CN106983753A - White adipose tissue brown sample becomes stimulant and prepares the application for resisting antiobesity agents - Google Patents
White adipose tissue brown sample becomes stimulant and prepares the application for resisting antiobesity agents Download PDFInfo
- Publication number
- CN106983753A CN106983753A CN201710189076.7A CN201710189076A CN106983753A CN 106983753 A CN106983753 A CN 106983753A CN 201710189076 A CN201710189076 A CN 201710189076A CN 106983753 A CN106983753 A CN 106983753A
- Authority
- CN
- China
- Prior art keywords
- medicine
- celastrol
- adipose tissue
- white adipose
- fat
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
Abstract
Become the application that antiobesity agents are resisted in stimulant preparation, and a kind of medicine for being used to stimulate white adipose tissue brown sample to become the invention discloses a kind of white adipose tissue brown sample.Heretofore described medicine is present in the form of each μ g/kg dosage ranges of Celastrol 0.1 10 are given.The C57BL/6 mouse that the present invention uses 60% High-fat diet is research objects, and the medicinal usage fat with treatment can significantly be resisted by making public for the first time low dosage Celastrol.Experimental result is shown：0.1 10 μ g/kg Celastrols can significantly stimulate white adipose tissue brown stain, promote lipolysis, suppress Fatty synthesis, can significantly prophylactic treatment it is fat, and toxicity is low and without metabolic inhibition, and new direction is provided for fat prevention and treatment.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to low dosage Celastrol prepares prevention and treatment antiobesity agents
Purposes.
Background technology
With the continuous improvement of people's living standards, it is fat turned into 21 century seriously threaten public health it is important because
Element.Obesity can cause a variety of metabolic diseases, such as dyslipidemia, type ii diabetes (T2DM) and cardiovascular and cerebrovascular disease, even
The incidence of disease of some cancers can be increased.2014, the whole world was overweight more than the adult of 1/3rd (39%), was grown up 500000000 more
People is listed in obesity.Such high incidence of disease and a variety of serious complication so that obesity turns into contemporary society and is badly in need of solving
The problem of, but at present it is not yet found that effect prevention and the fat medicine for the treatment of.
Celastrol (Celastrol) is the natural triterpene compound extracted from Celastraceae plant tripterygium wilfordii root,
Organic solvent is soluble in, water is insoluble in.Clinically it is mainly used in treating the disease such as rheumatic arthritis and rheumatoid arthritis,
In addition also have been reported that and show, Celastrol has significant inhibitory action to Partial tumors cell.2015 one be published in
《Cell》Article show that there is high concentration Celastrol significant losing weight to act on, high fat diet induction it is fat small
Mouse is after Celastrol is given, and fat mass significantly reduces 41.5%, and Celastrol mainly by reducing food ration, is alleviated interior
Matter net and stress increase the fat effect of the mechanisms plays such as hypothalamic leptin sensitiveness treatment.The same year is published in《Cell
Metabolism》An article propose that the fat effect of trypterygine extract for treating mainly passes through HSF1-PGC-1 alpha signals again
Path mediation is realized.
Although Celastrol in terms of obesity is treated with huge potentiality, because it has certain toxicity and exempts from
Epidemic disease inhibitory action, and it is insoluble in the characteristic of water so that Celastrol still suffers from certain obstacle as drug therapy obesity.
Therefore, low toxicity, no immunosuppressive action are found, but still is current urgency with the Celastrol dosage range that body weight reduction is acted on
The problem of need to solving.
The content of the invention
In order to overcome the existing defect of Celastrol, an object of the present invention is the thunder for providing appropriate concentration range
Celastrol is preparing the application in stimulating white adipose tissue brown sample change medicine.White adipose tissue brown sample becomes,
Be found within 2010, refer to white adipose tissue under some factors, be changed into it is light brown, and thereby consumption more multi-energy, its
Effect is fat-reducing, optimizes insulin sensitivity, improves glycolipid metabolism etc..
An object of the present invention is realized by following proposal：
White adipose tissue brown sample becomes application of the stimulant in medicine is prepared, and the white adipose tissue brown sample becomes
Stimulant is Celastrol.
Preferably, the medicine is the medicine fat for treating or preventing human or animal.
Preferably, the medicine is present in the form of each Celastrol 0.1-10 μ g/kg dosage ranges are given.
Preferably, the medicine is present in the form of each μ g/kg dosage of Celastrol 0.1 is given.
Preferably, the medicine is present in the form of each μ g/kg dosage of Celastrol 1.0 is given.
Preferably, the medicine is present in the form of each μ g/kg dosage of Celastrol 10 is given.
Preferably, the form given of the medicine is Intraperitoneal medication.
Preferably, the form given of the medicine is intravenously administrable or oral administration.
Preferably, the medicine is present in the form of being administered once a day.
The second object of the present invention is that the medicine that the stimulation white adipose tissue brown sample becomes is the medicine for fat-reducing
Thing.
The present invention is achieved by the following technical solutions：
A kind of medicine for being used to stimulate white adipose tissue brown sample to become, including Celastrol, and can pharmaceutically connect
Carrier, excipient or the complementary composition received.
Preferably, the form of the medicine be selected from tablet, pulvis, granule, capsule, oral liquid, sustained release agent, parenteral solution,
One kind in transfusion, injection sterile powder.
Experiment mice is divided into 0.1 μ g/kg, 1.0 μ g/kg, 10 μ g/kg Celastrol injection groups and compareed molten by the present invention
Agent (DMSO) injection group, measures body weight and food ration daily.After Celastrol is injected 7 days, by Western blot technologies,
Q-PCR technologies and immunofluorescence technique detection adipose tissue toffee sample become marker molecule (Uncoupling pro-tein-2,
Uncoupling Protein 1, UCP-1；PR domains include protein 16, PR Domain-containing 16, Prdm16；Cell
Death induction DFFA sample effect protein A, Cell Death-inducing Dff45 like Effector Protein A,
Cidea；A member of the TNF receptor family 9, Tumor Necrosis Factor Receptor Superfamily
Member 9, CD137；Transmembrane protein 26, Transmembrane Protein 26, Tmem26；T-box transcription regulatory factors 1,
T-box Transcription Factor 1, Tbx1) albumen and mRNA level in-site change.
The Celastrol of low dosage can significantly reduce body weight in the present invention, and food ration and metabolism are made without suppression
With.The invention provides a kind of low toxicity, no immunosuppressive action, and the effective dose of the Celastrol with fat-reducing effect,
And the stimulant that white adipose tissue brown sample becomes.
Brief description of the drawings
Fig. 1 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 100 for giving 60% High-fat diet respectively
Agent (DMSO) changes of weight situation afterwards.
Fig. 2 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 100 for giving 60% High-fat diet respectively
Agent (DMSO) food ration situation of change afterwards.
Fig. 3 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 1.0 for giving 60% High-fat diet respectively
Agent (DMSO) changes of weight situation afterwards.
Fig. 4 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 1.0 for giving 60% High-fat diet respectively
The situation of change of agent (DMSO) food ration afterwards.
Fig. 5 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 1.0 for giving 60% High-fat diet respectively
After agent (DMSO) 7 days in each position adipose tissue of mouse Ucp-1 mRNA level in-site change.
Fig. 6 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 1.0 for giving 60% High-fat diet respectively
Ucp-1, Prdm16, Cidea, CD137, Tmem26, Tbx1 mRNA water in groin white adipose tissue after agent (DMSO) 7 days
Flat change.
Fig. 7 is to giving the μ g/kg of C57 BL/6 mouse 1.0 of 60% High-fat diet using Western Blot technologies
Celastrol and Ucp-1 protein expression situations in control solvent (DMSO) afterwards mouse groin white adipose tissue (iWAT)
Testing result.
Fig. 8 is to giving the μ g/kg Thunder Gods of C57 BL/6 mouse 1.0 of 60% High-fat diet using immunofluorescence technique
The detection knot of rattan red pigment and Ucp-1 expressions in control solvent (DMSO) afterwards mouse groin white adipose tissue (iWAT)
Really.
Fig. 9 is the μ g/kg trypterygines of C57 BL/6 mouse 1.0 that 60% High-fat diet is given using metabolic cage measurement
Element and the testing result of control solvent (DMSO) respiratory quotient afterwards.
Figure 10 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 10 for giving 60% High-fat diet respectively
Agent (DMSO) changes of weight situation afterwards.
Figure 11 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 10 for giving 60% High-fat diet respectively
The situation of change of agent (DMSO) food ration afterwards.
Figure 12 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 10 for giving 60% High-fat diet respectively
After agent (DMSO) 7 days, Ucp-1 mRNA level in-site change in each position adipose tissue of mouse.
Figure 13 is molten with compareing for the μ g/kg Celastrols of C57 BL/6 mouse 10 for giving 60% High-fat diet respectively
After agent (DMSO) 7 days, Ucp-1 in groin white adipose tissue, Prdm16, Cidea, CD137, Tmem26, Tbx1 mRNA
Level changes.
Figure 14 is molten with compareing for the μ g/kg Celastrols of C57BL/6 mouse 0.1 for giving 60% High-fat diet respectively
The situation of change of body weight in agent (DMSO) 7 days.
Figure 15 is molten with compareing for the μ g/kg Celastrols of C57BL/6 mouse 0.1 for giving 60% High-fat diet respectively
The situation of change of food ration in agent (DMSO) 7 days.
Embodiment
Make further details of introduction to the present invention with reference to embodiment and accompanying drawing, but embodiments of the present invention are not limited
In this.
Used mouse is：SPF grades of C57 BL/6 mouse of 7-8 week old male, buy in Department Of Medicine, Peking University's experiment
Animal science portion.C57 BL/6 Mouse feeder conditions：22 ± 0.5 DEG C of environment temperature, 12 hours/12 hours light and shade alternatings.It is all
Experimental data represents with mean ± standard error, * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001, n=10.
Embodiment 1：Detect C57 BL/6 mouse weight of the 1.0 μ g/kg Celastrols to High-fat diet, food ration
And fatty brown stain marker molecule Ucp-1, Prdm16, Cidea, CD137, Tmem26, Tbx1 influence.
The high fat diet of C57 BL/6 mouse 60% is given, 1.0 μ g/kg Celastrols of injection 7 days, daily measurement each group is small
Mouse body weight and food ration.Under the concentration, body weight is significantly reduced after Celastrol is injected 7 days, and the concentration and 100 μ g/kg thunders
Celastrol is compared, and is not ingested and metabolic inhibition.Confirm that 1.0 μ g/kg Celastrols can significantly reduce body weight,
And without metabolic inhibition.As a result Fig. 1-4 is seen.
1.0 μ g/kg Celastrols are injected 7 days, take each position adipose tissue of whole body, are extracted tissue RNA, are utilized Q-PCR
Technology for detection groin white adipose tissue (iWAT), epididymal adipose tissues (eWAT), retroperitoneal fat (pWAT), perirenal fat
(rWAT) brown stain key point molecule in, mesenteric fat (mWAT), subcutaneous fat (sWAT) and brown adipose tissue (BAT)
Ucp-1 mRNA level in-site change.As a result show, 1.0 μ g/kg Celastrols can make Ucp-1 in iWAT, eWAT, rWAT, BAT
MRNA level in-site significantly raise.As a result Fig. 5 is seen.In addition, using Q-PCR technology for detection Celastrol to groin white adipose
The influence of fatty brown stain marker molecule mRNA level in-site in tissue.As a result find, 1.0 μ g/kg Celastrols are remarkably improved white
Ucp-1 in color adipose tissue, Prdm16, Cidea, CD137, Tmem26, Tbx1 mRNA level in-site.1.0 μ g/ in the prompting present invention
Kg Celastrol can significantly stimulate white adipose tissue brown stain, increase human body energy consumption, reduction fat storage.As a result
See Fig. 6.
1.0 μ g/kg Celastrols are injected 7 days, take iWAT, are extracted after histone by Western Blot experiment skills
Ucp-1 protein expression levels in art detection iWAT.It was found that 1.0 μ g/kg Celastrols can remarkably promote Ucp-1 tables in iWAT
Reach.As a result Fig. 7 is seen.Equally, take tissue to be fixed with 4% paraformaldehyde solution, cut into slices, 1.0 μ g/ are confirmed using immunofluorescence technique
Kg Celastrols are remarkably improved Ucp-1 expression quantity in iWAT, consistent with Western blot testing results.As a result Fig. 8 is seen.
Illustrate that the effect that the Celastrol of 1.0 μ g/kg in the present invention loses weight is that promoted white adipose tissue brown stain is realized.
After C57BL/6 mouse are placed in metabolic cage into habituation 1 day, 1.0 μ g/kg Celastrols and control are injected respectively
Solvent.It was observed that Celastrol group RER values are substantially less than control solvent group.As a result Fig. 9 is seen.Wherein RER represents respiratory quotient, refers to
Organism is within the same time, and the ratio between the volume of release carbon dioxide with absorbing oxygen or the ratio between molal quantity refer to respiration
The CO2 and the O2 absorbed molecular proportion discharged.RER values are lower, and the body consumption lipid level that represents is higher, and RER values are higher, generation
Table body consumption carbohydrate level is higher.In the prompting present invention, 1.0 μ g/kg Celastrol can significantly reduce the RER of mouse
Value, improves the consumption and utilization of body inner lipid.
Embodiment 2：Detect C57 BL/6 mouse weight of the 10 μ g/kg Celastrols to High-fat diet, food ration
And fatty brown stain marker molecule Ucp-1, Prdm16, Cidea, CD137, Tmem26, Tbx1 influence.
The high fat diet of C57 BL/6 mouse 60% is given, 10 μ g/kg Celastrols of injection 7 days, daily measurement each group is small
Mouse body weight and food ration.Under the concentration, body weight has a slight change after Celastrol is injected 7 days, and with 100 μ g/kg tripterygium wilfordiis
Red pigment compares no food rcstriction and metabolic inhibition.As a result Fig. 2, Figure 10-11 are seen.
After 10 μ g/kg Celastrols are injected 7 days, each position adipose tissue of whole body is taken, tissue RNA is extracted, utilizes Q-PCR
Technology for detection groin white adipose tissue (iWAT), epididymal adipose tissues (eWAT), retroperitoneal fat (pWAT), perirenal fat
(rWAT) brown stain marker molecule Ucp-1 in, mesenteric fat (mWAT), subcutaneous fat (sWAT) and brown adipose tissue (BAT)
MRNA level in-site change.As a result, it was confirmed that 10 μ g/kg Celastrols to the mRNA level in-site of Ucp-1 in white adipose tissue without aobvious
Write influence.As a result Figure 12 is seen.
After 10 μ g/kg Celastrols are injected 7 days, iWAT is taken, extracts and Q-PCR technology for detection white is utilized after tissue RNA
The mRNA level in-site of fatty brown stain marker molecule.As a result find, 10 μ g/kg Celastrols to Ucp-1, Prdm16, Cidea,
CD137, Tmem26, Tbx1 mRNA level in-site do not make significant difference.As a result Figure 13 is seen.
Embodiment 3：Detect C57BL/6 mouse weight of the 0.1 μ g/kg Celastrols to High-fat diet, food ration
Influence.
Give the high fat diet of C57 BL/6 mouse 60%, inject 0.1 μ g/kg Celastrol and control solvent 7 days, often
Day measures each group mouse weight and food ration.Under the concentration, body weight has a slight change after Celastrol is injected 7 days, and with 100
μ g/kg Celastrols are acted on and metabolic inhibition compared to no food rcstriction.As a result Fig. 2, Figure 14-15 are seen.
In summary, test result indicates that, 0.1-10 μ g/kg scopes Celastrols can stimulate white adipose tissue brown
Tinctorial pattern becomes, increase lipid consumption, and reduction fat storage loses weight, realizes the fat purpose of prevention and treatment, and with toxicity
It is low, without metabolic inhibition the characteristics of.
Above is the description to the specific embodiment of the invention, but embodiments of the present invention are not limited to above-described embodiment
Particular implementation, it without departing from essence of the invention and change, modification, simplification for being made under principle etc. is equivalent put that other are any
Mode is changed, is included within protection scope of the present invention.
Claims (10)
1. white adipose tissue brown sample becomes application of the stimulant in medicine is prepared, the white adipose tissue brown sample becomes thorn
Sharp agent is Celastrol.
2. application according to claim 1, it is characterised in that the medicine is to be used to treat or prevent human or animal's obesity
Medicine.
3. application according to claim 1, it is characterised in that the medicine is with each Celastrol 0.1-10 μ g/
The form that kg dosage ranges are given is present.
4. application according to claim 3, it is characterised in that the medicine is with each μ g/kg agent of Celastrol 0.1
The form given is measured to exist.
5. application according to claim 3, it is characterised in that the medicine is with each μ g/kg dosage of Celastrol 1
The form given is present.
6. application according to claim 3, it is characterised in that the medicine is with each μ g/kg agent of Celastrol 10
The form given is measured to exist.
7. the application according to one of claim 1~6, it is characterised in that the form given of the medicine is intraperitoneal
Administration.
8. the application according to one of claim 1~6, it is characterised in that the form given of the medicine for vein to
Medicine or oral administration.
9. a kind of medicine for being used to stimulate white adipose tissue brown sample to become, including Celastrol, and it is pharmaceutically acceptable
Carrier, excipient or complementary composition.
10. medicine according to claim 9, it is characterised in that the form of the medicine be selected from tablet, pulvis, granule,
One kind in capsule, oral liquid, sustained release agent, parenteral solution, transfusion, injection sterile powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710189076.7A CN106983753A (en) | 2017-03-27 | 2017-03-27 | White adipose tissue brown sample becomes stimulant and prepares the application for resisting antiobesity agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710189076.7A CN106983753A (en) | 2017-03-27 | 2017-03-27 | White adipose tissue brown sample becomes stimulant and prepares the application for resisting antiobesity agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106983753A true CN106983753A (en) | 2017-07-28 |
Family
ID=59412959
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710189076.7A Pending CN106983753A (en) | 2017-03-27 | 2017-03-27 | White adipose tissue brown sample becomes stimulant and prepares the application for resisting antiobesity agents |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106983753A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113181200A (en) * | 2021-04-26 | 2021-07-30 | 北京大学 | Application of panax japonicus saponin IV in preparation of medicine for preventing and/or treating obesity |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105920018A (en) * | 2016-06-15 | 2016-09-07 | 上海市内分泌代谢病研究所 | Application of tripterine and berberine to joint preparation of medicines for treating metabolic syndrome |
-
2017
- 2017-03-27 CN CN201710189076.7A patent/CN106983753A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105920018A (en) * | 2016-06-15 | 2016-09-07 | 上海市内分泌代谢病研究所 | Application of tripterine and berberine to joint preparation of medicines for treating metabolic syndrome |
Non-Patent Citations (3)
| Title |
|---|
| JUNLI LIU等: "Treatment of Obesity with Celastrol", 《CELL》 * |
| XINRAN MA等: "Celastrol Protects against Obesity and Metabolic Dysfunction through Activation of a HSF1-PGC1a Transcriptional Axis", 《CELL METABOLISM》 * |
| 杨晓宁: "HSF1-PGC1α 介导雷公藤红素代谢调节作用", 《生理科学进展》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113181200A (en) * | 2021-04-26 | 2021-07-30 | 北京大学 | Application of panax japonicus saponin IV in preparation of medicine for preventing and/or treating obesity |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9439874B2 (en) | Food composition for nourishing, maintaining and cultivating a variety of stem cells and a method for manufacturing the same | |
| CN110090221A (en) | A kind of Radix Pulsatillae extract treats the purposes in viral and/or bacteriosis drug in preparation | |
| CN111568945A (en) | Compound cyclocarya paliurus preparation | |
| WO2016043517A1 (en) | Pharmaceutical composition for treating and preventing degenerative neurological disorders, containing, as active ingredient, mixture extract of moutan root bark, angelica dahurica root and bupleurum root or fraction thereof | |
| US10736929B2 (en) | Method for preparing herbal composition having increased fat-solublepolyphenol content, herbal composition prepared thereby and use thereof | |
| CN106983753A (en) | White adipose tissue brown sample becomes stimulant and prepares the application for resisting antiobesity agents | |
| CN115400216A (en) | Pharmaceutical composition for thyroid undifferentiated carcinoma and application | |
| EP3616705A2 (en) | Composition for improving prevention and treatment of fatty liver containingamomum vilosum | |
| KR20200091925A (en) | Composition comprising a horse chestnut extract | |
| US9943560B2 (en) | Medical compositions containing liquorice extracts with synergistic effect | |
| CN114948937A (en) | Application of schisandrin in preparation of medicine for treating hepatotoxicity of regorafenib | |
| WO2017121333A1 (en) | Use of cistanche tubulosa extract and isoacteoside in protection of muscles | |
| Chan et al. | Capsaicin: Current understanding in therapeutic effects, drug interaction, and bioavailability | |
| CN110693873B (en) | Preparation and application of rabdosia rubescens active ingredient composition | |
| Yu et al. | Antibacterial, antidiarrheal, anti-inflammatory and analgesic activities of compound Shikuqin powder. | |
| US20210113643A1 (en) | A composition for preventing or treating obesity comprising natural mixture extracts | |
| CN102008534B (en) | Antitubercular pharmaceutical composition containing balloonflower root extract | |
| CN108066334B (en) | Mechanism of lycium ruthenicum red pigment for resisting alcoholic liver injury and application of liver protection product of lycium ruthenicum red pigment | |
| CN111700900A (en) | Natural immune activator, TIL cell promoter and application thereof | |
| CN110522784A (en) | A kind of drug and preparation method thereof can be used for intestines problem | |
| CN104825499A (en) | Application of grifron maitake extraction in preparation of anti-depression drug | |
| KR101588229B1 (en) | A pharmaceutical composition comprising extract of portulaca oleracea for preventing, improving or treating acute pancreatitis | |
| CN107648482A (en) | A kind of Chinese medicine composition for being used to treat nerve degenerative diseases | |
| CN110123871B (en) | Traditional Chinese medicine composition preparation for improving leucocyte and expelling toxin and preparation method thereof | |
| CN103191268B (en) | Traditional Chinese medicinal composition for treating lung cancer |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170728 |