy as protein, 43% as carbohydrates, and 39% fat supplemented with 0.1% cholesterol. Body weights were recorded weekly and food intake was monitored twice a week. The study was approved by the Animal Care and Use Committee, Western Regional Research Center, USDA, Albany, CA. 6.1.2 Plasma and Fabric Collection
    [00121] The hamsters were fasted for 12 hours and anesthetized with isoflurane (Phoenix Pharmaceutical). The blood was collected by cardiac puncture with syringes previously washed with a solution of EDTA potassium (15% by weight: v) and the plasma was separated after centrifugation at 2000 xg for 30 min at 4 ° C. The livers were removed, weighed, and immediately frozen in liquid nitrogen for analysis. 6.1.3 Plasma Biomarker Analysis
    [00122] Cholesterol in plasma lipoproteins was determined by size exclusion chromatography as previously described (German et al, 1996, Nutr Res. 16: 1239-49). Plasma triglycerides, total cholesterol, free cholesterol, and glucose were determined by enzymatic colorimetric assays using a Roche Diagnostics / Hitachi 914 Clinical Analyzer with assay kits (Roche Diagnostics and Wako Chemicals). The plasma concentrations of adiponectin (B-bridge International) and insulin (Mercodia) from feed-deprived hamsters were determined using adiponectin and insulin immunoassay kits from ultra-sensitive mice, as previously described (Hung et al, 2009, J. Diabetes . 1: 194-206). Blood glucose concentrations in feed-deprived rats were measured in tail vein samples using a OneTouch Ultrameter (LifeScan). 6.1.4 Liver Lipid Analysis
    [00123] Ground and freeze-dried liver samples were extracted using an accelerated solvent extractor (Dionex), at 100 ° C; 13.8 MPa with 75/25 hexane / 2-propanol. The sample extract was analyzed on a Roche Diagnostic / Hitachi 914 Clinical Analyzer (Roche Diagnostics) to determine liver triglycerides, total cholesterol and free cholesterol, using the kits described above. 6.1.5 Analysis of Fecal Bile Acids and Sterol
    [00124] Feces were collected for 3 consecutive days, just before when the hamsters were euthanized and were lyophilized, ground, and stored at -20 ° C. Bile acids and sterols were determined by HPLC as previously described (Hong et al, 2007, Agric Food Chem. 55: 9750-7). 6.1.6 Statistical Analysis
    [00125] All data are expressed as mean ± SE. Differences between control and different diet groups were determined by Student 2-tailed t-tests. When the variations in each group were uneven, the significance of the differences was determined using the Welch test. Pearson's correlation coefficients were calculated to investigate plasma total cholesterol ratios, plasma adiponectin concentrations, hepatic cholesterol, and triglyceride concentrations with the expression of liver genes (JMP 7 statistical program, SAS Institute). Significance was defined at P <0.05. 6.2 Results
    [00126] Chardonnay seed meal at 10% by weight of the diet showed reproducible results with Example 1. Animals fed the diet of Chardonnay seed meal at 10% by weight of the diet had the minimum weight gain of 35% on a fat diet compared to control animals.
    [00127] Chardonnay seed flour showed a dose-response relationship. The animals were fed 10%, 7% or 3% Chardonnay seed meal, as part of their diet for 4 weeks. The increase in response, indicated as the weight difference, was observed; the more the animals ate the less weight they added (Figure 12).
    [00128] Chardonnay seed extract showed some effect on weight, but not as dramatic as the direct addition of Chardonnay seed flour.
    [00129] Chardonnay seed extracts and Chardonnay seed extract residues showed some effect on cholesterol levels (Figure 13) and LDL / HDL ratio (Figure 14), but not as dramatic as the direct addition of seed meal from Chardonnay. Likewise, Chardonnay seed extracts showed some effect on organ weight (Figure 15), but not as dramatic as the direct addition of Chardonnay seed flour.
    [00130] Other white seed flours, for example, Sauvignon Blanc or White Riesling showed little or no difference in weights compared to control diets. Chardonnay has been compared side by side with four other varieties, and is clearly a standout. 7. EXAMPLE 3: EFFECTS OF CHARDONNAY SEED FLOUR ON RELATIVE ADIPOSIS AND HEPATIC EXPRESSION OF GENES 7.1 Materials and Methods 7.1.1 Hamsters and diets
    [00131] Syrian golden male hamsters (-80 g, LVG strain, Charles River) were acclimatized and received water and a 5001 rodent diet ad libitum (LabDiet, PMI International; protein, 239 g / kg; fat, 50 g / kg ; non-nitrogen substances, 487 g / kg; crude fiber, 51 g / kg; ash, 70 g / kg, energy, 17 MJ kg; and sufficient amounts of vitamins and minerals for healthy maintenance) for one week, before beginning of experimental diets. Hamsters were weighed and randomly assigned to 2 groups and fed either ad libitum-rich diets containing either 10% (by weight) Chardonnay grape seed flour or a control diet for 4 weeks. Grapes from which the flours were produced were grown in the valleys of the northern California coast. The treatments consisted of 18% energy as protein, 43% as carbohydrates, and 39% fat supplemented with 0.1% cholesterol. Body weights were recorded weekly and food intake was monitored twice a week. The study was approved by the Animal Care and Use Committee, Western Regional Research Center, USDA, Albany, CA. 7.1.2 Analysis of mRNA
    [00132] Quantitative PCR (qPCR) was used to measure mRNA expression of selected genes from inflammation, cholesterol, bile acids, and fatty acid pathways in adipose tissue and liver samples from hamsters fed or on a diet supplemented with Chardonnay seed flour or the control diet. 7.1.3 Statistical Analysis
    [00133] All data are expressed as mean ± SD. Means presented are relative values, comparing the levels of mRNA in adipose tissue or the liver of hamsters fed with a diet supplemented with Chardonnay seed meal to the levels of mRNA in adipose tissue or the liver of hamsters fed with the control diet. 7.2 Results
    [00134] Relative gene expression levels comparing gene expression in adipose tissue from hamsters fed a diet supplemented with Chardonnay seed meal for gene expression in adipose tissue from hamsters fed the control diet are shown in Figure 16. The relative gene expression levels comparing gene expression in the liver tissue of hamsters fed a diet supplemented with Chardonnay seed flour for gene expression in the liver tissue of hamsters fed the control diet are shown in Figure 17.
    [00135] The expression of the liver ACOX1 gene, CYP51, and CYP7al was notably elevated in hamsters fed the diet supplemented with Chardonnay seed meal, while the expression of the ABCG5 and SCD1 gene was notably decreased in hamsters fed the diet supplemented with Chardonnay seed meal. Chardonnay seed flour
    [00136] ACOX1 is involved in regulating fat oxidation, CYP51 is involved in regulating cholesterol biosynthesis, CYP7al is involved in regulating bile acid synthesis, SCD1 is involved in fat synthesis, and ABCG5 is involved in cholesterol transport back into the gut. Consequently, the results suggest that a diet supplemented with Chardonnay seed flour may lower cholesterol and / or bile re-absorption, leading to reduced levels in the liver. The results also suggest that a diet supplemented with Chardonnay seed flour can reduce weight gain by the positive liver regulation of genes for fat oxidation (ACOX1) and / or by the negative regulation of fat synthesis (SCD1). 8. EXAMPLE 4: COMPARISON OF HEALTH BENEFITS FROM CHARDONNAY SEED FLOUR AND CHARDONNAY GRAPE SEED EXTRACT WITH COMMERCIALLY AVAILABLE GRAPE SEED EXTRACTS 8.1 Materials and Methods 8.1.1 Hamsters and diets
    [00137] Syrian golden male hamsters (-80 g, LVG strain, Charles River) were acclimatized and given water and a 5001 ad libitum rodent diet (LabDiet, PMI International; protein, 239 g / kg; fat, 50 g / kg ; non-nitrogen substances, 487 g / kg; crude fiber, 51 g / kg; ash, 70 g / kg, energy, 17 MJ kg; and sufficient amounts of vitamins and minerals for healthy maintenance) for one week, before beginning of experimental diets. All grape seed extracts were characterized by HPLC methods, and their feed amounts were adjusted to provide the same amount of catechin as a 7% (weight / weight) of Chardonnay seed flour. Hamsters were weighed and randomly distributed into 10 groups of 8 hamsters each, and were fed diets high in fat ad libitum containing 7% (by weight) of Chardonnay seed flour (1 group), Vitacost® grape seed extract ( 2 groups), Mega Natural® BP grape seed extract (2 groups), Leucoselect® grape seed extract (2 groups), catechin (approximately 0.000785 g / g diet) (1 group), epicatechin (approximately 0.00104 g / g diet) (1 group), or a control diet (1 group) for 4 weeks. Catechin levels were used to normalize each grape seed extract to the amount of Chardonnay seed flour. Epicatechin and catechin were included in the feed diet as controls for these compounds, which have been implicated in other studies to be responsible for regulating blood pressure and lipids. Grapes from which Chardonnay seed flour was produced, were grown in the northern California coastal valleys. The treatments consisted of 18% energy as protein, 43% as carbohydrates, and 39% fat supplemented with 0.1% cholesterol. Body weights were recorded weekly and food intake was monitored twice a week. The study was approved by the Animal Care and Use Committee, Western Regional Research Center, USDA, Albany, CA. 8.1.2 Plasma and Fabric Collection
    [00138] The hamsters were fasted for 12 hours and anesthetized with isoflurane (Phoenix Pharmaceutical). The blood was collected by cardiac puncture with syringes previously washed with a solution of potassium EDTA (15% by weight: v) and the plasma was separated after centrifugation at 2000 xg for 30 minutes at 4 ° C. The livers were removed, weighed, and immediately frozen in liquid nitrogen for analysis. 8.1.3 Plasma Biomarker Analysis
    [00139] Cholesterol in plasma lipoproteins was determined by size exclusion chromatography as previously described (German et al, 1996. Res Nutr. 1996; 16: 1239-1249). Plasma triglycerides, total cholesterol, free cholesterol, and glucose were determined by enzymatic colorimetric assays using a Roche Diagnostics / Hitachi 914 Clinical Analyzer with assay kits (Roche Diagnostics and Wako Chemicals). The plasma concentrations of adiponectin (B-bridge International) and insulin (Mercodia) from feed-deprived hamsters were determined using adiponectin and insulin immunoassay kits from ultra-sensitive mice, as previously described (Hung et al, 2009, J. Diabetes 1: 194-206). Blood glucose concentrations in feed-deprived rats were measured in tail vein samples using a OneTouch Ultrameter (LifeScan). 8.1.4 Liver Lipid Analysis
    [00140] Ground and lyophilized liver samples were extracted using an accelerated solvent extractor (Dionex), at 100 ° C; 13.8 MPa with 75/25 hexane / 2-propanol. The sample extract was analyzed on a Roche Diagnostic / Hitachi 914 Clinical Analyzer (Roche Diagnostics) to determine liver triglycerides, total cholesterol and free cholesterol, using the kits described above. 8.1.5 Analysis of Fecal Bile Acids and Sterol
    [00141] Feces were collected for 3 consecutive days, just before when the hamsters were euthanized and were lyophilized, ground, and stored at -20 ° C. Bile acids and sterols were determined by HPLC as previously described (Hong et al, 2007, J Agric Food Chem. 55: 9750-7). 8.1.6 Statistical Analysis
    [00142] All data are expressed as mean ± SE. Differences between control and different diet groups were determined by Student 2-tailed t-tests. When the variations in each group were uneven, the significance of the differences was determined using the Welch test. Pearson's correlation coefficients were calculated to investigate plasma total cholesterol ratios, plasma adiponectin concentrations, hepatic cholesterol, and triglyceride concentrations with the expression of liver genes (JMP 7 statistical program, SAS Institute). Significance was defined at P <0.05. 8.2 Results
    [00143] Animals fed with Chardonnay seed meal had significantly decreased plasma levels of total cholesterol and LDL cholesterol compared to animals fed diets supplemented with commercially available grape seed extracts (Figures 18 and 19), with exception of one of the groups fed a diet supplemented with Leucoselect® grape seed extract (L7). These data show that Chardonnay seed flour was superior to all but one of the commercial grape seed extracts tested for lowering total cholesterol and LDL cholesterol. 9. EXAMPLE 5: EFFECTS OF CHARDONNAY SEED FLOUR ON MICROBIOTA LEVELS 9.1 Materials and Methods 9.1.1 Stool samples
    [00144] Feces were collected from the animals of Example 1 on day 0 (control) and on day 20 (diet supplemented with Chardonnay seed meal, diet supplemented with Cabernet seed meal, and control diet with a high fat content ). The feces were dried and frozen. 9.1.2 RNA Extraction and Quantification
    [00145] Frozen stool samples were added to 10 volumes of RNA / fer®-ICE (Applied Biosystems, Foster City, CA, USA) for at least 24 hours. Total RNA was prepared using the Total Stool RNA Purification Kit (Norgen Biotek Corp., Canada) following the manufacturer's protocols.
    [00146] Quantity and purity of the isolated RNA were confirmed by spectrophotometry (A260 / A280 ratio). The cDNA was prepared for each sample, using 250 ng of total RNA and a PrimeScript ™ RT reagent kit (Takara Bio Inc., Shiga, Japan) according to the manufacturer's protocols.
    [00147] Real-time PCR for the quantification of intestinal bacterial 16S rRNA gene expression was performed using the AB 7500 Real-Time PCR system (Applied Biosystems, Foster City, CA, USA). Amplification was performed in duplicate using SYBR Premix Ex Taq (Takara Bio Inc., Shiga, Japan). The amplifications, using the primers shown in Table 1, were performed with the following temperature profiles: one cycle at 95 ° C for 30 seconds, and 40 cycles of denaturation at 95 ° C for 5 to 10 seconds, matching at the optimum temperature at 5 ° C. at 15 seconds, and stretching at 72 ° C for 20 seconds. Table 1

    9.2 Results
    [00148] The results of quantitative real-time PCR of faecal samples from hamsters fed a high-fat diet containing Chardonnay or Cabernet seed flour revealed that the intestinal microbiota was modulated by the consumption of flour. The levels of total measured bacteria in the fecal matter of hamsters fed four diets are shown in Figure 20. The measured levels of subpopulations of bacteria are shown in Figures 21-26.
    [00149] Fecal samples from hamsters fed a high-fat diet supplemented with Chardonnay seed meal showed significantly reduced levels of Bifidobacterium spp., Lactobacillus spp., And Enterobacteriaceae, and levels of Enterococcus spp significantly increased., Clostridium de bacteria group IV and the group of Bacteroides fragilis compared to fecal samples from hamsters fed the high-fat control diet.
    [00150] Fecal samples from hamsters fed a high-fat diet supplemented with Cabernet seed flour showed significantly reduced levels of Enterobacteriaceae, and significantly increased levels of Enterococcus spp, and the Bacteroides fragilis group compared to fecal samples from hamsters fed with the high-fat control diet. 10. SPECIFIC MODALITIES AND INCORPORATION BY REFERENCE
    [00151] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated. to be incorporated by reference for all purposes.
    [00152] Although several specific modalities have been illustrated and described, it will be appreciated that various modifications can be made without departing from the spirit and scope of the invention (s).
    权利要求:
    Claims (10)
    [0001]
    1. Use of an effective amount of Chardonnay grape seed flour characterized by being for the manufacture of a composition for the treatment of metabolic syndrome, reduction of the weight of a liver, dyslipidemia, increase in lipid metabolism, obesity, dyslipoproteinemia, increase in the quantity of Bacteroides fragilis in the intestine, decrease in the amount of Enterobacteriaceae bacteria in the intestine, increase in the amount of Clostridium bacteria in the intestine or treatment of lactic acidosis in a mammal in need of it.
    [0002]
    2. Use according to claim 1, characterized by reducing cholesterol.
    [0003]
    Use according to claim 1, characterized by increasing the ratio of HDL to LDL.
    [0004]
    4. Use according to claim 1, characterized by reducing the organ weight.
    [0005]
    5. Use according to claim 4, characterized in that the organ is the liver.
    [0006]
    6. Use according to claim 1, characterized by reducing the weight of the epididymal adipose tissue.
    [0007]
    Use according to any one of claims 1 to 6, characterized in that the Chardonnay grape seed flour is cold-pressed Chardonnay grape seed, hot-pressed Chardonnay grape seed meal, Chardonnay bagasse meal or Chardonnay bagasse flour.
    [0008]
    Use according to any one of claims 1 to 7, characterized in that the mammal is a human being.
    [0009]
    9. Use of an effective amount of Chardonnay grape seed flour characterized by making a composition to prevent dyslipidemia or prevent blood dyslipoproteinemia levels, maintain healthy weight or maintain the colon health of a mammal in need of same.
    [0010]
    10. Composition characterized by comprising Chardonnay grape seed flour intended for use as defined in any one of claims 1 to 9 and suitable food materials.
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    同族专利:
    公开号 | 公开日
    US10772924B2|2020-09-15|
    US20190269748A1|2019-09-05|
    IL235349D0|2014-12-31|
    CN104519895B|2019-06-11|
    US10105409B2|2018-10-23|
    EA201491817A1|2015-04-30|
    CN110433230A|2019-11-12|
    BR112014026926A2|2017-06-27|
    NZ701607A|2017-04-28|
    AU2013256577A1|2014-11-20|
    JP6562837B2|2019-08-21|
    KR20150018784A|2015-02-24|
    KR102149348B1|2020-08-31|
    CA2871265C|2021-07-13|
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    WO2013165921A2|2013-11-07|
    JP2015523321A|2015-08-13|
    EP2844266A2|2015-03-11|
    US20150132419A1|2015-05-14|
    WO2013165921A3|2014-01-03|
    IL235349A|2020-11-30|
    US20210236579A1|2021-08-05|
    CN104519895A|2015-04-15|
    CA2871265A1|2013-11-07|
    IN2014DN09085A|2015-05-22|
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    法律状态:
    2018-01-23| B11A| Dismissal acc. art.33 of ipl - examination not requested within 36 months of filing|
    2018-03-13| B11N| Dismissal: publication cancelled|
    2018-03-20| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-01-28| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-02-11| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-11-24| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|
    2021-01-12| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-03-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 29/04/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201261640622P| true| 2012-04-30|2012-04-30|
    US61/640,622|2012-04-30|
    US201261691515P| true| 2012-08-21|2012-08-21|
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    US201361798992P| true| 2013-03-15|2013-03-15|
    US61/798,992|2013-03-15|
    PCT/US2013/038696|WO2013165921A2|2012-04-30|2013-04-29|Therapeutic use of chardonnay seed products|
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