CN117482079A - Application of nobiletin in treating amyotrophy - Google Patents

Application of nobiletin in treating amyotrophy Download PDF

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Publication number
CN117482079A
CN117482079A CN202310360504.3A CN202310360504A CN117482079A CN 117482079 A CN117482079 A CN 117482079A CN 202310360504 A CN202310360504 A CN 202310360504A CN 117482079 A CN117482079 A CN 117482079A
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China
Prior art keywords
nobiletin
skeletal muscle
protein
group
nob
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CN202310360504.3A
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Chinese (zh)
Inventor
任发政
孙亚楠
李依璇
王惠惠
王然
王鹏杰
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China Agricultural University
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China Agricultural University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

The invention provides an application of nobiletin in treating amyotrophy. The invention explores the influence of the nobiletin on the anabolism and catabolism of intramuscular proteins from the synthesis and decomposition of proteins respectively. The results show that nobiletin activates the classical signal path mTOR/AKT/P70S6K for regulating protein synthesis, and inhibits the protein degradation path FoXO3/MURF1/MAFBX through anti-inflammatory action, and the results suggest that Nob has potential for being applied to preparing muscle-increasing foods or medicines.

Description

Application of nobiletin in treating amyotrophy
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a new application of nobiletin.
Background
Sarcopenia (sarcopenia) is an aging disease in which muscle mass, strength and function are reduced, and in addition to severely damaging the mobility of the body, a variety of chronic diseases are induced, which impair the health of the body. With the increasing population aging, the number of elderly population over 60 years of the world is expected to double over the next 30 years of age, and the prevalence of sarcopenia will increase from 5000 tens of thousands in 2010 to 2 million in 2050. Sarcopenia not only impairs the mobility of the elderly, but also increases falls, fractures, disabilities and high mortality. In addition, sarcopenia is also associated with various diseases such as osteoporosis, heart disease, respiratory diseases and cognitive disorders, not only severely reducing the quality of life of the elderly but also increasing the economic cost year by year.
In clinical practice for the treatment of sarcopenia, the treatment regimen mainly consists of supplementation with proteins, amino acids, vitamin D, creatine, etc., and increases muscle mass and strength through resistance training. However, the elderly suffer from poor digestion and absorption of nutrients and poor mobility, and thus the therapeutic effect is not ideal. To date, there is no guideline approved drug for the treatment of sarcopenia. In clinical experiment medicines for sarcopenia, most of hormone medicines such as testosterone, growth hormone, insulin and the like, no enough evidence is provided for proving the effectiveness of any medicine, and the side effect on organisms is large. Therefore, there is a great need to develop new drugs or treatments.
Nobiletin (Nob) is a flavonoid small molecule with various biological activities in citrus peel, and has reported functions of resisting oxidation, resisting inflammation, improving mitochondrial productivity and the like. The main pathogenesis of sarcopenia is protein catabolism greater than anabolism, resulting in reduced myofibrillar protein content. Excessive oxidation, inflammation, is the primary cause of induction of protein degradation. Therefore, the nobiletin can effectively prevent the degradation of myofiber protein, thereby realizing the function of delaying the occurrence of sarcopenia.
Disclosure of Invention
The invention provides an application of nobiletin in treating amyotrophy. The invention develops animal experiments to intervene in the D-galactose induced myopic mice with nobiletin. 45 male C57BL/6J mice at 8 weeks of age were randomly divided into three groups: normal control group, D-galactose group, D galactose+nobiletin treated group. After the D-galactose and the nobiletin are intervened for 10 weeks, the results show that compared with a control group, the weight, lean meat percentage and skeletal muscle weight of each part of lower limbs of the D-galactose group mice are obviously reduced, the cross-sectional area of tibialis anterior myofiber is obviously reduced, the content of proteins of each component of myofibril is obviously reduced, and the physiological indexes can be obviously improved by the nobiletin intervention. The results show that the nobiletin disclosed by the invention can effectively treat amyotrophy.
Specifically, the invention provides the following technical scheme:
in a first aspect, there is provided the use of nobiletin in the manufacture of a medicament for the treatment of skeletal muscle atrophy; specifically, the nobiletin reverses skeletal muscle atrophy by increasing myofibrillar constituent protein expression and increasing the cross-sectional area of the myofibers.
In one embodiment, the myofibril constitutive protein comprises one or more of ACTA1, TMP1, TNNC2, TNNT1, TNNT3, MYH1, MYH2, MYH 4.
In a second aspect, there is provided the use of nobiletin in the preparation of a formulation for inhibiting skeletal muscle degradation protein expression or function; in particular, the skeletal muscle degrading proteins include one or more of FoXO3, MAFBX, MURF 1.
In a specific embodiment, nobiletin reduces its function by reducing the phosphorylation level of FoXO 3.
In another embodiment, nobiletin reduces the expression of MAFBX, MURF 1.
In a third aspect, there is provided the use of nobiletin in the preparation of a formulation for promoting the degree of phosphorylation of a key protein in skeletal muscle protein synthesis, said key protein being one or more of AKT, mTOR and P70S 6K.
In a fourth aspect, there is provided the use of nobiletin in the preparation of a formulation for reducing the concentration of inflammatory factors in serum; specifically, the inflammatory factors are one or more of TNF-alpha, IL-1 beta and LBP.
The beneficial effects of the invention are as follows:
nob intervention alleviates skeletal muscle atrophy caused by D-gal. Specific:
1) Myofibrils are the most abundant protein in muscle cells, and are also responsible for skeletal muscle movement, and Nob intervention increases the content of constituent proteins in myofibrillar proteins.
2) To clarify the mechanism of myogenic action of Nob, we explored the effects of Nob on intramuscularly protein anabolism and catabolism, respectively, from protein synthesis and breakdown. The results show that Nob activates the classical signaling pathway mTOR/AKT/P70S6K that regulates protein synthesis and inhibits the protein degradation pathway FoXO3/MURF1/MAFBX by anti-inflammatory effects.
Taken together, the results of the invention suggest that Nob has potential for application in preparing muscle-increasing foods or pharmaceuticals. Drawings
FIG. 1 effects of nobiletin on skeletal muscle mass: effects of (a) and (B) nobiletin on mouse body weight; (C) And (F) effects of nobiletin on mouse Gastrocnemius (GAS) mass and weight ratio; (D) And (G) the effect of nobiletin on the quality and weight ratio of the soleus muscle (Sol) of the mice; (E) And (H) the effect of nobiletin on lean muscle mass and weight ratio in mice.
FIG. 2 effect of nobiletin on tibialis anterior myofibrillar cross-sectional area: (A) Influence of nobiletin on the number of tibialis anterior muscle fibers; (B) And (C) a schematic view of tibialis anterior HE staining and a statistical view of the cross-sectional area of individual muscle fibers.
FIG. 3 effects of nobiletin on myofibrils: (A) myofibril SDS-PAGE electrophoresis; (B) Gray-scale statistics of the constituent proteins of myofibrils.
FIG. 4 effect of nobiletin on the synthesis of muscle cell proteins.
Detailed Description
The objects and functions of the present invention and methods for achieving these objects and functions will be elucidated with reference to the exemplary embodiments. However, the present invention is not limited to the exemplary embodiments disclosed below; this may be implemented in different forms. The essence of the description is merely to aid one skilled in the relevant art in comprehensively understanding the specific details of the invention.
1. Experimental materials
Nobiletin was purchased from derivative of Parker (IN 0210, medChemexpress) and D-galactose was purchased from Sigma (D-gal, G5388, sigma-Aldrich). An antibody: p-Ser2448-mTOR (5536T), p70S6K (9202S), p-p 70S6K (9234S), p-Ser473-AKT (4060S), AKT (4685S), p-FoxO3 (5538S), foxO3 (12829S), MAFBX (ab 168372), MURF1 (ab 172419), GAPDH (10494-1-AP) were purchased from Abcam, U.S. and U.S. Cell Signaling Technology and China Proteintech. Immunoblots, cell lysates (P0013B), protease inhibitors PMSF (ST 506), 5 XSDS-PAGE loading buffer (P0015L) were purchased from Shanghai Biyun biotechnology company. Mouse TNF-alpha ELISA kit (PT 512), IL-6 ELISA kit (PI 326) was purchased from Shanghai Biyun Biotech Co, cDNA reverse transcription kit (G592) was purchased from Aibi Meng Biotech Co., ltd., powerUp TM SYBR TM Green (A25742) was purchased from America Thermo Fisher Scientific A mouse LBP ELISA kit (ab 269542) was purchased from Abcam, america.
2. Animal experiment
2.1 grouping and administration of animals
45 male C57BL/6J mice at 8 weeks of age were randomized into three groups after one week of adaptive feeding: normal control group (CK, n=15), D-galactose model group (D-gal, n=15), D-galactose + nobiletin treated group (Nob, n=15). The D-gal group and Nob groups were intraperitoneally injected with 500mg/kg body weight of D-galactose daily for 10 weeks, and the CK group was injected with the same volume of physiological saline. After the group Nob mice were intraperitoneally injected with D-galactose, 100mg/kg body weight of nobiletin was lavaged. Every 5 mice were placed in a separate cage and the room was automatically controlled for illumination (12 hours light/dark cycle), temperature (24-26 ℃) and relative humidity (55-60%) with free access to food and water.
2.2HE staining
(1) Taking out tibialis anterior muscle from 70% ethanol, and sequentially soaking in 80% ethanol for 40min;95% ethanol for 60min; absolute ethanol I for 30min; absolute ethanol II for 30min; xylene I for 5min; xylene II for 5min; wax solution I for 60min; wax solution II for 60min.
(2) The wax solution is poured into the embedding box, and after the tissue block is placed, the wax holder is installed.
(3) The wax block was cut into continuous 4.5 μm wax strips with a manual microtome, and the wax strips were placed in a 42 ℃ water bath and allowed to adhere to the slide surface.
(4) Baking at 62deg.C for 60min.
(5) Sequentially immersing the slices in xylene I for 10min; xylene II for 10min; absolute ethanol I5 min; absolute ethanol II for 5min;95% ethanol I for 5min;95% ethanol II for 5min;80% ethanol for 5min;70% ethanol for 5min; distilled water for 5min.
(6) Dripping hematoxylin dye solution for dyeing for 1min; washing with distilled water for 2min for 3 times; differentiating the 1% hydrochloric acid alcohol solution for 5s; washing with distilled water for 3 times and 5min each time; dripping eosin dye liquor for dyeing for 1min; distilled water was washed 3 times for 2min each.
(7) Sequentially immersing the slices in 70% ethanol for 2s;95% ethanol for 5s; absolute ethanol for 5min; xylene I for 5min; xylene II for 5min;1 drop of neutral gum was added dropwise to the slide, the slide was blocked, and dried overnight. And observing and photographing under a microscope.
2.3 real-time fluorescent quantitative PCR
(1) Extracting RNA of a tibialis anterior sample by a Trizol method, and measuring the concentration and quality of the extracted RNA by an ultra-micro spectrophotometer;
(2) Mixing RNA samples with the reverse transcription kit as shown in the reagent instructionsII
SuperMix plus reagent, flick mix, and centrifuge; reverse transcription is carried out in a PCR instrument according to the conditions of a reagent instruction;
(3) According to the instruction, mixing water and fluorescent quantitative kit PowerUp TM SYBR TM Green reagent, upstream primer, downstream primer and cDNA sample, centrifuging; performing PCR amplification reaction in a fluorescent quantitative PCR instrument according to the conditions of a reagent specification; the results obtained were calculated and analyzed for significance using the GAPDH gene as an internal reference gene. Primer sequences are shown in the following table:
2.4 immunoblotting
Protein was separated by electrophoresis using SDS-PAGE gel (10% separation gel+5% concentration gel) under 90V 20min,120V 90min conditions; transferring the protein in the gel onto a PVDF membrane activated by methanol by a wet transfer method, wherein the transfer condition is 200mA for 2 hours; sealing PVDF film with 5% skimmed milk powder for 1h; diluting the primary antibody in a sealing solution at a ratio of 1:1000, and incubating overnight at 4 ℃; PBST membrane washing is carried out for 5 times, each time for 5min; diluting the HRP-labeled secondary antibody in a sealing solution at 1:5000, incubating overnight at 4 ℃, and washing the PBST film for 5 times, each time for 5min; the exposure was performed using ECL luminescence.
2.5 data statistics and analysis
Results are expressed as mean ± standard deviation, and group comparisons were performed using Graphpad prism 8.0 one-way analysis of variance (ANOVA). Differences between groups were compared using Duncan's post-hoc test. A value of p <0.05 is considered statistically significant.
3 results of experiments
3.1 effects of nobiletin on skeletal muscle quality
The weight gain per week was significantly lower in mice from the D-galactose model group (D-gal) than in the normal group (CK) and the nobiletin-interfered group (D-gal+ Nob) (p < 0.05), and there was no significant difference in the weight and weight gain in the D-gal+ Nob group compared to the CK group (FIGS. 1A and B). The lean mass of each group of mice is detected by the nuclear magnetic resonance of small animals, and the result shows that the lean mass and the weight ratio of the D-gal group of mice are obviously reduced (p is less than 0.05) compared with the CK group, and Nob intervention can effectively improve the lean mass (p is less than 0.05) of the D-galactose treated mice. The net weights and weight ratios of the gastrocnemius, soleus, and body weights of the mice in the D-gal group were significantly lower than those in the CK group, and Nob intervention significantly increased the net weights of the gastrocnemius and soleus muscles and their weight ratios (p < 0.05).
3.2 Effect of nobiletin on tibialis anterior myofibrillar cross-sectional area
The influence of the nobiletin on the quantity of muscle fibers and the cross-sectional area thereof is clear by panoramic scanning of tibialis anterior and HE staining. The results showed (fig. 2) that there was no significant difference in the number of muscle fibers of the tibialis anterior of each group of mice. The D-gal mice had a reduced tibialis anterior myofiber cross-sectional area compared to the CK group, and Nob intervention significantly increased the myofiber cross-sectional area (p < 0.05).
3.3 Effect of nobiletin on myogenic fibrin
The myofibrils of the tibialis anterior of each group of mice were extracted and subjected to SDS-PAGE, and the results showed that the expression level of the major constituent proteins of the myofibrils of the D-gal group, such as myosin heavy chain, myosin light chain, actin, etc., was reduced as compared with the CK group. The D-gal+ Nob mice had increased expression levels of each of the proteins described above as compared to the D-gal group (FIGS. 3A and B). D-galactose treatment reduced the transcript levels of actin (ACTA 1), tropomyosin (TMP 1), troponin (TNNC 1, TNNC2, TNNT1, TNNI1, TNNI 2) and myosin heavy chains (MYH 1, MYH2, MYH 4), and Nob intervention increased the transcript levels of ACTA1, TMP1, TNNC2, TNNT1, TNNT3, MYH1, MYH2, MYH4 (FIG. 3C).
3.4 Effect of nobiletin on the Synthesis of muscle cell protein
The effect of Nob on the phosphorylation degree of the key protein synthesized by the skeletal muscle protein of the mice and the total protein expression amount is detected by using an immunoblotting method. As shown in fig. 4, the degree of phosphorylation of AKT, mTOR and P70S6K was significantly down-regulated in the D-gal group compared to the CK group, and Nob intervention significantly increased the phosphorylation levels of the proteins.
3.5 Effect of nobiletin on myofiber protein degradation
The effect of Nob on the expression level of key protein of mouse skeletal muscle protein degradation is detected by an immunoblotting method. The results showed that D-gal treatment increased the level of FoXO3 phosphorylation and the amount of muscle wasting factors MAFBX, MURF1 expression downstream thereof. The D-gal+ Nob group significantly reduced FoXO3 phosphorylation levels and MAFBX and MURF1 expression levels compared to the D-gal group. The results of detecting the expression level of inflammatory factors in the serum of each group of mice by the ELISA kit show that compared with the CK group, the contents of TNF-alpha, IL-1 beta and LBP in the serum of the D-gal group of mice are obviously increased. Nob intervention effectively reduced TNF- α, IL-1β and LBP levels in serum.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that it will be apparent to those skilled in the art that several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the scope of the invention.

Claims (9)

1. Application of nobiletin in preparing medicine for treating skeletal muscle atrophy is provided.
2. The use according to claim 1, wherein said nobiletin reverses skeletal muscle atrophy by increasing myofibrillar constitutive protein expression and increasing the cross-sectional area of the muscle fibers.
3. The use according to claim 2, wherein the myofibrillar constituent proteins comprise one or more of ACTA1, TMP1, TNNC2, TNNT1, TNNT3, MYH1, MYH2, MYH 4.
4. Use of nobiletin in preparing preparation for inhibiting skeletal muscle degradation protein expression or function is provided.
5. The use of claim 3, wherein the skeletal muscle degrading proteins comprise one or more of FoXO3, MAFBX, MURF 1.
6. The use according to claim 5, wherein nobiletin reduces its function by reducing the phosphorylation level of FoXO 3; and/or reduced expression of MAFBX, MURF 1.
7. Use of nobiletin in the preparation of a formulation for promoting the degree of phosphorylation of a key protein for skeletal muscle protein synthesis, said key protein for skeletal muscle synthesis being one or more of AKT, mTOR and P70S 6K.
8. Application of nobiletin in preparing preparation for reducing concentration of inflammatory factor in serum is provided.
9. The use according to claim 8, wherein the inflammatory factor is one or more of TNF- α, IL-1β, LBP.
CN202310360504.3A 2023-04-06 2023-04-06 Application of nobiletin in treating amyotrophy Pending CN117482079A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104023735A (en) * 2011-12-26 2014-09-03 森永乳业株式会社 Muscular atrophy preventing agent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104023735A (en) * 2011-12-26 2014-09-03 森永乳业株式会社 Muscular atrophy preventing agent

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHIKAZAWA M, MORIWAKI Y, URAMOTO M, ET AL.: "Functional effect of nobiletin as a food-derived allosteric modulator of mouse CRFR2β in skeletal muscle", 《 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 》, vol. 529, 20 August 2020 (2020-08-20), pages 1 - 4 *
NOHARA K, MALLAMPALLI V, NEMKOV T, ET AL.: "Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge", NATURE COMMUNICATIONS, 28 August 2019 (2019-08-28) *

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