CN116570707A - Application of galectin 1 in medicines for preventing and treating sepsis - Google Patents

Application of galectin 1 in medicines for preventing and treating sepsis Download PDF

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Publication number
CN116570707A
CN116570707A CN202310757650.XA CN202310757650A CN116570707A CN 116570707 A CN116570707 A CN 116570707A CN 202310757650 A CN202310757650 A CN 202310757650A CN 116570707 A CN116570707 A CN 116570707A
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Prior art keywords
galectin
sepsis
mice
test
preventing
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李光
石杨
廖斌
李婧妍
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Southwest Medical University
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Southwest Medical University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention discloses an application of galectin 1 in medicines for preventing and treating sepsis. The galectin 1 has wide biological activity, can protect and regulate myocardial cells, can protect the sepsis heart dysfunction by taking the galectin 1 as a protein active drug, and can obviously regulate and control the immune system, inhibit excessive inflammatory reaction and reduce organ damage and dysfunction, thereby playing a role in preventing and treating sepsis.

Description

Application of galectin 1 in medicines for preventing and treating sepsis
Technical Field
The invention relates to the technical field of medicines, in particular to application of galectin 1 in medicines for preventing and treating sepsis.
Background
Sepsis is a highly heterogeneous syndrome caused by an unbalanced host response to infection. Sepsis is defined as a Systemic Inflammatory Response Syndrome (SIRS) caused by an infection, a life threatening organ dysfunction caused by a host's imbalance in the response to an infection. Notably, although infection is a triggering event in the definition of sepsis, an aberrant immune response is often still present after successful treatment of the infection. Sepsis places a significant burden on the world in terms of morbidity and mortality. Our understanding of the pathophysiology of sepsis has greatly progressed, while the development of targeted therapies for sepsis patients with disrupted host responses has failed, with a significant contrast. Disproportionate inflammatory response to invasive infection has been considered central to the onset of sepsis for many years, but it is now clear that host response is disturbed in a more complex manner, including sustained excessive inflammation and immunosuppression, and failure to restore normal homeostasis. It may be thought that during sepsis, there is not only an increase in inflammation and/or immunosuppression, but also a fundamental recombination of immune and metabolic cellular processes, measures of inflammation and suppression being a reflection of this acute cellular reprogramming. Furthermore, although animal studies and human observations have revealed pathological changes in many different components of the host response during sepsis, the key mechanisms of sepsis-related pathology are still difficult to form into an overall framework compared to secondary, less patient-prognosis-affecting disorders.
Clinical manifestations of sepsis vary widely depending on the initial site of infection, pathogenic microorganisms, the pattern of acute organ dysfunction, the underlying health of the patient, and the interval before initiation of treatment. Signs of infection and organ dysfunction may not be apparent, but acute organ dysfunction most often affects the respiratory and cardiovascular systems. Respiratory impairment is often manifested as Acute Respiratory Distress Syndrome (ARDS), defined as hypoxia with non-cardiac bilateral infiltration. Cardiovascular damage is primarily manifested by hypotension or elevated serum lactate levels. After sufficient expansion, hypotension often persists, requiring the use of vasopressors, and myocardial dysfunction may occur.
The mechanism of sepsis-related cardiac dysfunction appears to be multifactorial. In recent years, our understanding of the role of various mechanisms of circulatory heart inhibitors, calcium, NO, apoptosis, and mitochondrial dysfunction in the development of sepsis-associated myocardial dysfunction has been improved. Experiments and clinical studies have shown that ultrastructural abnormalities in cardiac mitochondria occur during sepsis. Furthermore, increased levels of NO and superoxide produced by cardiac mitochondria during sepsis may inhibit OXPHOS, reduce ATP production, and lead to "cytopathic hypoxia", i.e., impairment of cellular oxygen utilization and ATP production, which is a critical step in the development of sepsis-induced organ failure.
Early studies therefore emphasized strategies such as by improving endothelial and epithelial cell barrier function, bioenergy, and active inflammatory elimination pathways, or the adoption of cell therapy. However, since the molecular level cascade of sepsis systemic infections and organ dysfunction can occur simultaneously and often exhibit self-reinforcing characteristics, even if the heterogeneity of patients can be reduced and similar pathophysiological changes screened, it remains impractical to expect significant improvement in clinical prognosis by blocking one of the numerous pathways. At the same time, these treatment modalities are also limited by the limitations of preclinical models.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide the application of the galectin 1 in medicines for preventing and treating sepsis.
The technical scheme for solving the technical problems is as follows:
use of galectin 1 in medicine for preventing and/or treating sepsis.
Further, the medicament is a preparation prepared from an active ingredient and an auxiliary ingredient, wherein the active ingredient comprises galectin 1 and a pharmaceutically acceptable galectin 1 derivative (comprising derivative polypeptide), and the auxiliary ingredient comprises pharmaceutically acceptable auxiliary materials.
Further, galectin 1 was purchased from the company of the division of the holy biotechnology (Shanghai) of next.
The dosage forms of the medicine comprise oral preparations or injection preparations.
The invention has the following beneficial effects:
1) The invention discovers that the galectin 1 (galectin-1) molecule can play a protective role in the function of the septic heart dysfunction as a protein active drug through a mouse test.
2) The invention discovers that the effect of the galectin 1 molecule is very prominent aiming at complex changes caused by sepsis through a mouse test. Whereas galectin 1 can significantly regulate the immune system, inhibit excessive inflammatory reaction, and reduce organ damage and dysfunction.
3) The invention adopts the intraperitoneal injection of LPS to simulate sepsis of mice, thereby observing the heart function and heart damage of the mice. The model utilizes the characteristic that LPS can trigger in-vivo acute inflammatory reaction, well simulates the characteristics of heart function decline, myocardial damage and the like under the condition of sepsis, and meanwhile, due to the metabolizability of LPS, mice cannot generate excessive heterogeneity due to individual difference and the like unlike systemic infection of sepsis. Thus in this model, inhibition of hyperimmune by galectin 1 can be directly observed, as well as protection of the heart in hyperimmune.
Drawings
FIG. 1 is a flow chart of a test protocol of the present invention;
FIG. 2 is the results of the ultrasonic testing of the heart of the mice of example 1;
FIG. 3 is a photograph of a stained section of the heart of a mouse of example 2;
fig. 4 is an electron micrograph of mitochondrial staining of myocardial tissue of the mice of example 3.
FIG. 5 is a graph showing the calcium transient and cell contraction assays of the mouse cardiomyocytes of example 4.
Detailed Description
The examples given below are only intended to illustrate the invention and are not intended to limit the scope thereof. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1: ultrasonic test of mouse heart
(1) Experimental animal
18 wild C57BL/6J mice are subjected to standardized maintenance feed feeding in a constant temperature environment for at least 1 week before the experiment, and drinking water is not limited.
(2) Grouping
Mice 18 were divided into 3 groups: control 6, test 6, sepsis 6.
Injecting physiological saline into the abdominal cavity 1h after the start of the test of the control group, wherein the injection amount is 5mg/kg based on the weight of the mice;
the test group test begins to inject the galectin 1 into the mice with the injection amount of 10 mug/mouse, and the lipopolysaccharide is injected into the abdominal cavity after 1h, wherein the injection amount is 5mg/kg based on the weight of the mice;
lipopolysaccharide was injected into the abdominal cavity 1h after the start of sepsis group test, the injection amount was 5mg/kg based on the weight of mice.
(3) Test method
After 19 hours from the start of the test, three groups of mice were subjected to cardiac ultrasound, and the heart functions of the mice were determined by analyzing the left ventricular contractile function (EF) and the left ventricular contractile rate (FS) of the hearts of the mice by cardiac ultrasound.
(4) Test results
As shown in fig. 2, it can be seen from the graph that the left ventricular contractile function (EF) and the left ventricular shortening rate (FS) were significantly reduced in the mice of the sepsis group compared to the control group, indicating that the heart function was significantly reduced in the mice of the sepsis group, whereas the left ventricular contractile function (EF) and the left ventricular shortening rate (FS) were significantly increased in the mice of the test group injected with galectin 1 compared to the sepsis group, indicating that the heart function reduction caused by sepsis can be effectively treated after galectin 1 is injected.
Example 2: mouse heart staining section test
(1) Experimental animal
18 wild C57BL/6J mice are subjected to standardized maintenance feed feeding in a constant temperature environment for at least 1 week before the experiment, and drinking water is not limited.
(2) Grouping
Mice 18 were divided into 3 groups: control 6, test 6, sepsis 6.
Injecting physiological saline into the abdominal cavity 1h after the start of the test of the control group, wherein the injection amount is 5mg/kg based on the weight of the mice;
the test group test begins to inject the galectin 1 into the mice with the injection amount of 10 mug/mouse, and the lipopolysaccharide is injected into the abdominal cavity after 1h, wherein the injection amount is 5mg/kg based on the weight of the mice;
lipopolysaccharide was injected into the abdominal cavity 1h after the start of sepsis group test, the injection amount was 5mg/kg based on the weight of mice.
(3) Test method
After 25h from the beginning of the test, i.e. 24h after injection of physiological saline or lipopolysaccharide, the hearts of three groups of mice were taken out, fixed with paraformaldehyde, then paraffin-embedded, sectioned, stained with Masson kit and observed.
(4) Test results
The test results are shown in fig. 3, and it can be seen from the graph that the heart muscle injury of mice in the sepsis group has obvious fibrosis symptoms relative to the control group, and the test group injected with the galectin 1 has less fibrosis and compact myocardial structure relative to the sepsis group, so that the symptoms of the heart muscle injury caused by the sepsis after the galectin 1 is injected are relieved, and myocardial tissues are protected.
Example 3: mouse heart mitochondrion staining electron microscope test
(1) Experimental animal
18 wild C57BL/6J mice are fed with standard maintenance feed in a constant temperature environment for at least 1 week before the experiment, and the drinking water is not limited.
(2) Grouping
Mice 18 were divided into 3 groups: control 6, test 6, sepsis 6.
Injecting physiological saline into the abdominal cavity 1h after the start of the test of the control group, wherein the injection amount is 5mg/kg based on the weight of the mice;
the test group test begins to inject the galectin 1 into the mice with the injection amount of 10 mug/mouse, and the lipopolysaccharide is injected into the abdominal cavity after 1h, wherein the injection amount is 5mg/kg based on the weight of the mice;
lipopolysaccharide was injected into the abdominal cavity 1h after the start of sepsis group test, the injection amount was 5mg/kg based on the weight of mice.
(3) Test method
After 25 hours from the start of the test, i.e., 24 hours after injection of physiological saline or lipopolysaccharide, the heart was removed, myocardial tissue was sectioned, mitochondria stained, and the sections were observed by electron microscopy.
The test results are shown in fig. 4, and it can be seen from the graph that compared with the control group, the mitochondria of the mice in the sepsis group are broken and cavitation appears, and the mitochondria of the test group after the galectin 1 is injected are obviously protected, so that the symptoms of myocardial tissue cell mitochondria destruction caused by sepsis can be effectively protected by the galectin 1 injection.
Example 4: mouse cardiomyocyte calcium transient and cell contraction assay
(1) Experimental animal
18 wild C57BL/6J mice are fed with standard maintenance feed in a constant temperature environment for at least 1 week before the experiment, and the drinking water is not limited.
(2) Grouping
Mice 18 were divided into 3 groups: control 6, test 6, sepsis 6.
Injecting physiological saline into the abdominal cavity 1h after the start of the test of the control group, wherein the injection amount is 5mg/kg based on the weight of the mice;
the test group test begins to inject the galectin 1 into the mice with the injection amount of 10 mug/mouse, and the lipopolysaccharide is injected into the abdominal cavity after 1h, wherein the injection amount is 5mg/kg based on the weight of the mice;
lipopolysaccharide was injected into the abdominal cavity 1h after the start of sepsis group test, the injection amount was 5mg/kg based on the weight of mice.
(3) Test method
After 25 hours from the start of the test, i.e., 24 hours after injection of physiological saline or lipopolysaccharide, the heart was removed, cardiomyocytes were isolated, and cardiomyocytes were directly observed by simultaneous cell contraction observation for cardiomyocyte contraction and calcium transient.
The test results show that compared with the control group, the myocardial cell contraction amplitude and the calcium homeostasis of mice in the sepsis group are obviously affected, and the myocardial cell contraction function and the calcium homeostasis of the test group after the galectin 1 is injected are effectively protected.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.

Claims (3)

1. Use of galectin 1 in medicine for preventing and/or treating sepsis.
2. The use according to claim 1, wherein the medicament is a formulation prepared from an active ingredient comprising galectin 1 and a pharmaceutically acceptable galectin 1 derivative and an auxiliary ingredient comprising pharmaceutically acceptable excipients.
3. The use according to claim 1 or 2, wherein the dosage form of the medicament comprises an oral formulation or an injectable formulation.
CN202310757650.XA 2023-06-25 2023-06-25 Application of galectin 1 in medicines for preventing and treating sepsis Pending CN116570707A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103314102A (en) * 2010-12-09 2013-09-18 株式会社嘉尔药物 Galectin 9-secreting cell, production method for same, and application for same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103314102A (en) * 2010-12-09 2013-09-18 株式会社嘉尔药物 Galectin 9-secreting cell, production method for same, and application for same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LÍLIAN C. RODRIGUES 等: "Galectin-1 modulation of neutrophil reactive oxygen species production depends on the cell activation state", 《MOLECULAR IMMUNOLOGY》, vol. 116, 31 December 2019 (2019-12-31), pages 80 - 89, XP085917707, DOI: 10.1016/j.molimm.2019.10.001 *

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