KR-102961956-B1 - Composition including mexenone for s vascular permeability diseases

Abstract

The present invention relates to a composition for reinforcing the vascular endothelial barrier comprising mexenone, and more specifically, to a composition for reinforcing the vascular endothelial barrier that acts on the Y685 site of VE-cadherin to reinforce the vascular endothelial barrier and can exhibit a therapeutic effect in sepsis, etc.

Inventors

• 윤상억
• 최윤지
• 김지혜
• 이사빈
• 이보석
• 엄채영
• 안지민
• 이효희

Assignees

• 인제대학교 산학협력단
• 울산과학기술원

Dates

Publication Date

20260507

Application Date

20230309

Claims (3)

1. A composition for treating sepsis containing mexenone.
2. delete
3. delete

Description

Composition including mexenone for strengthening the vascular endothelial barrier in vascular permeability diseases The present invention relates to a composition for reinforcing the vascular endothelial barrier comprising mexenone, and more specifically, to a composition for reinforcing the vascular endothelial barrier comprising mexenone as an active ingredient, which acts on the Y685 site of VE-cadherin to reinforce the vascular endothelial barrier and exhibit a therapeutic effect in sepsis, etc. Sepsis is an inflammatory response triggered by the excessive activation of the body's immune system due to infection by pathogenic microorganisms; in severe cases, it can lead to shock and death. Sepsis is usually accompanied by a systemic inflammatory response, which can be caused by various factors. Specifically, sepsis is a systemic inflammatory response syndrome resulting from infection, occurring acutely primarily in immunocompromised infants, the elderly, or surgical patients. The term sepsis refers to a condition in which a systemic inflammatory response occurs due to infection by pathogenic microorganisms within the body. Treatment for sepsis begins with identifying the infection, and involves multifaceted approaches such as infection control, hemodynamic support, host immunomodulation, and metabolic/endocrine support. Above all, the most important aspect of sepsis treatment is diagnosing the condition quickly. The selection of antibiotics is crucial in the treatment of sepsis, and strong, broad-spectrum antibiotics are primarily used when the causative pathogen is unknown. In patients with severe sepsis or septic shock, administering appropriate antibiotics intravenously within one hour of diagnosis can reduce mortality. Along with the timing of antibiotic administration, the selection of specific drugs is also critical. It is known that combining one or more antibiotics effective against the likely causative pathogen yields good results. In addition to antibiotic treatment, fluid therapy, vasopressors, cardiac stimulants and blood products, insulin therapy, and corticosteroids may also be used (J Korean Med Assoc, 2013, 56(9), 819-826). Sepsis is a common infectious disease that accounts for the majority of deaths among critically ill patients and about 25-30% of hospitalized patients. It is a dangerous condition with a mortality rate of 30-60%, but there is no effective treatment. In the absence of effective treatments for sepsis, various attempts are being made to develop them. In particular, many efforts have been made to suppress inflammation; however, as various anti-inflammatory drugs frequently fail in clinical trials, new treatment strategies are needed that do not rely on suppressing inflammation. Among these, drugs widely used as treatments for hyperlipidemia (Simvastatin, Cerivastatin, Fluvastatin, Ulinastatin) are frequently used in sepsis research (Kidney International, 2006, 69, 1535-1542; J Pharm & Exp Therapeutics, 2000, 294(3), 1043-1046; J Pharm & Exp Therapeutics, 2006, 319(3), 1348-1354; Int J Molecular Medicine, 2017, 39(5), 1269-1276). These drugs show an effect of improving survival rates by about 40-60% when pretreated with Lipopolysaccharide (LPS), but the effect decreases when LPS is treated first. Various methods using stem cells are being attempted as other approaches for the treatment of sepsis. Although methods using adipose-derived stem cells, mesenchymal stem cells, bone marrow-derived stem cells, or umbilical cord blood stem cells are being attempted, they have not shown significant efficacy. In LPS-treated sepsis models, they have shown an effect of improving survival rates by about 30-40% compared to the LPS-treated group (J Cell Science, 2018, 131, jcs211151; Anesthesiology, 2017, 127(6), 1017-1034; J Cell Physiology, 2017, 9999, 1-13; Molecular Medicine reports, 2016, 14, 3862-3870; J Inflammation, 2012, 9, 33). Recently, it was found that in patients with sepsis, the activity and synthesis of SIRT1 protein are reduced compared to the normal group, and the content of sphingosine-1-phosphate (S1P) is reduced (Critical care, 2015, 19, 372; Free radical Biology and Medicine, 2017, 113, 291-303). S1P levels tend to decrease rapidly in sepsis patients, so attempts are being made to treat sepsis by using S1P agonists to increase S1P levels or inhibitors that inhibit enzymes that degrade S1P (Circulation research, 2008, 103, 1164-1172; Biochimica et Biophysica Acta, 2014, 1841, 1403-1412; J Pharmacol Exp Ther., 2015, 352, 61-66), and attempts are being made to increase the levels and activity of SIRT1 protein, which are reduced in sepsis patients. It has been reported that increasing SIRT1 activity not only suppresses inflammation but also reduces the permeability of vascular endothelial cells, thereby improving sepsis. The best methods to increase S1P content involve overproducing the gene that synthesizes S1P or knocking down or knocking out the enzyme that degrades S1P