CN116036082A - Application of NSC228155 in preparation of medicines for preventing and treating sepsis-related acute heart injury - Google Patents

Application of NSC228155 in preparation of medicines for preventing and treating sepsis-related acute heart injury Download PDF

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CN116036082A
CN116036082A CN202310038987.5A CN202310038987A CN116036082A CN 116036082 A CN116036082 A CN 116036082A CN 202310038987 A CN202310038987 A CN 202310038987A CN 116036082 A CN116036082 A CN 116036082A
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nsc228155
myocardial
sepsis
injury
lps
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CN116036082B (en
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游然
贾占军
张玥
吴梦秋
李延伟
姜彧滕
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Nanjing Childrens Hospital of Nanjing Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The invention discloses application of NSC228155 in preparing a medicament for preventing and treating sepsis-related acute heart injury, and in particular relates to application of NSC228155 in treating acute heart injury by protecting myocardial cells, improving cardiac insufficiency and inhibiting inflammation. NSC228155 is effective in recovering left ventricular function of mice of LPS model, improving cardiac insufficiency of mice, reducing serum level of myocardial zymogram, and inhibiting inflammatory reaction; and can be used for preventing and treating dysfunction and myocardial injury in human myocardial organoids. Thereby playing the role of preventing and treating sepsis related acute heart injury.

Description

Application of NSC228155 in preparation of medicines for preventing and treating sepsis-related acute heart injury
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a compound NSC228155 in preparing medicines for preventing and treating sepsis-related acute myocardial injury lesions through protecting myocardial cells, inhibiting inflammation and other action mechanisms.
Background
Acute myocardial injury is a common clinical lesion, and has high mortality and disability rate. The development of medicines for preventing and treating acute myocardial injury is urgent. Acute myocardial injury has a complex etiology, with sepsis-associated myocardial dysfunction (sepis-related myocardial dysfunction, SRMD) being common and one of the leading causes of death in sepsis patients. The pathology of sepsis-related acute myocardial injury is characterized by ventricular dilatation, systolic and diastolic dysfunction, etc., and its main pathological mechanism is myocardial injury induced by severe inflammation. Therefore, the heart function of the patient suffering from acute myocardial injury is improved, myocardial cells are protected, and the anti-inflammatory effect is important for preventing and treating sepsis-related acute myocardial injury.
NSC228155 is an activator of EGFR, binding to the dimerization domain II of sfgfr and modulating tyrosine phosphorylation of EGFR. NSC228155 has activity against cancer cell proliferation. In addition, NSC228155 has protective effect in acute and chronic kidney disease. CN111358790a and CN111358789a disclose the use of NSC228155 for the prevention and treatment of acute kidney injury and chronic kidney fibrosis, respectively. In addition, CN 113694063a discloses the use of NSC228155 in the preparation of topical pharmaceuticals, cosmetics or daily chemicals, which can solve the problem of hair loss or thin hair.
However, the pharmacological activity of NSC228155 in heart diseases has not been studied, and the effect of NSC228155 on inflammation has not been reported. Unlike cancer cells and kidney cells, cardiomyocytes are terminally differentiated cells, cannot proliferate, and have the functional characteristics of contractile rhythm and the like. Thus, cardiomyocytes cannot be mimicked by other cells, and the protective effects of cardiomyocytes are difficult to infer from other cytoprotective effects. There is no report of the use of NSC228155 in the treatment of sepsis acute cardiac injury.
Disclosure of Invention
The invention provides application of NSC228155 in preparing a medicament for preventing and treating sepsis-related acute heart injury, and solves the technical problems that pharmacological activity of NSC228155 in heart diseases and no proper medicament for inhibiting sepsis-related acute heart injury and improving cardiac insufficiency are not found in the prior art.
In particular to the application of NSC228155 in preparing medicines aiming at sepsis-related acute heart injury, thereby providing a novel candidate compound for treating sepsis-related acute heart injury.
The application can be specifically that NSC228155 obviously improves central dysfunction of an LPS-induced sepsis model, increases left ventricular ejection fraction and left ventricular short axis shortening index, and reduces serum myocardial zymogram CK-MB and LDH levels.
Furthermore, NSC228155 can be prepared into a composition for preventing and treating sepsis-related acute heart injury.
We studied the protective effect on acute cardiac injury by treating with NSC228155 in the LPS-induced acute cardiac injury mouse model and human iPSCs-induced differentiated myocardial organoids, respectively. As a result, it was found that the intervention treatment of acute cardiac injury occurring in the LPS model with NSC228155 significantly improved cardiac insufficiency in mice, reduced serum myocardial zymogram, and reduced myocardial and systemic inflammatory response. In LPS-stimulated human cardiomyocytes, NSC228155 restored myocardial contractile rhythm, reducing cellular damage. Thus, our findings would be highly likely to provide effective therapeutic agents for the prevention and treatment of acute cardiac injury.
Therefore, NSC228155 can be applied to prevention and treatment of sepsis-related acute heart injury, and has obvious effect of improving heart function damage of patients suffering from sepsis-related acute heart injury.
The animal experiments prove that NSC228155 can effectively improve cardiac insufficiency in a sepsis model and reduce the heart zymogram level in serum; and the myocardial organoid is obtained by utilizing the induction of human pluripotent stem cells (iPSCs), NSC228155 is found to be capable of effectively recovering the heart muscle beat rhythm in a heart muscle injury model, reducing the release of LDH by heart muscle cells, effectively protecting the heart muscle cells, and NSC228155 is found to be capable of remarkably inhibiting the inflammatory response of a sepsis model. NSC228155 is suggested to have important therapeutic potential for acute myocardial injury due to sepsis.
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FIG. 1 shows that NSC228155 improves heart function in a sepsis mouse model; wherein fig. 1A shows representative cardiac sonograms in each group; fig. 1B shows that NSC228155 significantly increases the declining Left Ventricular Ejection Fraction (LVEF) in the LPS model; FIG. 1C shows that NSC228155 significantly increases the decreasing left ventricular short axis shortening index (LVFS) in the LPS model;
FIG. 2 shows that NSC228155 reduces cardiac zymogram levels in serum of a sepsis mouse model; among them, fig. 2A shows that NSC228155 significantly reduced serum levels of CK-MB in the LPS mouse model; fig. 2B shows that NSC228155 significantly reduced serum levels of LDH in the LPS mouse model;
FIG. 3 shows that NSC228155 reduces heart tissue pathologic damage in a mouse sepsis model;
FIG. 4 shows that NSC228155 effectively protects LPS-induced dysfunction and myocardial damage in human iPSCs-induced myocardial organoids; wherein, FIG. 4A shows that differentiation has been successfully induced to obtain human myocardial organoids; fig. 4B shows that NSC228155 significantly restored LPS-induced heart muscle organoid beat rhythm decline; fig. 4C shows that NSC228155 significantly reduced LPS-induced LDH release in cardiac organoids; FIGS. 4D and 4E show that NSC228155 significantly induces the expression of the anti-apoptotic signal Bcl-2 in LPS-damaged myocardial organoids;
figure 5 shows that NSC228155 reduces the inflammatory response of sepsis mouse model serum and heart tissue.
Detailed Description
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings and detailed description.
Example 1NSC228155 improving cardiac function in a sepsis mouse model
1. Experimental materials
The C57BL/6 species mice used in the invention are purchased from experimental animal centers of Nanjing medical university, and NSC228155 (purity is more than or equal to 99%) is purchased from Selleck company.
2 Experimental methods
2.1 animal administration, modeling and sampling
Male C57BL/6 mice (7 week old, weight 20-24g at purchase) were housed in SPF-class barrier environment at experimental animal center of university of Nanjing medical science, and animals were fed freely with a circadian rhythm of 12 hours light and 12 hours darkness maintained. Laboratory temperature: 20-25 ℃ and humidity of 50+/-5%. Mice were randomized into control and NSC228155 groups (5 mg/kg) after 1 week of adaptive feeding. After grouping, the control mice and NSC228155 mice were given a total of 2 injections of either intraperitoneal injection vehicle (1% DMSO+35% PEG300+64% saline) or NSC228155 (5 mg/kg injection) per day, respectively. Two days later, half of the mice in each group were intraperitoneally injected with LPS (10 mg/kg). After LPS injection for 12 hours, the mice are sent to a south medical large Jiang Ning animal experiment center for cardiac ultrasonic examination (echo diagnosis), after 24 hours, the mice are subjected to blood sampling and euthanasia, cardiac tissues are taken, after atrium removal, the mice are stored at-80 ℃ for RNA and protein extraction, or after tissue is fixed by paraformaldehyde, pathology examination is carried out.
2.2 statistical analysis
Mean ± SEM are used to represent data. Inter-group comparisons were performed using analysis of variance (ANOVA). P <0.05 is statistically significant.
3. Experimental results
In the LPS model, mice develop cardiac insufficiency, manifested by a decrease in Left Ventricular Ejection Fraction (LVEF) and left ventricular short axis shortening index (LVFS). Sepsis mice were significantly improved in heart LVEF and LVFS treated with NSC228155 (fig. 1A-C). These results suggest that NSC228155 is able to ameliorate LPS-induced cardiac insufficiency in mice in the LPS model.
Example 2NSC228155 improves cardiac zymogram levels in serum of a mouse sepsis model.
1 Experimental materials and methods
The sources and uses of mice and NSCs 228155 were as described in example 1. The establishment method, tissue sampling and statistical test method of the mouse LPS model are the same as those of the embodiment 1.
1.1 biochemical serum test
Serum of mice is taken, and a biochemical analyzer is used for carrying out serum biochemical detection of myocardial zymogram, and the serum levels of CK-MB and LDH are detected.
3 results of experiments
Sepsis may lead to a dramatic rise in serum levels of the myocardial zymogram, manifested by abnormally elevated CK-MB and LDH indices, suggesting severe myocardial damage. NSC228155 significantly reduced serum levels of CK-MB and LDH in the sepsis mouse model, improving sepsis-associated acute myocardial injury (fig. 2A-B).
Example 3NSC228155 reduces the pathological damage to heart tissue in a mouse sepsis model.
1 Experimental materials and methods
The sources and uses of mice and NSCs 228155 were as described in example 1. The establishment method, tissue sampling and statistical test method of the mouse LPS model are the same as those of the embodiment 1.
1.1 examination of the pathology of the apical tissue
The tissue of the apex of the heart is fixed by paraformaldehyde and wrapped by paraffin, and histological examination is carried out after tissue sections. And (3) carrying out pathological examination by adopting H & E staining, and observing the pathological damage of heart tissue.
2 experimental results
To evaluate the effect of detecting NSC228155 on acute cardiac injury, we examined mouse apex pathology using H & E staining. The LPS group, heart showed significant inflammatory infiltrates, whereas NSC228155 showed a decrease in its corresponding inflammatory infiltrates after treatment (fig. 3). These results indicate that NSC228155 can reduce inflammatory infiltration of LPS-induced acute cardiac injury, suggesting that NSC228155 reduces sepsis-induced myocardial injury.
Example 4 NSC228155 effectively protected LPS-induced dysfunction and myocardial damage in human iPSCs-induced myocardial organoids.
1. Experimental materials and methods
The source and use of NSC228155 and statistical methods are as described in example 1. LDH cell supernatant assays were as described in example 2. Human iPSCs induced myocardial organoid agents: mTESR (stem cell), B27-InSulin Minus (50x,A1895601,Thermo Fisher), B27-InSulin (50x,17504044,Thermo Fisher), CHIR-99021 (10 mM, DMSO configuration), IWR-1 (10 mM, DMSO configuration), Y-27632 (10 mM, DMSO/H2O configuration), matrigel (354230, BD).
1) Human iPSCs induced myocardial organoids
1 ml/well of plating solution containing Matrigel was coated on a 6-well plate 1h in advance, and the plate was placed in an incubator at 37℃for 1-2 hours, during which time the resuscitator solution and the medium (mTER containing Y-27632) were allowed to re-warm at room temperature for about 30 minutes. The six-hole plate coated with the plating solution was taken out of the incubator, the plating solution was sucked off, 1 ml/hole of resuscitation solution was added, and the incubator was again placed at 37 ℃. The cells preserved by liquid nitrogen are quickly melted in a water bath at 37 ℃ and transferred into a 15ml centrifuge tube, 300g of culture medium is added for centrifugation for 5 minutes, the supernatant is discarded, and 1 ml/hole of resuscitation fluid is added for gentle blowing and mixing. Then 1 ml/hole of the uniformly mixed cell suspension is inoculated into a six-hole plate coated with resuscitation liquid, and the cross shake ensures that the cells are uniformly distributed. After incubation in a constant temperature incubator at 37℃for 24 hours, the medium (mESR without Y-27632) was changed.
When the cell density reached 95% or more, cardiomyocyte differentiation was performed by adding 6. Mu.mCHIR to the differentiation medium Media1 (BPM 1 1640+B27-minus-instrument) on the first day, closing the iPSC wnt signaling pathway, and changing the differentiation medium Media1 without CHIR on the third day for 2 consecutive days. The differentiation medium Media2 was changed from day four, and 5 μm IWR-1 was added to reopen the wnt signaling pathway to promote differentiation into mesoderm for 2 consecutive days. Media2 culture was started on day 6 with a change of differentiation medium, once daily for 4 days. On day 10, the differentiation medium was replaced with the cardiomyocyte purified solution, and after 48 hours of purification, the differentiation medium Media2 was replaced, and the culture was continued. Microscopic observation shows that the cardiomyocyte is in good state and the pulsation is normal.
2)Western blotting
RNA in the sample was extracted according to the instructions using RNAiso reagent from Takara, reverse transcribed into cDNA using reverse transcription kit from Vazyme, and RT-PCR detection was performed using SYBR green PCR mix in combination with the corresponding primers.
2. Experimental results
Myocardial organoids were induced using human pluripotent stem cells (iPSCs) (fig. 4A) and were beating normally per unit time. LPS stimulation significantly reduced the frequency of beats (fig. 4B), suggesting that LPS stimulation induced acute injury and dysfunction of the myocardial organoids. NSC228155 significantly restored the frequency of LPS-stimulated beating of the myocardial organoids (fig. 4B). Consistent with this, LPS stimulation resulted in myocardial organoids releasing the damage marker LDH, while NSC228155 significantly reduced LDH release (fig. 4C). Bcl-2 is an anti-apoptotic signal, LPS can lead to a significant decrease in Bcl-2 levels in myocardial organoids, while NSC228155 increases Bcl-2 levels suggesting that NSC228155 may protect against myocardial injury by upregulating anti-apoptotic signals (FIGS. 4D and 4E). These results suggest that NSC228155 has a significant ameliorating effect on acute myocardial injury.
Example 5NSC228155 reduces the serum and cardiac tissue inflammatory response of a sepsis mouse model.
1 Experimental materials and methods
The sources and uses of mice and NSCs 228155 were as described in example 1. The establishment method, tissue sampling and statistical test method of the mouse LPS model are the same as those of the embodiment 1.
1.1ELISA test
Mouse serum was taken and serum IL-1. Beta. Level was assayed according to the instructions using mouse IL-1. Beta. ELISA detection kit (1210122, dakewe, china).
1.2qPCR
Taking mouse left ventricle tissue, extracting mRNA by TRIZOL, performing reverse transcription, performing qPCR reaction, and detecting mRNA expression condition of inflammatory mediators in mouse myocardial tissue.
3 results of experiments
Sepsis can lead to severe inflammatory responses in systemic and cardiac tissues, manifested by elevated levels of inflammatory mediators such as IL-1 beta or pro-inflammatory cytokines or mRNA expression in serum and myocardial tissues, respectively. NSC228155 significantly reduced serum levels of IL-1β in a sepsis mouse model, improved systemic inflammatory responses in a sepsis mouse model (fig. 5A), and significantly reduced mRNA expression of inflammatory mediators COX-2, pro-inflammatory chemokines MCP-1, pro-inflammatory cytokines IL-6, IL-23, and IL-1β in myocardial tissue of a sepsis mouse model, in particular, fig. 5A shows that NSC228155 significantly reduced levels of pro-inflammatory cytokines IL-1β in serum of an LPS mouse model; FIG. 5B shows that NSC228155 significantly reduces the level of the inflammatory mediator COX-2 in heart tissue of the LPS mouse model; FIG. 5C shows that NSC228155 significantly reduces the level of inflammatory mediator MCP-1 in heart tissue of the LPS mouse model; FIG. 5D shows that NSC228155 significantly reduces the levels of the pro-inflammatory cytokine IL-6 in heart tissue of the LPS mouse model; FIG. 5D shows that NSC228155 significantly reduces the levels of the pro-inflammatory cytokine IL-23 in heart tissue of the LPS mouse model; 5E shows that NSC228155 significantly reduces the level of the pro-inflammatory cytokine IL-1β in heart tissue of LPS mouse model, suggesting that the inflammatory response of myocardial tissue is reduced.
In conclusion, the invention provides the application of NSC228155 in preparing medicines for preventing and treating sepsis-related acute heart injury, the inhibitor is administrated through an injection way, and the purpose of preventing and treating sepsis-related acute heart injury is achieved by protecting the action mechanism of myocardial cells, effectively improving the central function of a sepsis-related acute heart injury model, reducing the serum level of myocardial zymogram and inhibiting inflammatory reaction in the sepsis model.
While the foregoing is directed to embodiments of the present invention, other and further details of the invention may be had by the present invention, it should be understood that the foregoing description is merely illustrative of the present invention and that no limitations are intended to the scope of the invention, except insofar as modifications, equivalents, improvements or modifications are within the spirit and principles of the invention.

Claims (7)

  1. Use of nsc228155 in the manufacture of a medicament for the prevention and treatment of sepsis-related acute cardiac injury.
  2. 2. The use according to claim 1, wherein NSC228155 ameliorates LPS-induced cardiac insufficiency.
  3. 3. The use according to claim 1, wherein NSC228155 improves cardiac zymogram levels in serum of a mouse sepsis model.
  4. 4. The use according to claim 1, wherein NSC228155 reduces inflammatory infiltration of LPS-induced acute cardiac injury and reduces sepsis-induced myocardial injury.
  5. 5. The use according to claim 1, wherein NSC228155 protects the human iPSCs-induced LPS-induced dysfunction and myocardial damage in the myocardial organoids.
  6. 6. The use according to claim 1, wherein NSC228155 reduces the inflammatory response of sepsis mouse model serum and heart tissue.
  7. 7. The use of claim 6, wherein NSC228155 reduces the level of IL-1 β in serum, reduces the level of COX-2, MCP-1, IL-6, IL-23 and IL-1 β in myocardial tissue.
CN202310038987.5A 2023-01-12 2023-01-12 Application of NSC228155 in preparation of medicines for preventing and treating sepsis-related acute heart injury Active CN116036082B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111358789A (en) * 2019-12-25 2020-07-03 南京市儿童医院 Application of NSC228155 in preparation of medicine for preventing and treating chronic renal fibrosis
CN111358790A (en) * 2019-12-25 2020-07-03 江苏省肿瘤医院 Application of NSC228155 in preparation of medicine for preventing and treating acute kidney injury
CN113694063A (en) * 2021-08-31 2021-11-26 佛山市第一人民医院（中山大学附属佛山医院） Composition and application thereof
WO2022051847A1 (en) * 2020-09-08 2022-03-17 University Health Network Methods for generating neural progenitor cells with a spinal cord identity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111358789A (en) * 2019-12-25 2020-07-03 南京市儿童医院 Application of NSC228155 in preparation of medicine for preventing and treating chronic renal fibrosis
CN111358790A (en) * 2019-12-25 2020-07-03 江苏省肿瘤医院 Application of NSC228155 in preparation of medicine for preventing and treating acute kidney injury
WO2022051847A1 (en) * 2020-09-08 2022-03-17 University Health Network Methods for generating neural progenitor cells with a spinal cord identity
CN113694063A (en) * 2021-08-31 2021-11-26 佛山市第一人民医院（中山大学附属佛山医院） Composition and application thereof

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