CN113116929A - Therapeutic effect of cell-free fat extract on fatty liver and its complications - Google Patents

Therapeutic effect of cell-free fat extract on fatty liver and its complications Download PDF

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Publication number
CN113116929A
CN113116929A CN202010048629.9A CN202010048629A CN113116929A CN 113116929 A CN113116929 A CN 113116929A CN 202010048629 A CN202010048629 A CN 202010048629A CN 113116929 A CN113116929 A CN 113116929A
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fatty liver
fat
liver
cell
complications
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Inventor
王斌
赵莉
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Shanghai Seme Cell Technology Co Ltd
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Shanghai Seme Cell Technology Co Ltd
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Priority to CN202010048629.9A priority Critical patent/CN113116929A/en
Priority to PCT/CN2021/072553 priority patent/WO2021143912A1/en
Publication of CN113116929A publication Critical patent/CN113116929A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/35—Fat tissue; Adipocytes; Stromal cells; Connective tissues
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B1/00—Production of fats or fatty oils from raw materials
    • C11B1/02—Pretreatment
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B1/00—Production of fats or fatty oils from raw materials
    • C11B1/10—Production of fats or fatty oils from raw materials by extracting
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B1/00—Production of fats or fatty oils from raw materials
    • C11B1/10—Production of fats or fatty oils from raw materials by extracting
    • C11B1/108—Production of fats or fatty oils from raw materials by extracting after-treatment, e.g. of miscellae
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B3/00—Refining fats or fatty oils
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B3/00—Refining fats or fatty oils
    • C11B3/001—Refining fats or fatty oils by a combination of two or more of the means hereafter
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B3/00—Refining fats or fatty oils
    • C11B3/16—Refining fats or fatty oils by mechanical means

Abstract

The invention relates to a therapeutic effect of a cell-free fat extract on fatty liver and complications thereof. Specifically, the invention provides application of a cell-free fat extract in preparing a composition or a preparation, wherein the composition or the preparation is used for preventing and/or treating fatty liver and/or complications thereof. The cell-free fat extract of the present invention has an excellent therapeutic effect on fatty liver and/or its complications.

Description

Therapeutic effect of cell-free fat extract on fatty liver and its complications
Technical Field
The invention belongs to the technical field of biology, and particularly relates to a treatment effect of a cell-free fat extract on fatty liver and complications thereof.
Background
Fatty liver disease is one of common chronic liver diseases, can develop into hepatitis (NASH), liver cirrhosis, liver cancer and the like along with the progress of the disease process, becomes a global widely distributed disease influencing public health in recent decades, but currently, an ideal treatment method and a medicament are lacked, and a safe and effective biological preparation is searched for to become a problem to be solved urgently.
Therefore, there is a need in the art to develop a safe and effective drug for the treatment of fatty liver.
Disclosure of Invention
The purpose of the present invention is to provide a cell-free fat extract which is safe and effective for the treatment of fatty liver and/or its complications.
In a first aspect of the present invention, there is provided a use of a cell-free fat extract for the preparation of a composition or formulation for the prevention and/or treatment of fatty liver and/or complications thereof.
In another preferred example, the fatty liver is alcoholic or non-alcoholic fatty liver.
In another preferred example, the fatty liver is a high fat diet or fatty liver caused by obesity.
In another preferred embodiment, the fatty liver is obese fatty liver.
In another preferred example, the fatty liver is a fatty liver caused by a disorder of lipid metabolism.
In another preferred embodiment, the disorder of lipid metabolism is a disorder of lipid metabolism in the blood and/or a disorder of lipid metabolism in the liver.
In another preferred embodiment, the disorder of lipid metabolism is hyperlipidemia.
In another preferred embodiment, the disorder of lipid metabolism is selected from the group consisting of: high triglycerides, high cholesterol, low high low density lipoprotein, or combinations thereof.
In another preferred embodiment, the hyperlipidemia is selected from the group consisting of: high triglycerides, high cholesterol, low high low density lipoprotein, or combinations thereof.
In another preferred embodiment, said preventing and/or treating fatty liver and/or its complications comprises:
(i) inhibit, alleviate and/or reverse fatty liver growth;
(ii) reducing the weight of fatty liver;
(iii) improving the steatosis of liver tissue; and/or
(iv) Inhibit and/or improve liver fatty inflammation.
In another preferred embodiment, said preventing and/or treating fatty liver and/or its complications comprises (i) inhibiting, alleviating and/or reversing fatty liver growth.
In another preferred embodiment, said preventing and/or treating fatty liver and/or its complications comprises (ii) reducing the weight of fatty liver.
In another preferred embodiment, said preventing and/or treating fatty liver and/or its complications comprises (iii) ameliorating steatosis in liver tissue.
In another preferred embodiment, said preventing and/or treating fatty liver and/or its complications comprises (iv) inhibiting and/or ameliorating fatty inflammation of the liver.
In another preferred embodiment, the improvement of the steatosis of the liver tissue comprises:
(a) inhibit and/or reduce hepatic fat vacuoles.
In another preferred embodiment, the complication is selected from the group consisting of: hepatic fibrosis, liver cirrhosis, hepatocarcinoma, diabetes, cardiovascular diseases, kidney diseases, colorectal cancer, and endocrine diseases
In another preferred embodiment, the diabetes is type 2 diabetes.
In another preferred embodiment, the composition or preparation further comprises other medicines for preventing and/or treating fatty liver and/or complications thereof.
In another preferred embodiment, said other agent for preventing and/or treating fatty liver and/or its complications is selected from the group consisting of: a hepatoprotective agent, an insulin sensitizer, a lipid lowering agent, an anti-obesity agent, or a combination thereof.
In another preferred embodiment, the liver protecting drug is selected from the group consisting of: polyene phosphatidyl choline, Glutathione (GSH), silymarin (guest), S-adenosylmethionine (methionine), bicyclol, diammonium glycyrrhizinate, ursodeoxycholic acid (UDCA), or combinations thereof.
In another preferred embodiment, the insulin sensitizer is selected from the group consisting of: metformin, peroxisome proliferator-activated receptor (PPARs) agonists, PPAR γ agonists Thiazolidinediones (TZDs), PPAR α/δ agonists, glucagon-like peptide-1 (GLP-1) analogs, or combinations thereof.
In another preferred embodiment, the lipid lowering agent is selected from the group consisting of: statins (e.g., atorvastatin, rosuvastatin), fibrates (e.g., clofibrate, fibrat, bezafibrate, aluminum clofibrate, and bisfibrate), or combinations thereof.
In another preferred embodiment, the lipid lowering agent is selected from the group consisting of: orlistat, lorcaserin, phentermine-topiramate combinations, naltrexone, bupropion, liraglutide, or combinations thereof.
In another preferred embodiment, the composition or formulation comprises a pharmaceutical composition or formulation, a food composition or formulation, a nutraceutical composition or formulation, or a dietary supplement.
In another preferred embodiment, the composition or preparation further comprises a pharmaceutically, food, health product or dietary acceptable carrier.
In another preferred embodiment, the composition or the preparation is in the form of oral preparation, external preparation or injection preparation.
In another preferred embodiment, the composition or formulation is administered by topical, or subcutaneous injection.
In another preferred embodiment, the cell-free fat extract is cell-free and free of lipid droplets.
In another preferred embodiment, the fat droplets are oil droplets released after the fat cells are disrupted.
In another preferred embodiment, the term "free of fat droplets" means that the percentage of oil droplets in the cell-free fat extract is less than 1%, preferably less than 0.5%, more preferably less than 0.1% by volume of the total liquid.
In another preferred embodiment, the cell is selected from the group consisting of: endothelial cells, adipose-derived stem cells, macrophage cells, and stromal cells.
In another preferred embodiment, the term "cell-free" means that the average number of cells in 1ml of cell-free fat extract is less than or equal to 1, preferably less than or equal to 0.5, more preferably less than or equal to 0.1, or is 0.
In another preferred example, the cell-free fat extract is a naturally obtained nano fat extract without additional ingredients.
In another preferred embodiment, the term "free of added ingredients" means that no solution, solvent, small molecule, chemical, and biological additives are added during the preparation of the fat extract except for the rinsing step.
In another preferred embodiment, the fat extract is prepared by emulsifying fat tissue and centrifuging.
In another preferred embodiment, the fat extract contains, but is not limited to, one or more components selected from the group consisting of: growth factors IGF-1, BDNF, GDNF, TGF-beta, HGF, bFGF, VEGF, PDGF, EGF, NT-3, GH, G-CSF, or combinations thereof.
In another preferred embodiment, the cell-free fat extract is prepared by the following method:
(1) providing an adipose tissue material, cutting said adipose tissue material into pieces, and rinsing (e.g., with physiological saline) to obtain rinsed adipose tissue;
(2) centrifuging the rinsed adipose tissue to obtain a layered mixture;
(3) removing the upper oil layer and the lower water layer from the layered mixture, and collecting the middle layer (i.e., fat layer containing adipocytes);
(4) emulsifying the intermediate layer to obtain an emulsified fat mixture (also called nano-fat);
(5) centrifuging the emulsified fat mixture to obtain an intermediate liquid layer, namely a fat primary extract; and
(6) filtering and sterilizing the fat primary extract to obtain a cell-free fat extract.
In a second aspect of the present invention, there is provided a method for preparing a cell-free fat extract, the method comprising the steps of:
(1) providing an adipose tissue material, cutting said adipose tissue material into pieces, and rinsing (e.g., with physiological saline) to obtain rinsed adipose tissue;
(2) centrifuging the rinsed adipose tissue to obtain a layered mixture;
(3) removing the upper oil layer and the lower water layer from the layered mixture, and collecting the middle layer (i.e., fat layer containing adipocytes);
(4) emulsifying the intermediate layer to obtain an emulsified fat mixture (also called nano-fat);
(5) centrifuging the emulsified fat mixture to obtain an intermediate liquid layer, namely a fat primary extract; and
(6) filtering and sterilizing the fat primary extract to obtain a cell-free fat extract.
In another preferred embodiment, in the step (2), the centrifugation is performed at 2500 g-.
In another preferred embodiment, in the step (2), the centrifugation time is 1-15min, preferably 1-10min, more preferably 1-8min, and most preferably 1-5 min.
In another preferred embodiment, in the step (4), the emulsification is mechanical emulsification.
In another preferred embodiment, the mechanical emulsification is mechanical emulsification by repeated beating (e.g. 20-200 times, preferably 20-150 times, more preferably 20-100 times, more preferably 30-50 times) with a syringe.
In another preferred example, the blowing and beating mode is that 2 10ml injection syringes are connected with a three-way pipe and repeatedly pushed and beaten at a constant speed.
In another preferred example, in the step (4), the emulsifying is a method of breaking up by a tissue homogenizer.
In another preferred embodiment, in the step (5), before the emulsified fat mixture is processed by centrifugation, the emulsified fat mixture is frozen and then thawed.
In another preferred embodiment, after thawing treatment after freezing, the thawed mixture is used for centrifugation.
In another preferred embodiment, the freezing temperature is from-50 ℃ to-120 ℃, preferably from-60 ℃ to-100 ℃, more preferably from-70 ℃ to-90 ℃.
In another preferred embodiment, the thawing temperature is 20-40 deg.C, preferably 25-40 deg.C, more preferably 37 deg.C.
In another preferred embodiment, the number of cycles of freezing and thawing is 1-5 (preferably 1, 2, 3 or 4).
In another preferred example, in the step (5), after centrifugation, the emulsified fat mixture is layered into 4 layers, the first layer is an oil layer, the second layer is a residual fat tissue layer, the third layer is a liquid layer (i.e. an intermediate liquid layer), and the fourth layer is a cell/tissue debris precipitation layer.
In another preferred embodiment, in the step (5), the centrifugation is performed at 2500 g-.
In another preferred embodiment, in the step (5), the centrifugation time is 1-15min, preferably 1-10min, more preferably 2-8min, and most preferably 3-7 min.
In another preferred example, in the step (5), the first layer, the second layer, the third layer and the fourth layer are arranged from top to bottom in sequence.
In another preferred embodiment, in the step (5), the intermediate liquid layer is a transparent or substantially transparent layer.
In another preferred example, in the step (6), the filter bag can remove fat cells in the fat primary extract.
In another preferred embodiment, in the step (6), the filtration and sterilization are performed by a filter (e.g., a 0.22 μm microporous membrane).
In another preferred embodiment, the filter is a microfiltration membrane filter.
In another preferred embodiment, the pore size of the microfiltration membrane is 0.05 to 0.8. mu.m, preferably 0.1 to 0.5. mu.m, more preferably 0.1 to 0.4. mu.m, more preferably 0.15 to 0.3. mu.m, more preferably 0.2 to 0.25. mu.m, most preferably 0.22. mu.m.
In another preferred embodiment, in the step (6), the filtration and sterilization are performed by passing through a first cell-rejecting filter and then a second cell-rejecting filter (e.g., a 0.22 μm filter).
In another preferred example, the step (6) further comprises subpackaging the fat extract to form a subpackaged product. (the sub-packaged extract can be stored at-20 deg.C for use, or thawed at low temperature (such as-4 deg.C) or normal temperature for use directly, or thawed and stored at low temperature (such as 4 deg.C) for a period of time for use).
In a third aspect of the invention, there is provided a composition or formulation comprising (a) a cell-free fat extract according to the second aspect of the invention; and/or (b) a pharmaceutically, food, nutraceutical, or dietetically acceptable carrier or excipient.
In another preferred embodiment, the composition or the preparation is in the form of powder, granules, capsules, injection, tincture, oral liquid, tablets or buccal tablets.
In another preferred embodiment, the injection is intravenous injection or intramuscular injection.
In another preferred embodiment, the composition or formulation is in the form of a solid dosage form, a semi-solid dosage form, or a liquid dosage form, such as a solution, gel, cream, lotion, ointment, cream, paste, cake, powder, patch, and the like.
In another preferred embodiment, the mass percentage of the cell-free fat extract in the composition or preparation is 5 wt%, preferably 1-20 wt%, based on the total weight of the cosmetic composition.
In a fourth aspect of the invention, there is provided a method of preparing a composition or formulation, said method comprising the steps of: the cell-free fat extract according to the second aspect of the present invention is mixed with a pharmaceutically, food, nutraceutical or dietetically acceptable carrier or excipient to form a composition or formulation.
In a fifth aspect of the present invention, there is provided a method for preventing and/or treating fatty liver and/or complications thereof, the method comprising the steps of: administering said cell-free fat extract of the second aspect of the present invention to a subject in need thereof.
In another preferred embodiment, the subject is a human or non-human mammal.
In another preferred embodiment, the non-human mammal includes a rodent, such as a rat, a mouse.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a graph showing the wet weight of the liver of mice in the CHOW, PBS buffer and CEFFE treatment groups.
FIG. 2 is a graph showing histological staining of the liver of mice in the CHOW, PBS buffer and CEFFE-treated groups.
FIG. 3 is a graph showing the vacuolated area in the liver of mice in the CHOW, PBS buffer and CEFFE-treated groups.
Detailed Description
The present inventors have conducted extensive and intensive studies and, for the first time, have developed a cell-free fat extract which is effective in treating fatty liver and/or its complications. In the invention, animal experiments prove that the cell-free fat extracting solution can effectively prevent and/or treat fatty liver and/or complications thereof. The present invention has been completed based on this finding.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the term "fatty liver and/or complications thereof" is used interchangeably with "fatty liver and/or complications thereof".
Cell-free fat extract and preparation method thereof
As used herein, the terms "cell-free fat extract of the present invention", "fat extract of the present invention", and the like, which are used interchangeably, refer to an extract (or extract) derived from adipose tissue prepared without the addition of any solution, solvent, small molecule, chemical, and biological additive during the preparation of the fat extract (except for the rinsing step). A typical method of preparing an extract of the invention is as described above in the second aspect of the invention. Furthermore, it is to be understood that while the extract of the present invention does not require the addition of any additives (or additional ingredients) during the preparation process, some or a small amount of a safe substance (such as a small amount of water) that does not adversely or adversely affect the activity of the extract of the present invention may be added.
Fatty liver and/or its complications
Fatty liver (fatty liver) refers to a pathological condition of excessive fat accumulation in liver cells caused by various reasons, and is a common pathological change of liver. Normally, normal human liver tissue contains a small amount of fat, such as triglyceride, phospholipid, glycolipid, cholesterol, etc., and its weight is about 3% to 5% of the weight of the liver, and if the fat in the liver accumulates too much, it exceeds 5% of the weight of the liver or there is steatosis in more than 50% of the liver cells histologically, it is called fatty liver.
The formation of fatty liver is usually associated with obesity, high-fat diet, drinking, and other factors, which cause excessive accumulation of fat in liver cells, thereby causing fatty liver. Fatty liver disease can be classified into Alcoholic fatty liver disease (Alcoholic fatty liver disease) and Non-Alcoholic fatty liver disease (NAFLD) according to etiology classification. Among them, non-alcoholic fatty liver disease is a clinical pathological syndrome characterized by diffuse liver cell bullous steatosis without history of excessive drinking, and can progress into non-alcoholic hepatitis (NASH), liver cirrhosis, liver cancer and the like along with the progress of the disease.
Typically, the fatty liver according to the present invention includes (but is not limited to) one or more fatty liver selected from the group consisting of: alcoholic fatty liver, non-alcoholic fatty liver, fatty liver caused by high fat diet or obesity, and fatty liver caused by lipid metabolism disorder.
In a preferred example, the fatty liver caused by the disorder of lipid metabolism is a disorder of lipid metabolism in blood and/or a disorder of lipid metabolism in liver.
Typically, the disorder of lipid metabolism includes (but is not limited to): high triglycerides, high cholesterol, low high low density lipoprotein, or combinations thereof.
In another preferred embodiment of the present invention, the fatty liver complications include (but are not limited to): hepatic fibrosis, liver cirrhosis, hepatocarcinoma, diabetes, cardiovascular diseases, kidney diseases, colorectal cancer, and endocrine diseases
In another preferred embodiment, the diabetes is type 2 diabetes.
Use of
The cell-free fat extract of the present invention can be used for preventing and/or treating fatty liver and/or its complications.
As used herein, the term "preventing" refers to a method of preventing the onset of a disease and/or its attendant symptoms or protecting a subject from acquiring a disease. As used herein, "preventing" also includes delaying the onset of a disease and/or its attendant symptoms and reducing the risk of acquiring a disease in a subject.
As used herein, the term "treating" includes delaying and stopping the progression of the disease, or eliminating the disease, and does not require 100% inhibition, eradication, or reversal. In some embodiments, the cell-free fat extract or composition of the invention reduces, inhibits, and/or reverses fatty liver and/or its complications, e.g., by at least about 10%, at least about 30%, at least about 50%, or at least about 80%, as compared to levels observed in the absence of the cell-free fat extract of the invention.
Typically, the cell-free fat extraction of the present invention prevents and/or treats fatty liver and/or its complications by one or more means including (but not limited to) the following group:
(i) inhibit, alleviate and/or reverse fatty liver growth;
(ii) reducing the weight of fatty liver;
(iii) improving the steatosis of liver tissue; and/or
(iv) Inhibit and/or improve liver fatty inflammation.
As used herein, the term "reversal" includes elimination of an already-present disease, and does not require 100% elimination and reversal. In some embodiments, the cell-free fat extract or composition of the invention reverses fatty liver, e.g., by at least about 10%, at least about 30%, at least about 50%, or at least about 80%, as compared to levels observed in the absence of the cell-free fat extract of the invention.
As used herein, the term "ameliorating" includes reducing the progression of a disease, alleviating the symptoms of a disease, and the like.
In a preferred embodiment of the invention, the steatosis in liver tissue may be improved by inhibiting and/or reducing liver fat vacuoles.
The present invention also provides a method for preventing and/or treating fatty liver and/or complications thereof, the method comprising the steps of: administering the cell-free fat extract of the present invention to a subject in need thereof, thereby treating fatty liver.
In a preferred embodiment, the subject is a human or non-human animal.
In another preferred embodiment, the non-human animal is, for example, a rat, a mouse, a dog, a cat, a cow, a chicken, a duck, or the like.
Compositions and applications
The compositions of the present invention include (but are not limited to): pharmaceutical compositions, food compositions, health compositions, dietary supplements, and the like.
Typically, the acellular fat extract of the present invention may be prepared into pharmaceutical compositions such as tablets, capsules, powders, fine granules, solutions, troches, jellies, cream formulations, spirits, suspensions, tinctures, poultices, liniments, lotions, and aerosols. The pharmaceutical composition can be prepared by a generally known preparation technique, and a suitable pharmaceutical additive can be added to the drug.
The compositions of the present invention may also include pharmaceutically, comestibly, nutraceutically or dietetically acceptable carriers. "pharmaceutically, food, nutraceutical, or dietetically acceptable carrier" means: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of acceptable carrier parts for pharmaceutically, food, nutraceutical or dietetically acceptable carriers are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)
Figure BDA0002370313340000101
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The composition of the invention can also comprise other medicines for preventing and/or treating fatty liver and/or complications thereof. Preferably, the other agent for preventing and/or treating fatty liver and/or its complications is selected from the group consisting of: a hepatoprotective agent, an insulin sensitizer, a lipid lowering agent, an anti-obesity agent, or a combination thereof.
Typically, such liver protection includes (but is not limited to): polyene phosphatidyl choline, Glutathione (GSH), silymarin (guest), S-adenosylmethionine (methionine), bicyclol, diammonium glycyrrhizinate, ursodeoxycholic acid (UDCA), or combinations thereof.
Typically, the insulin sensitiser is selected from the group consisting of: metformin, peroxisome proliferator-activated receptor (PPARs) agonists, PPAR γ agonists Thiazolidinediones (TZDs), PPAR α/δ agonists, glucagon-like peptide-1 (GLP-1) analogs, or combinations thereof.
Typically, the lipid lowering agents include (but are not limited to): statins (e.g., atorvastatin, rosuvastatin), fibrates (e.g., clofibrate, fibrat, bezafibrate, aluminum clofibrate, and bisfibrate), or combinations thereof.
Typically, the lipid lowering agents include (but are not limited to): orlistat, lorcaserin, phentermine-topiramate combinations, naltrexone, bupropion, liraglutide, or combinations thereof.
The mode of administration of the composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular), topical, preferred modes of administration are oral and injection.
Solid dosage forms for oral administration or administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may comprise opacifying agents.
Liquid dosage forms for oral administration or administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration or administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The cell-free fat extract of the present invention may be administered or dosed alone, or in combination with other drugs for preventing and/or treating fatty liver and/or its complications.
The composition is administered in a safe and effective amount of the cell-free fat extract of the present invention to human or non-human animals (e.g., rats, mice, dogs, cats, cows, chickens, ducks, etc.) in need of treatment, wherein the administration is in an amount that is pharmaceutically, dietetically or nutraceutically acceptable as an effective administration dose. The term "safe and effective amount" as used herein, refers to an amount that produces a function or activity in and is acceptable to humans and/or animals. It will be understood by those skilled in the art that the safe and effective amount may vary with the form of the pharmaceutical composition, the route of administration, the excipients used, the severity of the disease, and the combination with other drugs. For example, the daily dose for a human of 60kg body weight is usually 0.1 to 1000mg, preferably 1 to 600mg, more preferably 2 to 300 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
1. Experimental methods
1.1 preparation of Cell free fat extract (CEFFE)
Fat was obtained by volunteers under informed consent. The preparation method of the cell-free adipose tissue extract comprises the following steps:
(1) the fat obtained by suction or surgical excision is cut into pieces and rinsed 3 times with normal saline.
(2) The rinsed adipose tissue was placed in a centrifuge tube and centrifuged at 1200g for 3 minutes in a centrifuge to obtain a layered mixture.
(3) The upper oil layer and the lower aqueous layer were removed from the layered mixture, and the middle layer (i.e., the fat layer containing adipocytes) was collected.
(4) And repeatedly pushing the middle layer for 30 times at constant speed by using 2 10ml injection syringes connected with a three-way pipe, so as to perform mechanical emulsification, and obtain a mechanically emulsified fat mixture (also called nano fat).
(5) Placing the mechanically emulsified fat mixture into a refrigerator at minus 80 ℃ for freezing, then carrying out water bath thawing at 37 ℃, after single freeze-thaw cycle, centrifuging the thawed fat mixture for 5 minutes at 1200g to obtain a layered mixture, wherein the layered mixture is divided into 4 layers in total, the first layer is an oil layer, the second layer is a residual fat tissue layer, the third layer is a liquid layer, the fourth layer is a cell/tissue fragment precipitation layer, removing the oil layer and the residual fat tissue layer, absorbing the liquid layer, and avoiding the pollution of the cell/tissue fragment precipitation layer in the absorbing process, thereby obtaining the primary fat extraction liquid.
(6) Filtering the obtained fat primary extract with 0.22 μm filter for sterilization, sterilizing and removing living cells, to obtain cell-free fat extract, subpackaging, freezing at-20 deg.C, and thawing at 4 deg.C.
1.2 mouse fatty liver model establishment, grouping and administration
C57 mice of 6 weeks old were purchased from Shanghai laboratory animal center, and the mice fatty liver model was induced by continuous 4-week high fat diet to obtain fatty liver model mice. 10 fatty liver model mice were randomly divided into two groups, a PBS buffer group and a CEFFE treatment group, each of which was 5, and in addition, 5 normal healthy mice that were not induced by high fat diet were used as a normal feeding group (CHOW group). The fatty liver model mice of the CEFFE treatment group were treated with CEFFE by tail vein injection at an injection dose of 250. mu.l, and the fatty liver model mice of the PBS buffer group were treated with PBS buffer by tail vein injection at a treatment period of 30 days, once every four days for a total of 7 times, during which the high-fat diet was continued for the mice of the PBS buffer group and the CEFFE treatment group, and in addition, the mice of the normal feeding group (CHOW group) were normally fed with a healthy diet as a blank control.
The PBS buffer injection group was used as a negative control, and the CHOW group was used as a blank control.
1.3 statistical analysis
The data were tested by one-way ANOVA using SPSS software, and statistical analysis was performed on the significance of the data differences, with the results being expressed as mean. + -. standard deviation.
2. Results of the experiment
2.1 mouse liver weight determination
After sacrifice of each group of mice on day 30 of treatment, the livers were stripped and weighed wet, and the results are shown in table 1 and fig. 1.
Table 1 wet weight of liver of mice in different experimental groups (Mean ± SD, n ═ 5)
Experimental group CHOW group PBS buffer group CEFFE treatment group
Mean±SD(g) 1.35±0.10 2.28±0.27 1.80±0.33
Remarking: pbs, p value 0.0002 x (< 0.01); CHOW vs. ceffe, p value 0.0474 ═ 0.5; PBS vs. ceffe, p-value 0.0318 (< 0.5).
As can be seen from Table 1 and FIG. 1, the wet weight of the liver was significantly increased in the fatty liver mice. Compared with the PBS buffer solution group, the liver wet weight of the CEFFE treatment group is remarkably reduced, which indicates that the CEFFE has remarkable treatment effect on the fatty liver.
2.2 histological evaluation
Mice were sacrificed on day 30 of treatment, livers were stripped, a portion of liver tissue was taken, soaked in 4% paraformaldehyde, fixed for 24H and paraffin embedded, paraffin sections were routinely made, H & E stained, photographed under an optical microscope (3 random fields/specimen), Image J software calculated the area of the vacuolated region, and the results are shown in table 2 and fig. 2-3.
Table 2 vacuole area in liver of mice of different experimental groups (Mean ± SD, n ═ 3)
Figure BDA0002370313340000131
Figure BDA0002370313340000141
CHOW vs.PBS，p<0.001**；CHOW vs.CEFFE，p<<0.001*；PBS vs.CEFFE<0.001**。
As can be seen from table 2, fig. 2 and fig. 3, compared with CHOW, large-area fatty vacuoles with local inflammation were observed in the PBS buffer group, while fatty vacuoles of liver were significantly reduced and inflammatory responses were reduced in the CEFFE-treated group, indicating that CEFFE can improve fatty liver steatosis in fatty liver mice for treating fatty liver.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. Use of a cell-free fat extract for the preparation of a composition or preparation for the prevention and/or treatment of fatty liver and/or its complications.
2. The use according to claim 1, wherein the fatty liver is alcoholic or non-alcoholic fatty liver disease.
3. The use according to claim 1, wherein the fatty liver is a high fat diet or fatty liver caused by obesity.
4. The use according to claim 1, wherein said prevention and/or treatment of fatty liver and/or its complications comprises:
(i) inhibit, alleviate and/or reverse fatty liver growth;
(ii) reducing the weight of fatty liver;
(iii) improving the steatosis of liver tissue; and/or
(iv) Inhibit and/or improve liver fatty inflammation.
5. The use of claim 1, wherein the complication is selected from the group consisting of: hepatic fibrosis, liver cirrhosis, hepatocarcinoma, diabetes, cardiovascular diseases, kidney diseases, colorectal cancer, and endocrine diseases.
6. The use according to claim 1, wherein the composition or formulation further comprises other agents for the prevention and/or treatment of fatty liver and/or its complications; preferably, the other agent for preventing and/or treating fatty liver and/or its complications is selected from the group consisting of: a hepatoprotective agent, an insulin sensitizer, a lipid lowering agent, an anti-obesity agent, or a combination thereof.
7. The use of claim 1, wherein the composition or formulation comprises a pharmaceutical composition or formulation, a food composition or formulation, a nutraceutical composition or formulation, or a dietary supplement.
8. The use of claim 1, wherein the composition or formulation is in the form of an oral formulation, a topical formulation or an injectable formulation.
9. The use according to claim 1, wherein the cell-free fat extract is prepared by:
(1) providing an adipose tissue material, cutting said adipose tissue material into pieces, and rinsing (e.g., with physiological saline) to obtain rinsed adipose tissue;
(2) centrifuging the rinsed adipose tissue to obtain a layered mixture;
(3) removing the upper oil layer and the lower water layer from the layered mixture, and collecting the middle layer (i.e., fat layer containing adipocytes);
(4) emulsifying the intermediate layer to obtain an emulsified fat mixture (also called nano-fat);
(5) centrifuging the emulsified fat mixture to obtain an intermediate liquid layer, namely a fat primary extract; and
(6) filtering and sterilizing the fat primary extract to obtain a cell-free fat extract.
10. A method for preventing and/or treating fatty liver and/or its complications, comprising the steps of: administering to a subject in need thereof a cell-free fat extract.
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