CN112843082B - Application of DNA tetrahedron in preparation of medicine for treating diabetes - Google Patents

Application of DNA tetrahedron in preparation of medicine for treating diabetes Download PDF

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CN112843082B
CN112843082B CN202110146040.7A CN202110146040A CN112843082B CN 112843082 B CN112843082 B CN 112843082B CN 202110146040 A CN202110146040 A CN 202110146040A CN 112843082 B CN112843082 B CN 112843082B
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insulin resistance
medicine
dna tetrahedron
tfnas
diabetes
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CN112843082A (en
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林云锋
李彦静
蔡潇潇
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Chengdu Yunhai Tetrahedral Biotechnology Co ltd
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
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    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention discloses an application of a DNA tetrahedron in preparing a medicament for treating diabetes, and belongs to the field of biological pharmacy. Experiments prove that the DNA tetrahedron has the effects of reducing blood sugar and relieving insulin resistance. Compared with the existing medicine for treating insulin resistance and diabetes, the medicine provided by the invention has the advantages of higher utilization rate, lower side effect and good application prospect because the DNA tetrahedron is easily taken by cells and has high biocompatibility.

Description

Application of DNA tetrahedron in preparation of medicine for treating diabetes
Technical Field
The invention belongs to the field of biological pharmacy.
Background
Insulin is an important hormone involved in the regulation of carbohydrate, lipid and protein metabolism, and has main physiological effects including promotion of glucose transfer into cells of tissues such as skeletal muscle and fat, promotion of glycogen synthesis, inhibition of glycogenolysis and gluconeogenesis, promotion of fat synthesis, inhibition of fat mobilization, promotion of protein synthesis and inhibition of protein degradation.
Insulin resistance means a decrease in the above physiological effects or a decrease in the tissue response to insulin. Insulin resistance can cause diseases such as partial metabolic syndrome, type 2 diabetes, hypertension, hyperuricemia, blood lipid disorder, cardiovascular and cerebrovascular diseases, polycystic ovary syndrome, Alzheimer disease, partial tumors and the like.
A specific treatment method for insulin resistance does not exist, and the general treatment comprises diet control, exercise enhancement, work and rest rule keeping, proper supplement of trivalent chromium ions, trace elements, vanadium and the like to relieve the insulin resistance, but the general treatment is only suitable for mild patients. For patients with severe symptoms, drugs such as thiazolidinedione and metformin can be used under the guidance of doctors, but these drugs have side effects such as heart failure, edema and gastrointestinal reactions, and are prone to drug resistance.
The literature indicates that miRNA plays an important role in the generation and development process of insulin resistance, and part of exogenous miRNA can promote glycogen synthesis through multiple mechanisms, such as miR-542-5p, miR-4454, miR-363-3p, miR-122-5p and the like. mirnas are a class of endogenous, small RNAs of about 20-24 nucleotides in length that have a regulatory effect on genes. However, miRNA is unstable, difficult to transport and store and high in synthesis cost.
Some traditional Chinese medicine monomers are also considered to have the capability of relieving insulin resistance, but the traditional Chinese medicine monomers have poor stability and water solubility, low cellular uptake efficiency and low in-vivo utilization rate, and can exert substantial effects only by using a larger dose.
DNA tetrahedron, also known as tetrahedral framework nucleic acids (tFNAs), is a tetrahedral structure formed by complementary base pairing of DNA and can be prepared by heating and denaturing 4 designed single-stranded DNAs and then rapidly cooling and renaturing the DNAs. The DNA tetrahedron is a nucleic acid with a structure more stable than miRNA, is easy to be taken in by cells, has high biocompatibility, can be used for constructing a structural base of an in vivo detection probe and a carrier of a part of medicines, and even has certain biological activity, such as promotion of neural stem cell proliferation.
The relationship between DNA tetrahedron and insulin resistance has not been reported.
Disclosure of Invention
The invention aims to solve the problems that: provides the use of DNA tetrahedra in the preparation of a medicament for the treatment of insulin resistance.
The technical scheme of the invention is as follows:
use of a DNA tetrahedron for the preparation of a medicament for the treatment of insulin resistance.
Further, the DNA tetrahedron is formed by 4 single-stranded DNAs through base complementary pairing;
preferably, the sequence of the 4 single-stranded DNAs is shown in SEQ ID NO. 1-4.
Further, the medicine is a medicine for treating metabolic syndrome caused by insulin resistance, type 2 diabetes, hypertension, hyperuricemia, blood lipid disorder, cardiovascular and cerebrovascular diseases, polycystic ovary syndrome, Alzheimer disease or tumors.
Use of a DNA tetrahedron in the preparation of a medicament for lowering blood glucose.
Further, the DNA tetrahedron is formed by 4 single-stranded DNAs through base complementary pairing;
preferably, the sequence of the 4 single-stranded DNAs is shown in SEQ ID NO. 1-4.
Preferably, the medicament is a medicament for the treatment of diabetes.
A medicament for treating insulin resistance is prepared by taking DNA tetrahedron as an active ingredient and adding a pharmaceutically acceptable carrier.
Further, the DNA tetrahedron is formed by 4 single-stranded DNAs through base complementary pairing;
preferably, the sequence of the 4 single-stranded DNAs is shown in SEQ ID NO. 1-4.
Further, the medicine is a medicine for treating metabolic syndrome caused by insulin resistance, type 2 diabetes, hypertension, hyperuricemia, blood lipid disorder, cardiovascular and cerebrovascular diseases, polycystic ovary syndrome, Alzheimer disease or tumor.
A hypoglycemic agent, which is characterized in that: the medicine is prepared by taking a DNA tetrahedron as an active ingredient and adding a pharmaceutically acceptable carrier.
Further, the DNA tetrahedron is formed by 4 single-stranded DNAs through base complementary pairing;
preferably, the sequence of the 4 single-stranded DNAs is shown in SEQ ID NO. 1-4.
Preferably, the medicament is a medicament for the treatment of diabetes.
Experiments prove that the DNA tetrahedron has the effects of relieving insulin resistance and reducing blood sugar, and can be prepared into medicaments for treating insulin resistance, medicaments for treating metabolic syndrome, type 2 diabetes, hypertension, hyperuricemia, blood lipid disorder, cardiovascular and cerebrovascular diseases, polycystic ovary syndrome, Alzheimer disease or tumors caused by insulin resistance, and hypoglycemic medicaments (can be used for treating diabetes).
Compared with the existing medicines for treating insulin resistance and diabetes, the medicine of the invention has higher utilization rate and lower side effect because the DNA tetrahedron is easy to be taken by cells and has high biocompatibility.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1: PAGE gel electrophoresis of tFNAs, partially single stranded complexes.
FIG. 2: capillary electrophoresis of tFNAs, partially single stranded complexes.
FIG. 3: transmission electron micrographs of tFNAs.
FIG. 4: the uptake rates of glucose by cells under different treatments were compared.
FIG. 5: trend of blood glucose over time and area under the curve in insulin resistance mouse model glucose tolerance (IPGTT) and insulin resistance (IPITT) experiments; a and B, corresponding to IPGTT experiment; c and D correspond to IPITT experiment; HFD, high fat high sugar diet.
FIG. 6: results of liver tissue staining in mice of different treatment groups. A is PAS dyeing; b is H & E staining; HFD, high fat high sugar diet.
Detailed Description
Example 1 Synthesis and characterization of tFNAs
1. Synthesis method
Four single-stranded DNAs (S1, S2, S3, S4) were dissolved in TM Buffer (10mM Tris-HCl,50mM MgCl2, pH 8.0) so that the final concentrations of the four single-stranded DNAs were 1000nM, and after thoroughly mixing, the four single-stranded DNAs were rapidly heated to 95 ℃ for 10 minutes, and then rapidly cooled to 4 ℃ for 20 minutes or more, thereby obtaining tFNAs.
The four single-stranded sequences (5 '→ 3') are as follows:
S1：
ATTTATCACCCGCCATAGTAGACGTATCACCAGGCAGTTGAGACGAACATTCCTAAGTCTGAA(SEQ ID NO.1)
S2：
ACATGCGAGGGTCCAATACCGACGATTACAGCTTGCTACACGATTCAGACTTAGGAATGTTCG(SEQ ID NO.2)
S3：
ACTACTATGGCGGGTGATAAAACGTGTAGCAAGCTGTAATCGACGGGAAGAGCATGCCCATCC(SEQ ID NO.3)
S4：
ACGGTATTGGACCCTCGCATGACTCAACTGCCTGGTGATACGAGGATGGGCATGCTCTTCCCG(SEQ ID NO.4)
2. identification
From the PAGE results, the tFNAs size was about 200bp (FIG. 1); as a result of capillary electrophoresis, the tFNAs is about 164bp in size (FIG. 2); the scattering point-like objects can be seen by transmission electron microscopy, and part of the point-like objects can be observed to present a tetrahedral shape (fig. 3).
From the foregoing identification results, it can be considered that tFNAs were successfully synthesized.
The invention will be further illustrated in the form of experimental examples in which the tFNAs used were prepared by the method of example 1.
Experimental example 1 in vitro experiments with tFNAs to alleviate insulin resistance
This example used HepG2 cells as the study cells for the in vitro model. HepG2 cell is a hepatoblastoma cell strain with a phenotype very similar to that of a normal human hepatocyte, is an ideal cell model for in vitro research on an insulin resistance mechanism and a drug action, and is widely accepted by scholars. Glucosamine (GlcN) is a commonly used insulin resistance-inducing agent and can produce insulin resistance by being commonly used to induce hepatocytes such as HepG 2.
1. Method of producing a composite material
The HepG2 cells were divided into 3 groups of 3 flasks, each flask having the same physiological state and quantity of cells, the blank group was not treated, glucosamine was added to the control group to a final concentration of 18mM, glucosamine was added to the treatment group to a final concentration of 18mM, and tFNAs was added to the treatment group to a final concentration of 250nM after 18 hours.
After 24 hours, the glucose concentration in the cell culture supernatant was measured using a glucose assay kit, and the glucose uptake by the cells was calculated.
2. As a result, the
Glucosamine can obviously reduce the glucose uptake capacity of HepG2 cells, the glucose uptake rate of the cells after the glucosamine treatment is as low as 53.59 percent, the glucose uptake rate of the cells after 62.5nM tFNAs is added is improved to 77.00 percent, the glucose uptake rate of the cells after 125nM tFNAs is added is improved to 83.81 percent, and the glucose uptake rate of the cells after 250nM tFNAs is added is improved to 91.10 percent.
The results of this experimental example show that tFNAs can relieve insulin resistance of cells, enhance the glucose uptake capability of cells, and have the ability of reducing blood sugar.
Experimental example 2 in vivo experiments with tFNAs to alleviate insulin resistance
1. Method of producing a composite material
(1) Insulin resistance was induced in C57BL/6Cnc male mice using high fat and high sugar feeding. And feeding normal feed to the control group, feeding high-fat high-sugar feed 8w to the modeling group, and establishing an insulin diabody internal model.
(2) Drug treatment was given after successful modeling. The control group was fed with normal diet, the modeling group was continued to be fed with high-fat high-sugar diet and injected with physiological saline, and the experimental group was continued to be fed with high-fat high-sugar diet and injected with 200 μ L of 250nM tFNAs physiological saline solution.
(3) The medicine is injected into abdominal cavity 1 time every 48 hours for 6 weeks.
(4) After the end of the administration, the glucose tolerance (IPGTT) and insulin resistance (IPITT) of the mice were measured.
IPGTT: after the mice were starved for 14 hours, 1g/kg glucose (20% aqueous solution) was intraperitoneally injected, and the blood glucose levels of the mice were measured at 0, 15, 30, 60, 90, and 120 minutes.
IPITT: after 4 hours of starvation, 0.75U/kg of an insulin aqueous solution was intraperitoneally injected, and the blood glucose content of the mice was measured at 0, 15, 30, 60, and 90 minutes.
(5) Mice were then sacrificed and livers were collected, H & E stained and PAS stained.
2. Results
IPGTT and IPITT results showed significant concentrations of blood glucose in the experimental mice below those of the modeled mice, comparable to the control group (figure 5). The tFNAs are shown to help mice reduce blood sugar and reduce insulin resistance.
As seen in PAS staining results of mouse livers, mice in the modeling group stained light, while mice in the experimental group stained dark, and the mice in the experimental group were basically restored to the level of the control group (FIG. 6). The results show that tFNAs can improve glycogen synthesis capacity of mouse liver and reduce insulin resistance.
The H & E staining result of the mouse liver is visible, the liver cells of the control mouse are closely arranged, and the hepatic sinus structure is clear; liver cells of a model building mouse become serious in fatness, vacuole and unclear hepatic sinus structure; the experimental mice had clear liver structure, compact cell arrangement, and less fatty degeneration, which tended to be normal (fig. 6). Fatty degeneration is an important pathological change of liver cells in insulin resistance, and the result shows that tFNAs can improve the fatty degeneration of liver and reduce the insulin resistance.
The experimental examples prove that tFNAs have the functions of reducing blood sugar and relieving insulin resistance from the body.
In conclusion, tFNAs have the functions of relieving insulin resistance and reducing blood sugar, and can be prepared into medicaments for treating insulin resistance, medicaments for treating metabolic syndrome, type 2 diabetes, hypertension, hyperuricemia, blood fat disorder, cardiovascular and cerebrovascular diseases, polycystic ovary syndrome, Alzheimer disease or tumors caused by insulin resistance, and hypoglycemic medicaments, so the tFNAs have very good application prospects.
SEQUENCE LISTING
<110> Sichuan university
Application of <120> DNA tetrahedron in preparation of medicine for treating diabetes
<130> GYKH1118-2020P0112236CC
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 63
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 1
atttatcacc cgccatagta gacgtatcac caggcagttg agacgaacat tcctaagtct 60
gaa 63
<210> 2
<211> 63
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 2
acatgcgagg gtccaatacc gacgattaca gcttgctaca cgattcagac ttaggaatgt 60
tcg 63
<210> 3
<211> 63
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 3
actactatgg cgggtgataa aacgtgtagc aagctgtaat cgacgggaag agcatgccca 60
tcc 63
<210> 4
<211> 63
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 4
acggtattgg accctcgcat gactcaactg cctggtgata cgaggatggg catgctcttc 60
ccg 63

Claims (3)

  1. Use of a DNA tetrahedron for the preparation of a medicament for the treatment of insulin resistance, wherein: the DNA tetrahedron is formed by 4 single-stranded DNAs through base complementary pairing; the sequence of the 4 single-stranded DNAs is shown in SEQ ID NO. 1-4.
  2. 2. Use according to claim 1, characterized in that: the medicine is used for treating type 2 diabetes caused by insulin resistance.
  3. 3. Use according to claim 2, characterized in that: the medicine can be used for treating type 2 diabetes by lowering blood sugar.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW201801750A (en) * 2016-04-06 2018-01-16 恩特斯普有限責任公司 Particles comprising subparticles or nucleic acid scaffolds
CN110292644A (en) * 2019-07-23 2019-10-01 四川大学 A kind of drug prevented and treated myocardial ischemia-reperfusion injury or treat heart ischemia disease
CN112007044A (en) * 2019-09-10 2020-12-01 四川大学 Medicine for preventing oxidative stress of retinal ganglion cells and wet macular degeneration

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069901A2 (en) * 1999-05-19 2000-11-23 Xencor, Inc. Proteins with insulin-like activity useful in the treatment of diabetes
EP1706137A2 (en) * 2004-01-21 2006-10-04 Chiron Corporation M-csf muteins and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW201801750A (en) * 2016-04-06 2018-01-16 恩特斯普有限責任公司 Particles comprising subparticles or nucleic acid scaffolds
CN110292644A (en) * 2019-07-23 2019-10-01 四川大学 A kind of drug prevented and treated myocardial ischemia-reperfusion injury or treat heart ischemia disease
CN112007044A (en) * 2019-09-10 2020-12-01 四川大学 Medicine for preventing oxidative stress of retinal ganglion cells and wet macular degeneration

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Antioxidative and Angiogenesis-Promoting Effects of Tetrahedral Framework Nucleic Acids in Diabetic Wound Healing with Activation of the Akt/Nrf2/HO 1 Pathway;Shiyu Lin et al.;《ACS Appl. Mater. Interfaces》;20200221;第12卷;第11397页摘要部分及第11398页表1；第11403页第3.5部分 *

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