CN117695396A - New application of miR-3104-5p inhibitor in diabetes treatment - Google Patents
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- CN117695396A CN117695396A CN202410161152.3A CN202410161152A CN117695396A CN 117695396 A CN117695396 A CN 117695396A CN 202410161152 A CN202410161152 A CN 202410161152A CN 117695396 A CN117695396 A CN 117695396A
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Abstract
The invention discloses a new application of miR-3104-5p inhibitor in diabetes treatment, and the invention discovers the correlation between miR-3104-5p and diabetes for the first time, provides a new thought and strategy for preparing a medicament for treating diabetes and a product for diagnosing diabetes, provides a new molecular target for targeted treatment of diabetes, is beneficial to early warning and early targeted intervention of diabetes, and has good clinical application prospect.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a novel application of a miR-3104-5p inhibitor, and more particularly relates to a novel application of the miR-3104-5p inhibitor in diabetes treatment.
Background
Diabetes is a polygenic hereditary complex disease formed by the combined action of genetic and environmental factors. The incidence rate of type 2 diabetes is continuously increased, and the incidence rate of type 2 diabetes accounts for more than 95% of the total incidence rate of diabetes. Diabetes, cardiovascular and retinal complications seriously affect the health of people, and cause huge social burden and economic cost. Recent studies have found that the early life environment has an important driving effect on the occurrence of adult chronic diseases. Early intervention in the early life adverse environment is extremely important. As one of major chronic diseases, early prevention and treatment of diabetes has important value. Numerous large epidemiological studies have shown that early prevention and early intervention, including early prevention, can delay diabetes onset, improving the prognosis of cardiovascular complications.
Currently, the most widely used clinical drugs for the treatment of type 2 diabetes mellitus are insulin stimulators, sulfonylureas and insulin sensitizers, biguanides. However, sulfonylureas can only stimulate insulin production by the pancreas, and the sensitivity of the target tissue of insulin to insulin is not effectively improved. Biguanides have some nephrotoxicity. Long-term administration places the pancreas in a stressed working state for a long period of time, eventually leading to the need for in vitro insulin to aid in lowering blood glucose, which can further lead to partial or total loss of islet function. At the same time, the blood sugar repeatedly rebounds, so that the viscosity of the blood is increased, the microcirculation of the blood is blocked, and finally, complications in the aspects of heart, brain, kidney, skin, nerves and the like still occur. Therefore, the exploration of potential molecular mechanisms and novel therapeutic targets of the type 2 diabetes has great significance for diabetes treatment.
MicroRNA (miRNA) is an endogenous class of small RNAs of about 20-24 nucleotides in length, which have a number of important regulatory roles within cells. mirnas are also intimately involved in sugar metabolism. Therefore, research of the correlation of miRNA and glucose metabolism disorder caused by bad environment in early life and search of miRNA markers related to occurrence and development of diabetes have important significance in revealing pathogenesis of diabetes and realizing early prevention and control of diabetes.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to find miRNA markers relevant to diabetes treatment and diagnosis. The inventor of the invention finds that miR-3104-5p is obviously up-regulated in mice exposed to high-fat diet in early life in research of diabetes pathogenesis, and further animal experiment research shows that inhibiting miR-3104-5p expression can obviously improve hepatocyte glycometabolism and play a role in treating diabetes. The present invention has been completed based on this finding.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the first aspect of the invention provides application of miR-3104-5p inhibitor in preparation of medicines for treating diabetes.
Further, the miR-3104-5p inhibitor includes an interfering molecule that inhibits expression of miR-3104-5 p.
Further, the miR-3104-5p inhibitor comprises any one or more of siRNA, shRNA, dsRNA, microRNA and antisense nucleic acid targeting miR-3104-5 p.
Further, the sequence of the siRNA targeting miR-3104-5p is shown as SEQ ID NO. 2.
In the present invention, the miRNA refers to micrornas, i.e., small non-coding RNA molecules, which are a class of endogenous, small RNAs of about 20-24 nucleotides in length that have a variety of important regulatory roles within cells. The expression of the gene (about 1/3 of the protein coding gene) is regulated mainly at the posttranscriptional level, so that apoptosis, proliferation, differentiation, metabolism, development of individuals and generation, development and drug resistance of tumors are controlled. mirnas exist in a variety of forms, most originally pri-mirnas, approximately 300-1000 bases in length; the pri-miRNA becomes pre-miRNA after one-time processing, namely miRNA precursor, and the length is about 70-90 bases; the pre-miRNA is subjected to enzyme digestion by Dicer enzyme to become mature miRNA with the length of about 20-24 nt.
In a specific embodiment of the invention, the sequence information of the miRNA biomarker miR-3104-5p can be obtained by inquiring in a miRBase database (http:// microna. Sanger. Ac. Uk /).
In some embodiments, the miR-3104-5p inhibitor of the invention comprises any biosynthetic substance, chemical synthetic substance, natural purification substance, modified natural purification substance, semisynthetic substance and/or any combinations thereof capable of inhibiting miR-3104-5p expression levels, including, but not limited to: siRNA, shRNA, dsRNA, micrornas, antisense nucleic acids targeting miR-3104-5p, constructs, small molecule compounds, and the like capable of expressing or forming the siRNA, shRNA, dsRNA, micrornas, antisense nucleic acids. The reagent for inhibiting miR-3104-5p expression is not limited to the siRNA targeting miR-3104-5p shown in SEQ ID NO. 2 used in the specific embodiment of the invention. Any agent capable of inhibiting the expression of miR-3104-5p is within the scope of the miR-3104-5p inhibitor.
In the present invention, diabetes refers to a disease characterized by prolonged high blood glucose levels, and may refer to all or any type of diabetes, including but not limited to: type 1 diabetes, type 2 diabetes, cystic fibrosis-related diabetes, surgical diabetes, gestational diabetes, mitochondrial diabetes, etc. In some embodiments, diabetes may be in the form of hereditary diabetes. In a specific embodiment of the invention, diabetes refers to diabetes caused by exposure to a high fat diet early in life.
In the present invention, the treatment generally relates to the treatment of humans or animals (e.g., for veterinary use), wherein certain desired therapeutic effects may be achieved, such as inhibiting the development of a disorder (including reducing the rate of development of a disorder, halting the development of a disorder), ameliorating a disorder, and curing a disorder. Also included are treatments as a prophylactic measure (e.g., prophylaxis). The use of patients who have not yet developed, but who are at risk of developing, a disorder is also included in the term treatment.
In the present invention, the siRNA refers to small interfering ribonucleic acids, i.e. double stranded nucleic acids of relatively short length or optionally longer precursors thereof. In some embodiments, the length of the siRNA useful in the present invention is preferably about 20 to 50 bp. However, there is no particular limitation on the length of the usable siRNA herein. For example, the siRNA may initially be present in the cell in a precursor form that is substantially different from the final or processed form of the siRNA that exhibits and exerts gene silencing activity upon or after delivery to the target cell. For example, a precursor form of an siRNA can include a precursor sequence element that is processed, degraded, altered, or cleaved upon or after delivery to produce an siRNA that has mediated gene silencing activity in a cell. In some embodiments, useful siRNAs have precursors of lengths of, for example, about 100 to 200 base pairs or 50 to 100 base pairs or less than about 50 base pairs that produce active, processed siRNAs within target cells. In other embodiments, useful sirnas or siRNA precursors are about 10 to 49 bp or 15 to 35 bp or about 21 to 30 bp in length.
In the present invention, the shRNA refers to short hairpin RNAs, which include two short inverted repeats. The shRNA cloned into the shRNA expression vector comprises two short inverted repeats, separated by a stem-loop (loop) sequence, forming a hairpin structure, controlled by a pol III promoter. Then, 5-6T's are attached as transcription terminators for RNA polymerase III. shRNA can be stably integrated into the genome of the cell, allowing for long-term gene knockout.
In the present invention, the dsRNA refers to double-stranded ribonucleic acid, and an RNA molecule formed by renaturation of two complementary strands can be cleaved by Dicer enzyme to form siRNA. dsRNA inhibits gene expression by RNA interference (RNAi), and dsRNA does not need to have 100% homology with the target gene sequence, so long as it can inhibit target gene expression.
In the present invention, the micrornas refer to micrornas (mirnas), which are non-coding RNAs about 22 nt long, widely present in various organisms ranging from viruses to humans. Mature mirnas are mainly responsible for negative regulation of post-transcriptional levels of genes, involved in many life processes such as cell proliferation, apoptosis, immunity, neuroendocrine, and stem cell differentiation by causing degradation of their target mRNA or disruption of the translation process.
In the present invention, the antisense nucleic acid means a nucleic acid comprising complementarity to a sequence encoding miR-3104-5 p. Antisense nucleic acids can be composed of DNA, RNA, or both. The antisense nucleic acid can contain non-complementary bases so long as it is capable of specifically hybridizing under stringent conditions. When an antisense nucleic acid is introduced into a cell, it binds to a target polynucleotide and inhibits transcription, RNA processing, or stability. In addition to antisense polynucleotides, antisense nucleic acids also include polynucleotide mimics that contain modified backbones, 3 'and 5' end portions. Such antisense nucleic acids can be appropriately designed based on the sequence information of miR-3104-5p and generated using methods well known to those skilled in the art.
In a second aspect, the invention provides the use of an agent that detects the level of miR-3104-5p expression in the preparation of a diagnostic product for diagnosing diabetes.
Further, the reagent for detecting the expression level of miR-3104-5p comprises a probe for specifically recognizing miR-3104-5p and/or a primer for specifically amplifying miR-3104-5 p.
Further, the sequence of the probe for specifically recognizing miR-3104-5p is shown as SEQ ID NO. 1.
Further, the level of miR-3104-5p expression in diabetics is significantly upregulated compared to miR-3104-5p in healthy controls.
In the present invention, the detection of the expression level of miR-3104-5p can be carried out by any method for detecting the expression level of miRNA, which is well known to those skilled in the art. In some embodiments, the method of detecting the expression level of a miRNA comprises a sequencing technique, a nucleic acid hybridization technique, a nucleic acid amplification technique. Wherein the nucleic acid amplification technique is selected from the group consisting of polymerase chain reaction, reverse transcription polymerase chain reaction, transcription mediated amplification, ligase chain reaction, strand displacement amplification and nucleic acid sequence based amplification, wherein the polymerase chain reaction is preferably a real-time fluorescent quantitative PCR reaction.
A third aspect of the invention provides any of the following applications, comprising:
(1) Application of miR-3104-5p in screening candidate drugs for treating diabetes mellitus, and screening candidate drugs for treating diabetes mellitus by detecting whether a test substance can inhibit expression of miR-3104-5 p;
(2) Use of a miR-3104-5p inhibitor in the preparation of a reagent for increasing glucose consumption of hepatocytes, wherein the miR-3104-5p inhibitor is a miR-3104-5p inhibitor described in the first aspect of the invention.
A fourth aspect of the invention provides any one of the following products comprising:
(1) A pharmaceutical composition for treating diabetes comprising a miR-3104-5p inhibitor as described in the first aspect of the invention;
(2) A pharmaceutical formulation for treating diabetes comprising a miR-3104-5p inhibitor as described in the first aspect of the invention;
(3) A diagnostic product for diagnosing diabetes comprising an agent for detecting miR-3104-5p expression levels described in the first aspect of the invention.
In some embodiments, the pharmaceutical composition or pharmaceutical formulation may further comprise a pharmaceutically acceptable carrier and/or adjuvant. In other embodiments, any one or more of the other drugs or agents that can be used to treat and/or prevent diabetes may also be included in the pharmaceutical composition or pharmaceutical formulation.
In some embodiments, the pharmaceutically acceptable carrier and/or adjuvant is described in detail in Remington's Pharmaceutical Sciences (19 th ed, 1995) which is used as needed to aid stability of the formulation or to aid in enhancing activity or its bioavailability or to produce an acceptable mouthfeel or odor in the case of oral administration. The pharmaceutical composition so formulated may be administered to a subject in need thereof by any suitable means known to those skilled in the art, as desired. In a specific embodiment of the invention, the subject is preferably a human.
In some embodiments, the pharmaceutically acceptable carrier and/or adjuvant includes, but is not limited to: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifying agents, such as wetting agents, e.g., sodium lauryl sulfate; a colorant; a flavoring agent; tabletting and stabilizing agent; an antioxidant; a preservative; non-thermal raw water; isotonic saline solution; and phosphate buffer, etc.
In some embodiments, the pharmaceutical composition or pharmaceutical formulation may be prepared as a variety of clinical pharmaceutical dosage forms as needed as a medicament for treating diabetes or various diseases caused by diabetes, including but not limited to: a dosage form for parenteral administration or an oral preparation, the parenteral administration dosage form including injection, aerosol, suppository or subcutaneous administration; the oral preparation comprises tablets, capsules, pills, granules, micro-caplets, suspension, dripping pills and oral liquid preparations.
In some embodiments, the appropriate dosage of the pharmaceutical composition or pharmaceutical formulation (or a therapeutically effective amount of the pharmaceutical composition or pharmaceutical formulation) may be prescribed in a variety of ways depending on the method of formulation, the mode of administration, the age, weight, sex, condition, diet, time of administration, route of administration, rate of excretion and sensitivity of the patient, and in general, the prescription and dosage of the drug for which the prescription is effective for the desired treatment can be readily determined by the skilled practitioner.
In some embodiments, the route of administration of the pharmaceutical composition or pharmaceutical formulation is not limited, so long as it is capable of exerting the desired therapeutic or prophylactic effect. In other embodiments, the route of administration includes, but is not limited to: topical, transdermal, intravenous, intraperitoneal, intraocular, intraarterial, intrapulmonary, oral, intrathecal, intramuscular, intratracheal, subcutaneous, inhalation, pleural, mucosal, dermal, gastrointestinal, intra-articular, intraventricular, rectal, vaginal, intracranial, intraurethral, intrahepatic. In some cases, the administration may be systemic, in some cases, local.
In some embodiments, the diagnostic product comprises a kit, a chip, a test strip. The kit further comprises instructions or a label for use, a positive control, a negative control, a buffer, an adjuvant or a solvent; the instructions or labels detail how to use the kit for detection and the kit for diagnosis and/or aiding in the diagnosis of diabetes.
Further, the kit of the present invention may comprise a variety of different reagents suitable for practical use (e.g., for different detection methods), and is not limited to the reagents listed in the present invention so far as reagents for diagnosing and/or aiding in the diagnosis of diabetes based on the detection of miR-3104-5p are included in the scope of the invention.
Further, the chips may be prepared using conventional methods of preparing biochips known to those skilled in the art, including but not limited to: the miRNA chip of the invention can be obtained by adopting a solid phase carrier of a modified glass slide or a silicon wafer, preparing an oligonucleotide probe into a solution by adopting a poly dT string with amino modification at the 5' end of the probe, then, spotting the oligonucleotide probe on the modified glass slide or the silicon wafer by adopting a spotting instrument, arranging the oligonucleotide probe into a preset sequence or an array, and then, standing overnight for fixation.
A fifth aspect of the invention provides a method comprising:
(1) A method of screening for a candidate drug for treating diabetes, the method comprising the steps of: treating a system expressing or containing miR-3104-5p with a test substance, detecting the expression of miR-3104-5p in the system, and selecting the test substance capable of inhibiting the expression of miR-3104-5p as a candidate drug;
(2) A method for non-therapeutic destination to increase hepatocyte glucose consumption, the method comprising the steps of: administering to the hepatocyte system a miR-3104-5p inhibitor as described in the first aspect of the invention.
Further, the system is selected from: a cellular system, a subcellular system, a solution system, a tissue system, an organ system, or an animal system.
Further, the test substances include, but are not limited to: interfering molecules, nucleic acid inhibitors, small molecule compounds, and the like designed for miR-3104-5 p.
Further, methods of detecting miR-3104-5p expression in the system include, but are not limited to: reverse transcription polymerase chain reaction (RT-PCR), competitive RT-PCR, real-time RT-PCR, ribonuclease Protection Assay (RPA), northern blotting, and DNA chip.
Further, reagents for detecting miR-3104-5p expression include, but are not limited to: primers, probes or antisense nucleotides. One skilled in the art can design primers, probes, or antisense nucleotides capable of specifically binding to miR-3104-5p based on sequence information of miR-3104-5 p.
Further, the candidate drug selected is a test substance capable of inhibiting the expression level of miR-3104-5p in the presence of the candidate drug as compared to the expression level of miR-3104-5p detected in the absence of the candidate drug.
The invention also provides a method for diagnosing and/or assisting in diagnosing diabetes, the method comprising the following steps: detecting the expression level of miR-3104-5p in a test sample derived from a subject, wherein if the expression level of miR-3104-5p in the test sample derived from the subject is significantly increased compared with a healthy control, the subject is diagnosed as a patient suffering from diabetes or a suspected patient diagnosed as having a higher risk of suffering from diabetes.
In some embodiments, the sample refers to a composition obtained or derived from a subject of interest comprising cellular entities and/or other molecular entities to be characterized and/or identified, e.g., based on physical, biochemical, chemical, and/or physiological characteristics. The sample may be obtained from blood and other fluid samples of biological origin from the subject, as well as tissue samples, such as biopsy tissue samples (e.g., liver tissue samples) or tissue cultures or cells derived therefrom. The source of the tissue sample may be solid tissue, such as tissue from fresh, frozen and/or preserved organs or tissue samples, biopsy tissue or aspirates; blood or any blood component; body fluid; cells from any time of gestation or development of an individual; or plasma. The sample includes biological samples that have been treated in any way after they have been obtained, such as by treatment with reagents, stabilization, or enrichment for certain components (such as proteins or polynucleotides), or embedding in a semi-solid or solid matrix for sectioning purposes. Samples described in the present invention include, but are not limited to: tissue, blood, serum, blood-derived cells, plasma, lymph fluid, synovial fluid, cell extracts, and combinations thereof.
In some embodiments, the subject of the invention refers to any animal, and also to human and non-human animals. The non-human animals include all vertebrates, for example, mammals, such as non-human primates (particularly higher primates), sheep, dogs, rodents (such as mice or rats), guinea pigs, goats, pigs, cats, rabbits, cattle, and any domestic animals or pets; and non-mammals, such as chickens, amphibians, reptiles, etc., in preferred embodiments, the subject is a human.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention provides a new application of miR-3104-5p inhibitor in diabetes treatment and diagnosis for the first time. The invention discovers the relativity between miR-3104-5p and diabetes for the first time, the miR-3104-5p is obviously up-regulated in mice exposed to high-fat diet in early life, the expression of miR-3104-5p is inhibited, the glycometabolism of liver cells can be obviously improved, the effect of treating diabetes is exerted, a new thought and strategy are provided for preparing medicines for treating diabetes and products for diagnosing diabetes, a new molecular target is provided for the targeted treatment of diabetes, early warning and early targeted intervention of diabetes are facilitated, and the invention has good clinical application prospect.
Drawings
Fig. 1: a graph of results corresponding to the effect of maternal high fat diet on glucose metabolism in offspring mice, wherein graph a: effect of maternal High Fat (HFD) diet on Oral Glucose Tolerance Test (OGTT) in offspring mice; b, drawing: area under OGTT blood glucose curve; c, drawing: maternal high-fat diet expressed liver miR-3104-5P in offspring mice with P <0.01.SD: a control feed; HFD: a high fat feed;
fig. 2: transfection of miR-3104-5p inhibitors improves the corresponding outcome profile of hepatocyte high glucose induced glucose uptake, wherein profile a: the miR-3104-5p of the liver cells is expressed relatively after being transfected by the miR-3104-5p inhibitor; b, drawing: effect of high glucose stimulation and miR-3104-5P inhibitor transfection on glucose uptake in mice primary hepatocytes, < 0.01P compared to normal glucose group (NG); # P <0.01 was compared to the high sugar (HG) treated group.
Detailed Description
The invention is further illustrated below in conjunction with specific examples, which are provided solely to illustrate the invention and are not to be construed as limiting the invention. One of ordinary skill in the art can appreciate that: many changes, modifications, substitutions and variations may be made to the embodiments without departing from the spirit and principles of the invention, the scope of which is defined by the claims and their equivalents. The experimental procedure, in which no specific conditions are noted in the examples below, is generally carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Reagents, biological materials, etc. used in the examples described below are commercially available unless otherwise specified.
Example 1 early in life high fat diet exposed mice liver miR-3104-5p expression was significantly upregulated
1. Experimental materials
C57BL/6J mice (Beijing Warcon Biotechnology Co., ltd.);
normal rodent diet (beijing verfukang biotechnology limited);
high fat feed (Beijing verruca Fukang biotechnology Co., ltd.);
glucose (Sigma);
glucometer (bayer bevacon);
blood glucose test paper (bayer bai' an kang);
TRIzol reagent (Sigma);
chloroform (Shanghai chemical Co., ltd.);
isopropyl alcohol (Shanghai chemical Co., ltd.);
reverse transcription kit (TaKaRa);
taqman miRNA detection kit (ABI);
ViiaA7 real-time quantitative PCR System (ABI);
taqman probe synthesis is shown in Table 1 below.
TABLE 1 miR-3104-5p Taqman probe sequences
2. Experimental method
C57BL/6J mice (Beijing Wallkukan Biotechnology Co., ltd., female 16, male 8) were purchased at 5 weeks of age. Female mice were randomly divided into normal diet group (SD, n=8) and high fat diet group (HFD, n=8). The normal diet group was given normal rodent diet (Beijing Fukang Biotechnology Co., ltd.) with an energy ratio of 10% fat, 20% protein, 70% carbohydrate. The high fat diet group was given high fat diet (Beijing Fukang Biotechnology Co., ltd.) with an energy ratio of 45% fat, 20% protein, and 35% carbohydrate. Free diet and ingestion. After 3 weeks, female mice were housed in 2:1 number with male mice (given normal feed). The first day of gestation is indicated for yin suppository. The pregnant mice continue to be given normal feed or high fat feed during pregnancy and lactation. The offspring were tested for oral glucose tolerance at 3 weeks of age, and were given a glucose solution (2 g/kg body weight) for gastric lavage for 10 hours on an empty stomach, 30 minutes, 60 minutes, 120 minutes of blood glucose before glucose loading was measured. Subsequently, the mice were sacrificed and livers were taken.
About 50 mg livers, 1 mL TRIzol reagent was added and homogenized. After homogenization, the mixture was allowed to stand at room temperature for 5 min. Then 0.2 mL chloroform was added. Incubate for 3 min at room temperature. Centrifuge at 12000 and g for 15 min at 4 ℃. After centrifugation, the uppermost supernatant was transferred to an RNase-free ep tube. 0.5. 0.5 mL isopropyl alcohol is added, and after mixing, the mixture is incubated at room temperature for 10 min and centrifuged at 12000 g at 4 ℃ for 10 min. The supernatant was discarded to obtain RNA precipitate. Reverse transcription was performed using a reverse transcription kit (TaKaRa). Obtaining a cDNA configuration real-time quantitative PCR reaction system. The following procedure was run on a real-time quantitative PCR instrument: 95 ℃ for 10 min;40 PCR cycles (95 ℃,10 sec;60 ℃,60 sec (fluorescence collection)). To establish a melting curve of the PCR product, the amplification reaction was completed at 95℃for 60℃for 60 sec and at 95℃for 15 secThe method comprises the steps of carrying out a first treatment on the surface of the And slowly heated from 60 ℃ to 99 ℃. By taking an action as an internal reference, detecting miR-3104-5p expression by using a real-time quantitative PCR method, and 2 -△△Ct The method was used for relative quantification.
3. Experimental results
As shown in fig. 1A-C, in the oral glucose tolerance test, 30 minutes, 60 minutes, and 120 minutes after glucose administration of mice exposed to the high fat diet in the early life, blood glucose was significantly increased (P < 0.01), and the area under the blood glucose curve was significantly increased (P < 0.01). Liver miR-3104-5P expression of mice exposed to high-fat diet is significantly up-regulated early in life (P < 0.01).
EXAMPLE 2 miR-3104-5p inhibitor improves hepatocyte glycometabolism
1. Experimental materials
Cell incubator (Thermo);
c57BL/6J mice (Beijing Warcon Biotechnology Co., ltd.);
DMEM medium (Gibco);
fetal bovine serum (Gibco);
glucose (Sigma);
lipofectamine RNAiMAX transfection kit (Thermo Fisher Co.);
glucose test kit (Beijing Soy Bao technology Co.).
2. Experimental method
Primary hepatocytes were isolated from C57BL/6J mouse livers. Isolated mouse primary hepatocytes were cultured in DMEM medium at 37 ℃ with 5% CO 2 Incubator culture. And (3) designing miR-3104-5p siRNA according to miR-3104-5p sequence, and synthesizing siRNA (Guangzhou Ruibo company). 24. 24 h seed before transfection about 1X 10 6 The individual/empty hepatocytes were plated in six well plates and when the cell density reached 70%, the medium was changed to serum-free medium. Mixing the diluted siRNA with Lipofectamine RNAiMAX transfection reagent, gently mixing, and incubating for 20 min at room temperature to form transfection complex. Then, the mixture was added to the cell culture medium, gently mixed, and mixed at 5% CO 2 Culturing in a 37 ℃ incubator, and replacing the complete culture medium after 6 h. 16 After h, the high sugar medium (33 mmol/L) was changed to treat hepatocytes.
After cell treatment 24 h, the culture supernatant was taken and the microplate reader was used to determine the empty OD values at 505 and nm, 3 wells per sample, as indicated by the glucose assay kit.
After 24 h cell treatments, the medium was aspirated and washed 2 times with PBS. 1 mL TRIzol reagent is added into each hole, and the mixture is repeatedly blown and evenly mixed, so that cells are fully lysed, and the mixture is kept stand for 10 min at room temperature. The lysate was transferred to the ep tube and 0.2 mL chloroform was added. Incubate for 3 min at room temperature. Centrifuge at 12000 and g for 15 min at 4 ℃. After centrifugation, the uppermost supernatant was transferred to an RNase-free ep tube. 0.5. 0.5 mL isopropyl alcohol is added, and after mixing, the mixture is incubated at room temperature for 10 min and centrifuged at 12000 g at 4 ℃ for 10 min. The supernatant was discarded to obtain RNA precipitate. Reverse transcription was performed using a reverse transcription kit (TaKaRa). And (3) obtaining cDNA, and configuring a real-time quantitative PCR reaction system. The following procedure was run on a real-time quantitative PCR instrument: 95 ℃ for 10 min;40 PCR cycles (95 ℃,10 sec;60 ℃,60 sec (fluorescence collection)). After the amplification reaction is completed, the melting curve of the PCR product is established according to the conditions (95 ℃,10 sec;60 ℃,60 sec;95 ℃ 15 sec); and slowly heated from 60 ℃ to 99 ℃. By taking an action as an internal reference, detecting miR-3104-5p expression by using a real-time quantitative PCR method, and 2 -△△Ct The method was used for relative quantification. Wherein the miR-3104-5p inhibitor sequence is shown in Table 2 below.
TABLE 2 miR-3104-5p inhibitors
3. Experimental results
As shown in FIGS. 1A-B, the level of miR-3104-5P was significantly reduced (P < 0.01) after the primary hepatocytes of the high-sugar stimulated mice were transfected with the miR-3104-5P inhibitor. Transfection of miR-3104-5P inhibitors into mouse primary hepatocytes improved the high sugar-induced decrease in glucose consumption (P < 0.01). Thus, miR-3104-5p inhibitor can improve hepatocyte glucose metabolism.
The above description of the embodiments is only for the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that several improvements and modifications can be made to the present invention without departing from the principle of the invention, and these improvements and modifications will fall within the scope of the claims of the invention.
Claims (10)
- Application of miR-3104-5p inhibitor in preparation of medicine for treating diabetes.
- 2. The use of claim 1, wherein the miR-3104-5p inhibitor comprises an interfering molecule that inhibits miR-3104-5p expression.
- 3. The use of claim 2, wherein the miR-3104-5p inhibitor comprises any one or more of siRNA, shRNA, dsRNA, microrna, antisense nucleic acids targeting miR-3104-5 p.
- 4. The use according to claim 3, wherein the sequence of the siRNA targeting miR-3104-5p is shown in SEQ ID NO. 2.
- 5. Use of a reagent for detecting miR-3104-5p expression levels in the preparation of a diagnostic product for diagnosing diabetes.
- 6. The use of claim 5, wherein the reagent for detecting the expression level of miR-3104-5p comprises a probe that specifically recognizes miR-3104-5p and/or a primer that specifically amplifies miR-3104-5 p.
- 7. The use according to claim 6, wherein the sequence of the probe specifically recognizing miR-3104-5p is shown in SEQ ID No. 1.
- 8. An application of any one of the following, the application comprising:(1) The application of miR-3104-5p in screening candidate drugs for treating diabetes is characterized in that candidate drugs for treating diabetes are screened by detecting whether a test substance can inhibit miR-3104-5p expression;(2) Use of a miR-3104-5p inhibitor in the preparation of a reagent for increasing glucose consumption in hepatocytes, wherein the miR-3104-5p inhibitor is a miR-3104-5p inhibitor of any one of claims 1-4.
- 9. A product of any one of the following, the product comprising:(1) A pharmaceutical composition for treating diabetes, comprising the miR-3104-5p inhibitor of any one of claims 1-4;(2) A pharmaceutical formulation for treating diabetes, comprising the miR-3104-5p inhibitor of any one of claims 1-4;(3) A diagnostic product for diagnosing diabetes comprising the agent of any one of claims 5-7 that detects miR-3104-5p expression levels.
- 10. A method of any one of the following, the method comprising:(1) A method of screening for a candidate drug for treating diabetes, the method comprising the steps of: treating a system expressing or containing miR-3104-5p with a test substance, detecting the expression of miR-3104-5p in the system, and selecting the test substance capable of inhibiting the expression of miR-3104-5p as a candidate drug;(2) A method for increasing hepatocyte glucose consumption at a non-therapeutic destination, the method comprising the steps of: administering the miR-3104-5p inhibitor of any one of claims 1-4 into a hepatocyte system.
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