CN115068457A - Application of short-chain fatty acid in preparation of medicine for treating acute pancreatitis - Google Patents

Application of short-chain fatty acid in preparation of medicine for treating acute pancreatitis Download PDF

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Publication number
CN115068457A
CN115068457A CN202210780381.4A CN202210780381A CN115068457A CN 115068457 A CN115068457 A CN 115068457A CN 202210780381 A CN202210780381 A CN 202210780381A CN 115068457 A CN115068457 A CN 115068457A
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China
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chain fatty
fatty acid
sap
short
acute pancreatitis
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祝荫
李雪洋
何丛
李年双
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First Affiliated Hospital of Nanchang University
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First Affiliated Hospital of Nanchang 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
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  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention provides application of short-chain fatty acid in preparation of a medicine for treating acute pancreatitis, wherein different Severe Acute Pancreatitis (SAP) animal models are used for verifying the effect of the short-chain fatty acid in SAP, and the effect of supplementing the short-chain fatty acid in the SAP is definitely found to obviously reduce the acute pancreatitis of mouse tissues. And the key role of an IL-17signal path in the repair of the injury of the SAP intestinal mucosa of the SCFAs-protected mice is found, and a new treatment target point is provided for the treatment of the SAP concurrent intestinal dysfunction.

Description

Application of short-chain fatty acid in preparation of medicine for treating acute pancreatitis
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of short-chain fatty acid in preparation of a medicine for treating acute pancreatitis.
Background
Acute Pancreatitis (AP) is usually caused by biliary obstruction, alcohol consumption, endoscopic retrograde cholangiopancreatography, and drugs, eventually leading to acinar cell death, inducing local and systemic inflammation. Approximately 15-20% of patients develop Severe Acute Pancreatitis (SAP). Microcirculation damage and hypovolemia appear in the SAP process, which can cause intestinal mucosa ischemia, then reperfusion injury, and cause intestinal barrier dysfunction and intestinal flora shift, and the intestinal bacteria shift caused by the intestinal mucosa barrier damage is a key link for causing pancreatic infection necrosis infection.
Intestinal flora forms a biological barrier of the intestinal mucosa, can prevent pathogen infection, and can provide energy for intestinal epithelial cells and play an important role in protecting the normal physiological function and the epithelial integrity of the intestinal mucosa barrier, except for the intestinal flora itself and Short Chain Fatty Acids (SCFAs) which are metabolites of the flora, including acetic acid, propionic acid and butyric acid. SCFAs can increase fecal acidification, increase the growth and diversity of intestinal flora by lowering intestinal pH. In addition, SCFAs promote the proliferation of some beneficial bacteria, such as Bifidobacteria (Bifidobacteria) and Lactobacilli (Lactobacilli). These beneficial bacteria in turn stimulate the synthesis of short chain fatty acids, reduce the pH value of the intestinal tract, inhibit the colonization of pathogenic bacteria, improve the barrier function of intestinal microorganisms and promote the stability of the intestinal tract internal environment. However, the mechanism of intestinal mucosa barrier damage of the intestinal flora-SCFAs in the SAP generation and development process is still unclear, so that the correction of the intestinal mucosa barrier dysfunction from the perspective of regulating the intestinal flora-SCFAs metabolic imbalance to reduce intestinal tract bacterial translocation has practical guiding significance for preventing SAP secondary pancreatic necrosis infection and improving patient prognosis.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a new application of short-chain fatty acid, namely an application of the short-chain fatty acid in preparing a medicament for treating acute pancreatitis.
In order to achieve the purpose, the invention adopts the technical scheme that short-chain fatty acid is applied to preparing a medicine for treating acute pancreatitis.
Preferably, the short chain fatty acid is one or more combinations of acetic acid, propionic acid, butyric acid.
Further, the short chain fatty acids have a medium acetic acid: propionic acid: the mass part ratio of butyric acid is 5: 2: 4.
preferably, an effective amount of the short chain fatty acid may be mixed with a pharmaceutically acceptable carrier to make a pharmaceutical composition.
Further, the administration form of the pharmaceutical composition includes a prodrug, a salt, an ester or a targeted release formulation.
Further, the prodrug is a drug which can release a specific short-chain fatty acid after biological metabolism or chemical decomposition;
the targeted release formulation comprises a carrier molecule covalently bonded to at least one short chain fatty acid;
the carrier comprises starch, gum, oligosaccharide or pectin carbohydrate.
Drawings
The application of the short-chain fatty acid in the preparation of the medicine for treating acute pancreatitis will be particularly clear from the following relevant experimental results, and the invention is further described with reference to the accompanying drawings and examples. It is obvious that the drawings in the following description are only some embodiments of the invention, and that for a person skilled in the art, other drawings can be derived from them without inventive effort.
FIG. 1 is a schematic diagram of SCFAs reducing pathological pancreatic injury and inflammatory cell infiltration in a mouse pancreatitis induced by ranunculin;
FIG. 2 is a schematic of SCFAs reducing pancreatic injury in the Bombesin and M3/ptf1 α mouse SAP model in combination with ranunculin;
FIG. 3 is a schematic illustration of SCFAs reducing SAP associated pathological damage to the gut and barrier dysfunction;
FIG. 4 is a schematic illustration of SCFAs inhibiting SAP-associated activation of the intestinal IL-17signaling pathway.
Detailed Description
The invention is further illustrated with reference to the following figures and specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example one
The drug effect of the short-chain fatty acid is researched:
healthy mice 40, divided into 4 groups (control group, ranophanin-Bombesin group, hM3/Ptf 1. alpha.) and 10 mice each, were treated as follows:
control and ranophanin group treatments: injecting 100ug/kg of ranophanin into the abdominal cavity of the ranophanin group, injecting equivalent normal saline into the abdominal cavity of the control group once per hour, continuously administering for 10 hours, timing from the first intraperitoneal injection, and killing the mice after 24 hours;
treatment with ranophanin in combination with Bombesin group: the mice were pre-intraperitoneally injected with Bombesin (concentration 1000ug/kg) for one week, intraperitoneally injected with ranolanin 100ug/kg on day 8, 1 time per hour, continuously for 10 hours, and the mice were sacrificed 24 hours later;
hM3/Ptf1 α group treatment: after one week induction of mice pre-intraperitoneal with tamoxifen at a dose of 100mg/kg, on day 8, mice were sacrificed 24 hours after intraperitoneal injection with CNO10mg/kg 1 time.
Pancreatic tissues of each group of mice are taken, frozen, sliced, stained and observed, the cell condition of the mouse tissue is specifically observed as shown in figures 1 to 3, and in figure 1, A is SCFAs to reduce the pancreatic pathology of the mice; b is SCFAs to reduce the pancreas weight ratio (mg/g) of SAP mice; c is the pathological score of pancreas of each group of mice; d is the serum amylase level of each group of mice; e is the serum lipase level of each group of mice; f is the expression of MPO and F4/80 in the pancreatic tissues of each group of mice;
in fig. 2, a is SCFAs mitigating pathological damage to the pancreas in a frogsinin in combination with Bombesin SAP mouse model; b is the pathological score of pancreas of each group of mice; c is SCFAs to reduce pathological damage of pancreas of M3/ptf1 alpha SAP mouse model; d is the pathological score of the pancreas of each group of mice;
in fig. 3, a is SCFAs reducing SAP-associated intestinal pathological damage; b is SCFAs to increase the expression of intestinal tight junction proteins occludin and claudin-1 of SAP mice; c is SCFAs reduces SAP mice serum D-lactate levels.
In this example, the mixed SCFAs were formulated at 50mg/ml acetic acid, 20mg/ml propionic acid and 40mg/ml butyric acid.
In this example, in all three SAP animal models (ranulin, ranulin combined with bomosine and M3/ptf1 α SAP), a significant reduction in pancreatic edema, inflammatory cell infiltration and acinar cell necrosis, a significant reduction in serum amylase and lipase content, and a significant reduction in pancreatic tissue MPO and F4/80 expression were observed in mice supplemented with SCFAs, indicating that SCFAs can reduce pancreatic lesions (as shown in fig. 1-2). We further investigated the effect of SCFAs on SAP-induced intestinal function, and as a result found that small intestinal villus damage was alleviated after SCFAs supplementation, and that SCFAs supplementation also protected SAP mice intestinal barrier function (fig. 3).
Secondly, the possible mechanism of reducing the mouse SAP by short-chain fatty acid is explored:
analyzing the change of SAP mouse small intestine tissue gene transcription level by an RNA-seq method and the influence of SCFAs intervention on the SAP mouse small intestine tissue gene transcription level, and respectively carrying out KEGG function enrichment analysis and GSEA analysis on the differential gene sets of each group. There were 223 differential genes between SAP tenant and control groups and 314 differential genes between SAP and SCFAs _ SAP groups. The result shows that the SAP generation and development process can cause the gene up-regulation of the IL-17signaling pathway proinflammatory pathway, and the SAP mice can cause the gene down-regulation of the IL-17signaling pathway proinflammatory pathway after being supplemented with SCFAs. We further find that the supplement of SCFAs can obviously reduce the expression of proteins such as IL-17A caused in the SAP process by detecting IL-17 in intestinal tissues of various groups of mice through related proteins (figure 4), so that we speculate that the SCFAs can reduce intestinal inflammation and relieve intestinal barrier injury by reducing IL-17signal paths;
in fig. 4, A, B and C are volcano plots and statistical plots of the number of differential genes in each group of mice; d and E are enrichment passages of the KEGG of each group of mice; f and G are SCFAs which can inhibit IL-17signal passage activation in intestinal tracts of SAP mice; h is SCFAs which can reduce the expression of IL-17A protein in intestinal tracts of SAP mice.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (6)

1. Application of short-chain fatty acid in preparing medicine for treating acute pancreatitis is provided.
2. Use according to claim 1, wherein the short chain fatty acid is one or more combinations of acetic acid, propionic acid, butyric acid.
3. Use according to claim 1, wherein the short chain fatty acids have a medium acetic acid: propionic acid: the mass part ratio of butyric acid is 5: 2: 4.
4. the use of claim 1, wherein the effective amount of the short chain fatty acid is admixed with a pharmaceutically acceptable carrier to form a pharmaceutical composition.
5. The use according to claim 4, wherein the pharmaceutical composition is administered in a form comprising a prodrug, salt, ester or targeted release formulation.
6. The use according to claim 5, wherein the prodrug is a drug which releases a specific short chain fatty acid upon biological metabolism or chemical decomposition;
the targeted release formulation comprises a carrier molecule covalently bonded to at least one short chain fatty acid;
the carrier comprises starch, gum, oligosaccharide or pectin carbohydrate.
CN202210780381.4A 2022-07-04 2022-07-04 Application of short-chain fatty acid in preparation of medicine for treating acute pancreatitis Pending CN115068457A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113866399A (en) * 2021-11-03 2021-12-31 上海交通大学医学院附属仁济医院 Application of liver ketone bodies in monitoring and treating acute pancreatitis
US20220142978A1 (en) * 2017-01-27 2022-05-12 Temple University-Of The Commonwealth System Of Higher Education Use of short chain fatty acids for the treatment and prevention of diseases and disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220142978A1 (en) * 2017-01-27 2022-05-12 Temple University-Of The Commonwealth System Of Higher Education Use of short chain fatty acids for the treatment and prevention of diseases and disorders
CN113866399A (en) * 2021-11-03 2021-12-31 上海交通大学医学院附属仁济医院 Application of liver ketone bodies in monitoring and treating acute pancreatitis

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FONS F VAN DEN BERG等: "Western-type diet influences mortality from necrotising pancreatitis and demonstrates a central role for butyrate" *
ZHENGJIAN WANG等: "The gut-lung axis in severe acute Pancreatitis-associated lung injury: The protection by the gut microbiota through short-chain fatty acids" *

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