Anti-fatigue agent for cancer-related fatigue

Abstract

To provide: an anti-fatigue agent which includes an oligosaccharide as an active ingredient and which is useful for improving cancer-related fatigue and is safely ingestible; and an oral composition which includes the anti-fatigue agent as an active ingredient and which is ingested for improving cancer-related fatigue.SOLUTION: An anti-fatigue agent for cancer-related fatigue includes an oligosaccharide having a digestion-resistant oligosaccharide or mannose ratio of 50 mass% or more as an active ingredient. A cancer patient blood sugar level improving agent includes an oligosaccharide having a mannose ratio of 50 mass% or more as an active ingredient. A cancer patient liver glycogen level improving agent includes an oligosaccharide having a mannose ratio of 50 mass% or more as an active ingredient. An oral composition for improving cancer-related fatigue includes an oligosaccharide having a digestion-resistant oligosaccharide or mannose ratio of 50 mass% or more as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an anti-fatigue agent that is useful for improving cancer-related fatigue and can be safely ingested, and to a food, beverage, or dietary supplement that contains an oral composition that contains the anti-fatigue agent as an active ingredient and is ingested to improve cancer-related fatigue. [Background technology]

[0002] The group of intestinal bacteria in the human intestine is called the intestinal flora, and the maintenance and health of the intestinal flora is considered to be important for human health. An effective method for maintaining and health of the intestinal flora is the intake of prebiotics. Known examples of prebiotics include dietary fiber such as inulin and oligosaccharides such as galactooligosaccharides and fructooligosaccharides.

[0003] One of the prebiotics is oligosaccharides mainly composed of D-mannose. Coffee extraction residue contains a large amount of insoluble mannan, and methods for producing the oligosaccharides have been developed using enzymatic hydrolysis (Non-Patent Document 1) and thermal hydrolysis (Non-Patent Document 2). One of the characteristics of prebiotics is their selective assimilation. When selective assimilation tests were conducted under pure culture conditions using isolated and purified β-1,4-mannobiose, β-1,4-mannotriose, β-1,4-mannotetraose, and β-1,4-mannopentaose, using 56 species of intestinal bacteria from 19 genera of human origin, it was reported that, among the Bifidobacterium genus bacteria, they were well assimilated only by Bifidobacterium adolescentis, while they were not assimilated at all by many other strains such as Clostridium perfringens and Escherichia coli, which are considered harmful bacteria, and no difference in assimilation was observed depending on the degree of polymerization (Non-Patent Document 2). Furthermore, it has been reported that when subjects were given oligosaccharides primarily composed of D-mannose over a long period of time, the frequency and number of days with defecation during the test period tended to increase in proportion to the amount of the oligosaccharides ingested, and that the occupancy rate of Bifidobacterium bacteria also increased significantly (Non-Patent Document 3).

[0004] In addition, an important partial structure of the glycan of human glycoproteins contains oligosaccharides in which D-mannose is linked by β-1,4 bond, and it is expected that these will be used not only as ingredients for food and drink but also as ingredients for medicines. For example, it has been reported that the oral intake of oligosaccharides whose constituent sugar is mannose reduces the levels of total cholesterol and neutral fat in serum (see, for example, Patent Document 1).

[0005] On the other hand, cancer-related fatigue is defined as "a persistent and subjective sense of fatigue accompanied by pain related to cancer or cancer treatment" and is one of the symptoms that frequently appears in cancer patients. Unlike general physical fatigue, it is difficult to improve even with rest and has the characteristic of continuing chronically, significantly reducing the QOL of cancer patients. Previous studies have shown that cancer-induced fatigue model mice have reduced blood glucose levels and liver glycogen levels, which are part of the causes of fatigue, and it is believed that increased production of energy sources such as sugar or fatty acids is necessary to improve cancer-induced fatigue. For example, it has been reported that fatigue-like behavior in mice administered cisplatin is improved by administration of sucrose and glucose (Non-Patent Document 3). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2006-169256 A [Non-patent literature]

[0007] [Non-Patent Document 1] Sachslehner, et al., Journal of Biotechnology, 2000,vol.80, p.127-134. [Non-Patent Document 2] Ichiro Asano et al., Journal of the Agricultural Chemical Society of Japan, 2001, Vol. 75, No. 10, pp. 1077-1083. [Non-Patent Document 3] Yoshizawa, et al., CANCER DIAGNOSIS & PROGNOSIS, 2021, vol.1, p.95-102. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention aims to provide an anti-fatigue agent that contains oligosaccharides as an active ingredient, is useful for improving cancer-related fatigue, and can be safely ingested, and an oral composition that contains the anti-fatigue agent as an active ingredient and is ingested to improve cancer-related fatigue. [Means for solving the problem]

[0009] The present inventors have found that cancer-related fatigue can be improved by orally taking an oligosaccharide in which 2 to 20 molecules of mannose-based monosaccharide are linked together, and have completed the present invention.

[0010] [1] An anti-fatigue agent for cancer-related fatigue, containing resistant oligosaccharides as its active ingredient. [2] An anti-fatigue agent for cancer-related fatigue, the active ingredient of which is an oligosaccharide with a mannose ratio of 50% or more by mass. [3] The anti-fatigue agent according to [2], wherein the oligosaccharide is derived from coffee beans. [4] A blood sugar level improving agent for cancer patients, the active ingredient of which is an oligosaccharide with a mannose ratio of 50% or more by mass. [5] An agent for improving liver glycogen levels in cancer patients, the active ingredient of which is an oligosaccharide with a mannose ratio of 50% or more by mass. [6] An oral composition for improving cancer-related fatigue, containing indigestible oligosaccharides as an active ingredient. [7] An oral composition for improving cancer-related fatigue, comprising an oligosaccharide having a mannose ratio of 50% by mass or more as an active ingredient. [8] The oral composition of [7] above, which improves blood glucose levels or liver glycogen levels in cancer patients. [9] Any of the oral compositions according to [6] to [8] above, which is taken in combination with an anticancer drug.

[10] The oral composition according to any one of [6] to [9] above, which is a food or drink.

[11] Any of the oral compositions according to [6] to [9] above, which is a dietary supplement. Effect of the Invention

[0011] The anti-fatigue agent according to the present invention can be orally ingested very safely because it contains, as an active ingredient, a poorly digestible oligosaccharide, in particular an oligosaccharide in which 2 to 20 molecules of monosaccharides mainly composed of mannose are bonded together. Therefore, foods, beverages, dietary supplements, etc. containing the anti-fatigue agent according to the present invention are suitable as oral compositions to be ingested to improve cancer-related fatigue. [Brief description of the drawings]

[0012] [Figure 1] FIG. 2 shows an experimental schedule for the treadmill test in Example 1. [Diagram 2] FIG. 1 shows the results of evaluating fatigue in a treadmill running experiment for the following groups in Example 1: a group administered PBS and given standard feed on Day 0 (PBS_ND group), a group administered C26 cells and given standard feed (C26_ND group), a group administered C26 cells and given 1% MOS feed (C26_1% MOS group), a group administered C26 cells and given 5% MOS feed (C26_5% MOS group), and a group administered C26 cells and given 5% Dextrin feed (C26_5% Dext group). [Diagram 3] 1 shows the results of measuring the cell viability (%) of C26 cells in the presence of 0.01 to 100 mM MOS in Example 2. FIG. [Figure 4] This figure shows the results of measuring blood glucose and blood lactate levels in cancer-induced fatigue model mice when MOS was administered in Example 3. [Diagram 5] FIG. 13 shows the results of measuring liver glycogen levels in cancer-induced fatigue model mice when MOS was administered in Example 4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In the present invention and this specification, "oligosaccharide" refers to a compound in which about 2 to 20 monosaccharides are bonded together via glycosidic bonds. In the present invention and this specification, "oligosaccharide" includes not only a single type of oligosaccharide, but also a mixture (composition) of multiple types of oligosaccharides with different degrees of polymerization. In the case of a mixture of multiple types of oligosaccharides with different degrees of polymerization, the degree of polymerization of the oligosaccharides means the average degree of polymerization of the oligosaccharides contained in the mixture. In other words, a mixture with an average degree of polymerization of 2 to 20 corresponds to "oligosaccharide" in the present invention and this specification.

[0014] In the present invention and the present specification, the degree of polymerization of an oligosaccharide may be expressed as "DP". DP means the number of monosaccharides that constitute the oligosaccharide. An oligosaccharide composed of four mannose units has a degree of polymerization of 4, that is, "DP4".

[0015] In the present invention and this specification, "oligosaccharides in which 2 to 20 molecules of mannose-based monosaccharides are bonded" refers to oligosaccharides in which the ratio of mannose to the total constituent monosaccharides (the ratio of mannose residues in the oligosaccharide; hereinafter, sometimes referred to as "mannose ratio") is 50% or more. "Oligosaccharides in which 2 to 20 molecules of mannose-based monosaccharides are bonded" is sometimes referred to as "mannooligosaccharides (MOS)."

[0016] The anti-fatigue agent of the present invention is an anti-fatigue agent for cancer-related fatigue, and contains indigestible oligosaccharide as an active ingredient. Cancer-related fatigue can be alleviated by taking the anti-fatigue agent of the present invention. In the following, unless otherwise specified, "anti-fatigue effect" means an effect of improving cancer-related fatigue, and "fatigue improving effect" means an effect of improving cancer-related fatigue.

[0017] The active ingredient of the anti-fatigue agent of the present invention is not particularly limited as long as it is a resistant oligosaccharide. Here, the resistant oligosaccharide means an oligosaccharide that is not decomposed by digestive enzymes and is not absorbed when ingested by an animal. The resistant oligosaccharide that is the active ingredient of the anti-fatigue agent of the present invention may be one type or a mixture of two or more types.

[0018] Examples of the resistant oligosaccharides in humans include fructooligosaccharides, galactooligosaccharides, xylooligosaccharides, and agarooligosaccharides. The resistant oligosaccharides used as the active ingredient of the anti-fatigue agent according to the present invention may be chemically synthesized products or compositions extracted and purified from natural products. Examples of the resistant oligosaccharides derived from natural products include mannooligosaccharides derived from coffee beans and raffinose derived from beets.

[0019] As the active ingredient of the anti-fatigue agent of the present invention, oligosaccharides with a mannose ratio of 50% by mass or more, i.e., mannooligosaccharides, are particularly preferred. As the mannooligosaccharides used as the active ingredient of the anti-fatigue agent of the present invention, mannooligosaccharides with a mannose ratio of 70% by mass or more are preferred, and mannooligosaccharides with a mannose ratio of 80% by mass or more are more preferred. By having a sufficiently high ratio of mannose residues, the effect of mannooligosaccharides can be obtained more effectively, and by having a relatively low content of other monosaccharides such as glucose, the sweetness can be kept low, making it easy to apply widely to foods, beverages, supplements, medicines, etc.

[0020] The bond type between each monosaccharide of the "mannooligosaccharide" used in the present invention is not particularly limited, and the bond types in one molecule may be all the same type or different types. The "mannooligosaccharide" used in the present invention is preferably one in which the majority of the bond types in one molecule are not hydrolyzed or absorbed in the upper part of the human digestive tract, and more preferably one in which the majority of the bond types in one molecule are β-1,4 bonds. Among them, the "mannooligosaccharide" used in the present invention is preferably a mannooligosaccharide having at least one structure in which mannose residues are bonded to each other by β-1,4 bonds in one molecule, more preferably a mannooligosaccharide in which all mannose residues in one molecule are bonded to each other by β-1,4 bonds, and particularly preferably a mannooligosaccharide (β-1,4-mannooligosaccharide) in which the mannose ratio is 100% and all mannose residues in one molecule are bonded to each other by β-1,4 bonds.

[0021] The degree of polymerization of the "mannooligosaccharides" used in the present invention is not particularly limited as long as it is within the range of 2 to 20. As the active ingredient of the anti-fatigue agent according to the present invention, mannooligosaccharides having a degree of polymerization within the range of 2 to 15 are preferred, mannooligosaccharides having a degree of polymerization within the range of 2 to 10 are more preferred, and mannooligosaccharides having a degree of polymerization within the range of 2 to 6 are even more preferred.

[0022] When the "mannooligosaccharides" used in the present invention have a mannose ratio of less than 100%, the constituent monosaccharides other than mannose are not particularly limited, and various monosaccharides such as glucose, galactose, fructose, threose, ribose, xylose, arabinose, aldohexose, ribulose, psicose, and sorbose can be used in appropriate combination. The "mannooligosaccharides" used in the present invention are preferably mannooligosaccharides in which the constituent monosaccharides other than mannose are one or more selected from the group consisting of glucose, galactose, and fructose.

[0023] The "mannooligosaccharide" used in the present invention is preferably a mannooligosaccharide whose constituent monosaccharide is composed only of mannose (having only mannose as a constituent unit), i.e., an oligosaccharide in which 2 to 20 mannose molecules are bonded together. In this case, it is more preferable that the 2 to 20 mannose molecules are all bonded together via β-1,4-mannooligosaccharide.

[0024] The anti-fatigue agent according to the present invention may consist of only resistant oligosaccharides, or may contain other components. Such other components include oligosaccharides other than resistant oligosaccharides, monosaccharides, polysaccharides, etc. The content of resistant oligosaccharides in the anti-fatigue agent according to the present invention is preferably 30% by mass or more, more preferably 50% by mass or more, even more preferably 60% by mass or more, and even more preferably 80% by mass or more, based on the total solid content.

[0025] When the active ingredient of the anti-fatigue agent of the present invention is mannooligosaccharide, the content of mannooligosaccharide in the anti-fatigue agent of the present invention is preferably 30% by mass or more, more preferably 50% by mass or more, even more preferably 60% by mass or more, and even more preferably 80% by mass or more, relative to the total solids content.

[0026] The anti-fatigue agent according to the present invention preferably has a free mannose content of 50% by mass or less, more preferably 30% by mass or less, since this can suppress the bitterness derived from the monosaccharide mannose.

[0027] The "mannooligosaccharide" used in the present invention is preferably one obtained by hydrolysis of mannan. In the present invention and this specification, the term "mannan" is intended to broadly include mannan, which is a polysaccharide whose constituent unit is only D-mannose, as well as galactomannan and glucomannan, which are polysaccharides whose constituent units are mannose and galactose or glucose. D-mannose is an aldohexose in which the steric configuration of the hydroxyl group bonded to the carbon adjacent to the carboxyl group in D-glucose is reversed.

[0028] Here, the raw mannan can be obtained by extracting, for example, copra meal obtained from coconut palm, huaca palm, South African palm plant Huacra Palm, tsukuneimo mannan, and yam mannan. The mannan obtained in this manner is treated by one or more methods selected from acid hydrolysis, high-temperature heat hydrolysis, enzyme hydrolysis, and microbial fermentation, and is preferably purified by activated carbon treatment, adsorption resin treatment, ion exchange resin treatment, ion exchange membrane treatment, etc., to obtain a sugar mixture. The mixture contains the above-mentioned "mannooligosaccharides". Therefore, the composition obtained in this manner is used as an active ingredient of the anti-fatigue agent of the present invention. Furthermore, "mannooligosaccharides" may be produced by treating glucomannan contained in konjac, lilies, daffodils, red spider lilies, etc., or galactomannan contained in locust bean gum, guar gum, etc., with one or more methods selected from acid hydrolysis, high-temperature heat hydrolysis, enzymatic hydrolysis, and microbial fermentation, and then isolating and purifying with methods such as activated carbon treatment, adsorption resin treatment, ion exchange resin treatment, and ion exchange membrane treatment to increase the proportion of mannose as a constituent sugar.

[0029] The "mannooligosaccharides" used in the present invention are preferably derived from coffee beans. Specifically, for example, they can be obtained by treating raw coffee beans or roasted coffee beans with one or more methods selected from acid hydrolysis, high-temperature thermal hydrolysis, enzymatic hydrolysis, and microbial fermentation, and purifying them with methods such as activated carbon treatment, adsorption resin treatment, ion exchange resin treatment, and ion exchange membrane treatment. Alternatively, they can be obtained by treating used coffee extraction residue with one or more methods selected from acid hydrolysis, high-temperature thermal hydrolysis, enzymatic hydrolysis, and microbial fermentation, and purifying them with methods such as activated carbon treatment, adsorption resin treatment, ion exchange resin treatment, and ion exchange membrane treatment. In general, when roasted and ground coffee is extracted with a commercial extractor, galactose, which is a side chain of galactomannan contained in the roasted coffee, is solubilized, and arabinogalactan is solubilized by hydrolysis. Therefore, it is presumed that mannan is abundant in the coffee extraction residue and has a linear structure. On the other hand, cellulose is difficult to decompose and remains as a residue, but mannooligosaccharides can be obtained by appropriately selecting conditions for specifically hydrolyzing mannan without decomposing cellulose.

[0030] In particular, methods for decomposing coffee extract residue include, but are not limited to, hydrolysis using acid and / or high temperature, decomposition using enzymes, and decomposition using microbial fermentation. Methods for hydrolysis using acid and / or high temperature are disclosed in JP-A-61-96947 and JP-A-2-200147. Used coffee extract residue from a commercial multi-stage coffee extraction system can be hydrolyzed by adding an acid catalyst in a reaction vessel, or can be hydrolyzed at high temperature for a short time without adding an acid catalyst. Although a method using a tubular plug flow reactor is convenient, good results can be obtained using any reactor as long as it is suitable for a method of performing a reaction at a relatively high temperature for a short time. By adjusting the reaction time and reaction temperature, mannan with DP10-40 can be decomposed into mannooligosaccharides with DP2-20 by solubilization and hydrolysis, and then separated from the coffee extract residue to obtain mannooligosaccharides. The term "coffee extraction residue" used herein refers to so-called coffee extraction grounds remaining after roasted and ground coffee is extracted with a solvent such as water in the atmosphere or under pressurized conditions.

[0031] When using "mannooligosaccharides" derived from coffee beans, i.e., coffee beans (including roasted coffee beans and roasted and ground coffee beans) and / or coffee extract residue obtained by hydrolysis treatment, there is no particular limitation on the type or origin of the coffee beans used, and any coffee beans such as Arabica, Robusta, and Liberica can be used, and coffee beans from any origin such as Brazil and Colombia can be used. Only one type of bean can be used alone, or two or more types of beans can be blended. Even poor quality coffee beans or small coffee beans that are usually discarded as having no commercial value can be used. Coffee beans roasted to a very light roast, light roast, medium roast, or dark roast using a commonly used roasting machine (direct fire, hot air, far infrared, charcoal fire, etc.), and roasted and ground coffee (including various shapes such as coarse ground, medium coarse ground, medium ground, medium fine ground, and fine ground) obtained by grinding the roasted coffee beans using a common grinding machine, roll mill, etc. can also be used.

[0032] Furthermore, the coffee extraction residue that can be used is any coffee extraction residue obtained after roasted and ground coffee has been extracted in a normal liquid coffee or instant coffee production process, whether extracted under normal pressure or under pressure, and of any origin and production method.

[0033] Here, the hydrolysis treatment will be described in some detail. In the method of decomposing with an enzyme, for example, the coffee extract residue is suspended in an aqueous medium, to which, for example, commercially available cellulase and hemicellulase are added and suspended under stirring. There is no particular problem with the amount of enzyme, the temperature at which it is allowed to act, and other conditions, so long as they are the amount, temperature, and conditions used in a normal enzyme reaction, and these may be appropriately selected depending on the optimal amount, temperature, conditions, and other factors for the enzyme to be used. In a method of decomposing mannan by microbial fermentation, for example, a microorganism that produces cellulase, hemicellulase, etc. may be inoculated into the coffee extract residue suspended in an aqueous medium and then cultured. The microorganism to be used may be any microorganism that produces an enzyme that decomposes mannan in the coffee extract residue, such as bacteria or basidiomycetes, and the culture conditions may be appropriately selected depending on the microorganism to be used. Alternatively, an oligosaccharide composition obtained by simply heat-treating a coffee extract residue at 180 to 250° C. can be used as the mannooligosaccharide, which is the active ingredient of the anti-fatigue agent according to the present invention.

[0034] The reaction solution containing "mannooligosaccharides" obtained by the above method can be purified as necessary. Examples of purification methods include decolorization and deodorization using bone charcoal, activated carbon, carbonic acid adsorption, adsorption resin, magnesia method, solvent extraction, etc., and desalting and deacidification using ion exchange resin, ion exchange membrane, electrodialysis, etc. The combination of purification methods and purification conditions may be appropriately selected depending on the amounts of pigments, salts, acids, etc. in the reaction solution containing mannooligosaccharides and other factors.

[0035] The state of fatigue in humans can be evaluated by sensory evaluation. Symptoms of cancer-related fatigue include weakness, malaise, exhaustion, lethargy, shortness of breath, insomnia, loss of appetite, impaired concentration and judgment, etc. If the intensity of these symptoms is lower after ingestion of the anti-fatigue agent according to the present invention than before ingestion, it can be evaluated that the anti-fatigue agent according to the present invention has an effect of improving fatigue.

[0036] In cancer patients, cancer-related fatigue is thought to be caused by the Warburg effect, i.e., the production of lactic acid in the presence of oxygen (aerobic glycolysis). In fact, in cancer-induced fatigue model mice, blood glucose levels and liver glycogen levels have been observed to decrease, and blood glucose levels and liver glycogen levels are restored along with the improvement of fatigue (Non-Patent Document 3). Therefore, the fatigue-improving effect of the anti-fatigue agent according to the present invention can be evaluated by blood glucose levels or liver glycogen levels. In a cancer patient who has taken the anti-fatigue agent according to the present invention, if the blood glucose level is significantly higher than before the intake, it can be evaluated that the intake of the anti-fatigue agent has an effect of improving fatigue. Similarly, in a cancer patient who has taken the anti-fatigue agent according to the present invention, if the liver glycogen level is significantly higher than before the intake, it can be evaluated that the intake of the anti-fatigue agent has an effect of improving fatigue.

[0037] The improvement of fatigue by taking the anti-fatigue agent according to the present invention can also improve the decrease in blood glucose level and liver glycogen amount observed in cancer patients. Therefore, the indigestible oligosaccharides including mannooligosaccharides, which are the active ingredient of the anti-fatigue agent according to the present invention, can also be used as the active ingredient of an agent for improving blood glucose level or liver glycogen amount in cancer patients.

[0038] The reason why taking the anti-fatigue agent of the present invention has the effect of improving fatigue is not clear, but it is presumed that this is because the prebiotic function of the active ingredient, mannooligosaccharides and other indigestible oligosaccharides, leads to the production of energy sources such as sugars and fatty acids.

[0039] The anti-fatigue agent according to the present invention may contain other ingredients as long as they do not impair the fatigue-improving effect of mannooligosaccharides. For example, various substances used as excipients, binders, flow improvers (anti-caking agents), stabilizers, preservatives, pH adjusters, solubilizers, suspending agents, emulsifiers, thickeners, flavoring agents, sweeteners, acidulants, flavorings, coloring agents, etc. may be appropriately contained according to the desired product quality.

[0040] The content of mannooligosaccharide in the anti-fatigue agent of the present invention is not particularly limited as long as the mannooligosaccharide is an amount that can obtain the fatigue improving effect.For example, the content of mannooligosaccharide in the total mass of the anti-fatigue agent is preferably 10% by mass or more, more preferably 25% by mass or more, even more preferably 50% by mass or more, even more preferably 75% by mass or more, and may be 100% by mass.

[0041] The dosage form of the anti-fatigue agent according to the present invention is not particularly limited, and various dosage forms can be applied. The anti-fatigue agent according to the present invention exerts its effect by oral ingestion, so it is preferable that it is suitable for oral administration. Examples of the dosage form include tablets, capsules, granules, powders, syrups, etc.

[0042] The anti-fatigue agent according to the present invention is mainly composed of indigestible oligosaccharides such as mannooligosaccharides, and can be orally administered very safely. Therefore, the anti-fatigue agent according to the present invention can be contained in oral compositions such as food and drink and dietary supplements (supplements) taken to improve cancer-related fatigue. The oral composition for improving cancer-related fatigue according to the present invention (hereinafter sometimes referred to as the "composition according to the present invention") contains the anti-fatigue agent according to the present invention as an active ingredient, and is a composition orally administered to cancer patients to improve cancer-related fatigue. For example, cancer-related fatigue can be improved by continuously taking food and drink or dietary supplements containing the anti-fatigue agent according to the present invention. The anti-fatigue agent according to the present invention is also preferably used as a raw material for feed and medicines. The oral composition containing the anti-fatigue agent according to the present invention can be an oral composition taken by cancer patients to improve blood glucose level or liver glycogen amount.

[0043] Examples of beverages that may contain the anti-fatigue agent of the present invention include beverages, fruit juice beverages, soft drinks, lactic acid bacteria beverages, milk beverages, etc. The beverages include tea beverages such as black tea, green tea, oolong tea, and matcha, herbal tea, coffee, cocoa, and mixtures thereof. Examples of ingredients for herbal tea include hibiscus, rosehip, peppermint, chamomile, lemongrass, lemon balm, and lavender.

[0044] Examples of foods to which the anti-fatigue agent of the present invention can be blended include soups such as consomme soup, potage soup, and cream soup; and confectioneries such as chocolate, cookies, biscuits, crackers, wafers, ice cream, and jelly.

[0045] For example, a composition prepared by hydrolyzing coffee extract residue with acid and / or heat to contain mannooligosaccharides at a high purity can be added to liquid coffee, instant coffee, etc. as is, or after purification such as decolorization, deodorization, and deacidification using activated carbon, ion exchange resin, solvent, etc. as necessary, to produce a coffee beverage suitable for ingesting for the purpose of improving cancer-related fatigue. Here, examples of liquid coffee include coffee beverages (or those called coffee-containing beverages) that are commercially available in cans or so-called PET bottle containers. Examples of instant coffee include soluble powdered coffee, which is obtained by removing moisture from an extract obtained by extracting roasted and ground coffee with hot water by spraying or freeze-drying. Examples of coffee mix beverages include beverages obtained by adding sugar, creaming powder, etc. to soluble powdered coffee and mixing them.

[0046] The content of the anti-fatigue agent according to the present invention in the oral composition according to the present invention, for example, in oral compositions such as food and drink, dietary supplements, medicines, and feeds containing the anti-fatigue agent according to the present invention, is not particularly limited as long as the fatigue improving effect of mannooligosaccharides is obtained, and can be appropriately determined taking into consideration the type of oral composition, frequency of ingestion, dosage form, pathology of the cancer patient to be ingested, etc. For example, the content of the anti-fatigue agent relative to the total mass of the oral composition is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, even more preferably 1.0% by mass or more, even more preferably 5.0% by mass or more, and particularly preferably 10.0% by mass or more, in terms of mannooligosaccharides.

[0047] The daily intake of the oral composition according to the present invention is not particularly limited as long as the fatigue improving effect of mannooligosaccharides is obtained, and can be appropriately determined in consideration of the frequency of intake, the species, sex, age, body weight, presence or absence of underlying disease, pathology, etc. of the cancer patient. For example, the daily intake of an adult is preferably 1.0 to 100 mg / kg (body weight), more preferably 5.0 to 80 mg / kg (body weight), even more preferably 10 to 50 g / kg (body weight), and even more preferably 15 to 50 g / kg (body weight) in terms of mannooligosaccharides. Such a dosage can be administered once or in several divided doses.

[0048] The oral composition according to the present invention is preferably administered to humans or non-human animals, such as mammals including cows, pigs, horses, sheep, goats, monkeys, dogs, cats, rabbits, mice, rats, hamsters, and guinea pigs.

[0049] The oral composition according to the present invention is preferably an oral composition to be ingested by a cancer patient, and more preferably an oral composition to be ingested in combination with an anticancer drug. By being ingested in combination with an anticancer drug, fatigue caused by the anticancer drug can be improved more effectively. Ingestion in combination with an anticancer drug includes not only an embodiment in which the composition is orally administered simultaneously with the anticancer drug, but also an embodiment in which the composition is ingested independently of the anticancer drug during the treatment period with the anticancer drug.

[0050] The mannooligosaccharide content, ingredients other than mannooligosaccharides, dosage form, usage pattern, etc. of the blood glucose level improving agent for cancer patients according to the present invention, the liver glycogen amount improving agent for cancer patients according to the present invention, and the cancer cell proliferation inhibitor according to the present invention can be the same as those of the anti-fatigue agent according to the present invention. EXAMPLES

[0051] Next, the present invention will be described in more detail by showing examples, but the present invention is not limited to the following examples.

[0052] <Test animals> Eight-week-old male BALB / c mice (obtained from Japan SLC) were used in the experiment. The animals were kept in a constant environment with a 12-hour light / dark cycle (8:00-20:00) and a room temperature of 23±1°C. A maximum of six mice were kept per cage, and water and food were provided ad libitum. The experiment was conducted in accordance with the Tokyo University of Science animal experiment guidelines.

[0053] <Test cells> A mouse colon cancer cell line (C26; obtained from the RIKEN Bioresource Center) was used for the experiment. The cells were cultured in RPMI-1640 (containing L-glutamine and phenol red) medium (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) supplemented with penicillin-streptomycin (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and 10% fetal bovine serum (FBS; Lot#CP19-2870, manufactured by CAPRICORN SCIENTIFIC) in a 5% CO2, 37°C incubator.

[0054] <Reagents used> MOS powder (Ajinomoto AGF) and dextrin powder (Ajinomoto AGF) were used at the respective dosage settings. MOS powder is a dried powder of MOS sugar liquid (25% by mass of solids is mannose, and 75% by mass is β-1,4-mannooligosaccharides with DP2 to DP10) obtained by re-extracting coffee extract residue under high temperature and pressure, and purifying the extract using activated carbon and ion exchange resin.

[0055] <Feed used> D10001Rpx (manufactured by Research Diet) was used as the feed. This feed was made by removing carbohydrates from rodent feed (AIN-76A) developed by the National Institute of Nutrition, and its composition is shown in Table 1. Corn starch "whey" (manufactured by Pfizer) was used as the carbohydrate for the corn starch. A feed containing 60% by mass of corn starch and 40% by mass of D10001Rpx was used as the standard feed in the experiment. The MOS-containing feed was prepared by adding MOS powder to the standard feed at doses of 1% by mass and 5% by mass. In addition, a feed containing 5% by mass of dextrin, an additive in MOS powder, was used. The composition of each feed is shown in Table 2.

[0056] [Table 1]

[0057] [Table 2]

[0058] <Statistical processing> Data are shown as mean ± standard error (SEM). One-way analysis of variance was used for statistical testing of data, with the Bonferroni method used as post hoc test. All statistical analyses were performed using Prism version 8 (GraphPad Software).

[0059] [Example 1] We administered MOS to cancer-induced fatigue model mice and examined its effect on improving fatigue.

[0060] <Cancer-induced fatigue model mouse> The cancer-induced fatigue model mice were generated using C26 cells (5.0 × 10 5 C26 cells were suspended in phosphate-buffered saline (PBS; Fujifilm Wako Pure Chemical Industries, Ltd.) at 5.0 × 10 5The mice were administered a dose of 100 μL (cells / 100 μL). To determine whether the administration was successful in the tumor-bearing model, the lungs were harvested, the nodules were fixed with Bouin's solution, and the number of nodules was counted 72 hours later. The mice were allowed to feed ad libitum using a powder feeder (Shinano Seisakusho) for 14 days from the start of the experiment, and the amount of food consumed was measured every two days.

[0061] <Fatigue evaluation using a treadmill system> Using the prepared cancer-induced fatigue model mice, fatigue was evaluated using a treadmill system. The experimental schedule is shown in Figure 1. One day before the start of the test ("Pre-Treadmill" in Figure 1), a running experiment using the treadmill system was conducted. The running experiment mode is shown in Table 3. First, animals that could run were selected by a 10-minute practice run, and then the running distance and running time until exhaustion were measured with acceleration of 2 m / min every 4 minutes with a 10° incline. In addition, exhaustion was defined as a state in which the animal remained in the current area for about 10 seconds continuously. On the next day (day 0), C26 cells were administered, and on the 13th day (day 13) after the start of the test, a running experiment using the treadmill was conducted again. Using the values ​​of the running distance and running time, the running endurance rate (%) was calculated from the following formula.

[0062]

number

[0063] [Table 3]

[0064] A group that was administered PBS on Day 0 and fed a standard diet (PBS_ND group), a group that was administered C26 cells and fed a standard diet (C26_ND group), a group that was administered C26 cells and fed a 1% MOS diet (C26_1%MOS group), a group that was administered C26 cells and fed a 5% MOS diet (C26_5%MOS group), and a group that was administered C26 cells and fed a 5% Dextrin diet (C26_5%Dext group) were set up, and fatigue was evaluated in a running experiment using a treadmill (n = 6). The results (mean ± SEM) are shown in Fig. 2 (in the figure, ***: p < 0.005 vs. PBS_ND group, +: p < 0.05 vs. C26_ND group).

[0065] As shown in Fig. 2(A) and Fig. 2(B), a significant decrease in running endurance was observed in the C26_ND group compared to the PBS_ND group. Also, the fatigue-like behavior caused by C26 cell administration was significantly improved in the MOS-containing diet groups (Fig. 2(A) and Fig. 2(B)), but not in the group (C26_5%Dext group) that ingested a 5% Dextrin diet containing dextrin, which is a major additive of MOS powder, instead of MOS powder (Fig. 2(B)). From these results, it was found that MOS has an effect of improving cancer-induced fatigue.

[0066] [Example 2] MOS was added to the culture solution of C26 cells to examine the effect of MOS on cancer cells. Specifically, the cell viability at each concentration of MOS (equivalent to 0.01 - 100 mM) was measured using a Cell Counting kit-8.

[0067] <Measurement of cell viability by WST-8>[ C26 cells were seeded (4×10 4 cells / cm 2 ) in a 96-well plate (manufactured by AS ONE Corporation). After incubation for 48 hours, the medium was removed, and MOS at each concentration (0.01 - 100 mM) dissolved in a new medium was added. Further, after 24 hours, a color reaction with WST-8 (manufactured by Dojindo Laboratories) was performed for 1 hour, and then the absorbance (450 nm) was measured using a microplate reader (manufactured by Corona Electric Co., Ltd.) (n = 2 - 3).

[0068] The results of measuring the cell viability (%) of each cell type (mean ± SEM of three independent experiments) are shown in Figure 3 (***: p<0.005 vs. MOS 0mM administration group, ****: p<0.0001 vs. MOS 0mM administration group). As shown in Figure 3, the addition of 100mM equivalent of MOS caused a significant decrease in the viability of C26 cells. These results demonstrated that MOS does not have the effect of promoting the proliferation of cancer cells.

[0069] [Example 3] Cancer-induced fatigue model mice were made to take MOS, and blood glucose and blood lactate levels were examined. Cancer-induced fatigue model mice were made in the same manner as in Example 1.

[0070] Specifically, first, C26 cells (5.0 × 10 5 C26 cells / 100μL) was administered to the tail vein of mice. On day 0, three groups were administered PBS and standard feed (PBS_ND group), C26 cells and standard feed (C26_ND group), and C26 cells and 5% MOS feed (C26_5%MOS group). Blood was collected from the orbital plexus of the mice 14 days after administration, and blood glucose and lactate levels were measured (n=6). Blood glucose levels were measured using a commercially available measurement kit "Precision Exceed" (Abbott Japan), and lactate levels were measured using a commercially available measurement kit "Lactate Pro 2" (Arkray).

[0071] The measurement results of blood glucose and blood lactate levels (mean ± SEM) for each group are shown in Figure 4 (A) and Figure 4 (B), respectively (in the figures, *: p<0.05 vs. PBS_ND group, +: p<0.05 vs. C26_ND group). As shown in Figure 4, blood glucose levels were significantly lower and blood lactate levels were significantly higher in the C26_ND group compared to the PBS_ND group. On the other hand, blood glucose and blood lactate levels in the C26_5%MOS group were both similar to those in the PBS_ND group. From these results, it was confirmed that the fatigue state caused by the administration of C26 cells, specifically, the decrease in blood glucose levels and the increase in blood lactate levels, were improved by the administration of MOS.

[0072] [Example 4] Cancer-induced fatigue model mice were made to take MOS, and the amount of glycogen in the liver was examined. Cancer-induced fatigue model mice were made in the same manner as in Example 1.

[0073] Specifically, first, C26 cells (5.0 × 10 5 cells / 100μL) was administered to the tail vein of mice. On day 0, a group was administered with PBS and given a standard feed (PBS_ND group), a group was administered with C26 cells and given a standard feed (C26_ND group), and a group was administered with C26 cells and given a 5% MOS feed (C26_5%MOS group). Livers were excised from the mice on the 14th day after administration, and the amount of liver glycogen was measured (n=6). The amount of liver glycogen was measured as follows. First, about 100mg of the excised liver was placed in a solution of 30% by mass potassium hydroxide aqueous solution to which sodium sulfate was added until saturation, and glycogen was extracted by treating at 100°C. The extracted glycogen was converted to glucose by adding concentrated sulfuric acid, and then colored with phenol. The absorbance of the obtained glucose solution was measured (maximum sensitivity wavelength 530nm) using an absorption spectrometer (manufactured by Ushio Inc.), and the amount of glycogen was calculated. Statistical significance was determined by one-way analysis of variance using the Bonferroni test.

[0074] The measurement results of liver glycogen amount in each group (mean ± SEM) are shown in Figure 5 (in the figure, *: p<0.05 vs. PBS_ND group). As shown in Figure 5, a significant decrease in liver glycogen amount was observed in the C26_ND group compared to the PBS_ND group. On the other hand, although no significant difference was observed in the C26_5%MOS group, the liver glycogen amount that decreased in the C26_ND group increased. From these results, it was confirmed that the fatigue state caused by the administration of C26 cells, specifically, the decrease in liver glycogen amount, was improved by the administration of MOS.

Claims

1. An anti-fatigue agent for cancer-related fatigue, containing indigestible oligosaccharides as its active ingredient.

2. An anti-fatigue agent for cancer-related fatigue, comprising as an active ingredient an oligosaccharide having a mannose ratio of 50% by mass or more.

3. The anti-fatigue agent according to claim 2 , wherein the oligosaccharide is derived from coffee beans.

4. A blood sugar level improving agent for cancer patients, comprising as an active ingredient an oligosaccharide having a mannose ratio of 50% by mass or more.

5. An agent for improving liver glycogen levels in cancer patients, comprising as an active ingredient an oligosaccharide having a mannose ratio of 50% by mass or more.

6. An oral composition for improving cancer-related fatigue, comprising indigestible oligosaccharides as an active ingredient.

7. An oral composition for improving cancer-related fatigue, comprising an oligosaccharide having a mannose ratio of 50% by mass or more as an active ingredient.

8. The oral composition of claim 7 , which improves blood glucose levels or liver glycogen levels in cancer patients.

9. The oral composition according to claim 6 or 7, which is taken in combination with an anticancer drug.

10. The oral composition according to claim 6 or 7, which is a food or drink.

11. 8. The oral composition of claim 6 or 7, which is a dietary supplement.

Images