CN109200056A - Purposes of the poly IC in prevention and treatment pancreatitis and its associated disease - Google Patents
Purposes of the poly IC in prevention and treatment pancreatitis and its associated disease Download PDFInfo
- Publication number
- CN109200056A CN109200056A CN201811383421.1A CN201811383421A CN109200056A CN 109200056 A CN109200056 A CN 109200056A CN 201811383421 A CN201811383421 A CN 201811383421A CN 109200056 A CN109200056 A CN 109200056A
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- Prior art keywords
- pancreatitis
- polycytidylicacid
- product
- polyinosinic acid
- pancreatic
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/153—Nucleic acids; Hydrolysis products or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/13—Nucleic acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
Abstract
This application provides purposes of the poly IC in prevention and treatment pancreatitis and its associated disease.The application specifically provides application of poly IC (i.e. polyinosinic acid-polycytidylicacid, the poly I:C) active material in preparation prevention, the product for alleviating, assisting in the treatment of and/or treating pancreatitis and its associated disease；Serum pancreatic lipase is reduced in preparation, reduces myeloperoxidase enzyme level in pancreatic tissue, to reduce proinflammatory factor (such as IL-1 β and/or CXCL1 and/or CXCL2) transcriptional expression in pancreatic tissue horizontal and/or prevents or mitigates application in the product of pancreatic cell damage；And Related product and method.
Description
Technical field
The application belongs to biotechnology and field of medicaments.Specifically, this application involves poly IC (also referred to as polyinosinic acids-
Poly or poly I:C) purposes of the active material in prevention and treatment pancreatitis (such as acute pancreatitis) and its associated disease.
Background technique
Pancreatitis is the inflammatory disease of pancreas.In the disease, pancreas may occur in which oedema, hyperemia, bleeding even necrosis, face
There are the symptoms such as abdominal pain, abdominal distension, Nausea and vomiting, fever on bed.According to statistics, in annual every 100,000 people, 30 people is about had and are suffered from
Suffer from acute pancreatitis；And in annual every 100,000 people, the new case of eight chronic pancreatitis can be had more.In the U.S., there are about ten thousand/
Five people's suffering from chronic pancreatitis.Nineteen ninety, the whole world have about 83,000 people therefore to get killed, and by 2013, because of pancreatitis
Lethal number has then risen to 123,000 people[1].Find can treat, assist in the treatment of and/or prevent pancreatitis drug or
Person's food, the corresponding prevention and treatment method of pathogenesis and exploitation for pancreatitis are particularly important.
Clinical pancreatitis is divided into acute and chronic pancreatitis two major classes.Acute pancreatitis is mainly due to pancreatin excessive secretion
Activation causes pancreas digestion itself to cause to damage, and main pathological index, pathomechanism and infective inflammation disease etc. are completely not
Together, as a result, its prevent and treat method also with the prevention and treatment different from of other inflammation diseases.Chronic pancreatitis is primarily due to urgency
Property pancreatitis recurrent exerbation caused by a kind of disease destroyed of the chronic progressive of pancreas.Both pancreatitis have similar morbidity
Mechanism and clinical manifestation, as serum pancreatic lipase, myeloperoxidase enzyme level improve, proinflammatory factor IL-1 β in pancreatic tissue,
CXCL1 and/or CXCL2 transcriptional expression level improves, pancreatic cell damages etc..
Interferon (IFN) inducer polyinosinic acid-polycytidylicacid (alias: poly IC, Poly I:C) is artificial synthesized
The double-strand poly RNA analog being made of poly and poly can generate a large amount of I type by induction
IFN (IFN-I) activates interferon-' alpha '/beta receptor (IFNAR) downstream signal, has broad-spectrum disease resistance toxic action, antitumor action[2],
It can be clinically used for the treatment of infectious diseases (such as shingles zoster, herpetic keratitis)[3].In addition, Poly I:C still have it is immune
The effect of adjuvant can stimulate reticuloendothelial system, enhance the phagocytic function of phagocyte, enhance the formation of antibody, stimulate of the same race
Allograft reaction and delayed hypersensitivity.Poly I:C mainly acts on Toll-like receptor 3 (TLR3), Induced by Retinoic Acid gene I
Sample receptor (retinoic acid inducible gene I-like receptor, RIR) activates Interferon regulatory factor-3
(interferon regulatory factor 3, IRF-3) and Nuclear factor kappa B (NF- κ B) raises I type interferon and proinflammatory
The expression of the factor.It is immune that available data shows that polyI:C can be activated, and induces inflammation[4,5].But poly I:C is applied to suppression
The experimental result of inflammation processed there is no report.
To sum up, there is an urgent need in the art to develop new way, the novel drugs of prevention and treatment pancreatitis.
Summary of the invention
The application provides just a kind of new way treated, assist in the treatment of and/or prevent pancreatitis, that is, uses poly
I:C prevents and treats pancreatitis and its associated disease and/or symptom.
In the first aspect of the application, provide polyinosinic acid-polycytidylicacid active material preparation prevention, alleviate,
Application in the product of adjuvant treatment and/or treatment pancreatitis and its associated disease and/or symptom.
In some embodiments, the polyinosinic acid-polycytidylicacid active material is selected from the group: the poly- born of the same parents of polyinosinic acid-
Thuja acid, polyinosinic acid-polycytidylicacid kanamycins, (such as polyinosinic acid-polycytidylicacid exists polyinosinic acid-polycytidylicacid derivative
Pharmacological or physiological acceptable salt and/or ester), polyinosinic acid-polycytidylicacid dry powder, polyinosinic acid-polycytidylicacid note
Penetrate agent and other polyinosinic acid-polycytidylicacid derivatives known in the art or product.
In some embodiments, the weight average molecular weight of the polyinosinic acid-polycytidylicacid active material is 1.5~8kb
Or the commercially available obtainable polyinosine with other molecular weight in any number and numberical range within the scope of this or this field
Acid-poly active material.
In some embodiments, the polyinosinic acid-polycytidylicacid active material accounts for the product total weight
0.001-99.9wt%, such as 0.1-99wt%, 1-95wt%, 5-90wt%, 10-80wt%.
In some embodiments, the pancreatitis or its associated disease and/or symptom be one of be selected from the group or
It is a variety of: acute pancreatitis (including mild acute pancreatitis, Severe Acute Pancreatitis SAP, Operation treatment), chronic pancreatitis, urgency
The ictal pancreatitis of property, chronic paroxysmal pancreatitis；Caused by one or more in aforementioned pancreatitis: the relevant rush of pancreatitis
Inflammatory factor (such as IL-1 β, CXCL1 and/or CXCL2) level improves, the relevant myeloperoxidase enzyme level of pancreatitis improves,
The relevant serum of pancreatitis or amylase in urine level improve, the relevant serum pancreatic lipase level of pancreatitis improves, pancreatitis phase
The relevant Multiple Organ Dysfunction Syndrome of systemic inflammatory response syndrome, pancreatitis of pass, pancreatic cell (such as pancreatic acini
Cell) damage.
In some embodiments, the prevention, alleviate, adjuvant treatment and/or treatment include it is selected from the group below a kind of or
It is a variety of: to reduce the level of the relevant proinflammatory inflammation factor (such as IL-1 β, CXCL1 and/or CXCL2) of pancreatitis, or prevent its liter
It is high；The relevant myeloperoxidase enzyme level of pancreatitis is reduced, or prevents its raising；Reduce the relevant serum of pancreatitis or urine starch
Enzyme level, or prevent its raising；It is horizontal to reduce the relevant serum pancreatic lipase of pancreatitis, or prevents its raising；Alleviate pancreatitis
Relevant systemic inflammatory response syndrome, or prevent it from occurring and/or developing；Alleviate the relevant multiple organs dysfunction of pancreatitis
Syndrome, or prevent it from occurring and/or developing；Protection pancreatic cell (such as pancreatic acinar cell) is injury-free or reduces its damage
Wound.
In some embodiments, the product is selected from the group: drug, health care product, food, drink, enteral nutrition preparation,
Dietary supplements, veterinary drug, feed or feed addictive.
In some embodiments, the product also includes: pharmacy, physiology, health care conduct and learning, bromatology, veterinarily
Acceptable carrier, excipient, auxiliary material；Pancreatitis or its correlation are alleviated, assist in the treatment of and/or are treated in one or more preventions
Other substances of illness, such as growth hormone release inhibiting hormone, Gabexate, antacids, anticholinergic agents, antibiotic, pancreatin inhibitor.
In some embodiments, the form of the product is suitable for one or more giving mode in the following group: through stomach and intestine to
It gives；It is non-to be given through stomach and intestine, for example, through in vein, mucous membrane, nasal cavity, intraperitoneal, encephalic, tumor, sublingual, cheek, transdermal (such as ion is led
Enter), liposome method.
In some embodiments, the product are as follows: tablet, powder agent, injection, granule, syrup, capsule, solution
Agent, suppository or ointment.
In the another aspect of the application, providing polyinosinic acid-polycytidylicacid active material in preparation reduces serum pancreas
Lipase, reduce myeloperoxidase enzyme level in pancreatic tissue, reduce proinflammatory factor transcriptional expression in pancreatic tissue it is horizontal and/or
Prevent or mitigate the application in the product of pancreatic cell damage.
In some embodiments, the polyinosinic acid-polycytidylicacid active material in the product is selected from: polyinosinic acid-
Poly, polyinosinic acid-polycytidylicacid kanamycins, polyinosinic acid-polycytidylicacid derivative, polyinosinic acid-polycytidylicacid
Dry powder, polyinosinic acid-polycytidylicacid injection and other polyinosinic acid-polycytidylicacid derivatives known in the art or production
Product.
In some embodiments, the serum pancreatic lipase to be reduced, myeloperoxidase enzyme level in pancreatic tissue,
Proinflammatory factor transcriptional expression level is improved because of pancreatitis in pancreatic tissue；
In some embodiments, the proinflammatory factor is one of to be selected from the group or a variety of: IL-1 β, CXCL1 and
CXCL2。
In some embodiments, the product is selected from the group: drug, health care product, food, drink, enteral nutrition preparation,
Dietary supplements, veterinary drug, feed or feed addictive；
In some embodiments, the product also includes one of to be selected from the group or a variety of: pharmacy, health care conduct and learning,
Bromatology, veterinarily acceptable carrier, excipient, auxiliary material；One or more preventions are alleviated, assist in the treatment of and/or are treated
Other of pancreatitis or its associated disease substance, for example, growth hormone release inhibiting hormone, Gabexate, antacids, anticholinergic agents, antibiotic,
Pancreatin inhibitor.
In some embodiments, the form of the product is suitable for one or more giving mode in the following group: through stomach and intestine to
It gives；It is non-to be given through stomach and intestine, for example, through in vein, mucous membrane, nasal cavity, intraperitoneal, encephalic, tumor, sublingual, cheek, transdermal (such as ion is led
Enter), liposome method.
In the another aspect of the application, a kind of product comprising polyinosinic acid-polycytidylicacid active material is provided,
For: pancreatitis or its associated disease are alleviated, assist in the treatment of and/or are treated in prevention；It reduces serum pancreatic lipase, reduce pancreas
Myeloperoxidase enzyme level in tissue, to reduce proinflammatory factor transcriptional expression in pancreatic tissue horizontal and/or prevent or mitigate pancreas
Cellular damage.
In one embodiment, the product also include pharmaceutically, it is health care conduct and learning, bromatology, veterinarily acceptable
Carrier, excipient, auxiliary material；One or more preventions are alleviated, adjuvant treatment and/or treatment pancreatitis or its associated disease
Other substances, such as growth hormone release inhibiting hormone, Gabexate, antacids, anticholinergic agents, antibiotic, pancreatin inhibitor.
In the another aspect of the application, provide it is a kind of prevention, alleviate, adjuvant treatment and/or treatment pancreatitis or its
Associated disease；Serum pancreatic lipase is reduced, myeloperoxidase enzyme level in pancreatic tissue is reduced or reduces proinflammatory in pancreatic tissue
Factor transcription expression and/or the method for preventing or mitigating pancreatic cell damage, which comprises it is in need right to give
As a effective amount of polyinosinic acid-polycytidylicacid active material and/or product as described in the present invention.
It should be understood that those skilled in the art can carry out any combination without de- to technical solution above-mentioned and technical characteristic
From inventive concept of the invention and protection scope.Other aspects of the invention are due to this disclosure, to the skill of this field
It is obvious for art personnel.
Detailed description of the invention
The present invention will be further explained below with reference to the attached drawings, and wherein these displays are only for illustrating reality of the invention
Scheme is applied, rather than in order to limit to the scope of the present invention.
Fig. 1: with the pathological change of the method observation pancreatic tissue of hematoxylin-eosin (HE) dyeing.Wherein, " physiological saline "
Indicate that control group, " CER-AP " indicate acute pancreatitic model group, " poly I:C+CER " indicates poly I:C processing group.
Fig. 2: with neutrophil leucocyte marker in MPO antibody label pancreatic tissue.Wherein: " physiological saline " indicates control
Group, " CER-AP " indicate acute pancreatitic model group, and " poly I:C+CER " indicates polyI:C processing group.
Fig. 3 A: with the amylase activity in serum starch enzyme reagent kit measurement mice serum, poly I:C processing is compared
The degree of inflammation of group and pancreatitis model group.Wherein: " physiological saline " indicates that control group, " CER-AP " indicate acute pancreatitis mould
Type group, " poly I:C+CER " indicate poly I:C processing group；*: P < 0.05.
Fig. 3 B: with the pancreatic lipase activity in serum pancreatic lipase enzyme reagent kit measurement mice serum, poly I is compared:
The degree of inflammation of C processing group and pancreatitis model group.Wherein: " physiological saline " indicates that control group, " CER-AP " indicate acute pancreas
Adenositis model group, " poly I:C+CER " indicate poly I:C processing group；*: P < 0.05.
Fig. 4: it with the change level of the cellular inflammation factor in real-time fluorescence PCR method measurement mice pancreatic tissue, compares
The degree of inflammation of poly I:C processing group and inflammatory model group.Wherein: " physiological saline " indicates that control group, " CER-AP " indicate anxious
Property pancreatitis model group, " poly I:C+CER " indicate poly I:C processing group；*: P < 0.05.
Fig. 5 A: activity caused by being damaged using DCFH-DA probe in detecting Bile Salts inducing mouse pancreatic acinar cell
Oxygen cluster (ROS, reactive oxygen species).Wherein: " MOCK " indicates that control group, " TAU " indicate Bile Salts
Group, " polyI:C+TAU " indicate polyI:C processing group.
Fig. 5 B: living caused by being damaged using western blot method detection Bile Salts inducing mouse pancreatic acinar cell
Property oxygen promote induction HO-1 protein expression.Wherein: " MOCK " indicates that control group, " TAU " indicate Bile Salts group, " polyI:C
+ TAU " indicates polyI:C processing group.
Specific embodiment
Present inventor by long-term in-depth study, it was unexpectedly found that: with poly I in the prior art:
C can induce the contents known (such as referring to bibliography [4] and [5]) of inflammation on the contrary, poly I:C is not only dynamic without promoting to aggravate
The pancreatitis of object model shows, and all shows excellent preventive and therapeutic effect to Animal Model of Acute Pancreatitis and cell model instead,
The degree of inflammation of pancreas can be significantly reduced, to have fabulous application value in the prevention and treatment of pancreatitis.
Specifically, inventor has found that poly I:C plays protective effect to the acute pancreatitis mice that tree toad element induces,
MPO expression quantity in its level and pancreatic tissue for can significantly reduce pancreatitis mice serum amylase and pancreatic lipase, effectively
Proinflammatory inflammation factor in pancreatic tissue is reduced, to significantly reduce degree of inflammation, and pancreas is protected not interfered by pancreatitis；Furthermore
Poly I:C also has protective effect to pancreatic cell damage, so as to the protection and treatment for pancreas.Poly I:C can make
Pancreatitis protective agents are prepared for effective component or with prevention and treatment pancreatitis other drugs combination, reduce the hair of clinically pancreatitis
Raw, development and degree of inflammation.
Related definition and explanation
All numberical ranges provided herein be intended to clearly include fall in all numerical value between endpoints of ranges and it
Between numberical range.The feature that the feature or embodiment that can be mentioned to the present invention are mentioned is combined.This specification is taken off
All features shown can be used in combination with any composition form, and each feature disclosed in specification any can provide phase
The alternative characteristics of same, impartial or similar purpose replace.Therefore except there is special instruction, revealed feature is only impartial or similar
The general example of feature.
As used herein, " containing ", " having " or " comprising " include "comprising", " mainly by ... constitute ", " substantially
By ... constitute " and " by ... constitute ".Herein, it is of the invention to indicate that various composition can be applied to together for term " containing "
In product/composition.Therefore, term " mainly by ... form " and " consist of " were included in term " containing ".
Herein, term " effective quantity " refer to by mode of the invention using when be enough to obtain the effect of needs and without excessively not
Good side reaction (such as toxicity, stimulation and allergy), that is, have the amount of the ingredient of reasonable benefit/risk ratio.Obviously, specifically
" effective quantity " is different because of various factors, such as age, the patient's condition of the required object given.
Herein, term " individual " and " object " are used interchangeably herein, and refer to the mammal with pancreas, including
But be not limited to people, orangutan, ape, monkey, horse, ox, sheep, pig, cat, dog, other raising/farming animals etc..
Referred to the term of term " prevention and treatment ", " treatment " and " prevention and/or treatment " and the like in this article and is obtained
Pharmacology required for obtaining and/or physiologic effect.The effect can be for it prevents all or part of a kind of disease or symptom
It is preventative, and/or for it treats a kind of disease and/or the adverse effect as caused by disease partially or completely can be to control
The property treated." prevention and treatment " includes related prevention and/or treatment, the especially mankind to pancreatitis or its associated disease herein
Disease includes (a) preventing the symptom of disease or disease from having neurological susceptibility to the disease at those but is not yet diagnosed as suffering from the disease
Occur on individual；(b) inhibit disease, that is, prevent the development of disease；(c) disease is mitigated or eliminated, that is, causes the recession of disease.
Unless otherwise indicated, terms used herein " polyinosinic acid-polycytidylicacid ", " poly I:C " etc. can be " poly- with term
Inosinicacid-poly active material " is used interchangeably, and refers to polyinosinic acid (Poly I) and poly- cytimidine nucleic acid (Poly C)
Copolymer, preparation or derivative, for example, be added on the basis of its copolymer a small amount of kanamycins and calcium ion preparation (such as
Poly I:Ckca), the pharmacological or physiological acceptable salt of polyinosinic acid-polycytidylicacid or ester.For the application embodiment party
Poly I:C or its preparation in formula are commercially available, such as are purchased from Sigma company, Invivogen company etc. as reagent,
It can be used as bulk pharmaceutical chemicals or drug (such as injection) obtained from pharmaceutical factory is commercially available.
Product
A kind of product provided herein, it includes: (a) polyinosinic acid-polycytidylicacid active material；(b) pharmacy, life
Neo-Confucianism, health care conduct and learning, bromatology, veterinarily acceptable carrier, excipient, auxiliary material；And (c) optionally, a kind of or more
Kind of prevention is alleviated, other substances of adjuvant treatment and/or treatment pancreatitis or its associated disease, such as growth hormone release inhibiting hormone, plus shellfish
Ester, antacids, anticholinergic agents, antibiotic, pancreatin inhibitor.
Product herein can be drug, health care product, food, drink, enteral nutrition preparation, dietary supplements, veterinary drug, feeding
Material or feed addictive can be used for effectively preventing and/or treating pancreatitis, reduce serum pancreatic lipase, reduce pancreatic tissue
Middle myeloperoxidase enzyme level reduces proinflammatory factor (such as IL-1 β and/or CXCL1 and/or CXCL2) transcription table in pancreatic tissue
Up to level and/or prevent or mitigate pancreatic cell damage.In general, when the product is health care product, polyinosine contained therein
Acid-poly active material amount will be lower than pharmaceutical composition.
As used herein, term " acceptable carrier, excipient, auxiliary material " refer to be contained in the application product itself simultaneously
It is not necessary active constituent, and is not with or without the various substances of excessive toxicity after applying.Suitable carrier, excipient,
Auxiliary material etc. is well known to those of ordinary skill in the art.For example, pharmaceutically acceptable carrier is recorded in " Remington medicine in detail
Object science " (Remington ' s Pharmaceutical Sciences, Mack Pub.Co., N.J.1991).
Available carrier can contain liquid, such as water, salt water, glycerol and ethyl alcohol.In addition, in these substances, there is likely to be auxiliary
The substance of helping property, such as filler, disintegrating agent, lubricant, glidant, effervescent agent, wetting agent or emulsifier, corrigent, pH buffering
Substance etc..In general, these substances can be formulated in nontoxic, inert and pharmaceutically acceptable aqueous carrier medium,
Middle pH is usually about 5-8, preferably, pH is about 6-8.
It in some embodiments, is available common type in pharmaceutical field for the carrier in the application product,
Including but not limited to: the adhesive of oral preparation, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, nothing
Pigment, corrigent etc.；Preservative, solubilizer, stabilizer of injectable formulation etc.；Matrix, diluent, the profit of topical formulations
Lubrication prescription, preservative etc..
In some embodiments, polyinosinic acid-polycytidylicacid active material can account for the 0.001- of product total weight
99.9wt%；For example, being the 1-95wt%, 5-90wt%, 10-80wt% of product total weight.Surplus can be carrier and other
The substances such as additive.
In another preferred embodiment of the invention, product is unit dosage form or multi-form.As used herein, term
" unit dosage forms " refer to take or easy to use, and product is prepared into single administration or uses required dosage form, including but
It is not limited to various solid formulations (such as tablet), liquid agent, capsule, sustained release agent.Pharmaceutical preparation can by oral administration or parenteral
(such as in intravenous, subcutaneous, peritonaeum or part) administration, if some drugs be under the conditions of stomach it is unstable, can be by it
It is configured to enteric coated tablets.
It should be understood that the effective dose of active material used can be (such as right with the individual instances for the object that need to prevent or treat
As weight, age, physical condition, the required effect reached) it determines, this range that may determine that in skilled practitioners or nutritionist
It is interior.
The product of this paper can be solid-state (such as granule, tablet, freeze-dried powder, suppository, capsule, sublingual lozenge) or liquid
(such as oral solution, injection, solution or syrup) or other suitable forms.For example, in some embodiments, this paper's
The palatable formulation of product (such as tablet, capsule, solution or suspension)；Injectable formulation (solution or suspension of such as injectable,
Either thousand dry powder of injectable, water for injection is added before the injection to be used immediately)；Topical formulations (such as ointment or molten
Liquid) etc..
Method of application
The product of the application can be applied by conventional route, including (but being not limited to): take orally, injection, spray,
The approach such as in nasal cavity or transdermal.The form of product should match with method of application.
In some embodiments, the product of this paper can be used directly, can also with it is other active compound combined or combine and apply
With.Other described active materials can be selected from: prevention is alleviated, the object of adjuvant treatment and/or treatment pancreatitis or its associated disease
Matter；Reduce serum pancreatic lipase, reduce pancreatic tissue in myeloperoxidase enzyme level, reduce pancreatic tissue in proinflammatory factor (such as
IL-1 β and/or CXCL1 and/or CXCL2) transcriptional expression is horizontal and/or prevents or mitigates the substance of pancreatic cell damage.It is described
Other substances include but is not limited to: growth hormone release inhibiting hormone, Gabexate, antacids, anticholinergic agents, antibiotic, pancreatin inhibitor.
The product of this paper can also be usually used in prevention, alleviation, adjuvant treatment and/or treatment pancreatitis or its related diseases with other
Disease, reduce serum pancreatic lipase, reduce pancreatic tissue in myeloperoxidase enzyme level, reduce pancreatic tissue in proinflammatory factor (such as
IL-1 β and/or CXCL1 and/or CXCL2) transcriptional expression is horizontal and/or prevents or mitigates the method or means of pancreatic cell damage
It combines.These methods or means include but is not limited to: operative treatment, acupuncture, rational diet etc..
Beneficial effect
The beneficial effect of this technology includes but is not limited to:
(a) have found polyinosinic acid-polycytidylicacid active material in prevention and treatment pancreatitis (especially acute pancreatitis) for the first time
In effect, and demonstrate it in serum pancreatic lipase, serum amylase, the inflammatory cell release level of enzyme MPO, tissue
Pro-inflammatory cytokine (such as IL-1 β and/or CXCL1 and/or CXCL2) all has significant reducing effect, and can reduce pancreas
The damage of cell, for clinically or it is daily in or veterinary science in effectively prevent pancreatitis and its associated disease provides new production
Product, thinking and means；
(b) polyinosinic acid-polycytidylicacid active material is large-scale production and is clinically used (such as exempting from
Epidemic disease regulator) a kind of matured product, existing certain understanding such as this field prepares it, saves, safety, dosage form, metabolism.
As a result, new application disclosed herein faster can more easily be able to apply and promote.
Embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.Those skilled in the art can make modification appropriate, variation to the present invention, these modifications
It is within the scope of the present invention with variation.
In the following examples, the experimental methods for specific conditions are not specified, the conventional method in this field can be used, such as join
Examine " Molecular Cloning:A Laboratory guide " (third edition, New York, CSH Press, New York:Cold Spring
Harbor Laboratory Press, 1989) or according to condition proposed by supplier.The sequencing approach of DNA is that this field is normal
The method of rule can also provide test by commercial company.
Unless otherwise stated, otherwise percentage and number are calculated by weight.Unless otherwise defined, as used herein all
Professional and scientific terms have the same meanings as commonly understood by one of ordinary skill in the art.In addition, any similar or equal to described content
Deng method and material can be applied to the method for the present invention.Preferred implement methods and materials described in the text only present a demonstration it
With.
The foundation of 1. acute pancreatitic model of embodiment
8 week old female C57B/L6 mouse are randomly divided into control group (physiological saline, saline), acute pancreatitis group
(CER-AP, tree toad element-acute pancreatitic model group) and poly I:C processing group (poly I:C+CER-AP), every group each 3,
It raises in SPF environment.
Give control group mice and disease group mouse (including acute pancreatitis group and poly respectively by the way of intraperitoneal injection
I:C processing group) injecting normal saline (0.90%) and tree toad element (CER, be purchased from MCE company, catalog number (Cat.No.): HY-A0190 is dissolved in life
Manage salt water, 200 micrograms/kg body weight)；Injection is primary per hour, and co-injection 12 times.Processing group is 8 before injecting the modeling of tree toad element
Hour, intraperitoneal injection poly I:C it is primary (Invivogene company, CAS number:31852-29-6, is dissolved in physiological saline,
10 micrograms/kg body weight).
After experiment (after starting modeling 12 hours), blood is taken to collect separation serum by eyeball；At cervical dislocation
After dead mouse, abdominal cavity splits removing and obtains pancreas internal organs.
Embodiment 2.polyI:C alleviates chmice acute pancreatitis pancreatic tissue oedema and inflammatory infiltration degree
Using hematoxylin-eosin (HE) decoration method, 1 control group of embodiment (physiological saline), inflammatory model will be taken respectively from
Group (CER-AP), poly I:C processing group (poly I:C+CER-AP) pancreas through fixation, dehydration, dyeing, dewaxing, it is transparent and
The dyeing of the standardization programs such as mounting, observes the tissue integrity, pancreas oedema degree and inflammatory cell infiltration degree of pancreatic tissue.
As a result as shown in Figure 1.As the result is shown: the pancreatic tissue structure of control group is closely knit, without obvious crackle；CER-AP group is small
The pancreatic tissue short texture of mouse has obvious oedema and inflammatory infiltration phenomenon；And tissue morphology, the water of polyI:C+CER-AP group
Swollen and inflammatory infiltration degree improves significantly compared with CER-AP group.
The above result shows that: after poly I:C processing, the degree that mouse suffers from acute pancreatitis is significantly improved, and is mentioned
Show that poly I:C can be used for the prevention and treatment of acute pancreatitis.
The expression of pancreatic tissue myeloperoxidase when embodiment 3.Poly I:C resists acute pancreatitis occurrence and development
The activation of leucocyte (especially neutrophil leucocyte) is as the important ring in pathogenesis of acute pancreatitis, at it
Extremely important effect is played in pathologic process.Myeloperoxidase (Myeloperoxidase, MPO) is neutrophil leucocyte
Function mark and activation marker, horizontal and activity change represent ploymorphonuclear neutrophilic leukocyte function and active shape
State.There are MPO in neutrophil leucocyte, and the amount of MPO enzyme contained by each cell be it is certain, account for about the 5% of dry cell weight.It should
Enzyme has the ability for making hydrogen-peroxide reduction, can analyze the vigor of enzyme using this feature, and measure the number of neutrocyte
Mesh.MPO activation degree is higher, shows that neutrophil leucocyte quantity is more in sample, to reflect that the inflammation of pancreatitis is more serious.
The principle combined using antigen-antibody is combined by MPO antibody (#ab9535, Abcam company, the San Francisco USA)
Pancreatic tissue is sliced the MPO albumen in (pancreatic tissue obtained from embodiment 1), then anti-through two anti-binding of horseradish peroxidase
After MPO antibody, comparative analysis of making film after being developed the color with DAB.The positive sample of colour developing is in brown color, and wherein MPO vigor is higher, color
Deeper, positive range is bigger.
As the result is shown (reference can be made to Fig. 2): the pancreatic tissue of acute pancreatitis group is positive, and brown color dyeing is obvious and dyes
Range shows its MPO vigor and more normally organizes obvious rising substantially throughout whole visual field；And it is only small in polyI:C processing group
Portion of tissue has shallower brown color positive staining, and tone is indicated above its more acute pancreas of MPO vigor substantially close to control group
Adenositis group is decreased obviously.
The above result shows that: the pancreas MPO vigor of modeling mouse is significantly lowered after poly I:C processing, acute pancreatitis
Occurrence and development be improved.
Embodiment 4.poly I:C reduces the level of serum amylase (amylase) when acute pancreatitis occurs
Data with existing shows that the amylase content in 90% or more patients with acute pancreatitis serum can all increase.Therefore, I
The Function detection amylase content that starch generates glucose, maltose and dextrin can be hydrolyzed based on amylase.It is dense in substrate
Known to degree and in excessive situation, iodine solution is added and unhydrolysed starch generates blue complex, it can according to the depth of blue
The amount of starch of hydrolysis is extrapolated, to calculate the vigor of amylase.
Blood standing is collected after 30 minutes, passes through 5000rpm and is centrifuged 5 minutes acquisition sample serum.Life is built up using Nanjing
The starch enzyme reagent kit of object company detects amylase activity (cat:C016-1).
As the result is shown (reference can be made to Fig. 3 A): the serum amyloid enzyme activity of acute pancreatitis group is 4803.57 ± 235.12un/
ML, the vigor (2015.36 ± 312.32un/ML) compared with control group obviously rise (p < 0.05 *)；And the shallow lake of poly I:C processing group
Powder enzyme activity (2245.77 ± 122.52un/ML) is decreased obviously (p < 0.05 *) compared with acute pancreatitis group, with control group vigor without
Notable difference.
The above result shows that: the serum amyloid enzyme activity of acute pancreatitis mice is significantly lowered after poly I:C processing,
To prompt the occurrence and development of acute pancreatitis to be improved.
Embodiment 5.poly I:C reduces the level of serum pancreatic lipase when acute pancreatitis occurs
Serum lipase (lipase) activity after pathogenesis of acute pancreatitis increases, and can be used for the measurement of acute pancreatitis.
And the specificity of the enzyme is higher, the duration is longer.Therefore, being determined to serum lipase vigor further to verify
The accuracy of experiment conclusion.
Blood standing is collected after 30 minutes, passes through 5000rpm and is centrifuged 5 minutes acquisition sample serum.Life is built up using Nanjing
The fatty enzyme reagent kit of object company detects amylase activity (cat:A054-2).
As the result is shown (reference can be made to Fig. 3 B): the serum pancreatic lipase activity (451 ± 30.23u/L) of CER-AP mouse is more right
(p < 0.05 *) is significantly improved according to a group mouse (67.53 ± 5.3u/L)；And the serum pancreas fat of poly I:C+CER-AP group mouse
Enzymatic activity (133.32 ± 4.5u/L) obviously lowers (p < 0.05 *) compared with acute pancreatitis group mouse.
The above result shows that: after poly I:C processing, table of the acute pancreatitis mice serum pancreatic lipase in serum
It is significantly reduced up to level, so that the occurrence and development of acute pancreatitis be prompted to be improved.
Embodiment 6.poly I:C reduces the release of inflammatory factor in acute pancreatitis mice pancreatic tissue
In acute pancreatitis, IL-1 β, CXCL1, CXCL2 are proinflammatory factors, IL-1 β after acute pancreatitis occurs,
CXCL1, CXCL2 high expression.The raising of these proinflammatory factors is blocked to can reduce inflammatory conditions.IL-I β is in acute pancreatitis early stage
It increases, can not only stimulate the release of itself, the release of CXCL1, CXCL2 can also be promoted.It is detected by RT-PCR method
IL-1 β, CXCL1, CXCL2 in embodiment 1 in gained pancreatic tissue.
Reverse transcription the primer difference is as follows, and wherein L32 primer is for the ribosomal protein L 32 as internal reference:
Reverse Transcriptase kit used is purchased from Takara Shuzo company (catalog number (Cat.No.) RR036Q, Tokyo).With following group
Part prepares RT reaction solution on ice.Reaction system: 5 × PrimeScript RT Master Mix (Perfect Real Time)
2μl；1 μ g of total serum IgE；DdH without RNase2O 10μl。
Reaction condition is as follows: it is soft mix after carry out reverse transcription reaction, 37 DEG C 15 minutes (reverse transcription reaction), 85 DEG C 5 seconds
(inactivation reaction of reverse transcriptase).
QPCR kit used is purchased from Takara Shuzo company (catalog number (Cat.No.) RR420Q, Tokyo).With following component
PCR reaction solution is prepared on ice.Reaction system: TB Green Premix Ex Taq (Tli RNaseH Plus) (2 ×) 5 μ l；
PCR Forward Primer(1μM)1μl；PCR Reverse Primer (1 μM): 1 μ l；DNA profiling: 3 μ l.
Reaction condition is as follows: 1. initial denaturations: 1,95 DEG C of recurring number 30 seconds；2.PCR reaction: 40,95 DEG C of recurring number 3 seconds, 60
DEG C 30 seconds.
As the result is shown (reference can be made to Fig. 4): IL-1 β, CXCL1, CXCL2 expression are lower in control group pancreatic tissue；
IL-1 β, the equal highest of CXCL1, CXCL2 expression in CER-AP group mice pancreatic tissue, and be significantly higher than control group (* p <
0.05)；And IL-1 β, CXCL1, CXCL2 expression be then compared with CER-AP group in poly I:C+CER-AP group mice pancreatic tissue
Be significantly improved (p < 0.05 *).
The above result shows that: after poly I:C processing, the occurrence and development of chmice acute pancreatitis are significantly improved.
Embodiment 7:polyI:C reduces the mice pancreatic acinar cell damage of Bile Salts induction
In acute pancreatitis, often along with the enrichment of reactive oxygen species (ROS), the ROS of middle and high concentration passes through cellular damage
Cellular oxidation stress reaction, which induces cell apoptosis, even results in its necrosis.The negative-feedback factor that HO-1 albumen is reacted frequently as ROS
Cellular Oxidation stress damage is adjusted, its expression represents injury severity score to a certain extent.
In the test of the present embodiment, by 266-6 cell, (immortalized mouse pancreatic acinar cell is purchased from ATCC, 10% tire
+ 1640 culture medium of cow's serum, 5%CO2Under the conditions of cultivate) be laid in 6 orifice plates (50,000/hole), control group is respectively set
(DMSO), modeling group (Bile Salts 0.5M is purchased from Beijing Suo Laibao Science and Technology Ltd, article No. T8510), administration group are (same
When be added 100 mcg/ml of poly I:C+Bile Salts 0.5M).
Cell is collected after 24 hours, DCFH-DA probe is carried out on flow cytometer, and (the green skies biotechnology in Shanghai is limited
Company, article No. S0033) label detection (Fig. 5 A), and carry out Western blot detection (Fig. 5 B).In Western blot experiment
The RIPA being related to is purchased from the green skies Biotechnology Co., Ltd in Shanghai, and article No. P0013B detects the antibody: (U.S. α-tubulin
CST company, article No. 3873), HO-1 (CST company of the U.S., article No. 70081), equal 1:1000 configuration.
As the result is shown (reference can be made to Fig. 5 A and Fig. 5 B):
1. as shown in Figure 5A, DCFH-DA fluorescence probe intensity is lower in control group；DCFH-DA fluorescence probe is strong in TAU group
Highest is spent, and is significantly higher than control group (p < 0.05 *)；And polyI:C+TAU group DCFH-DA fluorescence probe intensity is then compared with TAU group
It is decreased significantly (p < 0.05 *)；
2. as shown in Figure 5 B, cell HO-1 protein expression is minimum in control group；Cell HO-1 protein expression is most in TAU group
Height, and it is significantly higher than control group (p < 0.05 *)；And under polyI:C+TAU group cell HO-1 protein expression then has significantly compared with TAU group
It drops (p < 0.05 *).
The above result shows that the cellular damage of acute pancreatitis cell model is significantly changed after poly I:C processing
It is kind.Result prompt poly I:C can protect pancreatic cell from cellular damage caused by acute pancreatitis or significantly reduce the damage
Hurt degree, so as to the prevention and treatment for pancreatitis.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Bibliography:
[1]Mole D J,Webster S P,Uings I,Zheng X,Binnie M,Wilson K,Hutchinson
J P,Mirguet O,Walker A,Beaufils B,Ancellin N,Trottet L,Beneton V,Mowat C G,
Wilkinson M,Rowland P,Haslam C,Mcbride A,Homer N Z,Baily J E,Sharp M G,Garden
O J,Hughes J,Howie S E,Holmes D S,Liddle J,Iredale J P.Kynurenine-3-
monooxygenase inhibition prevents multiple organ failure in rodent models of
acute pancreatitis[J].Nat Med,2016,22(2):202-209.
[2]Fortier M E,Kent S,Ashdown H,Poole S,Boksa P,Luheshi G N.The viral
mimic,polyinosinic:polycytidylic acid,induces fever in rats via an
interleukin-1-dependent mechanism[J].Am J Physiol Regul Integr Comp Physiol,
2004,287(4):R759-766.
[3]Wang Y Z,Li J L,Wang X,Zhang T,Ho W Z.(-)-Epigallocatechin-3-
gallate enhances poly I:C-induced interferon-lambda1 production and inhibits
hepatitis C virus replication in hepatocytes[J].World J Gastroenterol,2017,23
(32):5895-5903.
[4] Zhao Keting, Long Xiaoru, Li Wei, Xie Jun, Ren Luo, Deng Yu, Xie Xiaohong, Zang Na, Wang Lijia, Liu's grace plum respiratory tract
Syncytial virus infection later period Poly (I:C) induces airway of mice inflammation and its Mechanism Study [J] Chinese Journal of Contemporary Pediatrics,
2016,18(05):455-459.
[5] Chen Yao, Li Yunzhu, Yu Shanchang, Shao Jie .Poly (I:C) simulate application of the RNA virus in airway inflammation research
[J] clinical pediatric magazine, 2009,27 (08): 768-771.
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Claims (10)
1. polyinosinic acid-polycytidylicacid active material is in preparation prevention, alleviation, adjuvant treatment and/or treatment pancreatitis and its phase
Close the application in the product of illness and/or symptom.
2. application as described in claim 1, wherein the polyinosinic acid-polycytidylicacid active material has selected from the group below
One or more features:
The polyinosinic acid-polycytidylicacid active material is selected from: polyinosinic acid-polycytidylicacid, polyinosinic acid-polycytidylicacid card that
(such as polyinosinic acid-polycytidylicacid is pharmaceutically or physiologically acceptable salt for mycin, polyinosinic acid-polycytidylicacid derivative
And/or ester), polyinosinic acid-polycytidylicacid dry powder, polyinosinic acid-polycytidylicacid injection and known in the art other are poly-
Inosinicacid-poly derivative or product；And/or
The weight average molecular weight of the polyinosinic acid-polycytidylicacid active material are as follows: 1.5~8kb；And/or
The polyinosinic acid-polycytidylicacid active material accounts for the 0.001-99.9wt% of the product total weight, such as 0.1-
99wt%, 1-95wt%, 5-90wt%, 10-80wt%.
3. application as described in claim 1, wherein the pancreatitis or its associated disease and/or symptom are in being selected from the group
It is one or more:
Acute pancreatitis (including mild acute pancreatitis, Severe Acute Pancreatitis SAP, Operation treatment), chronic pancreatitis, urgency
The ictal pancreatitis of property, chronic paroxysmal pancreatitis；
One or more illnesss relevant to pancreatitis and/or symptom selected from the group below: the relevant proinflammatory inflammation factor (example of pancreatitis
Such as IL-1 β, CXCL1 and/or CXCL2) level improves, the relevant myeloperoxidase enzyme level of pancreatitis improves, pancreatitis is related
Serum or amylase in urine level improves, the relevant serum pancreatic lipase level of pancreatitis improves, the relevant whole body of pancreatitis is scorching
The relevant Multiple Organ Dysfunction Syndrome of disease response syndrome, pancreatitis, pancreatic cell (such as pancreatic acinar cell) damage.
4. application as described in claim 1, wherein the prevention, alleviation, adjuvant treatment and/or treatment include being selected from the group
It is one or more:
The level of the relevant proinflammatory inflammation factor (such as IL-1 β, CXCL1 and/or CXCL2) of pancreatitis is reduced, or prevents its raising；
The relevant myeloperoxidase enzyme level of pancreatitis is reduced, or prevents its raising；Reduce the relevant serum of pancreatitis or amylase in urine
Level, or prevent its raising；It is horizontal to reduce the relevant serum pancreatic lipase of pancreatitis, or prevents its raising；Alleviate pancreatitis phase
The systemic inflammatory response syndrome of pass, or prevent it from occurring and/or developing；It is comprehensive to alleviate the relevant multiple organs dysfunction of pancreatitis
Simulator sickness, or prevent it from occurring and/or developing；Protection pancreatic cell (such as pancreatic acinar cell) is injury-free or reduces its damage
Wound.
5. application as described in claim 1, wherein the product is selected from the group: drug, health care product, food, drink, enteral
Nutritional preparation, dietary supplements, veterinary drug, feed or feed addictive.
6. application as described in claim 1, wherein the product, which also has, one of to be selected from the group or various features:
The product also includes one or more substances selected from the group below: pharmacy, physiology, health care conduct and learning, bromatology, veterinary science
Upper acceptable carrier, excipient, auxiliary material；Pancreatitis or its phase are alleviated, assist in the treatment of and/or are treated in one or more preventions
Close other substances of illness, such as growth hormone release inhibiting hormone, Gabexate, antacids, anticholinergic agents, antibiotic, pancreatin inhibitor；
And/or
The form of the product gives mode suitable for one or more in the following group: giving through stomach and intestine；It is non-to be given through stomach and intestine, such as through
Vein, mucous membrane, nasal cavity, intraperitoneal, encephalic, in tumor, sublingual, cheek, transdermal (such as electro-ionic osmosis), liposome method；And/or
The product are as follows: tablet, powder agent, injection, granule, syrup, capsule, solution, suppository or ointment.
7. the marrow peroxidating in preparation reduction serum pancreatic lipase, reduction pancreatic tissue of polyinosinic acid-polycytidylicacid active material
Object enzyme level reduces proinflammatory factor transcriptional expression level in pancreatic tissue and/or prevents or mitigates the product that pancreatic cell damages
In application.
8. application as claimed in claim 8, wherein product has one or more features selected from the group below:
(a) the polyinosinic acid-polycytidylicacid active material is selected from: polyinosinic acid-polycytidylicacid, polyinosinic acid-polycytidylicacid
Kanamycins, polyinosinic acid-polycytidylicacid derivative, polyinosinic acid-polycytidylicacid dry powder, polyinosinic acid-polycytidylicacid injection
Agent and other polyinosinic acid-polycytidylicacid derivatives known in the art or product；
(b) the serum pancreatic lipase to be reduced, myeloperoxidase enzyme level in pancreatic tissue, proinflammatory factor in pancreatic tissue
Transcriptional expression level is improved because of pancreatitis；
(c) proinflammatory factor is one of to be selected from the group or a variety of: IL-1 β, CXCL1 and CXCL2；
(d) product is selected from the group: drug, health care product, food, drink, enteral nutrition preparation, dietary supplements, veterinary drug, feeding
Material or feed addictive；
(e) product also includes one of to be selected from the group or a variety of: pharmacy, bromatology, can veterinarily connect health care conduct and learning
Carrier, excipient, the auxiliary material received；Pancreatitis or its associated disease are alleviated, assist in the treatment of and/or are treated in one or more preventions
Other substances, such as growth hormone release inhibiting hormone, Gabexate, antacids, anticholinergic agents, antibiotic, pancreatin inhibitor；
(f) form of the product gives mode suitable for one or more in the following group: giving through stomach and intestine；It is non-to be given through stomach and intestine, example
Such as through in vein, mucous membrane, nasal cavity, intraperitoneal, encephalic, tumor, sublingual, cheek, transdermal (such as electro-ionic osmosis), liposome method.
9. a kind of product comprising polyinosinic acid-polycytidylicacid active material, is used for: prevention, alleviate, adjuvant treatment and/or
Treat pancreatitis or its associated disease；Serum pancreatic lipase is reduced, myeloperoxidase enzyme level in pancreatic tissue is reduced, reduces pancreas
Proinflammatory factor transcriptional expression is horizontal in glandular tissue and/or prevents or mitigates pancreatic cell damage.
In one embodiment, the product also include pharmaceutically, health care conduct and learning, bromatology, veterinarily acceptable load
Body, excipient, auxiliary material；Other of one or more preventions, alleviation, adjuvant treatment and/or treatment pancreatitis or its associated disease
Substance, such as growth hormone release inhibiting hormone, Gabexate, antacids, anticholinergic agents, antibiotic, pancreatin inhibitor.
10. pancreatitis or its associated disease are alleviated, assist in the treatment of and/or are treated in a kind of prevention；Reduce serum pancreatic lipase, drop
Myeloperoxidase enzyme level in low pancreatic tissue reduces that proinflammatory factor transcriptional expression is horizontal in pancreatic tissue and/or prevents or subtracts
The method of light pancreatic cell damage, which comprises it is living to give a effective amount of polyinosinic acid-polycytidylicacid of object in need
Property substance and/or product as claimed in claim 9.
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Cited By (1)
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| CN117771361A (en) * | 2024-02-27 | 2024-03-29 | 天津中逸安健生物科技有限公司 | Lipid nanoadjuvant of polyinosinic acid-polycytidylic acid compound, and preparation method and application thereof |
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