CN107088190A - Application of the fumarate in treatment liver disease drug is prepared - Google Patents
Application of the fumarate in treatment liver disease drug is prepared Download PDFInfo
- Publication number
- CN107088190A CN107088190A CN201611046597.9A CN201611046597A CN107088190A CN 107088190 A CN107088190 A CN 107088190A CN 201611046597 A CN201611046597 A CN 201611046597A CN 107088190 A CN107088190 A CN 107088190A
- Authority
- CN
- China
- Prior art keywords
- liver
- fumarate
- dmf
- mmf
- application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
Abstract
The invention discloses application of the fumarate in treatment liver disease drug is prepared, including dimethyl fumarate (dimethyl fumarate,) and application of the monomethyl fumarate (monomethyl fumarate, MMF) in a variety of liver diseases are treated DMF.In the present invention, using nuclear factor E2-related factor 2 (nuclear factor E2 related factor 2 in a variety of human hepatocarcinoma cells of DMF, MMF activation, mouse liver cell,) and the expression of antioxidant genes downstream Nrf2, most important Keap1 Nrf2 ARE paths in active cell Antioxidation Mechanism, moreover, damage of the oxidative stress to liver in mouse hepatopathy model can be also prevented and treated, there is good liver protection effect.With the potential developed into for the related hepatosis treating medicine of oxidativestress damage, there is important development prospect in the treatment of a variety of liver diseases such as fatty liver disease, DILD, cholestatic liver disease, virus hepatitis, hepatic sclerosis, liver cancer.
Description
Technical field
The present invention relates to chemical medicine.Specifically related to fumarate is in a variety of liver diseases medicines for the treatment of are prepared
Using.
Background technology
Oxidative stress refers to body when by various destructive stimuluses, internal high activity molecule such as active oxygen radical
(ROS) produced excessively with active nitrogen free radical (RNS), degree of oxidation exceeds the removing of oxide, and causes tissue damage.Liver
As important metabolic organ, often in the allogene and other chemical substances of higher concentration.Although liver possesses one
Row resist the mechanism of harmful chemical and its metabolite, but still are vulnerable to oxidative damage caused by intermediate active material.Oxygen
Change stress be the common pathogenesis of many liver diseases, and oxidative damage and most hepatopathys are closely related, including：Fatty liver
Disease, DILD, cholestatic hepatic injury, virus hepatitis, even hepatic sclerosis, liver cancer, so Antioxidation Treatment pair
Preventing and treating liver diseases play the role of important.
Nrf2 is a kind of nuclear factor mediated by oxidative stress newfound in recent years, is believed with Keap1-Nrf2-ARE
The transcription of number path mediation II phases detoxication enzyme and antioxidant genes, it is considered to be most important path in cellular anti-oxidant mechanism.
Nrf2 and a variety of protective genes downstream activation are expressed, and can induce a series of detoxication enzymes, metabolizing enzymes, allogenic material row
The expression of outer transporter, increases the oxidation resistance of body.Research shows that Nrf2 activation is in confrontation liver oxidativestress damage
In play an important roll.The research such as Robert H. finds that DMF and MMF can be increased by the Nrf2 signal pathways in active cell
The protective effect to cell, makes it preferably be resistant to oxidative stress by force.
DMF, is a kind of NF-Kappa B activation inhibitor, can play immunological regulation and neuroprotection, clinically
It is mainly used in treatment multiple sclerosis (multiple sclerosis, MS).Clinical research shows that DMF can be by activating Nrf2
Path plays the effect for mitigating cellular inflammation and response to oxidative stress ability.DMF by oral administration after, can be rapidly by internal esterase hydrolyzed
It is safely absorbed for the metabolin of most bioactivity --- MMF, subsequent MMF in small intestine.It is oral 5-6 hours in DMF, MMF blood
Starch concentration peaking；DMF half-life period is 12 minutes, and MMF half-life period is 36 hours, and MMF biological effects are sustainable longer
Time.
Although DMF, MMF have activation Nrf2, path plays the effect for mitigating cellular inflammation and response to oxidative stress ability,
And Nrf2 is significant in confrontation liver oxidative stress, but DMF and MMF is in the treatment liver related to oxidativestress damage
Not yet reported with the presence or absence of effect in dirty disease, and at present in the world there is not yet someone is furtherd investigate.
The content of the invention
The present invention is to dimethyl fumarate (dimethyl fumarate, DMF) and monomethyl fumarate (monomethyl
Fumarate, MMF) influence in liver cell to Nrf2 signal pathways, and its pair liver disease related to oxidativestress damage
The treatment of disease is furtherd investigate.Research shows：Fumarate including DMF, MMF, which can be used for preparing, treats a variety of
The medicine of hepatopathy (including fatty liver disease, DILD, cholestatic liver disease, virus hepatitis, hepatic sclerosis, liver cancer etc.)
Thing.Researcher confirms that two kinds of medicines can activate a variety of human liver cancer cells and Mouse Liver by substantial amounts of scientific research
Intracellular Nrf2 signal pathways, moreover, can also prevent and treat damage of the oxidative stress to liver in mouse hepatopathy model, there is good
Good liver protection effect.Wherein, above-mentioned human liver cancer cell is HepG2 cells, Huh7 cells, and mouse liver cell is that AML-12 is thin
Born of the same parents.
Preferably, the formulation of the medicine is pulvis.The method of administration of the medicine includes local topical, vein and abdominal cavity
Injection etc..
In a word, the present invention is by substantial amounts of experimental studies have found that DMF and MMF can activate a variety of human liver cancer cells and mouse
Nrf2 signal pathways in liver cell, can also prevent and treat damage of the oxidative stress to liver in mouse hepatopathy model, there is good shield
Liver acts on, and illustrates that DMF and MMF can be used for the medicine for preparing treatment hepatopathy.Therefore, the present invention is for a variety of liver diseases (bag
Include fatty liver disease, DILD, cholestatic liver disease, virus hepatitis, hepatic sclerosis, liver cancer etc.) treatment in terms of have
There is important development prospect.
Brief description of the drawings
Fig. 1：Influence (10uM DMF processing of the DMF to Nrf2 in human hepatoma HepG2 cell and its anti-oxidant expression of target gene
HepG2 cell WB/PCR)；
Fig. 2：(DMF processing Huh7 is thin for the influence of DMF Nrf2 intracellular to human liver cancer Huh7 and its anti-oxidant expression of target gene
Born of the same parents WB/PCR)；
Fig. 3：DMF Nrf2s intracellular to mouse liver cell AML-12 and its anti-oxidant expression of target gene influence (10uM
DMF processing AML-12 cell WB/PCR)；
Fig. 4：Influence (10uM MMF processing of the MMF to Nrf2 in human hepatoma HepG2 cell and its anti-oxidant expression of target gene
HepG2 cell WB/PCR)；
Fig. 5：MMF Nrf2s intracellular to human liver cancer Huh7 and its anti-oxidant expression of target gene influence (10uM MMF processing
Huh7 cell WB/PCR)；
Fig. 6：MMF Nrf2s intracellular to mouse liver cell AML-12 and its anti-oxidant expression of target gene influence (10uM
MMF processing AML-12 cell WB/PCR)；
Fig. 7：(left figure amplifies 100 times, right figure amplification 200 for performance of the normal liver tissue of blank control group under light microscopic
Times)；
Fig. 8：Performance of the murine liver tissue for the Alcoholic Liver Disease Model control group that DMF is treated under light microscopic is not given (left
100 times of figure amplification, right figure amplifies 200 times)；
Fig. 9：Giving performance of the model mice hepatic tissue of low dose of DMF oral administration gavages administration under light microscopic, (left figure is put
Big 100 times, right figure amplifies 200 times)；
Figure 10：Giving performance of the model mice hepatic tissue of heavy dose of DMF oral administration gavages administration under light microscopic, (left figure is put
Big 100 times, right figure amplifies 200 times).
Embodiment
Embodiment 1
The path experiment of DMF Activation In Vitro cell Nrf2 signals
Selected cell line includes human hepatoma HepG2 cell, human liver cancer Huh7 cells, mouse liver cell AML-12.Take pair
Number growth period cell is inoculated in 6 orifice plates, and cell is separately added into DMF cultures 0, after 2,4,6,12,24 hours, takes out culture plate,
Total protein of cell and cell total rna are extracted, using Western blot, QPCR technologies, intracellular Nrf2 is detected and its anti-oxidant
The expression of target gene (GCLC, HO1).
As a result as Figure 1-3, DMF can strengthen the table of Nrf2 and its anti-oxidant target gene (GCLC, HO1) in liver cell
Reach.
Embodiment 2
The path experiment of MMF Activation In Vitro cell Nrf2 signals
Selected cell line includes human hepatoma HepG2 cell, human liver cancer Huh7 cells, mouse liver cell AML-12.Take pair
Number growth period cell is inoculated in 6 orifice plates, and cell distinguishes dosing (MMF) culture 0, after 2,4,6,12,24 hours, takes out culture
Plate, extracts total protein of cell and cell total rna, using Western blot, QPCR technologies, detects intracellular Nrf2 and its antioxygen
Change the expression of target gene (GCLC, HO1).
As a result as Figure 4-Figure 6, MMF can strengthen the table of Nrf2 and its anti-oxidant target gene (GCLC, HO1) in liver cell
Reach.
Embodiment 3
Effect studies of the DMF in preventing and treating AML mouse liver oxidativestress damage
Testing the C57BL/6 mouse that selected mouse provides for this Leco Corp. of Shanghai, (male, 8 week old, body weight are
18-21g).4 groups are randomly divided into, raises in common barrier environment, mouse Alcoholic Liver Disease Model is built using NIAAA methods.Mould
Type randomly selects the DMF oral administration gavages administration that two groups of mouse give various dose respectively after successfully constructing, one time a day, altogether administration
10 days.4 groups of mouse are euthanized after 10 days, take hepatic tissue to be soaked in formalin, each group hepatic tissue is contaminated using HE
Color, and observed under 100 times and 200 light microscopics.
As a result as is seen in figs 7-10, DMF can prevent and treat damage of the oxidative stress to liver in mouse hepatopathy model, there is good
Liver protection effect.
Claims (5)
1. application of the fumarate in treatment liver disease drug is prepared.
2. application as claimed in claim 1, it is characterised in that the fumarate includes DMF and MMF.
3. application as claimed in claim 1, it is characterised in that the hepatopathy includes fatty liver disease, DILD, bile
Cholestatic hepatic injury, virus hepatitis, hepatic sclerosis and liver cancer.
4. application as claimed in claim 1, it is characterised in that the formulation of the medicine is pulvis.
5. application as claimed in claim 1, it is characterised in that the method for administration of the medicine includes local topical, vein and
Intraperitoneal injection.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611046597.9A CN107088190A (en) | 2016-11-23 | 2016-11-23 | Application of the fumarate in treatment liver disease drug is prepared |
| PCT/CN2017/093253 WO2018095056A1 (en) | 2016-11-23 | 2017-07-18 | Applications of fumarates in preparing medicament for treating liver diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611046597.9A CN107088190A (en) | 2016-11-23 | 2016-11-23 | Application of the fumarate in treatment liver disease drug is prepared |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107088190A true CN107088190A (en) | 2017-08-25 |
Family
ID=59649155
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611046597.9A Pending CN107088190A (en) | 2016-11-23 | 2016-11-23 | Application of the fumarate in treatment liver disease drug is prepared |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN107088190A (en) |
| WO (1) | WO2018095056A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109364058A (en) * | 2018-12-05 | 2019-02-22 | 中南大学湘雅医院 | The application of fumarate and its officinal salt in the drug of preparation treatment iron death related disease |
| CN111373032A (en) * | 2017-11-24 | 2020-07-03 | 渥太华医院研究所 | Compositions and methods for enhancing the production, growth, spread, or oncolytic and immunotherapeutic efficacy of interferon-sensitive viruses |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220073985A (en) * | 2020-11-27 | 2022-06-03 | 주식회사 큐라클 | Pharmaceutical composition for preventing or treating organ fibrosis comprising monomethyl fumarate as an active ingredient |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040054001A1 (en) * | 2001-01-12 | 2004-03-18 | Joshi Rajendra Kumar | Fumaric acid derivatives as nf-kappab inhibitors |
| KR20080094466A (en) * | 2007-04-20 | 2008-10-23 | 주식회사 머젠스 | Pharmaceutical composition for treatment of metabolic syndrome |
| WO2015128492A1 (en) * | 2014-02-28 | 2015-09-03 | Maghazachi Azzam A | Monomethyl- and dimethylfumarate for nk cell activation |
-
2016
- 2016-11-23 CN CN201611046597.9A patent/CN107088190A/en active Pending
-
2017
- 2017-07-18 WO PCT/CN2017/093253 patent/WO2018095056A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040054001A1 (en) * | 2001-01-12 | 2004-03-18 | Joshi Rajendra Kumar | Fumaric acid derivatives as nf-kappab inhibitors |
| KR20080094466A (en) * | 2007-04-20 | 2008-10-23 | 주식회사 머젠스 | Pharmaceutical composition for treatment of metabolic syndrome |
| WO2015128492A1 (en) * | 2014-02-28 | 2015-09-03 | Maghazachi Azzam A | Monomethyl- and dimethylfumarate for nk cell activation |
Non-Patent Citations (1)
| Title |
|---|
| K.S. RAO 等.: "Antihepatotoxic activity of monomethyl fumarate isolated from Fumaria indica.", 《JOURNAL OF ETHNOPHARMACOLOGY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111373032A (en) * | 2017-11-24 | 2020-07-03 | 渥太华医院研究所 | Compositions and methods for enhancing the production, growth, spread, or oncolytic and immunotherapeutic efficacy of interferon-sensitive viruses |
| CN109364058A (en) * | 2018-12-05 | 2019-02-22 | 中南大学湘雅医院 | The application of fumarate and its officinal salt in the drug of preparation treatment iron death related disease |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018095056A1 (en) | 2018-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Shi et al. | Baicalein and baicalin alleviate acetaminophen-induced liver injury by activating Nrf2 antioxidative pathway: The involvement of ERK1/2 and PKC | |
| Li et al. | An essential role of Nrf2 in American ginseng-mediated anti-oxidative actions in cardiomyocytes | |
| Wang et al. | Activation of PPARγ is required for hydroxysafflor yellow A of Carthamus tinctorius to attenuate hepatic fibrosis induced by oxidative stress | |
| Gu et al. | Cardioprotective effects of genistin in rat myocardial ischemia-reperfusion injury studies by regulation of P2X7/NF-κB pathway | |
| Han et al. | Si Miao Formula attenuates non-alcoholic fatty liver disease by modulating hepatic lipid metabolism and gut microbiota | |
| CN107088190A (en) | Application of the fumarate in treatment liver disease drug is prepared | |
| Mohamed et al. | Cucurbitacin E glucoside alleviates concanavalin A-induced hepatitis through enhancing SIRT1/Nrf2/HO-1 and inhibiting NF-ĸB/NLRP3 signaling pathways | |
| Thakur et al. | 1-Deoxynojirimycin, its potential for management of non-communicable metabolic diseases | |
| Wei et al. | Effect of alcohol extract of Acanthus ilicifolius L. on anti-duck hepatitis B virus and protection of liver | |
| CN113318002A (en) | Anti-inflammation acne-removing composition and cosmetic | |
| Holanda et al. | Polysaccaride-rich extract of Caesalpina ferrea stem barks attenuates mice acute inflammation induced by zymosan: Oxidative stress modulation | |
| Su et al. | Suppression effect of plant-derived berberine on cyprinid herpesvirus 2 proliferation and its pharmacokinetics in Crucian carp (Carassius auratus gibelio) | |
| CN110072517A (en) | The method for treating the viral hepatitis type b that how there is drug resistance to liver | |
| Calis et al. | Naringenin prevents inflammation, apoptosis, and DNA damage in potassium oxonate-induced hyperuricemia in rat liver tissue: roles of Cytochrome C, NF-κB, Caspase-3, and 8-hydroxydeoxyguanosine | |
| Zhou et al. | Magnesium isoglycyrrhizinate ameliorates lipopolysaccharide-induced liver injury by upregulating autophagy and inhibiting inflammation via IL-22 expression | |
| He et al. | Suppression of endoplasmic reticulum stress-associated pathways and hepatocyte apoptosis participates in the attenuation of betulinic acid on alcohol-provoked liver injury in mice | |
| Chen et al. | Essential oil from Artemisia argyi alleviated liver disease in zebrafish (Danio rerio) via the gut-liver axis | |
| Devi et al. | Evaluation of hepatoprotective activity of Lilium candidum L. in experimental animal models | |
| Zhu et al. | Evaluation of the anti-inflammatory material basis of Lagotis brachystachya in HepG2 and THP-1ácells | |
| Lee et al. | The wound healing effect of Hydnocarpi Semen extract on ulcer in diabetic mice | |
| JP2005500995A (en) | Use of Filanthus components for the treatment or prevention of infections caused by hepatitis B virus | |
| Du et al. | Evaluation of the therapeutic effect of a flavonoid prescription against rabbit hemorrhagic disease in vivo | |
| Balakrishnan et al. | Corosolic acid suppresses the expression of inflammatory marker genes in CCL4-induced-hepatotoxic rats. | |
| Kim | The Effects of Anti-Inflammatory and Liver Function using Heat-Treated Cabbage | |
| Pei et al. | Progress in research and application of silymarin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170825 |
|
| WD01 | Invention patent application deemed withdrawn after publication |