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WO2008034117A2 - Procédés d'utilisation de peptides de soja pour inhiber l'acétylation de h3, réduire l'expression de hmg-coa réductase et augmenter le récepteur ldl et l'expression sp1 chez un mammifère - Google Patents

Procédés d'utilisation de peptides de soja pour inhiber l'acétylation de h3, réduire l'expression de hmg-coa réductase et augmenter le récepteur ldl et l'expression sp1 chez un mammifère Download PDF

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Publication number
WO2008034117A2
WO2008034117A2 PCT/US2007/078585 US2007078585W WO2008034117A2 WO 2008034117 A2 WO2008034117 A2 WO 2008034117A2 US 2007078585 W US2007078585 W US 2007078585W WO 2008034117 A2 WO2008034117 A2 WO 2008034117A2
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lunasin
mammal
expression
soy
peptides
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PCT/US2007/078585
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English (en)
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WO2008034117A3 (fr
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Alfredo Flores Galvez
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Alfredo Flores Galvez
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Priority claimed from US11/532,528 external-priority patent/US7731995B2/en
Application filed by Alfredo Flores Galvez filed Critical Alfredo Flores Galvez
Publication of WO2008034117A2 publication Critical patent/WO2008034117A2/fr
Publication of WO2008034117A3 publication Critical patent/WO2008034117A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • This disclosure relates generally to a class of peptides that provide mammals with a variety of health related benefits. More specifically, the present disclosure related to using soy peptides to inhibit H3 acetylation, reduce expression of HMG-CoA reductase and increase LDL receptor and Sp1 expression in a mammal. [0004] BACKGROUND ART
  • the present invention relates generally to a class of peptides that provide mammals with a variety of health related benefits. More specifically, the present invention involves using soy peptides to inhibit H3 acetylation, reduce expression of HMG-CoA reductase and increase LDL receptor and Sp1 expression in a mammal.
  • a method of inhibiting PCAF from acetylating H3 in a mammal includes providing an effective amount of lunasin peptides to a mammal to inhibit H3 acetylation in the mammal.
  • a method of reducing expression of HMG-CoA reductase in a mammal includes providing an effective amount of lunasin peptides to a mammal to reduce expression of HMG-CoA reductase in the mammal.
  • a method of increasing LDL receptor expression in a mammal includes providing an effective amount of lunasin peptides to a mammal to increase LDL receptor expression in the mammal.
  • a method of increasing Sp1 transcriptional activator expression in a mammal includes providing an effective amount of lunasin peptides to a mammal to increase Sp1 transcriptional activator expression in the mammal.
  • the effective amount of lunasin peptides that inhibit H3 acetylation, reduce expression of HMG-CoA reductase, increase LDL receptor expression or increases Sp1 transcriptional activator expression in a mammal is 25 to 100 mg daily.
  • the lunasin peptides include lunasin peptides or lunasin peptide derivatives.
  • the lunasin peptides are obtained from, soy, seed bearing plants other than soy, using recombinant DNA techniques and synthetic polypeptide production or any combination thereof.
  • the method includes providing an effective amount of one or more protease enzyme inhibitors to the lunasin peptides.
  • Figure 1 shows the 2S albumin protein encoded by Gm2S 1 cDNA (SEQ ID NO 2). Arrows indicate endoproteolytic sites that give rise to small subunit (lunasin) (SEQ ID NO 2) and the large subunit (methionine rich protein). Important regions in both subunits are indicated.
  • FIG. 2 is a photograph of a Western blot analysis (top) and a table (below) showing densitometer values indicating the relative levels of expression of HMG-CoA reductase in HepG2 cells that were (CFM+LS (24)) or were not (CFM) treated with lunasin for 24 hours prior to incubation in cholesterol free media (CFM) for 24 hours to activate sterol regulatory element binding proteins (SREBP.) After incubations, total protein was extracted and 10 ug protein was loaded onto 10% Tris-glycine gels, electroblotted onto nitrocellulose membrane, and immunostained with primary antibodies raised against HMG-CoA reductase and actin (to show equal loading of proteins.) Spot densitometer values represent mean and standard deviation of data from three separate experiments.
  • FIG. 3 is a photograph of a Western blot analysis (top) and a table (below) showing densitometer values indicating the relative levels of expression of LDL receptor in HepG2 cells that were (CFM +LS(24)) or were not (CFM) treated with lunasin for 24 hours prior to incubation in cholesterol free media (CFM) for 24 hours to activate SREBP. After incubations, total protein was extracted and 10 ug protein was loaded onto 10% Tris-glycine gels, electroblotted onto nitrocellulose membrane, and immunostained with primary antibodies raised against LDL-receptor and actin (to show equal loading of proteins.) Spot densitometer values represent mean and standard deviation of data from three separate experiments.
  • Figure 4 is a photograph of a Western blot analysis (top) and a table (below) showing densitometer values indicating the relative levels of expression of Sp1 in HepG2 cells that were grown from confluence in growth media for 24 hours before growth media was replaced with fresh growth media (Media), media with lunasin (Media + LS) or cholesterol free media with lunasin (CFM +LS) or without lunasin (CFM). Samples were then incubated for 24 or 48 hours as indicated.
  • Media fresh growth media
  • Media + LS media with lunasin
  • CFM +LS cholesterol free media with lunasin
  • CFM lunasin
  • FIG. 5 shows the western blots from experiments on PCAF reaction products demonstrating that lunasin caused a dramatic reduction in histone H3 acetylation.
  • Acid extracted protein from untreated (untrt) HeLa cells was used as template in histone acetylase reactions using HAT enzyme, PCAF, in the presence or absence of 10 uM lunasin. Reaction products were immunoblotted and stained with antibodies against diacetylated histone H3.
  • Untrt (-) is the histone template control
  • NaB (+) correspond to acid extracted histones from NaButyrate treated HeLa cells (positive control). Boxed signal indicates significant decrease in H3 acetylation upon addition of 10 uM lunasin compared with no lunasin application. Numbers in parenthesis indicate densitometer readings relative to the untreated control (set as 1 ) in PCAF HAT reaction products.
  • FIG. 6 shows the western blots from experiments on PCAF HAT reaction products demonstrating that lunasin caused a dramatic reduction in histone H3 acetylation.
  • Acid extracted histones isolated from untreated (untrt) HeLa cells were used in PCAF HAT reactions, immunoblotted and stained with antibodies to H3 Ac-Lys9 and H3 Ac-Lys14.
  • Untrt (-) is the histone template control
  • NaB (+) correspond to acid extracted histones from NaButyrate treated HeLa cells (posititve control)
  • + Lun correspond to 10 uM lunasin treated histone template
  • - Lun correspond to non- lunasin treated.
  • Boxed signal indicate decreased H3 Lys 14 acetylation by PCAF acetylase enzyme in the presence of lunasin. Numbers in parenthesis indicate densitometer readings relative to the signal level of lunasin/lunasin treatment (set as 1 ) in immunoblots stained with Ac-Lys14 H3.
  • This biological model was chosen because activation of SREBPs by sterol depletion results in the increased acetylation of histone H3 but not histone H4, by the histone acetylase enzyme PCAF, in chromatin proximal to the promoters of HMG-CoA reductase and the LDL receptor genes (8) and SREBP activation results in the increased recruitment of co-regulatory factors, CREB to the promoter of HMG-CoA reductase gene, and Sp1 to the promoter of LDL receptor gene (8).
  • Fig. 1 shows the 2S albumin protein and the small lunasin subunit. It has been shown that constitutive expression of the lunasin gene in mammalian cells disturbs kinetochore formation and disrupts mitosis, leading to cell death (2). When applied exogenously in mammalian cell culture, the lunasin peptide suppresses transformation of normal cells to cancerous foci that are induced by chemical carcinogens and oncogenes.
  • lunasin (a) is internalized through its RGD cell adhesion motif, (b) colocalizes with hypoacetylated chromatin in telomeres at prometaphase, (c) binds preferentially to deacetylated histone H4, which is facilitated by the presence of a structurally conserved helical motif found in other chromatin-binding proteins, (d) inhibits histone H3 and H4 acetylation, and (e) induces apoptosis in E1 A-transfected cells (4).
  • a method of inhibiting H3 acetylation in a mammal includes providing an effective amount of lunasin peptides to a mammal to inhibit H3 acetylation in the mammal.
  • a method of reducing expression of HMG-CoA reductase in a mammal includes providing an effective amount of lunasin peptides to a mammal to reduce expression of HMG-CoA reductase in the mammal.
  • a method of increasing LDL receptor expression in a mammal includes providing an effective amount of lunasin peptides to a mammal to increase LDL receptor expression in the mammal.
  • a method of increasing Sp1 transcriptional activator expression in a mammal is provided. The method includes providing an effective amount of lunasin peptides to a mammal to increase Sp1 transcriptional activator expression in the mammal.
  • the effective amount of lunasin peptides that inhibit H3 acetylation, reduce expression of HMG-CoA reductase, increase LDL receptor expression or increases Sp1 transcriptional activator expression in a mammal is 25 to 100 mgs daily. It should be appreciated that the effective amount of lunasin will depend, at least in part, on the size, weight, health and desired goals of the mammals consuming the compositions. Accordingly, it is believed that in at least one embodiment, the effective amount of lunasin provided to the mammal is 25 mg to 100 mg daily.
  • the lunasin peptides include lunasin peptides or lunasin peptide derivatives. It should also be appreciated that the present invention includes the use of lunasin peptide derivatives, which are any peptides that contain the same functional units as lunasin. It should also be appreciated the products and compositions of the present invention can be used in, foods, powders, bars, capsules, shakes and other well known products consumed by mammals or used separately.
  • the lunasin peptides are obtained from, soy, seed bearing plants other than soy, using recombinant DNA techniques and synthetic polypeptide production or any combination thereof.
  • the method includes providing an effective amount of one or more protease enzyme inhibitors with or without the lunasin peptides.
  • the protease enzyme inhibitors act to protect lunasin from digestion and facilitate absorption and delivery to the appropriate target areas.
  • appropriate protease enzyme inhibitors include, but are not limited to, pancreatin, trypsin and/or chymotrypsin inhibitors. It should be appreciated that the scope of the present inventions includes the use of the lunasin and/or lunasin derivatives with any other composition or product that is known or believed to facilitate lunasin's absorption or delivery in a mammal.
  • SREBP Sterol Regulatory Element-Binding Protein -1 and -2
  • HepG2 cells (1 x 10 6 ) were treated with or without 10 uM synthetic lunasin in DMEM with 10% FBS for 24 hours before growth media was replaced with cholesterol-free media to activate SREBP. After 24 hours, total protein was extracted and 10 ug protein was loaded onto 10% Tris-glycine gels, electroblotted onto nitrocellulose membrane, and immunostained with primary antibodies raised against HMG-CoA reductase and actin (to show equal loading of proteins). Spot densitometer values are obtained by digital scanning and Un-Scan It software, and represent mean and standard deviation of data from three separate experiments. The results are shown in Figure 2.
  • FIGs 2 and 3 show the upregulation of HMG-CoA reductase (98% increase) and LDL-receptor (34% increase) when HepG2 cells are grown in cholesterol-free media for 24 hours.
  • lunasin is added to the cholesterol-free media
  • the expression of the HMG-CoA reductase is reduced by more than 50% ( Figure 2)
  • the expression of LDL-receptor has increased by more than 60% ( Figure 3).
  • This effect of lunasin is similar to statin drugs that reduces endogenous cholesterol synthesis by inhibiting HMG-CoA reductase activity, which leads to increased LDL receptor expression.
  • statin drugs that reduces endogenous cholesterol synthesis by inhibiting HMG-CoA reductase activity, which leads to increased LDL receptor expression.
  • the mode of action of lunasin is believed to differ from statin drugs in that it appears to inhibit expression of HMG-CoA reductase at the transcriptional level, rather than on inhibiting its enzyme activity.
  • lunasin up regulates the expression of LDL-receptor gene.
  • SREBP activation of LDL-receptor by sterol depletion requires increased recruitment of Sp1 co-activator to a site adjacent to SREBP in the promoter/regulatory sequence of LDL-receptor gene (25).
  • the up regulation of LDL-receptor by lunasin (LS) in cholesterol-free media may be due to increased availability and recruitment of the Sp1 coactivator to the LDL-receptor promoter/regulatory sequence.
  • the level of Sp1 was determined in lunasin-treated growth media and cholesterol-free media by Western analysis using Sp1 antibody, as follows: HepG2 cells (1 x 10 6 ) were grown from confluence in DMEM with 10% FBS for 24 hours before growth media was replaced with fresh growth media or cholesterol-free media (to activate SREBP) and treated with, or without 10 uM synthetic lunasin. After 24 hours, total protein was extracted from each treatment and 10 ug protein loaded onto 10% Tris-glycine gels, electroblotted onto nitrocellulose membrane, and immunostained with primary antibodies raised against Sp1 and actin (to show equal loading of proteins). Spot densitometer values were obtained by digital scanning and Un-Scan It software and represent data from one experiment.
  • FIG. 4 shows that Sp1 levels in control and lunasin-treated growth media were not significantly different. However, Sp1 levels increased in cholesterol-free media by 23%, compared to the growth media. The addition of lunasin in the cholesterol-free media further increased Sp1 levels by almost 60%, which closely mirrors the increase in LDL-receptor levels in lunasin-treated, cholesterol-free media.
  • the data from these experiments indicate that the increase in LDL-receptor expression by lunasin in sterol-depleted media could be attributed to the increased availability of the Sp1 transcriptional co-activator.
  • the other (II) is electroblotted onto nitrocellulose membrane and incubated with affinity-purified lunasin polyclonal antibody (Pacific Immunology, Ramona, California) followed by HRP-conjugated donkey anti-rabbit secondary antibody (Amersham Biosciences, Piscataway, New Jersey).
  • lunasin immunosignals (indicated by arrow) are detected using the ECL Western blotting kit from Amersham.
  • Formulated lunasin-enriched soy concentrate (LeSC) and LeSC supplemented with soy flour (SF) contain significant amounts of lunasin.
  • This experiment evaluated the amount of lunasin in lunasin-enriched soy concentrate (LeSC) and LeSC supplemented with soy flour.
  • Lunasin-enriched soy concentrate was produced by first identifying commercially available soy protein preparations that contain significant amounts of lunasin by Western blot analysis using lunasin polyclonal antibody, as described in Example 3. The soy protein concentrate identified to contain the most lunasin was used as starting material in a one-step buffer extraction procedure (0.1 X PBS pH 7.2) followed by centrifugation to separate the supernatant. Two volumes of acetone were added to supernatant and precipitate was separated by centrifugation with filter bags before vacuum drying to get the lunasin-enriched soy concentrate.
  • compositions of the present invention that comprise naturally derived lunasin can be optimized for use in particular methods of the present invention by varying the amount of total protein and lunasin content, which can be controlled by the amount of soy concentrate used, and varying the amount of lunasin protection from digestion, which can be controlled by the amount of minimally heated soy flour used.
  • a composition comprising lunasin and soy flour is optimized through preparation methods describe herein or known to one skilled in the art, to have a level of protease inhibitors sufficient to protect lunasin biological activity during digestion but not sufficient to have levels of anti-nutritional elements that are undesirable for oral use.
  • the present invention teaches improved methods of determining lunasin concentration in starting materials and final products of the present invention, so as to maximize the concentration of lunasin and therefore the activity of compositions of treatment in cholesterol related applications.
  • the ratio of soy flour to soy concentrate is between 10:90 and 50:50, more preferably between 20:80 and 40:60, more preferably approximately 30:70 soy floursoy concentrate. This ratio for minimally heated soy flour and soy concentrate was determined to provide a biologically active concentration of lunasin and as well as sufficient protection from digestion by the soy flour.
  • Synthetic lunasin reduced acetylation of histone H3 by the histone acetylase enzyme, PCAF, using core histones isolated from chicken erythrocyte (Upstate/Millipore, Billerica, MA) as template for the HAT assay.
  • PCAF histone acetylase enzyme
  • Around 10 ug of sample protein was incubated with 1 ug of core histones before undergoing HAT reaction with PCAF enzyme and acetyl CoA substrate. Reaction products were run on 16% Tris-Tricine gels and electroblotted onto nitrocellulose membrane.
  • Partial digestion of formulated LeSC + SF increases biological activity of lunasin.
  • a confirmatory experiment to determine the biological activity of digested and undigested LeSC and LeSC + SF was conducted using a different core histone template. This time we used the core histones extracted from HeLa tumor cells. Unlike the chicken erythrocyte cells, core histones from sodium butyrate treated HeLa cells are commercially available (Upstate/Millipore, Piscataway, NJ), and can be used as a positive control for histone acetylation. The core histones isolated from untreated HeLa cells were used as a negative control (low levels of histone acetylation) and as template for the HAT assay.
  • the HAT bioactivity assay was conducted using acid extracted core histones from HeLa cells (Upstate/Millipore) as a template (temp (-) control) for the PCAF catalyzed HAT reaction.
  • Core histones from sodium butyrate (NaB) treated HeLa cells were used as a positive control since NaB is a histone deacetylase inhibitor known to increase histone acetylation.
  • the inhibitory effect of synthetic lunasin (+synL) on histone H3 acetylation by PCAF was used to compare the effect of lunasin-enriched soy concentrate (A), digested LeSC (A dig), LeSC + SF (B) and digested LeSC + SF (B dig).
  • LeSC and LeSC + SF were partially digested by adding pancreatin at 1 :0.5 (w/w) and incubating at 38 0 C for 15 min.
  • the numbers below the legend indicate relative densitometer readings normalized using immunosignal from the template (temp). Low numbers indicate presence of lunasin biological activity.
  • LeSC + SF was partially digested by mixing it with freshly prepared pancreatin solution (10 ug/mL of distilled water) in a 1 :0.5, (w/w) ratio. Mixture was incubated at 38 0 C for 15 min. before proteases and digestive enzymes were inactivated by boiling for 5 min and then quenching in ice. Under these digestion conditions the lunasin in the LeSC soy extract was digested and inactivated while that of LeSC + SF were more biologically active. However, the conditions for the partial digestion of LeSC + SF has to be determined empirically by analyzing digestion products for lunasin content and biological activity using the HAT assay.
  • Variations in the sources of pancreatin and protease enzymes, the age of the protease enzyme, or incubation conditions can lead to variability in digestion conditions. For example, the use of one month old preparations of pancreatin for partial digestion led to the degradation and loss of activity of lunasin under similar incubation conditions described above. Therefore, in a preferred embodiment of the present invention, acceptable ranges for concentration of and incubation time with the protease enzymes are determined using an assay such as the HAT assay used above to evaluate biological activity of the treated compositions.
  • Chymotrypsin inhibitors protect the bioactivity of lunasin. To determine which protease inhibitors found in soy protects lunasin from digestion, soybean trypsin inhibitor and trypsin + chymotrypsin inhibitors were obtained from Sigma and mixed with LeSC on 1 :1 w/w ratio. The mixtures were digested with pancreatin, and digestion products immunostained with lunasin antibody.
  • HAT bioactivity assay was conducted using core histones from chicken erythrocyte cells (Upstate/Millipore) as a template for the PCAF catalyzed HAT reaction.
  • the inhibitory effect of synthetic lunasin (+synL) on histone H3 acetylation by PCAF as compared to the negative untreated control (- synL) was used to compare the effect of digested LeSC (A), digested LeSC + try + chy (B), digested LeSC + try (C), undigested LeSC (D) and undigested LeSC +SF (E.)
  • the results showed that in the LeSC ⁇ trypsin + chymotrypsin inhibitors sample lunasin was better protected from digestion than in the LeSC ⁇ trypsin inhibitor sample.
  • Reaction mixture was incubated at 3O 0 C while shaking at 250 rpm for 1 h. Reaction was stopped by adding Laemmli stop buffer (1 :1 v/v) with beta- mercaptoethanol, and boiling for 5 min. before quenching in ice for 15 min.
  • the products of PCAF HAT reaction were run on 16% SDS-PAGE, blotted onto nitrocellulose membrane and immunostained with primary antibodies raised against diacetylated histone H3 (Ac-Lys 13 + Ac-Lys14 H3) followed by HRP-conjugated anti- rabbit secondary antibody.
  • the in vivo activity of the presently described compositions, as well as treatment utilization of kits and treatment methods, may be optionally determined by either of the following procedures.
  • Male dogs (beagles, ranging from about 9 to about 14 kilograms, 1 to 4 years old) are fed a standard dog feed supplemented with 5.5% lard and 1 % cholesterol. Baseline blood samples are drawn from fasted dogs prior to initiating the study to obtain reference values for plasma cholesterol. Dogs are then randomized to groups of five animals with similar plasma cholesterol levels. The animals are dosed in accordance with a treatment method described herein immediately prior to diet presentation for seven days. Blood samples are obtained 24 hours after the last dose for plasma cholesterol determinations. Plasma cholesterol levels are determined by a modification of the cholesterol oxidase method using a commercially available kit.
  • hamsters are separated into groups of six and given a controlled cholesterol diet containing 0.5% cholesterol for seven days. Diet consumption is monitored to determine dietary cholesterol exposure.
  • the animals are dosed in accordance with a treatment method described herein once daily beginning with the initiation of diet. Dosing is by oral gavage. All animals moribund or in poor physical condition are euthanized. After seven days, the animals are anesthetized by intramuscular (IM) injection of ketamine and sacrificed by decapitation. Blood is collected into vacutainer tubes containing EDTA for plasma lipid analysis and the liver is excised for tissue lipid analysis.
  • IM intramuscular
  • Lipid analysis is conducted as per published procedures (e.g., Schnitzer-Polokoff et al., Comp. Biochem. Physiol., 99A, 4 (1991 ), pp. 665-670 and data is recorded as percent reduction of lipid versus control.

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Abstract

Selon l'invention, des études contrôlées révèlent que des procédés utilisant des peptides se rapportant au soja inhibent l'acétylation de H3, réduisent l'expression de la réductase HMG-CoA et augmentent le récepteur LDL et l'expression Sp1 chez les mammifères. L'invention concerne d'une manière générale l'utilisation de peptides de lunasine et/ou de dérivés de peptides de lunasine pour 1) inhiber l'acétylation de H*, 2) réduire l'expression de la réductase HMG-CoA, 3) augmenter l'expression du récepteur LDL ou 4) augmenter l'expression Sp1 chez un mammifère. Dans au moins un mode de réalisation, à titre d'exemple, l'invention concerne une dose efficace de peptides de lunasine ou de dérivés de peptides de lunasine et au moins un inhibiteur d'enzyme qui sont fournis à un mammifère pour 1) inhiber l'acétylation de H3, 2) réduire l'expression de la réductase HMG-CoA, 3) augmenter l'expression du récepteur LDL ou 4) augmenter l'expression Sp1 chez un mammifère.
PCT/US2007/078585 2006-09-16 2007-09-15 Procédés d'utilisation de peptides de soja pour inhiber l'acétylation de h3, réduire l'expression de hmg-coa réductase et augmenter le récepteur ldl et l'expression sp1 chez un mammifère WO2008034117A2 (fr)

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US96652906P 2006-09-16 2006-09-16
US11/532,528 2006-09-16
US11/532,528 US7731995B2 (en) 2006-09-16 2006-09-16 Methods for using soy peptides to inhibit H3 acetylation, reduce expression of HMG CoA reductase, and increase LDL receptor and Sp1 expression in a mammal
US60/966,529 2006-09-16

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Publication number Priority date Publication date Assignee Title
WO2001072784A2 (fr) * 2000-03-24 2001-10-04 Filgen Biosciences, Inc. Therapie anti-cancereuse : peptides therapeutiques avec motif se liant specifiquement a des histones h3 et h4 non acetyles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072784A2 (fr) * 2000-03-24 2001-10-04 Filgen Biosciences, Inc. Therapie anti-cancereuse : peptides therapeutiques avec motif se liant specifiquement a des histones h3 et h4 non acetyles

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