Synthetic oligonucleotide that regulates NF-κb and SOX4 transcription factors, and composition for preventing or treating complications of diabetes, comprising same

Abstract

The present invention relates to a decoy oligodeoxynucleotide that regulates NF-κB and SOX4 transcription factors, and a composition for preventing or treating complications of diabetes, comprising same, the decoy oligodeoxynucleotide inhibiting the expression of NF-κB or SOX4, or simultaneously inhibiting the expressions of NF-κB and SOX4, thereby being usefully employable for the prevention, reduction, or treatment of complications of diabetes, i.e., vascular complications of diabetes.

Description

Synthetic oligonucleotide regulating NF-κB and SOX4 transcription factors and composition for preventing or treating diabetic complications comprising the same

[0001] The present invention relates to a decoy oligodeoxynucleotide that regulates NF-κB and SOX4 transcription factors and a composition for preventing or treating diabetic complications comprising the same.

[0002]

[0003] Diabetes mellitus is a metabolic disease characterized by high blood glucose levels due to insufficient secretion of insulin or failure to function normally, and is defined as causing various symptoms and signs due to high blood glucose and excreting glucose in the urine.

[0004] If blood sugar levels remain uncontrolled and remain hyperglycemic, various acute and chronic complications can occur. Chronic complications of diabetes are a major cause of diabetes-related illness and death. Chronic complications of diabetes are broadly divided into vascular and non-vascular complications, and vascular complications are further divided into microvascular and macrovascular complications. Microvascular complications include retinopathy, nephropathy, and neuropathy, while macrovascular complications include coronary artery disease, peripheral artery disease, and cerebrovascular disease.

[0005] In particular, macrovascular complications of diabetes are caused by atherosclerosis in medium-sized or larger blood vessels and are the leading cause of death in patients with diabetes. Atherosclerosis occurs at a higher rate, progresses more rapidly, and is more extensive in patients with diabetes than in the general population.

[0006] To prevent these macrovascular complications of diabetes, risk factors for atherosclerosis are typically addressed through measures such as smoking cessation, diet, exercise, blood pressure control, anticoagulation, hyperlipidemia treatment, and blood sugar control. However, these treatments fail to address the underlying cause. Furthermore, these treatments are ineffective in preventing and treating macrovascular complications in advanced diabetes, making early detection and prevention crucial. Furthermore, while numerous treatments for atherosclerosis rely on lowering plasma lipid levels, their overall efficacy remains low. With a rising global prevalence, atherosclerosis remains a serious public health problem.

[0007] In addition, persistent hyperglycemia in diabetes activates NF-κB, which induces the expression of various cytokines and cell adhesion molecules, and overexpression of NF-κB increases apoptosis and inflammatory processes that play a major role in cell damage and complications, and causes endothelial cell dysfunction and atherosclerosis and calcification, leading to vascular complications.

[0008] Overexpression of SOX4, well known to promote tumorigenesis, suppresses hormone release and insulin secretion in diabetic patients, increasing the risk of diabetes. Furthermore, as SOX4 is expressed in diverse cell types and its various aspects are becoming known, research is needed to understand its function, mechanisms, and effects on the regulation of vascular complications of diabetes.

[0009] Meanwhile, gene therapy is a technology that treats and prevents diseases by delivering gene expression regulators to the patient's cells and tissues to control the expression of specific genes. Decoy oligodeoxynucleotides are synthetic gene therapeutics containing a base sequence that binds to a target transcription factor. They effectively suppress disease-related gene expression by inhibiting the activity of the transcription factor. Specifically, by binding the DNA binding site of the transcription factor to the decoy oligodeoxynucleotide, the transcription factor is prevented from binding to the promoter of the target gene, inhibiting its activity and reducing the expression of the specific gene.

[0010] Accordingly, the present inventors produced a decoy oligodeoxynucleotide that simultaneously regulates the expression of NF-κB and SOX4, and confirmed that the decoy oligodeoxynucleotide significantly reduces an indicator of arteriosclerosis and effectively reduces an inflammatory response in an animal model of vascular complications of diabetes, thereby completing the present invention.

[0011]

[0012] The present invention aims to provide a decoy oligodeoxynucleotide that regulates NF-κB or SOX4 transcription factors.

[0013] In addition, the present invention aims to provide a composition for preventing or treating diabetic complications, which comprises a decoy oligodeoxynucleotide that regulates NF-κB or SOX4 transcription factors.

[0014]

[0015] To achieve the above purpose, the present invention provides an NF-κB decoy oligodeoxynucleotide comprising the base sequence of SEQ ID NO: 1 and a pharmaceutical composition for preventing or treating diabetic complications comprising the same.

[0016] In addition, the present invention provides a SOX4 decoy oligodeoxynucleotide comprising the base sequence of SEQ ID NO: 2 and a pharmaceutical composition for preventing or treating diabetic complications comprising the same.

[0017] In addition, the present invention provides an NF-κB / SOX4 decoy oligodeoxynucleotide in which an NF-κB decoy oligodeoxynucleotide including a base sequence of SEQ ID NO: 1 and a SOX4 decoy oligodeoxynucleotide including a base sequence of SEQ ID NO: 2 are linked, and a pharmaceutical composition for preventing or treating diabetic complications including the same.

[0018] In addition, the present invention provides a method for preventing or treating diabetic complications, comprising administering to a non-human subject an NF-κB decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 1, a SOX4 decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 2, or an NF-κB / SOX4 decoy oligodeoxynucleotide in which an NF-κB decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 1 and a SOX4 decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 2 are linked.

[0019] The above diabetic complication may be a vascular complication, the vascular complication may be a macrovascular complication, and the macrovascular complication may be arteriosclerosis.

[0020]

[0021] The decoy oligodeoxynucleotide of the present invention can be usefully used for preventing, improving or treating diabetic complications, i.e., vascular complications of diabetes, by inhibiting the expression of NF-κB or SOX4 or simultaneously inhibiting the expression of NF-κB and SOX4.

[0022]

[0023] Figure 1 shows a schematic diagram of NF-κB and SOX4 decoy oligodeoxynucleotides.

[0024] Figure 2 shows the results of confirming the stability of NF-κB / SOX4 decoy oligodeoxynucleotide by confirming the expression of fluorescently labeled NF-κB / SOX4 decoy oligodeoxynucleotide in the heart and abdominal aorta of an animal model.

[0025] Figure 3 shows the results of confirming NF-κB and Sox4 binding activity in an animal model, and confirming the NF-κB and SOX4 expression inhibitory effect of NF-κB / SOX4 decoy oligodeoxynucleotide.

[0026] Figure 4 shows H&E staining images of the abdominal aorta and heart of an animal model, showing the results confirming the inhibitory effect of NF-κB / SOX4 decoy oligodeoxynucleotide on damage to aortic and heart tissue.

[0027] Figure 5 shows the results of confirming the inhibitory effect of NF-κB / SOX4 decoy oligodeoxynucleotide on TNF-α, IL-1β, and IL-6 expression in arterial tissue in an animal model.

[0028] Figures 6 and 7 show the results of confirming the effect of NF-κB / SOX4 decoy oligodeoxynucleotide on inhibiting the expression of vascular adhesion factors in arterial tissue in an animal model.

[0029] Figure 8 shows the results of confirming the inhibitory effect of NF-κB / SOX4 decoy oligodeoxynucleotide on arterial tissue elastin fragmentation and collagen deposition in an animal model.

[0030] Figure 9 shows the results of confirming the inhibitory effect of NF-κB / SOX4 decoy oligodeoxynucleotide on the expression of fibrosis-related factors and atherosclerotic factors in arterial tissue in an animal model.

[0031] Figure 10 shows the results of confirming the inhibitory effect of NF-κB / SOX4 decoy oligodeoxynucleotide on the expression of NF-κB and SOX4 signaling pathway factors in an animal model.

[0032]

[0033] Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention may be implemented in various forms and is not limited to the embodiments and examples described herein.

[0034] Throughout this specification, whenever a part is said to "include" a component, this means that it may include other components, but not to the exclusion of other components, unless otherwise stated.

[0035] The present invention provides a synthetic oligonucleic acid that regulates NF-κB or SOX4 transcription factors and a composition for preventing or treating diabetic complications comprising the same.

[0036] The present invention provides a synthetic oligonucleotide that regulates the NF-κB or SOX4 transcription factor, an NF-κB decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 1, a SOX4 decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 2, and an NF-κB / SOX4 decoy oligodeoxynucleotide in which the NF-κB decoy oligodeoxynucleotide and the SOX4 decoy oligodeoxynucleotide are linked.

[0037] The decoy oligodeoxynucleotide (decoy ODN) of the present invention is a synthetic oligonucleotide (oligonucleic acid) that has high affinity for a specific transcription factor and can transform target cells, bind to the target, and alter gene transcription.

[0038] In the present invention, the decoy oligodeoxynucleotide comprises a stem-loop structure or a hairpin structure.

[0039] The above stem-loop structure is also called a hairpin structure, and is a structure having a stem portion formed by hydrogen bonding between complementary inverted repeat sequences of single-stranded RNA or DNA and a loop portion in the shape of a loop.

[0040] In the present invention, the stem may be a portion capable of binding to a DNA binding site of a transcription factor, and the loop may be composed of at least four bases, preferably composed of AAAA bases, but is not limited thereto.

[0041] The NF-κB decoy oligodeoxynucleotide of the present invention may include a base sequence of SEQ ID NO: 1, and may include a base sequence having 70% to 99% or more homology with the base sequence represented by SEQ ID NO: 1.

[0042] The above NF-κB decoy oligodeoxynucleotide has a complementary binding structure formed by the GGGAAATCCC base and the GGGATTTCCC base in the base sequence of sequence number 1, and the AAAA base can form a loop.

[0043] The above NF-κB decoy oligodeoxynucleotide can bind to and inhibit NF-κB.

[0044] The "NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells)" of the present invention is a family of transcription factor protein complexes that regulate DNA transcription, cytokine production, and cell survival, and is found in almost all animal cell types, is involved in cell responses to various stimuli, and plays an important role in inflammatory responses.

[0045] The SOX4 decoy oligodeoxynucleotide of the present invention may include a base sequence of SEQ ID NO: 2, and may include a base sequence having 70% to 99% or more homology with the base sequence represented by SEQ ID NO: 2.

[0046] The above SOX4 decoy oligodeoxynucleotide has a complementary structure in which the AACAAAG base and the CTTTGTT base in the base sequence of sequence number 2 form a complementary bond structure, and the AAAA base can form a loop.

[0047] The above SOX4 decoy oligodeoxynucleotide can bind to and inhibit SOX4.

[0048] The "SOX4 (SRY-box 4)" of the present invention is one of the SOX (SRY-related HMG-box) transcription factor family members in which the HMG domain, which is a DNA binding domain, is highly conserved, and plays an important role in embryonic development.

[0049] The NF-κB / SOX4 decoy oligodeoxynucleotide of the present invention may be a NF-κB decoy oligodeoxynucleotide including the base sequence of SEQ ID NO: 1 and a SOX4 decoy oligodeoxynucleotide including the base sequence of SEQ ID NO: 2 linked together, and the linkage may be ligation by ligase, but is not limited thereto.

[0050] The above NF-κB / SOX4 decoy oligodeoxynucleotide may be a GAATTC base at the 5' end of an NF-κB decoy oligodeoxynucleotide including the base sequence of SEQ ID NO: 1 and a GAATTC base at the 5' end of a SOX4 decoy oligodeoxynucleotide including the base sequence of SEQ ID NO: 2, which are complementarily linked by ligase.

[0051] The above NF-κB / SOX4 decoy oligodeoxynucleotide may comprise one stem portion and two loop-shaped ring portions.

[0052] The above NF-κB / SOX4 decoy oligodeoxynucleotide can bind to and inhibit NF-κB and SOX4.

[0053] The above NF-κB / SOX4 decoy oligodeoxynucleotide can be prepared by denaturing, annealing, and ligating an NF-κB decoy oligodeoxynucleotide including the base sequence of SEQ ID NO: 1 and a SOX4 decoy oligodeoxynucleotide including the base sequence of SEQ ID NO: 2.

[0054] In addition, the present invention provides a composition for preventing or treating diabetic complications, comprising a synthetic oligonucleotide that regulates NF-κB or SOX4 transcription factors, comprising an NF-κB decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 1, a SOX4 decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 2, or a pharmaceutical composition for preventing or treating diabetic complications, comprising an NF-κB decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 1 and a SOX4 decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 2 linked to each other.

[0055] The above diabetes refers to a metabolic disease in which high blood sugar levels persist for a long period of time, and the diabetes includes type 1 diabetes, type 2 diabetes, gestational diabetes, and steroid diabetes, and may preferably be type 2 diabetes, but is not limited thereto.

[0056] The above diabetic complications refer to all complications that occur in various organs due to prolonged hyperglycemia caused by diabetes, and the diabetic complications include acute complications and chronic complications, and may preferably be chronic complications. The chronic complications include vascular complications and non-vascular complications, and may preferably be vascular complications. The vascular complications include microvascular complications and macrovascular complications, and may preferably be macrovascular complications. The macrovascular complications include coronary artery disease, peripheral arterial disease, cerebrovascular disease, etc., and the diseases may include hypertension, dyslipidemia, angina pectoris, arterial spasm, cardiac arrhythmia, cardiac hypertrophy, cerebral infarction, congestive heart failure, arteriosclerosis, coronary heart disease, myocardial infarction, etc., and may preferably be arteriosclerosis, but are not limited thereto.

[0057] The pharmaceutical composition of the present invention may be formulated as a powder, granule, tablet, coated tablet, pill, dragee, capsule, liquid, suspension, gel, syrup, slurry, suppository, emulsion, paste, ointment, cream, lotion, powder, spray, or suspension. The pharmaceutical composition may additionally include excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and diluents commonly used for the formulation, and in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used, but are not limited thereto.

[0058] The above pharmaceutical composition can be administered parenterally or orally depending on the intended method, and the dosage range varies depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and disease severity. In addition, the therapeutically effective amount of the above composition may vary depending on the administration method, intended site, and patient's condition, and when used in the human body, the dosage should be determined as an appropriate amount considering both safety and efficacy.

[0059] The pharmaceutical composition of the present invention may additionally include an adjuvant in addition to the active ingredient. Any adjuvant known in the art may be used without limitation.

[0060] In addition, the present invention provides a method for preventing or treating diabetic complications, comprising administering to a non-human subject an NF-κB decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 1, a SOX4 decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 2, or an NF-κB / SOX4 decoy oligodeoxynucleotide in which an NF-κB decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 1 and a SOX4 decoy oligodeoxynucleotide comprising a base sequence of SEQ ID NO: 2 are linked.

[0061] The term "prevention" used in the present invention means any act of suppressing or delaying gastrointestinal diseases, etc. by administering the composition according to the present invention, and "treatment" means any act of improving or beneficially changing the symptoms of a subject suspected of having or developing a gastrointestinal disease by administering the composition.

[0062] The term "expression suppression" as used in the present invention means causing a decrease in the expression (into mRNA) or translation (into protein) of a target gene, preferably such that target gene expression becomes undetectable or is present at an insignificant level.

[0063] In the present invention, “%” used to indicate the concentration of a specific substance is (w / w) % for solid / solid, (w / v) % for solid / liquid, and (v / v) % for liquid / liquid, unless otherwise specified.

[0064]

[0065] The advantages and features of the present invention, and the methods for achieving them, will become clearer with reference to the detailed examples described below. The present invention will now be described in detail through examples. However, these examples are intended to specifically illustrate the present invention and are not intended to limit the scope of the present invention.

[0066]

[0067] [Example 1] Production of decoy oligodeoxynucleotides

[0068] The base sequences of the NF-κB / SOX4 decoy oligodeoxynucleotide (decoy ODN) and Scr (scramble) oligodeoxynucleotide (Scr ODN) of the present invention are as shown in Table 1 below. Scr ODN is an oligodeoxynucleotide with no effect and was used as a comparison group.

[0069] NF-κB oligodeoxynucleotides and SOX4 oligodeoxynucleotides each formed a stem-loop structure. They were denatured at 95°C for 3 minutes and then annealed while lowering the temperature from 80°C to 25°C. The annealed NF-κB / SOX4 decoy oligodeoxynucleotides were ligated with T4 ligase for 16 to 18 hours to produce spherical NF-κB / SOX4 decoy oligodeoxynucleotides (see Fig. 1).

[0070] SEQ ID NO: Name Base Sequence (5'→3')1NF-κB ODNGAATTCAGGGAAATCCCTTCAAGAAAACTTGAAGGGATTTCCCT2SOX4 ODNGAATTCCGTAACAAAGAGGAAAACCTCTTTGTTACG3Scr ODNGAATTCAATTCAGGGTACGGCAAAAAATTGCCGTACCCTGAATT

[0071]

[0072] [Example 2] Establishment of a model of macrovascular complications of diabetes

[0073] To establish a model of arteriosclerosis, which is the main mechanism of vascular complications of diabetes, C57BLKS / J-db / db mice, which are commonly used as a mouse model of type 2 diabetes, and age-matched healthy control C57BLKS / Jm + / m + Five-week-old mice were purchased and allowed to stabilize for approximately 7 days. Afterwards, the model was established by intraperitoneally injecting lipopolysaccharide (LPS) at 2 mg / kg once a week for 8 weeks and feeding atherogenic rodent diet (AD) ad libitum. LPS is an endotoxin that secretes toxins, causing fever, shock, hypotension, thrombosis, and organ damage that can lead to death. In addition, NF-κB / SOX4 decoy oligodeoxynucleotides and Scr oligodeoxynucleotides were administered at a concentration of 10 μg once a week for 8 weeks. At this time, 10 μg of decoy oligodeoxynucleotides was mixed with 600 μl of TransIT solution and administered via the tail vein.

[0074]

[0075] [Example 3] Confirmation of the stability of NF-κB / SOX4 decoy ODN

[0076] The stability of NF-κB / SOX4 decoy oligodeoxynucleotide fluorescently labeled with FITC was confirmed by injecting the mouse tail vein with the heart and aorta 24 and 48 hours later.

[0077] As a result, as shown in Fig. 2, FITC-labeled NF-κB / SOX4 decoy oligodeoxynucleotide (green) was confirmed in the heart and aorta, and NF-κB / SOX4 decoy oligodeoxynucleotide expression in the nucleus was confirmed.

[0078]

[0079] [Example 4] Confirmation of the inhibitory effect of NF-κB / SOX4 decoy ODN on NF-κB and SOX4 expression

[0080] To confirm whether the NF-κB / SOX4 decoy oligodeoxynucleotide suppresses the expression of the corresponding gene, the abdominal aorta of the mouse was removed after the experiment in the diabetic vascular complication mouse model of Example 2 and EMSA (Electrophoresis Mobility Shift Assay) was performed.

[0081] As a result, as disclosed in Fig. 3, the db / db group treated with NF-κB / SOX4 decoy ODN showed a significant decrease in the expression of NF-κB and SOX4 compared to the non-diabetic group and the untreated diabetic db / db group. In addition, the group treated with Scr ODN in the LPS+AD db / db model showed no significant change in the expression of NF-κB and SOX4, whereas the group treated with NF-κB / SOX4 decoy ODN in the LPS+AD db / db model showed a significant decrease in the expression of NF-κB and SOX4.

[0082]

[0083] [Example 5] Confirmation of the inhibitory effect of NF-κB / SOX4 decoy ODN on aortic and heart tissue damage.

[0084] In the mouse model of vascular complications of diabetes in Example 2 above, the abdominal aorta and heart were removed, and then paraffin sections were prepared and H&E staining was performed to observe changes in the tissue.

[0085] As a result, as shown in Fig. 4, it was confirmed that the blood vessel wall thickened in the db / db group and the LPS+AD+Scr ODN-treated db / db group, whereas it decreased in the NF-κB / SOX4 decoy ODN-treated db / db group and the LPS+AD+NF-κB / SOX4 decoy ODN-treated db / db group.

[0086] In addition, H&E staining of cardiac tissues confirmed a systematic and uniform appearance in the non-diabetic group, but the arrangement of myocardial fibers appeared disordered in the db / db group, and the db / db group treated with LPS+AD+Scr ODN showed irregular structural abnormalities. On the other hand, it was confirmed that the above histological changes were significantly alleviated in the db / db group treated with LPS+AD+NF-κB / SOX4 decoy ODN.

[0087]

[0088] [Example 6] Confirmation of the inhibitory effect of NF-κB / SOX4 decoy ODN on inflammation-related factors

[0089] In the mouse model of vascular complications of diabetes in Example 2 above, proteins from the aorta were isolated and the expression of inflammatory factors was confirmed by Western blot.

[0090] As a result, as shown in Fig. 5, the expression of TNF-α, IL-1β, and IL-6 increased in the db / db group and the LPS+AD+Scr ODN-treated db / db group, and it was confirmed that the expression of inflammatory factors was significantly increased due to LPS+AD. It was confirmed that the expression of these inflammatory factors decreased when treated with NF-κB / SOX4 decoy ODN.

[0091]

[0092] [Example 7] Confirmation of the inhibitory effect of NF-κB / SOX4 decoy ODN on vascular adhesion factor expression

[0093] The expression changes of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in paraffin sections of the abdominal aorta of the mouse model of vascular complications of diabetes in Example 2 and the isolated proteins were confirmed by tissue immunochemical staining and Western blotting. It is known that the expression of ICAM-1 and VCAM-1 increases when endothelial cells are activated by inflammatory cytokines.

[0094] As a result, as shown in Figures 6 and 7, the expression of ICAM-1 and VCAM-1 was increased in the db / db group and the db / db group treated with LPS+AD+Scr ODN, whereas the expression of ICAM-1 and VCAM-1 was decreased when treated with NF-κB / SOX4 decoy ODN.

[0095]

[0096] [Example 8] Confirmation of the inhibitory effect of NF-κB / SOX4 decoy ODN on elastin fragmentation and collagen deposition.

[0097] Verhoeff-Van Gieson and Masson's trichrome staining was performed on paraffin sections of the abdominal aorta of the mouse model of vascular complications of diabetes in Example 2 above.

[0098] As a result, as shown in Fig. 8, lesions of arteriosclerosis, which is a mechanism of vascular complications of diabetes, such as fragmentation and irregular changes of elastin and deposition of collagen, were confirmed in the db / db group and the LPS+AD+Scr ODN-treated db / db group, and it was confirmed that these changes were reduced similarly to the non-diabetic group when treated with NF-κB / SOX4 decoy ODN.

[0099]

[0100] [Example 9] Confirmation of the inhibitory effect of NF-κB / SOX4 decoy ODN on the expression of fibrosis-related factors and signaling pathway factors.

[0101] The abdominal aortic protein of the mouse model of vascular complications of diabetes according to Example 2 above was isolated, and the expression of fibrosis-related factors and signaling mechanism factors was confirmed by Western blot.

[0102] As a result, as shown in Fig. 9, the expression of ABCA1, which maintains cellular cholesterol homeostasis, decreased in the db / db group and the db / db group treated with LPS+AD+Scr ODN, but showed expression levels similar to those of the non-diabetic group when treated with NF-κB / SOX4 decoy ODN. In addition, the expression of Collagen1, fibronectin, PAI1, and α-SMA increased in the db / db group and the db / db group treated with LPS+AD+Scr ODN, but decreased when treated with NF-κB / SOX4 decoy ODN.

[0103] In addition, as shown in Fig. 10, the expression of proteins related to the TLR4 / JAK2 signaling pathway and SOX4 and NF-κB signaling pathways was significantly increased in the db / db group treated with LPS+AD+Scr ODN, but decreased when treated with NF-κB / SOX4 decoy ODN. In addition, the expression of nuclear NF-κB and Sox4 was also confirmed to be increased in the db / db group treated with LPS+AD+Scr ODN, but decreased by NF-κB / SOX4 decoy ODN.

Claims

1. NF-κB decoy oligodeoxynucleotide comprising the base sequence of sequence number 1.

2. SOX4 decoy oligodeoxynucleotide containing the base sequence of sequence number 2.

3. An NF-κB / SOX4 decoy oligodeoxynucleotide comprising an NF-κB decoy oligodeoxynucleotide having a base sequence of sequence number 1 and a SOX4 decoy oligodeoxynucleotide having a base sequence of sequence number 2.

4. A pharmaceutical composition for preventing or treating diabetic complications, comprising a decoy oligodeoxynucleotide according to any one of claims 1 to 3.

5. A composition according to claim 4, wherein the diabetic complication is a vascular complication.

6. A composition according to claim 5, wherein the vascular complication is a macrovascular complication.

7. A composition according to claim 6, wherein the macrovascular complication is arteriosclerosis.

8. A method for preventing or treating diabetic complications, comprising administering a decoy oligodeoxynucleotide according to any one of claims 1 to 3 to a subject other than a human.

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