US20220202897A1 - Use of cyclo(his-pro) (chp) for preventing, ameliorating, or treating fibrosis - Google Patents
Use of cyclo(his-pro) (chp) for preventing, ameliorating, or treating fibrosis Download PDFInfo
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- US20220202897A1 US20220202897A1 US17/599,211 US202017599211A US2022202897A1 US 20220202897 A1 US20220202897 A1 US 20220202897A1 US 202017599211 A US202017599211 A US 202017599211A US 2022202897 A1 US2022202897 A1 US 2022202897A1
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Definitions
- the present invention relates to a use of Cyclo-HisPro (CHP) for preventing, ameliorating, or treating fibrosis and, more particularly, to a pharmaceutical composition for preventing or treating fibrosis comprising CHP, a health functional food composition for preventing or ameliorating, an antifibrotic composition, a method of preventing, or treating fibrosis by using CHP, and/or a use of CHP in the manufacture of the pharmaceutical composition for preventing or treating fibrosis.
- CHP Cyclo-HisPro
- Fibrosis is a disease in which abnormal production, accumulation and deposition of extracellular matrix by fibroblasts occurs, and is caused by fibrosis of an organ or tissue. Fibrosis is a very fatal disease that causes long-term damage. For example, idiopathic pulmonary fibrosis (IPF) appears as a result of relapsing alveolar epithelial cell injury associated with fibroblast accumulation and myofibroblast differentiation, and is a chronic, progressive, and lethal disease that causes excessive accumulation of extracellular matrix (ECM) with irreversible destruction of lung parenchyma tissue.
- IPF idiopathic pulmonary fibrosis
- ECM extracellular matrix
- Korean Patent Laid-Open Publication No. 10-2013-0006170 discloses a composition for blood sugar regulation comprising soybean hydrolysate with high CHP (CYCLO(His-Pro), but the antifibrotic effect of CHP is not known.
- One aspect of the present invention is directed to providing a pharmaceutical composition for preventing or treating fibrosis comprising Cyclo-HisPro.
- Another aspect of the present invention is directed to providing a health functional food composition for preventing or ameliorating fibrosis comprising Cyclo-HisPro.
- Another aspect of the present invention is directed to providing an antifibrotic composition comprising Cyclo-HisPro.
- Another aspect of the present invention is directed to providing a method of preventing, or treating fibrosis by using Cyclo-HisPro.
- Another aspect of the present invention is directed to providing a use of Cyclo-HisPro in the manufacture of the pharmaceutical composition for preventing or treating fibrosis.
- the present invention provides a pharmaceutical composition for preventing or treating fibrosis comprising Cyclo-HisPro or a pharmaceutically acceptable salt thereof.
- the present invention provides a health functional food composition for preventing or ameliorating fibrosis comprising Cyclo-HisPro or a sitologically acceptable salt thereof.
- the present invention also provides a method for preventing or treating fibrosis comprising administering to a subject in need thereof an effective amount of Cyclo-HisPro.
- the present invention also provides a use of Cyclo-HisPro in the manufacture of a pharmaceutical composition for preventing or treating fibrosis.
- the fibrosis may develop in any one or more selected from the group consisting of: kidney, liver, lung, skin, heart, pancreas, urinary system, genital system, sweat gland, nerve, brain, bone marrow, muscle and joint.
- the fibrosis may be any one or more selected from the group consisting of: pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury or lung fibrosis, pulmonary edema, cystic fibrosis, liver fibrosis, endomyocardial fibrosis, myocardial infarction, artrial fibrosis, glial scar, renal fibrosis, myelofibrosis, arthrofibrosis, fat fibrosis, skin fibrosis, neurofibrosis and myofibrosis.
- pulmonary fibrosis idiopathic pulmonary fibrosis, radiation-induced lung injury or lung fibrosis, pulmonary edema, cystic fibrosis, liver fibrosis, endomyocardial fibrosis, myocardial infarction, artrial fibrosis, glial scar, renal fibrosis, myelofibrosis, arthrofibrosis, fat fibrosis, skin
- the present invention also provides an antifibrotic composition comprising Cyclo-HisPro.
- composition comprising Cyclo-HisPro of the present invention is effective for preventing, ameliorating or treating fibrosis by inhibiting fibrosis occurring in various tissues or organs such as kidney, liver, lung, skin, heart, pancreas, urinary system, genital system, sweat glands, nerves, brain, bone marrow, muscles and joints.
- FIG. 1 shows the process of cell isolation and primary culture from human glomeruli and renal tubules (left: glomerulus, right: tubule);
- FIG. 2 shows the morphological changes of cells according to CHP treatment (4, 20 and 100 ⁇ g/ml, respectively) by concentration in a human-derived proximal tubule epithelial cell fibrosis model;
- FIG. 3 shows a result of confirming changes in the expression level of E-cadherin, fibronectin and pSTAT3 proteins by Western blot according to CHP treatment (4, 20 and 100 ⁇ g/ml, respectively) by concentration in a human-derived proximal tubule epithelial cell fibrosis model;
- FIG. 4 shows the morphological changes of cells according to CHP treatment (40 and 100 ⁇ g/ml, respectively) by concentration in a human-derived glomerular endothelial cell fibrosis model
- FIG. 5A shows a band result of confirming changes in the expression level of fibronectin protein by Western blot according to CHP treatment (62.5, 125 and 250 ng/ml, respectively) by concentration in a human-derived liver cell fibrosis model
- FIG. 5B is a graph of quantifying the size of the band
- FIG. 6A shows a band result of confirming changes in the expression level of fibronectin protein by Western blot according to CHP treatment (5 and 35 mg/kg, respectively) by concentration in an animal model of liver fibrosis
- FIG. 6B is a graph of quantifying the size of the band
- FIG. 7A shows a band result of confirming changes in the expression level of fibronectin protein by Western blot according to CHP treatment (62.5 and 125 ng/ml, respectively) by concentration in a human-derived lung cell fibrosis model
- FIG. 7B is a graph of quantifying the size of the band
- FIG. 8 is a graph showing changes in the expression level of TGF ⁇ and Collagen 3 genes according to CHP administration (5 and 35 mg/kg, respectively) by concentration in an animal model of lung fibrosis;
- FIG. 9A shows a band result of confirming changes in the expression level of fibronectin protein by Western blot according to CHP treatment (62.5, 125, 250 and 500 ng/ml, respectively) by concentration in a human-derived skin cell fibrosis model
- FIG. 9B is a graph of quantifying the size of the band
- FIG. 10 is a graph showing changes in the expression level of fibrosis markers TGF ⁇ , Fibronectin, Collagen 1, Collagen 2, Collagen 3 and Collagen 4 genes according to CHP administration (5 and 35 mg/kg, respectively) by concentration in an animal model of cardiac fibrosis;
- FIG. 11 is a graph showing changes in the expression level of fibrosis markers TGF ⁇ , Fibronectin, Collagen 3, CTGF genes according to CHP administration (5 and 35 mg/kg, respectively) by concentration in an animal model of fat fibrosis.
- Cyclo-HisPro is effective in preventing, ameliorating, or treating fibrosis by inhibiting fibrosis occurring in various tissues or organs, and completed the present invention.
- the present invention provides a pharmaceutical composition for preventing or treating fibrosis comprising Cyclo-HisPro or a pharmaceutically acceptable salt thereof and/or a health functional food composition for preventing or ameliorating fibrosis comprising Cyclo-HisPro or a sitologically acceptable salt thereof.
- the present invention also provides an antifibrotic composition comprising Cyclo-HisPro.
- Cyclo-HisPro is a naturally occurring circular dipeptide composed of histidine-proline which is a metabolite of thyrotropin-releasing hormone (TRH) or a physiologically active dipeptide that is also synthesized in the body through the TRH metabolic process and de novo, and refers to a substance widely distributed throughout the brain and in spinal cord and gastrointestinal tract.
- the CHP may be synthesized or commercially available. In addition, it can be used after purification from substances containing CHP, for example, prostate extract and soybean hydrolysate.
- purified it is intended to mean that CHP is in a concentrated form compared to a form obtainable from a natural origin, such as a prostate extract. Purified ingredients can be concentrated from their natural sources or obtained through chemical synthesis methods.
- fibrosis is used interchangeably with “fibrotic condition”, “fibroproliferative condition”, “fibrotic disease”, “fibroproliferative disease”, “fibrotic disorder” and “fibroproliferative disorder”, and refers to a condition, disease or disorder characterized by dysregulated proliferation or activity of fibroblasts, abnormal accumulation of fibronectin and/or pathological or excessive accumulation of collagenous tissue. Typically, such conditions, diseases or disorders are treatable by administration of a compound having antifibrotic activity.
- the fibrosis may develop, for example, in any one or more selected from the group consisting of: kidney, liver, lung, skin, heart, pancreas, urinary system, genital system, sweat gland, nerve, brain, bone marrow, muscle and joint.
- the fibrosis of the present invention may be any one or more selected from the group consisting of: pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury or lung fibrosis, pulmonary edema, cystic fibrosis, liver fibrosis, endomyocardial fibrosis, myocardial infarction, artrial fibrosis, glial scar, renal fibrosis, myelofibrosis, arthrofibrosis, fat fibrosis, skin fibrosis, neurofibrosis and myofibrosis, but is not limited thereto.
- the CHP according to the present invention has therapeutic effects on the various fibrosis described herein.
- a first aspect relates to renal fibrosis, which is fibrosis occurring in the kidney.
- Kidney disease is classified into acute renal failure or chronic renal failure depending on the progression status, or depending on the cause of disease, divided into glomerulonephritis due to deposition of vascular complexes, diabetic kidney disease accompanying diabetes or hypertensive renal disease accompanying hypertension, toxic nephropathy caused by drug administration such as antibiotics or anticancer agents, bacterial infection, and the like.
- the causative kidney disease if the glomerular filtration rate is reduced to 50% or less due to chronic renal dysfunction, in most cases, the glomerular filtration rate continues to decrease, ultimately leading to end-stage renal failure, developing complications such as hematologic abnormalities, nervous system complications, gastrointestinal complications, immunological complications, infections, or osteodystrophy, and in severe cases, leading to death.
- Chronic renal failure is a state in which the renal function gradually decreases in one direction (irreversibly), and the homeostasis of the living body cannot be maintained. All kidney diseases involve fibrosis of the kidneys, eventually leading to end-stage renal failure. In particular, since chronic renal function decline is deeply related to the progression of renal fibrosis, inhibition of the progression of fibrosis may lead to inhibition of the progression of chronic renal failure.
- renal fibrosis includes all diseases in which fibrosis occurs in the kidney due to various causes, and the fibrosis may include, but is not limited to, those caused by any one or more selected from the group consisting of: catheter installation, glomerulosclerosis, glomerulonephritis, nephritis, acute renal failure, chronic renal failure, end-stage renal disease, and metabolic disease.
- nephritis may include, but is not limited to, for example, any interstitial nephritis, for example, lensacoccal ( Streptococcus sp.) nephritis, staphylococcal nephritis; viral nephritis accompanying alastrim, hepatitis B, hepatitis C, HIV, etc.; nephritis caused by parasitic infections such as malaria; fungal nephritis, infectious interstitial nephritis accompanying mycoplasma nephritis, systemic erythematosus (lupus nephritis), systemic scleroderma (collagen disease kidney), interstitial nephritis accompanying collagen diseases such as Sjgren's syndrome, purpura nephritis, polyarteritis, nephritis accompanying vascular immune diseases such as rapidly progressive glomerul
- CHP has a fundamental antifibrotic effect by restoring the expression of the splicing marker E-cadherin protein and reducing the expression of fibronectin and pSTAT3 protein in the proximal tubular epithelial cells induced by fibrosis, and therefore, regardless of the cause that induces fibrosis, it can be applied to treat various renal fibrosis.
- a second aspect relates to liver fibrosis, which is fibrosis occurring in the liver.
- liver fibrosis refers to a symptom in which fibrous tissue proliferates due to chronic damage to the liver, and may include, but is not limited to, those caused by any one or more selected from the group consisting of: chronic liver disease, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, alcoholic liver disease or non-alcoholic steatohepatitis, metabolic disease, protein deficiency, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha-1 antitrypsin deficiency, primary biliary cirrhosis, drug reactions and toxins.
- Liver fibrosis is a precursor to cirrhosis and is initiated by the action of various cytokines and growth factors as a result of severe liver damage, leading to chronic liver disease.
- liver fibrosis consists of reversible and thin fibrils, and when there is no nodule formation and the cause of liver damage is temporary, the extracellular matrix (ECM) increased by the process of apoptosis and matrix metalloproteinases (MMP) is decomposed, and normal recovery is possible, but if the liver fibrosis process continues repeatedly, it forms thick fibrils and progresses to nodular cirrhosis.
- ECM extracellular matrix
- MMP matrix metalloproteinases
- liver cirrhosis is induced through the process of liver fibrosis, in which hepatocytes are damaged by various inflammatory factors and so abnormal extracellular matrix proteins including collagen are accumulated, and it is important to control the accumulation of extracellular matrix to control the expression of cirrhosis.
- Inflammatory response when hepatocytes are damaged activates resting hepatic stellate cells to secrete extracellular matrix and various cytokines and chemokines, among which TGF- ⁇ 1 acts as a strong growth inhibitory agent.
- TGF- ⁇ 1 is a 25 kD substance, which binds to the latent TGF- ⁇ 1 binding protein and is secreted in the form of an inactive latent, and it exists in a state combined with extracellular matrix such as type 1 and 4 collagen, laminin and decorin, and is activated by various stimuli.
- TGF- ⁇ 1 regulates collagen expression by decreasing the production of collagenase or increasing the production of collagenase inhibitors, increases the production of TNF- ⁇ , IL-1 and PDGF in macrophages, and play an important role in the fibrosis process.
- TGF- ⁇ 1 plays an important role in liver fibrosis, since TGF- ⁇ 1 is expressed only in areas where fibrosis has progressed and is not expressed in normal liver tissues or inactive areas.
- non-alcoholic fatty liver can be caused by causes such as obesity, diabetes, hyperlipidemia, drugs, etc. regardless of drinking alcoholic, and depending on the progress, refers to a wide range of diseases including from simple steatosis without inflammatory response to non-alcoholic steatohepatitis (NASH) showing hepatocellular inflammatory response, advanced fibrosis and liver cirrhosis.
- NASH non-alcoholic steatohepatitis
- NAFLD nonalcoholic fatty liver disease
- an animal model of liver fibrosis induced by a high-fat diet was established, and it was confirmed that CHP exhibits the effect of reducing fibronectin protein expression in the model.
- Fatty liver is not a pathological condition in itself, and is a reversible symptom that naturally recovers when the causative substance is removed.
- steatohepatitis occurs, and as a result, hepatocyte necrosis and regeneration occur repeatedly, during which the fibrous extracellular matrix (ECM) increases, leading to liver fibrosis.
- ECM extracellular matrix
- liver fibrosis is a disease clearly distinguished from fatty liver, which is a reversible symptom, and refers to any disease in which liver function is reduced by changing liver tissue to fibrotic tissue such as regenerative nodules.
- CHP reduces the expression level of fibronectin protein, a fibrotic protein, in fibrosis-induced liver cells
- CHP reduces the expression of fibronectin protein in an animal model in which liver fibrosis is induced, thereby exhibiting a fundamental antifibrotic effect, so it can be applied to the treatment of liver failure and liver cancer that have progressed from cirrhosis, as well as various liver fibrosis, regardless of the cause of fibrosis.
- a third aspect relates to pulmonary fibrosis, which is fibrosis occurring in the lung.
- pulmonary fibrosis refers to a disease in which chronic inflammatory cells infiltrate into the alveolar wall of the lung tissue and induce tissue fibrosis to cause serious structural changes in the lung tissue. Once fibrosis is progressed due to any cause, the lung tissue hardens and the alveolar wall thickens, thereby reducing the amount of oxygen supplied by the blood, which makes breathing difficult.
- pulmonary fibrosis refers to the development of scarred (fibrous) tissue due to the formation or development (fibrosis) of excessive fibrous connective tissue in the lung.
- pulmonary fibrosis is a chronic disease that causes swelling and scarring of the alveoli and interstitial tissues of the lungs.
- scar tissue replaces healthy tissue and causes inflammation, and chronic inflammation can be identified as a precursor of fibrosis. Due to such damage to the lung tissue, the lungs may become stiff, and it may become difficult for the individual to breathe on their own.
- Pulmonary fibrosis in the present invention may include, but is not limited to, any one or more selected from the group consisting of: idiopathic pulmonary fibrosis, radiation-induced lung injury, nonspecific interstitial pneumonia, acute interstitial pneumonia, respiratory bronchiolitis associated interstitial lung, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, diffuse pulmonary fibrosis, pulmonary edema, cystic fibrosis, and pulmonary fibrosis due to metabolic disease.
- the pulmonary fibrosis may be caused by various causes, for example, microscopic damage to the lungs induced by inhalation of fine particles (asbestos, stone dust, metal dust, particles present in cigarette smoke, silica dust, etc.).
- pulmonary fibrosis may also occur as a secondary effect of other diseases (such as autoimmune diseases, viral or bacterial infections) and may be caused by certain drugs such as cytotoxic agents (such as bleomycin, busulfan and methotrexate); antibiotics (such as nitrofurantoin and sulfasalazine); antiarrhythmic drugs (such as amiodarone and tocainide); anti-inflammatory drugs (such as gold and penicylamine); illegal drugs (such as narcotics, cocaine and heroin), and the idiopathic pulmonary fibrosis may be caused by other unknown causes other than causes above.
- long-term intake of high-fat diet induces pulmonary fibrosis, which appears to be due to increased inflammatory levels following high
- CHP reduces the expression level of fibronectin protein, a fibrotic protein, in fibrosis-induced lung cells
- CHP reduces the expression of TGF ⁇ and Collagen 3 genes, which are major fibrosis markers, in a pulmonary fibrosis-induced animal model, thereby exhibiting a fundamental antifibrotic effect, and therefore, regardless of the cause that induces fibrosis, it can be applied to treat various pulmonary fibrosis.
- a fourth aspect relates to skin fibrosis.
- skin fibrosis is excessive scarring on the skin and is a result of a pathological wound healing response.
- fibrotic skin diseases There is a wide range of fibrotic skin diseases: scleroderma, renal fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, sclerosing edema, and eosinophilic fasciitis. Exposure to chemicals or physical agents (for mechanical trauma, burn wounds) is also a potential cause of fibrotic skin disease. Skin fibrosis may be driven by immune, autoimmune and inflammatory mechanisms. The balance of collagen production and degradation in fibroblasts plays an important role in the pathophysiological process of skin fibrosis.
- TGF- ⁇ transforming growth factor- ⁇
- IL-4 interleukin-4
- skin fibrosis is also meant to include “scleroderma”.
- Scleroderma is a chronic autoimmune connective tissue disease of unknown cause characterized by sclerotic changes and vascular abnormalities in which the skin of a part or the whole body becomes hard and thickened due to excessive accumulation of collagen in the dermis. Collagen forms connective tissue and serves to support and connect the tissues of the body. There are several forms of scleroderma, some showing symptoms only in a specific part of the body, while others appearing all over the body including internal organs.
- systemic scleroderma in which only a part of the skin becomes hard
- systemic scleroderma which exhibits fibrosis symptoms due to the increase in collagen not only in the skin but also in internal organs such as the lungs, digestive organs, kidneys and heart.
- Systemic scleroderma is further classified into limited type and diffuse type according to the degree of invasion of the skin and internal organs, prognosis, and immunological examination findings.
- skin fibrosis may include, but is not limited to, any one or more selected from the group consisting of: scars, hypertrophic scars, keloid scars, localized scleroderma and systemic scleroderma.
- tissue fibrosis is thought to play an important role.
- scleroderma The early symptoms of scleroderma are very diverse, especially in the latter stage, the skin symptoms become clear. Common symptoms of scleroderma include joint pain, morning stiffness, fatigue, and weight loss. In addition, exposure to cold also temporarily limits the blood supply to fingers, toes, nose and ears. These symptoms are early symptoms of scleroderma patients and are one of the frequent symptoms.
- the skin of patients with scleroderma becomes hard. This hardening of the skin spreads widely and typically occurs on both sides of the body. Eventually, the tissue is damaged, and the skin is pigmented.
- Localized scleroderma is 2.6 times more common in women than in men. Localized scleroderma occurs in 75% of patients between 20 and 50 years of age, and linear scleroderma tends to occur at an earlier age. Localized scleroderma is classified into localized scleroderma, systemic localized scleroderma, linear localized scleroderma, or subcutaneous localized scleroderma.
- Localized scleroderma often starts with erythema or reddish-purple patches, and the border with the surrounding normal skin becomes clear, and the skin in a certain area loses elasticity and becomes hard. The area will be brown or, in many cases, discolored, giving it a white color. Most of the time it occurs in one place, but sometimes there are several, and they vary in size and can range from the size of a coin to the size of an adult palm. It causes cosmetic problems but does not progress to systemic scleroderma. In some patients, even without treatment, the hard skin softens and recovers on its own.
- Systemic localized scleroderma is a severe form of localized scleroderma, in which the skin in a large area becomes hard and hyperpigmentation is observed. Extensive hardening of the skin of the trunk, buttocks, and legs. However, it is distinguished from systemic sclerosis because there is no Raynaud's phenomenon or internal organ involvement.
- Linear localized scleroderma is a case in which the skin becomes long and hard in a straight line, and it occurs most often in the order of the legs, arms, forehead, and chest, in particular, if it is depressed in a vertical line on the forehead, it is called en coup de sabre and causes cosmetic problems.
- linear scleroderma involves not only the skin but also the underlying muscle and periosteum tissue and is fixed in the underlying tissue. It occurs more frequently in children and can sometimes cause severe skeletal developmental anomaly in the limbs and face.
- Subcutaneous localized scleroderma is characterized by sclerosis of the fat layer, fascia, muscle and sometimes bone, and joint movement may be limited. Because the lesion appears in the deep part, the characteristic skin pigment change of scleroderma is not observed.
- Systemic scleroderma occurs four times more often in women than in men, and can occur at any age, but usually occurs between the ages of 30 and 50.
- the diffuse type is known to occur at a younger age than the limited type.
- Raynaud's phenomenon is the first symptom of systemic scleroderma, followed by sclerosis of the skin and internal organs. Systemic scleroderma is divided into skin symptoms and internal organ symptoms.
- esophagus Internal organ symptoms occur in the gastrointestinal tract, lungs, heart, or kidneys.
- the esophagus In the gastrointestinal tract, the esophagus is the most frequently involved part and is involved in more than 90% of cases. In the esophagus, peristaltic dysfunction, dysphagia, and reflux esophagitis are common. Symptoms such as constipation, diarrhea, and malabsorption may appear due to decreased intestinal motility.
- the most important cause of death in patients with systemic scleroderma is due to pulmonary symptoms, occurring in about 70% of patients. Due to fibrosis of the lungs, people complain of difficulty in breathing and cough during exercise. Alveolitis is a common occurrence, and pulmonary function continues to decline.
- Cardiac symptoms may include cardiac conduction disorder, heart failure, and pericarditis, and myocardial sclerosis may occur in 50-70% of patients. Kidney symptoms occur in approximately 45% of patients with systemic scleroderma. It appears as sudden onset of acute renal failure, hypertension, etc., and uremia that progresses slowly may occur.
- skin fibrosis encompasses, without limitation, fibrosis occurring in any part of: internal cavities of organs or glands such as blood vessels and veins, ducts of submandibular, gallbladder, thyroid follicles, sudoriferous ducts, ovaries, kidneys; epithelial cells of the gums, tongue, palate, nose, larynx, esophagus, stomach, intestines, rectum, anus and vagina; and any skin tissue and epithelial cells, including the dermis, scars, skin and scalp.
- organs or glands such as blood vessels and veins, ducts of submandibular, gallbladder, thyroid follicles, sudoriferous ducts, ovaries, kidneys
- epithelial cells of the gums, tongue, palate, nose, larynx, esophagus, stomach, intestines, rectum, anus and vagina and any skin tissue and epithelial cells,
- CHP exhibits a fundamental antifibrotic effect by reducing the expression level of fibronectin protein, a fibrotic protein, in fibrosis-induced skin cells, and therefore, regardless of the cause that induces fibrosis, it can be applied to treat various skin fibrosis (scleroderma).
- a fifth aspect relates to fibrosis, which is cardiac fibrosis occurring in the heart.
- cardiac fibrosis refers to a phenomenon in which the heart hardens due to excessive deposition of matrix proteins between heart cells and also refers to a phenomenon that occurs mainly in the heart of patients with myocardial infarction and is the main cause of decreased heart function, and may include, but not limited to, any one or more selected from the group consisting of: endomyocardial fibrosis, atrial fibrosis, heart failure, myocardial infarction, and cardiac fibrosis due to metabolic disease.
- Cardiac fibrosis is characterized by a disproportionate accumulation of fibrosing collagen that occurs after cardiomyocyte death, inflammation, increased workload, hypertrophy and stimulation by a number of hormones, cytokines and growth factors.
- Cardiac fibrosis may also refer to abnormal thickening of heart valves due to disproportionate proliferation of cardiac fibroblasts, but more generally refers to proliferation of fibroblasts in the heart muscle.
- Fibrocyte cells normally act to secrete collagen and provide structural support for the heart. When overactivated, this process leads to valve thickening and fibrosis.
- cardiac fibrosis may be interpreted to encompass heart failure and/or myocardial infarction caused by cardiac fibrosis.
- CHP exhibits a fundamental antifibrotic effect by reducing the expression of Fibronectin, Collagen 1, Collagen 2, Collagen 3 and Collagen 4 genes, which are major fibrosis markers, in a fibrosis-induced animal model, and therefore, regardless of the cause that induces fibrosis, it is useful for the treatment of various cardiac fibrosis.
- composition of the present invention for preventing, ameliorating or treating fibrosis
- a sixth aspect relates to fat fibrosis.
- fat fibrosis is meant to encompass all diseases in which fibrosis occurs in adipose tissue.
- the present inventors established an animal model of fat fibrosis induced by a high-fat diet and checked the expression changes of the fibrosis markers TGF ⁇ , Fibronectin, Collagen 3, and CTGF genes according to CHP administration.
- CHP exhibits an antifibrotic effect by remarkably reducing the expression of the fibrosis markers, and thus is useful for the treatment of fat fibrosis.
- CHP exhibits antifibrotic activity by reducing the expression of various fibrosis marker genes or proteins in various fibrosis-induced tissue cells and animal models, therefore, it can be expected that it can be effectively applied to prevent, ameliorate, or treat fibrosis occurring in various tissues and/or organs in the body, including kidney, liver, lung, skin, heart, pancreas, urinary system, genital system, sweat glands, nerves, brain, bone marrow, muscles and joints.
- the terms “prevent”, “ameliorate” and/or “treat” refer to any act that inhibits or delays the onset of a disease or disease symptom, any act that ameliorates or beneficially alters the state of a disease or disease symptom, and any act that delays, stops or reverses the progression of a disease or disease symptom.
- the term “pharmaceutically acceptable” refers to those that are physiologically acceptable and do not normally cause allergic reactions or similar reactions when administered to humans, and the salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid.
- the pharmaceutically acceptable salt may be an acid addition salt formed using an organic acid or an inorganic acid, and the organic acid include, for example, formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxy acetic acid, benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid.
- the organic acid include, for example, formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic
- the inorganic acid includes, for example, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid or boric acid.
- the acid addition salt may preferably be in the form of hydrochloride salt or acetate salt, and more preferably in the form of hydrochloride salt.
- additional salts are available in the form of GABA salt, gabapentin salt, pregabalin salt, nicotinate salt, adipate salt, hemimalonate salt, cysteine salt, acetylcysteine salt, methionine salt, arginine salt, lysine salt, ornithine salt or aspartate salt etc.
- the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration.
- Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
- Carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like.
- it may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid.
- Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
- benzalkonium chloride methyl- or propyl-paraben and chlorobutanol.
- other pharmaceutically acceptable carriers reference may be made to those described in the following literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).
- the pharmaceutical composition of the present invention may be administered to mammals, including humans by any method.
- it may be administered orally or parenterally, and parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration.
- the pharmaceutical composition of the present invention may be formulated as a formulation for oral administration or parenteral administration according to the administration route as described above.
- it may be prepared using one or more buffers (e.g., saline or PBS), carbohydrates (e.g., glucose, mannose, sucrose, or dextran, etc.), antioxidants, bacteriostatic agents, chelating agents (e.g., EDTA or glutathione), fillers, extending agents, binding agents, adjuvants (e.g. aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrating agents or surfactants, diluents or excipients.
- buffers e.g., saline or PBS
- carbohydrates e.g., glucose, mannose, sucrose, or dextran, etc.
- antioxidants e.g., bacteriostatic agents, chelating agents (e.g., EDTA or glutathione)
- fillers extending agents, binding agents, adj
- Solid formulations for oral administration include tablets, pills, powders, granules, liquids, gels, syrups, slurries, suspensions or capsules, etc., and these solid formulations may be prepared by mixing the pharmaceutical composition of the present invention with at least one or more excipients, for example, starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethyl cellulose and hydroxypropylmethyl-cellulose or gelatin, etc.
- excipients for example, starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol malti
- Liquid formulations for oral use may include suspensions, internal liquid formulations, emulsions, or syrups, and various excipients, such as wetting agents, sweetening agents, air fresheners, or preservatives in addition to water or liquid paraffin, which are commonly used simple diluents.
- cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrating agent, and an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, and a preservative may be additionally included.
- the pharmaceutical composition of the present invention may be formulated according to methods known in the art in the form of injections, transdermal administration agents and nasal inhalants together with suitable parenteral carriers.
- suitable parenteral carriers In the case of the injection, it must be sterilized and protected from contamination of microorganisms such as bacteria and fungi.
- suitable carriers for injection may include, but are not limited to, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and/or a solvent or dispersion medium containing vegetable oil.
- suitable carriers may include Hanks' solution, Ringer solution, phosphate buffered saline (PBS) with triethanolamine or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose, etc.
- PBS phosphate buffered saline
- isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose, etc.
- it may further include various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- the injection may further include an isotonic agent such as sugar or sodium chloride.
- transdermal administration agent forms such as ointment, cream, lotion, gel, external solution, pasta, liniment, and air roll are included.
- transdermal administration means that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin by topically administering the pharmaceutical composition to the skin.
- the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or nebulizers using a suitable propellant, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- a suitable propellant for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- gelatin capsules and cartridges for use in inhalers or insufflators may be formulated to contain a compound and a suitable powder base powder mixture such as lactose or starch.
- Formulations for parenteral administration are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pa. 18042, Chapter 87: Blaug, Seymour, a
- the pharmaceutical composition of the present invention contains Cyclo-HisPro in an effective amount, it is possible to provide a desirable effect of preventing, ameliorating or treating fibrosis.
- the term “effective amount” refers to an amount that exhibits a response greater than that of a negative control group, and preferably refers to an amount sufficient to prevent, ameliorate or treat fibrosis.
- the pharmaceutical composition of the present invention may contain 0.01 to 99.9% of Cyclo-Hispro, and the remaining amount may be occupied by a pharmaceutically acceptable carrier.
- the effective amount of Cyclo-HisPro included in the pharmaceutical composition of the present invention will vary depending on the form in which the composition is commercialized.
- the total effective amount of the pharmaceutical composition of the present invention may be administered to a patient as a single dose, and may be administered by a fractionated treatment protocol in which multiple doses are administered for a long period of time.
- the pharmaceutical composition of the present invention may vary the content of active ingredients according to the severity of the disease. For example, it may be administered in one to several divided doses to be administered in an amount of preferably 0.001 to 100 mg, more preferably 0.01 to 10 mg per 1 kg of body weight per day based on Cyclo-HisPro.
- the effective dosage for a patient is determined in consideration of various factors such as administration route of the pharmaceutical composition and number of treatments, as well as the patient's age, weight, health status, sex, disease severity, diet, and excretion rate, in consideration of this point, one of ordinary skill in the art will be able to determine an appropriate effective dosage of the Cyclo-HisPro according to a specific use for preventing, treating or ameliorating fibrosis.
- the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as the effect of the present invention is exhibited.
- the pharmaceutical composition for preventing or treating fibrosis of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, or biological response modifiers.
- the pharmaceutical composition for preventing or treating fibrosis of the present invention may also be provided in the formulation of an external application containing Cyclo-HisPro.
- the composition of the present invention may be a quasi-drug composition for preventing or ameliorating fibrosis and a quasi-drug comprising the composition.
- the external application may be directly applied to the skin or oral cavity.
- the pharmaceutical composition for preventing or treating fibrosis of the present invention may further contain adjuvants commonly used in the field of dermatology, such as any other ingredients commonly used for external applications for skin including fatty substance, organic solvent, solubilizer, thickening and gelling agent, emollient, antioxidant, suspending agent, stabilizer, foaming agent, air freshener, surfactant, water, ionic emulsifier, nonionic emulsifier, filler, sequestering agent, chelating agent, preservative, vitamin, blocking agent, wetting agent, essential oil, dye, pigment, hydrophilic active agent, lipophilic active agent or lipid vesicle.
- the above ingredients may be introduced in an amount generally used in the field of dermatology.
- the composition of the present invention may be in the formulation of a liquid, ointment, patch, gel, cream or spray, but is not limited thereto.
- the quasi-drugs of the present invention may include toothpaste, oral care products including mouthwash and mouth spray, ointments, masks, poultices, plasters, and transdermal absorbents.
- composition of the present invention When the composition of the present invention is used as a quasi-drug composition, Cyclo-HisPro may be added as it is or may be appropriately used in combination with other quasi-drug ingredients according to a conventional method.
- the mixing amount of the active ingredients may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment).
- the contents of the pharmaceutical composition and health functional food composition of the present invention may be applied mutatis mutandis to the quasi-drug composition and quasi-drug of the present invention.
- health functional food includes both the meanings of “functional food” and “health food”.
- the term “functional food” is the same term as food for special health use (FoSHU), and refers to food with high medical effects processed to efficiently exhibit bioregulatory functions in addition to nutritional supply.
- health food refers to food having an active health maintenance or promotion effect compared to general food
- health supplement food refers to food for the purpose of health supplementation.
- functional food, health food, and health supplement food are used interchangeably.
- the above food may be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. in order to obtain a useful effect in improving and recovering liver function.
- composition As a specific example of such a functional food, by using the composition, it is possible to produce a processed food with good storage properties while at the same time being transformed by taking advantage of the characteristics of agricultural products, livestock products or aquatic products.
- the health functional food composition of the present invention may also be prepared in the form of nutritional supplements, food additives and feeds, and is intended for consumption by animals, including humans or livestock.
- Food compositions of this type can be prepared in various forms according to conventional methods known in the art. It may be prepared as regular food by adding Cyclo-HisPro to the following food including, but not limited to, beverages (including alcoholic beverages), fruits and their processed foods (e.g., canned fruit, bottled, jam, marmalade, etc.), fish, meat and their processed foods (e.g., ham, sausages, corn beef, etc.), breads and noodles (e.g., udon noodles, soba noodles, ramen, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, yeot (Korean hard taffy), dairy products (e.g., butter, cheese, etc.), edible vegetable oils and fats, margarine, vegetable protein, retort food, frozen food, various seasonings (e.g., soybean paste, soy sauce, sauce, etc.).
- beverages including alcoholic beverages
- fruits and their processed foods e.g., canned fruit, bottled, jam, m
- the Cyclo-HisPro may be prepared in the form of tea, juice, and drink and ingested by liquefaction, granulation, encapsulation, and powder so that it can be drinkable (as health drink), but it is not limited thereto.
- the Cyclo-HisPro in order to use the Cyclo-HisPro in the form of a food additive, it may be prepared and used in the form of a powder or a concentrate.
- it may be prepared in the form of a composition by mixing the Cyclo-HisPro with an active ingredient known to be effective in preventing or ameliorating fibrosis.
- the health drink composition may contain various flavoring agents or natural carbohydrates as additional ingredients, like a conventional drink.
- the above-mentioned natural carbohydrates may be monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; or sugar alcohols such as xylitol, sorbitol, and erythritol.
- sweetening agents natural sweetening agents such as taumatine and stevia extract, synthetic sweetening agents such as saccharin and aspartame, or the like may be used.
- the proportion of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 mL of the composition of the present invention.
- Cyclo-HisPro may be contained as an active ingredient in a food composition for preventing or ameliorating fibrosis, and the amount may be an effective amount to obtain the preventing or ameliorating effect, for example, preferably 0.01 to 100% by weight based on the total weight of the total composition, but not particularly limited thereto.
- the food composition of the present invention may be prepared by mixing Cyclo-HisPro with other active ingredients known to be effective in preventing or ameliorating fibrosis.
- the health functional food of the present invention may include various nutritional supplements, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid, pectic acid salts, alginic acid, alginic acid salts, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, or carbonating agents, and the like.
- the health food of the present invention may contain fruit flesh for the production of natural fruit juice, fruit juice beverage, or vegetable beverage. These ingredients may be used independently or in combination. The proportion of these additives is not particularly important, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
- the present invention also relates to a method for preventing or treating fibrosis comprising administering to a subject in need thereof an effective amount of Cyclo-HisPro.
- the term “subject” includes any animal (e.g., human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig or rodent), but is not limited thereto. These terms do not denote a specific age or sex. Accordingly, whether female or male, adult and neonatal subjects as well as fetuses are intended to be included.
- a patient refers to a subject with a disease or disorder. The term patient includes human and veterinary subjects.
- the present invention also provides a use of Cyclo-HisPro in the manufacture of a pharmaceutical composition for preventing or treating fibrosis.
- human-derived glomerular endothelial cells and human-derived proximal tubular epithelial cells which can be used for cell experiments, were purely isolated and cultured by isolating glomeruli and tubular interstitial tissue from normal adult kidney tissue and primarily culturing them.
- Example 1-1 By inducing cell fibrosis in human-derived proximal tubular epithelial cells that were isolated and primarily cultured in Example 1-1 by treating recombinant TGF ⁇ (2 ng/ml) to the cells, cytoskeletal remodeling and morphological changes (became thin, elongated and structure disappeared) were occurred, which confirming that fibrosis was properly induced ( FIG. 2 ).
- Example 1-2 Under the same conditions as in Example 1-2, the expression levels of proteins of E-cadherin, a junction marker, fibronectin, a fibrosis marker, and pSTAT3, a fibrosis transcription factor, after CHP administration were checked by Western blot.
- Example 1-1 As in the human-derived proximal tubular epithelial cell fibrosis model of Example 1-1, by inducing cell fibrosis in glomerular endothelial cells by treatment with rTGF ⁇ (2 ng/ml), cytoskeletal remodeling and morphological changes were occurred, which confirming that fibrosis was properly induced ( FIG. 4 ).
- DMEM medium and FBS were purchased from Hyclone for culturing the Huh7 liver cell line, and TGF ⁇ for inducing fibrosis was purchased from R&D Systems.
- the cells were cultured in a DMEM medium supplemented with 10% FBS in a 5% CO 2 incubator at 37° C., treated with TGF ⁇ at a concentration of 2 ng/ml and treated with CHP at 0, 62.5, 125, or 250 ng/ml, and cells were harvested at 48 hours of treatment.
- RIPA lysis buffer and HaltTM protease and phosphatase inhibitor cocktails was purchased from Thermo to analyze the expression of fibronectin protein, a fibrotic protein, and for protein quantification, BCA protein quantification kit was purchased from Thermo.
- BCA protein quantification kit was purchased from Thermo.
- the antibody of fibronectin protein, a marker of liver fibrosis, and the GAPDH antibody used as a loading control were purchased from Abcam. 100 ul of RIPA buffer containing protease and phosphatase inhibitors was added to the harvested Huh7 cells, and the cells were lysed by pipetting.
- the size of the appearing band was quantified using the ImageJ program and corrected by dividing the fibronectin band size value by the GAPDH band size value. Statistical significance was analyzed using Student's t-test statistical method with the control group. #p ⁇ 0.05 (negative control group: TGF ⁇ treated control group).
- liver fibrosis Long-term high-fat diet intake is known to be a risk factor for liver fibrosis.
- An inflammatory environment is induced in the liver tissue due to insulin resistance and increased blood fatty acids, adipokines, and cytokines that appear when a fatty diet is consumed for a long period of time, and the interaction of immune cells accumulated in the liver tissue proceeds with fibrosis, in particular, IL-13 cytokine secreted by Th2 CD4+ T cells causes macrophages to produce large amounts of TGF ⁇ , a key inducing factor for fibrosis.
- TGF ⁇ Transduction by TGF ⁇ causes transformation of cells in liver tissue and promotes fibrosis progression (Rosselli, M et al., Current Pharmaceutical Design, 20(31), 5010-5024, 2014; Wu. D et al., Science, 332:243-7, 2011; J Investig Med, 60(8): 1147-1150, 2012; Fichtner-Feigl S et al., Nat Med, 12:99-106, 2006; Lee C G et al., J Exp Med, 194:809-21, 2001).
- liver fibrosis was observed, which can be confirmed through the expression of fibronectin, a representative fibrosis marker protein (Kim, I. H et al., AGE, 38(4), 291-302, 2016; Chen, H. J., & Liu, J., Biomedicine & Pharmacotherapy, 97, 1386-1396, 2018.1-2).
- C57BL/6 mice fed a high-fat diet containing 60% fat for 6 weeks were purchased from Jackson, USA, and Research diets D12492, a 60% fat-containing high-fat dietary feed purchased from Saeron Bio, were ingested for 17 weeks. Mice were bred to allow free access to feed and water in an environment of 24 ⁇ 3° C.
- C57BL/6 mice fed a high-fat diet for 6 weeks were acclimatized to the breeding environment for 1 week, and their weights were measured and evenly divided into 3 groups as shown in Table 1.
- CHP was orally administered to each group at a concentration of 5 mg/kg or 35 mg/kg once a day for 16 weeks, and the same amount of distilled water was orally administered to the control group in the same manner.
- Isoflurane required for anesthesia and dissection of mice was purchased from Hana Pharmaceutical, and Vetequip's RC2 Rodent Circuit Controller Anesthesia System was prepared.
- Phosphate buffered saline (PBS) was purchased from Hyclone.
- PBS Phosphate buffered saline
- To isolate the mouse liver tissue the mice were anesthetized by respiratory anesthesia with 3-3.5% isoflurane. After blood was drawn from the heart of anesthetized mice, the liver tissue was immediately excised and washed with PBS. Then, 50 mg of the liver tissue was cut out and placed in 500 ul of RIPA buffer containing protease and phosphatase inhibitors, and was pulverized using IKA's T10 homogenizer.
- Example 3-2 After leaving on ice for 15 minutes, centrifugation was performed at 15,000 rpm at 4° C. Western blotting was performed in the same manner as in Example 3-2 to analyze the expression of fibronectin protein, a fibrotic protein. Statistical significance was analyzed using the Student's t-test statistical method with HFD control group (*p ⁇ 0.05, **p ⁇ 0.01).
- MEM medium and FBS were purchased from Hyclone for culturing the L-132 lung cell line, and TGF ⁇ for inducing fibrosis was purchased from R&D Systems.
- the cells were cultured in a MEM medium supplemented with 10% FBS in a 5% CO 2 incubator at 37° C., treated with TGF ⁇ at a concentration of 2 ng/ml and treated with CHP at 0, 62.5, or 125 ng/ml, and cells were harvested at 48 hours of treatment.
- Pulmonary fibrosis is caused by prolonged high-fat diet intake. This appears to be due to an increase in the level of inflammation caused by high fat intake, and it has been reported that pulmonary fibrosis appeared when normal mice were fed a high-fat diet containing 60% fat for 15 weeks (Ge, X. N et al., Experimental Lung Research, 39(9), 365-378, 2016). Specifically, long-term intake of high-fat diet induces obesity, and adipokines and cytokines secreted by hypertrophic adipose tissue and immune cells gathered here disrupt the migration of immune cells from bone marrow to lungs and cause chronic inflammatory response (de Vries A et al., Clin Exp Allergy, 39:731-739, 2009).
- IL-13 cytokine secreted by Th2 CD4+ T cells causes large amounts of TGF ⁇ , a key fibrosis-inducing factor, to be produced, and signal transduction by TGF ⁇ promotes lung tissue transformation and fibrosis (Fichtner-Feigl S et al., Nat Med, 12:99-106, 2006; Lee C G et al., J Exp Med, 194:809-21, 2001). Pulmonary fibrosis can be confirmed through the expression level of the TGF ⁇ gene increased compared to normal (Ge, X. N et al., Experimental Lung Research, 39(9), 365-378, 2016).
- Example 4-1 For pulmonary fibrosis experiments in animals, an animal model of pulmonary fibrosis was established in the same manner as in Example 4-1.
- mice Isoflurane required for anesthesia and dissection of mice was purchased from Hana Pharmaceutical, and Vetequip's RC2 Rodent Circuit Controller Anesthesia System was prepared. Phosphate buffered saline (PBS) was purchased from Hyclone. To isolate the mouse lung tissue, the mice were anesthetized by respiratory anesthesia with 3-3.5% isoflurane. After blood was drawn from the heart of the anesthetized mice, the lung tissue was immediately excised, 50 mg of the lung was cut out, and 500 ⁇ L of NucleoZOL was added thereto, followed by pulverization using a T10 homogenizer from IKA.
- PBS Phosphate buffered saline
- RNA was extracted according to NucleoZOL's Total RNA Isolation protocol, and cDNA was synthesized from 1 ⁇ g of RNA by reverse transcription polymerase chain reaction using the iScript cDNA synthesis kit.
- the synthesized cDNA was analyzed by real-time PCR with iQ SYBR Green Supermix using forward/reverse primer sets corresponding to each gene. The expression value of each gene was corrected by dividing by the expression value of GAPDH, a housekeeping gene.
- Primers for real-time PCR were synthesized and used by Bioneer with the sequence shown in Table 2.
- DMEM medium and FBS were purchased from Hyclone for culturing the HS68 skin fibroblast-derived cell line, and TGF ⁇ for inducing fibrosis was purchased from R&D Systems.
- the cells were cultured in a DMEM medium supplemented with 10% FBS in a 5% CO 2 incubator at 37° C., treated with TGF ⁇ at a concentration of 2 ng/ml and treated with CHP at 0, 62.5, 125, 250, or 500 ng/ml, and cells were harvested at 48 hours of treatment.
- Heart fibrosis Risk factors for heart fibrosis are well known, including poor diet, obesity, and high cholesterol. When a high-fat diet is consumed for a long period of time, hypervolemia due to obesity occurs, overloading the heart, and causing deformation of the contractile and diastolic functions of the heart.
- mice Isoflurane required for anesthesia and dissection of mice was purchased from Hana Pharmaceutical, and Vetequip's RC2 Rodent Circuit Controller Anesthesia System was prepared. Phosphate buffered saline (PBS) was purchased from Hyclone. To isolate the mouse heart tissue, the mice were anesthetized by respiratory anesthesia with 3-3.5% isoflurane. After blood was drawn from the heart of the anesthetized mice, the heart tissue was immediately excised, 50 mg of the heart was cut out, and RNA extraction and gene expression analysis were performed in the same manner as in Example 6-2. Primers for real-time PCR were synthesized and used by Bioneer with the sequence shown in Table 3. The expression value of each gene was corrected by dividing by the expression value of ( ⁇ -actin, a housekeeping gene.
- PBS Phosphate buffered saline
- fibrosis of adipose tissue occurs when normal mice are fed a high-fat diet containing 60% fat for 16 to 24 weeks (Hu, M et al., Evidence-Based Complementary and Alternative Medicine, 1-12, 2018; Kwon, E. Y, & Choi, M. S., Nutrients, 10(10), 1415, 2018; Nakazeki, F et al., Scientific Reports, 8(1), 2018; Muniappan, L et al.
- adipocytes expand due to excessive nutrition, causing triglyceride accumulation, adipocyte death, production of adipokines and cytokines, endoplasmic reticulum stress, adipose tissue hypoxia, etc., resulting in infiltration of immune cells into adipose tissue and occurrence of chronic inflammation (Schenk S et al., J Clin Invest, 118:2992-3002, 2008; Sun K, Kusminski C M, Scherer P E, J Clin Invest, 121:2094-101, 2011).
- TGF ⁇ a key inducing factor for fibrosis, which causes adipose tissue to be deformed, leading to fat fibrosis
- Fichtner-Feigl S et al., Nat Med, 12:99-106, 2006 Pessin, J. E., & Kwon, H, Journal of Investigative Medicine, 60(8), 1147-1150, 2012.
- Fibrosis of adipose tissue can be confirmed through changes in the expression of representative fibrosis gene markers that are increased compared to normal adipose tissue.
- mice Isoflurane required for anesthesia and dissection of mice was purchased from Hana Pharmaceutical, and Vetequip's RC2 Rodent Circuit Controller Anesthesia System was prepared. Phosphate buffered saline (PBS) was purchased from Hyclone. To isolate the mouse adipose tissue, the mice were anesthetized by respiratory anesthesia with 3-3.5% isoflurane. After blood was drawn from the heart of the anesthetized mice, the epididymal adipose tissue (EAT) was immediately excised, 100 mg of the fat was cut out, and RNA extraction and gene expression analysis were performed in the same manner as in Example 6-2. Primers for real-time PCR were synthesized and used by Bioneer with the sequence shown in Table 4. The expression value of each gene was corrected by dividing by the expression value of GAPDH, a housekeeping gene.
- PBS Phosphate buffered saline
- EAT epididymal adipose tissue
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PCT/KR2020/004354 WO2020197359A1 (ko) | 2019-03-28 | 2020-03-30 | 섬유증의 예방, 개선 또는 치료를 위한 chp (사이클로-히스프로)의 용도 |
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EP4122484A4 (en) | 2020-03-20 | 2024-03-27 | Novmetapharma Co Ltd | USE OF CYCLO-HIS-PRO (CHP) FOR LOWERING BLOOD PRESSURE |
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US20220193073A1 (en) * | 2020-12-18 | 2022-06-23 | NovMeta Pharma Co., Ltd. | Method of treating fibrosis |
WO2023249049A1 (ja) * | 2022-06-23 | 2023-12-28 | 学校法人 愛知医科大学 | 腹膜劣化抑制組成物、腹膜劣化抑制組成物キット、腹膜透析液、および腹膜透析液キット |
KR20240054851A (ko) * | 2022-10-19 | 2024-04-26 | 이화여자대학교 산학협력단 | 티플락스티닌을 포함하는 복막 섬유증의 개선, 예방 또는 치료용 조성물 |
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