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JP-2026074728-A - Agents and methods for modulating creatine kinase expression

JP2026074728AJP 2026074728 AJP2026074728 AJP 2026074728AJP-2026074728-A

Abstract

[Problem] To provide a technology that can regulate the expression of creatine kinase (CK). [Solution] A CK expression regulator comprising chondroitin sulfate oligosaccharide as an active ingredient. The expression regulator according to the present invention may be used to reduce CK in the blood, to suppress CK expression in the kidney, or to promote CK expression in muscle tissue. According to the present invention, it is expected that excessive or inappropriate enhancement of CK, or excessive or inappropriate reduction, can contribute to the prevention or improvement of diseases and ill health conditions in which the onset or worsening of these conditions is a factor. [Selection Diagram] Figure 3

Inventors

  • 宮本 宜之

Assignees

  • 丸共バイオフーズ株式会社

Dates

Publication Date
20260507
Application Date
20241021

Claims (11)

  1. A creatine kinase expression regulator containing chondroitin sulfate oligosaccharide as the active ingredient.
  2. The agent according to claim 1, used to reduce creatine kinase levels in the blood.
  3. The agent according to claim 2, used to suppress muscle tissue damage.
  4. The agent according to claim 2, used to suppress abnormal bleeding.
  5. The agent according to claim 1, used to suppress the expression of creatine kinase in the kidney.
  6. The agent according to claim 5, used to suppress the decline in renal function.
  7. The agent according to claim 1, used to promote the expression of creatine kinase in muscle tissue.
  8. The agent according to claim 7, used to improve muscle strength and/or muscle endurance.
  9. The agent according to any one of claims 1 to 8, wherein the number of constituent sugars of the chondroitin sulfate oligosaccharide is 2 to 38.
  10. A method for regulating creatine kinase expression, comprising the step of regulating creatine kinase expression in a human or animal by administering chondroitin sulfate oligosaccharide to the human or animal.
  11. Use of chondroitin sulfate oligosaccharides for the production of creatine kinase expression regulators.

Description

This invention relates to an agent and method for regulating creatine kinase expression using chondroitin sulfate oligosaccharide as an active ingredient, and to the use of chondroitin sulfate oligosaccharide for producing a creatine kinase expression regulator. Creatine kinase (EC 2.7.3.2) is a dimeric enzyme with a molecular weight of approximately 82,000, consisting of two subunits. Creatine kinase (CK), also known as creatine phosphokinase (CPK), catalyzes the production of creatine and ATP (adenosine-5'-triphosphate) from creatine phosphate and ADP (adenosine-5'-bisphosphate), as well as the reverse reaction. CK is abundant in muscles and the brain, supplying the large amounts of ATP required by these tissues during metabolic turnover. Specifically, during rest, when ATP concentration is high, CK synthesizes creatine phosphate, a storage substance for high-energy compounds. During metabolic turnover, it resynthesizes ATP from ADP and creatine phosphate. The direct energy source for muscle contraction is ATP. The supply pathways for ATP include its production through oxidative phosphorylation during aerobic respiration and its resynthesis from creatine phosphate and ADP during anaerobic respiration. CK plays a role in the latter pathway, and the rate at which phosphate groups are transferred from creatine phosphate to ADP by CK is greater than the maximum rate of ATP production through oxidative phosphorylation, thus enabling rapid ATP supply in tissues. There are two types of CK subunits: type B (brain type) and type M (muscle type). In humans, each subunit possesses a gene that codes for it. Combinations of these two subunits result in three types of CK isozymes (CK-MM, CK-MB, and CK-BB) present in the cytoplasm. CK-MM is abundant in skeletal muscle, CK-MB in cardiac muscle, and CK-BB in the brain and smooth muscle. Additionally, mitochondria contain mitochondral CK (MtCK), which has two isoforms: sarcomeric MtCK (sMtCK) and ubiquitous MtCK (uMtCK). Because CK leaks into the bloodstream when the muscle tissue it inhabits is damaged, the amount (activity level) or type of CK in the blood is used as an indicator of specific diseases. Diseases showing high levels of CK in the blood include rhabdomyolysis, hypothyroidism, diabetes mellitus, alcohol-induced mental and behavioral disorders, muscular dystrophy, acute myocardial infarction, myocarditis, polymyositis, dermatomyositis, hypoparathyroidism, and cerebrovascular disease. Conversely, diseases showing low levels of CK in the blood include hyperthyroidism, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome (Non-Patent Literature 1). Furthermore, it has been reported that high blood CK activity may increase the risk of blood coagulation disorders or bleeding because CK in the blood reduces ADP (which is necessary for platelet aggregation) by consuming it as a substrate (Non-Patent Literature 2). Abnormal bleeding poses a particularly significant risk to individuals using antiplatelet drugs, for example, in the treatment of thrombosis. According to Non-Patent Literature 2, when CK was added to human plasma, ADP-induced platelet aggregation was suppressed in a dose-dependent manner. It was also shown that in the plasma of healthy men, the higher the endogenous CK activity, the less ADP-induced platelet aggregation was observed. Additionally, ADP-induced platelet aggregation disappeared in plasma with high blood CK activity after strenuous exercise, while it returned to the normal range in plasma with normal CK activity after rest. On the other hand, chondroitin sulfate (CS) is a type of glycosaminoglycan with a structure in which sulfate groups are attached to a long sugar chain consisting of a disaccharide repeating structure of uronic acid and N-acetyl-D-galactosamine. Due to the presence of numerous sulfate groups, it is strongly negatively charged and possesses excellent water retention and elasticity. In the body, it is widely found in all tissues, including cartilage, connective tissue such as skin, and the brain. It interacts with cell growth factors and extracellular matrix components, regulating various cellular activities such as cell adhesion, migration, proliferation, differentiation, and morphogenesis. In particular, it is known to play an important role in the cushioning effect in cartilage. The present inventors have successfully developed a technology to produce chondroitin sulfate oligosaccharides (CS oligosaccharides) with excellent solubility and bioavailability by hydrolyzing CS under high temperature and high pressure conditions to reduce its molecular weight (Patent Document 1). Patent No. 6146733 PHC Group, LSI Medience, HOME > Products & Services > Clinical Tests > Web Comprehensive Test Guide > Biochemical Tests > Enzymes > CK (CPK), [online], [Searched October 11, 2024], Internet <https://data.medience.co.jp/guide/guide-01030008.html>Horjus, D. L. et al., Creatine kinase inhibits ADP-induced platelet aggr