CN107468699A - Medicine and application of 2 deoxyglucoses as treatment psoriasis - Google Patents
Medicine and application of 2 deoxyglucoses as treatment psoriasis Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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Abstract
Application of 2 deoxyglucoses as treatment mammal psoriasis, the medicine for being used to treat psoriasis containing 2 deoxyglucoses, the medicine for being used to treat the mankind or mouse psoriasis containing 2 deoxyglucoses, the formulation for being used for the medicine for treating psoriasis is injection or oral agents.
Description
Technical field
The invention belongs to field of medicaments, and in particular to medicine and application of the 1,5-anhydroglucitol as treatment psoriasis.
Background technology
Psoriasis (psoriasis) is a kind of chronic inflammatory skin, it is characterized in that hyperproliferative epidermal, angling are not
Entirely, blood vessel outgrowth expansion and inflammatory cell infiltration [J.E.Greb, A. M.Goldminz, J.T.Elder,
M.G.Lebwohl,D.D.Gladman,J.J.Wu,N.N. Mehta,A.Y.Finlay,andA.B.Gottlieb,
“Psoriasis,”Nat.Rev.Dis.Prim., vol.2,p.16082,Nov.2016.].Psoriasis is specifically fallen ill machine at present
Make it is indefinite, environmental factor (such as infection, wound and pressure) and inherent cause etc. determine private medical service [L.C. Tsoi,
P.E.Stuart,C.Tian,J.E.Gudjonsson,S.Das,M.Zawistowski,E. Ellinghaus,
J.N.Barker,V.Chandran,N.Dand,K.C.Duffin,C. T.Esko,A.Franke,
D.D.Gladman,P.Hoffmann,K.Kingo,S. G.G.Krueger,H.W.Lim,A.Metspalu,
U.Mrowietz,S.Mucha,P. Rahman,A.Reis,T.Tejasvi,R.Trembath,J.J.Voorhees,
S.Weidinger,M. Weichenthal,X.Wen,N.Eriksson,H.M.Kang,D.A.Hinds,R.P.Nair,
G.R.Abecasis,andJ.T.Elder,“Largescalemeta-analysischaracterizes
geneticarchitectureforcommonpsoriasisassociatedvariants.,”Nat. Commun.,vol.8,
p.15382,May2017.].Just because of this, psoriasis there is no radical cure medicine, state of an illness Chang Fanfu, have a strong impact on minimal invasive treatment's matter
Amount.
Early treatment uses the inanimate immunodepressant such as steroids, methotrexate (MTX) more, but such non-specific immune
Inhibitor be respectively provided with considerable degree of side effect [M.A.Lowes, A.M. Bowcock, andJ.G.Krueger,
“Pathogenesisandtherapyofpsoriasis.,” Nature,vol.445,no.7130,pp.866–73,
Feb.2007.].Recent study finds numerous inflammatory factors, and such as TNF-α and IL-17 play an important role in psoriasis, its
For obstruct the monoclonal antibody Etanercept acted between inflammatory factor and acceptor (Etanercept, TNF-α monoclonal antibody) and
Secukinumab (Su Jin monoclonal antibodies, IL-17 monoclonal antibodies) etc. be also used for middle severe curing psoriasis [S.T.Hwang,
T.Nijsten,andJ.T.Elder,“RecentHighlightsin PsoriasisResearch.,”
J.Invest.Dermatol.,vol.137,no.3,pp.550–556, Mar.2017.].Because the inflammatory factor of appropriateness is people
Indispensable in body normal body immune response, long-term extra-inhibitory inflammatory factor can also cause the side effects such as infection, tuberculosis,
The state of an illness is easy repeatedly after drug withdrawal.Cri dernier cri disease learns investigation and shows current China psoriatic 6,500,000, and independent research China has
The curing psoriasis medicine of intellectual property is imperative.
The content of the invention
The present invention is big in order to solve above-mentioned existing treatment psoriasis side effect, and the state of an illness is not easily repeatedly after drug withdrawal
It is sufficient, and it is an object of the present invention to provide a kind of 1,5-anhydroglucitol as treatment psoriasis medicine and application.
The invention provides a kind of application of 1,5-anhydroglucitol as treatment mammal psoriasis.
The invention provides a kind of application of 1,5-anhydroglucitol as treatment mammal psoriasis, can also have
There is such feature, it is characterised in that：Wherein, the mammal is mouse or the mankind.
The invention provides a kind of medicine for being used to treat psoriasis containing 1,5-anhydroglucitol.
The invention provides a kind of medicine for being used to treat psoriasis containing 1,5-anhydroglucitol, can also have so
Feature, it is characterised in that：Wherein, the formulation for being used for the medicine for treating psoriasis is injection or oral agents.
The invention provides a kind of medicine for being used to treat the mankind or mouse psoriasis containing 1,5-anhydroglucitol.
Wherein, the formulation for being used to treat the medicine of people's parapsoriasis is injection or oral agents.
It is used for the medicine for treating the mankind or mouse psoriasis the invention provides a kind of 1,5-anhydroglucitol, can also has
Such feature, it is characterised in that：Wherein, the formulation for being used to treat the medicine of mouse psoriasis is injection or oral agents.
It is used for the medicine for treating the mankind or mouse psoriasis the invention provides a kind of 1,5-anhydroglucitol, can also has
Such feature, it is characterised in that：Wherein, the administration frequency for being used to treat mouse psoriasis is more than or equal to daily one
It is secondary, it is administered within more days, administration daily dose is 1g/kg.
The effect of invention and effect
Psoriasis illing skin keratinocyte growth microenvironment is very similar with tumour, all with hyper-proliferative, divides
The features such as change is not complete, and metabolism enlivens.Cellular energy is mainly derived from glucose metabolism.Glucose can by oxidative phosphorylation and
Two kinds of approach of glycolysis provide energy.Unlike normal cell mainly by oxidative phosphorylation approach generate ATP, tumour cell is about
50% ATP from glycolytic pathway (Warburg effects) [M.G.VanderHeidenandR.J. DeBerardinis,
“UnderstandingtheIntersectionsbetweenMetabolismand CancerBiology.,”Cell,
vol.168,no.4,pp.657–669,Feb.2017.].Glycolytic pathway is directly reduced after glucose is converted into pyruvic acid
ATP is produced for lactic acid, in-between product provides material base for cell propagation.
According to application of the 1,5-anhydroglucitol provided by the present invention as treatment psoriasis, because 2- deoxy-glucoses
(also referred to as 2-DG, 1,5-anhydroglucitol and 2-DG；On synthetic method, Japanese patent application publication No. is referred to
54-041384) be hydrogen substituted hydroxy on No. 2 position carbon atoms of glucose compound, can competitive binding hexokinase, with reference to
Product can not be further converted to fructose-1, 6-diphosphate by glucose-6-phosphate isomerase and make it that glycolysis terminates, and causes cell to increase
Grow termination.And oxidative phosphorylation is cell main energy sources in normal cell, therefore 1,5-anhydroglucitol will not to normal cell
Generation has a strong impact on.
Therefore there is good therapeutic effect using 1,5-anhydroglucitol as treatment psoriasis, and due to 2- deoxidations
The cure mechanism of glucose understands that will not normal affecting cells will not also be suppressed with inflammatory factor for it therefore and traditional treatment medicine
Thing is compared to that will not bring serious side effect, and the state of an illness is not easy repeatedly after drug withdrawal.
Brief description of the drawings
Fig. 1 is control group and the contrast photo of model group in parapsoriasis mouse model；
Fig. 2 is control group and the pathology H＆E of model group section (i.e. hematoxylin eosin stainings in parapsoriasis mouse model
Section) photo；
Fig. 3 is the imiquimod induction period skin thickness change curve of model group in parapsoriasis mouse model；
Fig. 4 uses miaow while being mouse 1,5-anhydroglucitol intraperitoneal injection treatment and control PBS (phosphate buffer)
The not special induction gross examination of skeletal muscle photo of quinoline；
H＆E is induced to cut using imiquimod while Fig. 5 is mouse 1,5-anhydroglucitol intraperitoneal injection treatment and control PBS
Piece photo；
Fig. 6 uses imiquimod induced skin while being mouse 1,5-anhydroglucitol intraperitoneal injection treatment and control PBS
Thickness profiles figure；And
Fig. 7 is the Hacat cell growth curve figures of 1,5-anhydroglucitol before and after the processing.
Embodiment
In order that the technical means, the inventive features, the objects and the advantages of the present invention are easy to understand, it is real below
Apply example combination accompanying drawing to 1,5-anhydroglucitol provided by the invention as treatment psoriasis medicine and application operation principle with
And beneficial effect is specifically addressed.
Embodiment 1
Treatment of the 2- deoxy-glucoses sugar to mouse psoriasis.
Step 1, the foundation and identification of mouse parapsoriasis model.
Back shaving is carried out after mouse isoflurane anesthesia, shaving area is 2cm*3cm, then will be corresponding with Veet depilatory creams
Region hair removing is clean, forms preserved skin area.Using external used medicine imiquimod (Aldara, 3MHealthCareLimited)
Preserved skin area is applied to, dosage is 62.5mg/, the vaseline such as preserved skin area smearing of control group, continuous coating 5 days.
The mouse that imiquimod processing is not used is control group, and the mouse handled using imiquimod is model group.
The skin thickness of two groups of mouse smear zones of vernier caliper measurement is used daily.
Anesthetized mice after the completion of modeling, take pictures at the skin lesion to two groups of mouse, subtract and take skin at skin lesion, using 4%
Paraformaldehyde is fixed, and makes H＆E pathological sections.Identified from substantially phenotype and Pathological levels.
Fig. 1 is control group and the contrast photo of model group in parapsoriasis mouse model.
Fig. 2 is control group and the pathology H＆E of model group section photos in parapsoriasis mouse model.
Fig. 3 is the imiquimod induction period skin thickness change curve of model group in parapsoriasis mouse model.
As shown in figure 1, compared with control group, the mouse skin visible red color spot after imiquimod is smeared 5 days in model group
Block, and with a large amount of sheet scales of skin that peel offs, there is similar Pigs with Psoriasis.
As shown in H＆E coloration result in Fig. 2, after imiquimod is smeared 5 days, mouse skin epidermis in control group compared with
It is thin, and the parakeratosis of skin of mouse is obvious in model group, epidermis stratum spinosum epidermidis is thickened, and the skin lesion of similar psoriasiform is formed.
As shown in figure 3, mouse skin thickness in 5 days in control group is without significant change, model group after imiquimod is smeared
In mouse skin thickness with smear number of days increase and gradually increase.
Therefore the psoriasis model prepared using imiquimod is as small muroid psoriasis model in the present embodiment.
Step 2, mouse parapsoriasis is treated using 2- deoxy-glucoses sugar.
18 female 6-8 week old BALB/c mouses (the western pul in Shanghai-Bi Kai experimental animals Co., Ltd) are taken, are divided into 3 groups
Blank control group, model group and model+1,5-anhydroglucitol group after being treated with 1,5-anhydroglucitol to model group, every group
6.Back shaving will be carried out after 18 mouse anesthesias, shaving area is 2cm*3cm, then with Veet depilatory creams by respective regions hair
Hair removes clean.
Occurred using the method Topical Imiquimod inducing mouse parapsoriasis of step 1, establish mouse parapsoriasis mould
Type.The mouse peritoneal multiple injection to model+1,5-anhydroglucitol group contains the solution of 0.2ml2- deoxy-glucoses sugar, day simultaneously
Dosage is 1g/kg, then carries out PBS injections to naive mice and model group mouse with same metering and frequency.
Anesthetized mice after 5 days, taken pictures respectively at the skin lesion to three groups of mouse, subtract and take skin at skin lesion, more than 4%
Polyformaldehyde is fixed, and makes H＆E pathological sections.From substantially phenotype and Pathological levels are carried out.
While Fig. 4 is mouse 1,5-anhydroglucitol intraperitoneal injection treatment and control PBS using imiquimod induction substantially
Observe photo.
H＆E is induced to cut using imiquimod while Fig. 5 is mouse 1,5-anhydroglucitol intraperitoneal injection treatment and control PBS
Piece photo.
Fig. 6 uses imiquimod induced skin while being mouse 1,5-anhydroglucitol intraperitoneal injection treatment and control PBS
Thickness profiles figure.
Such as Fig. 4-shown, compared with the mouse skin of model group, the model+2- deoxidations Portugal after 1,5-anhydroglucitol is treated
The skin lesion symptom of the mouse of grape sugar group substantially mitigates, and skin is more smooth, and the scales of skin that peel off is less, and erythema shoals.
As shown in figure 5, compared with the mouse skin of model group, the model+2- deoxidations Portugal after 1,5-anhydroglucitol is treated
The mouse skin layer of grape sugar group is more smooth, and parakeratotic cell significantly reduces, and skin layer thickness is significantly lower than model group.
As shown in fig. 6, find that the epidermis of model group mouse is obvious by the epidermis vertical thickness for measuring three groups of mouse
Thicken, the epidermis of model+1,5-anhydroglucitol group mouse thickens relatively low, and the difference compared with model group is statistically significant
(P<0.01)。
It can be found by the observation to substantially phenotype and Pathological levels, the small muroid silver bits of model+1,5-anhydroglucitol group
Sick incidence has notable mitigation compared with model group mouse, therefore it is obvious to may determine that 1,5-anhydroglucitol has to mouse psoriasis
Curative effect.
Embodiment 2
The above embodiments 1 to intravital mouse inject 1,5-anhydroglucitol before and after psoriasis the effect of carried out experiment opinion
Card, tests influence of the 1,5-anhydroglucitol to cell using the isolated cells of human body further below.
Psoriasis is characterized in hyperproliferative epidermal, parakeratosis, blood vessel outgrowth expansion and inflammatory cell leaching
Profit.Hacat cell behaviours normal skin immortalizes the cell that cutin is formed, with the normal Keratinocyte differentiation characteristic phase of people
Seemingly, it is mainly used to replace the research normal keratinocyte of people, available for detecting various medicines, compound, chemical factors etc. pair
The influence of the normal keratinocyte of people.
2- deoxy-glucoses sugar influences to test on Hacat cell growths.
Hacat cells are digested with 0.25% pancreatin first, trained respectively with control medium and dosing after centrifugation
Support base (1,5-anhydroglucitol 5mM) to be resuspended, adjust cell suspension final concentration of 6 × 104Individual/mL, with every hole 3 × 104Individual cell
(500 μ L) is inoculated in 24 orifice plates.
Each each 18 hole of experimental group, calculate 3 holes every time, calculate 3 times per hole, respectively bed board 0h, 24h, 48h, 72h,
After 96h, 120h, cell concentration is calculated with cell counting count board, and cell doubling time is calculated with formula, is during which changed every other day corresponding
Culture medium.
It is finally that ordinate draws cell growth curve using the time as abscissa, cell number.
Fig. 7 is 1,5-anhydroglucitol Hacat cells growth curve figure before and after the processing.
As shown in fig. 7, obtain cell growth curve by cell counting, can be calculated pair by the cell formula that doubles
It it is 28.9 hours according to group doubling time, the 1,5-anhydroglucitol group doubling time is 136.3 hours.When 1,5-anhydroglucitol group doubles
Between be approximately 4.7 times of the control group doubling time.The Hacat cells and control group treated as can be seen here through 1,5-anhydroglucitol
Hacat cells compare there is obvious inhibiting effect to the multiplication capacities of Hacat cells.
It is excessive to human epidermal and too fast that 1,5-anhydroglucitol can be seen that by the test result of the isolated cells of human body
Increment has good inhibition, further it is considered that having the effect of certain to people's psoriasis.
The 1,5-anhydroglucitol that the present embodiment provides is done in detail as the treatment medicine of psoriasis and the principle of application below
Describe in detail bright.
Cellular energy is mainly derived from glucose metabolism.Glucose can pass through two kinds of approach of oxidative phosphorylation and glycolysis
Energy is provided.Unlike normal cell mainly generates ATP, the ATP sources of tumour cell about 50% by oxidative phosphorylation approach
In glycolytic pathway (Warburg effects) [M.G.VanderHeidenandR.J.DeBerardinis,
“Understandingthe IntersectionsbetweenMetabolismandCancerBiology.,”Cell,
vol.168, no.4,pp.657–669,Feb.2017.].Glycolytic pathway is that glucose is converted into after pyruvic acid and directly gone back
Originally it was that lactic acid produces ATP, in-between product provides material base for cell propagation.Metabolism group research shows psoriatic's body
Interior lactic acid content dramatically increase [H.Kang, X.Li, Q.Zhou, C.Quan, F.Xue, J.Zheng, andY.Yu,
“Explorationofcandidate biomarkersforhumanpsoriasisbasedongaschromatography-
mass spectrometryserummetabolomics.,”Br.J.Dermatol.,vol.176,no.3,pp. 713–722,
Mar.2017.], the related important albumen (GLUT1, HK2, PKM2) of a variety of glycolysis in Psoriatic Lesions compared with Normal human epidermal
Expression is increased, and this all shows the horizontal increase of psoriatic skin horn cell glycolysis.Therefore 1,5-anhydroglucitol treatment silver is utilized
Bits disease has theoretical foundation.
In embodiment 1, using continuous by the way that mode is injected intraperitoneally in imiquimod inducing mouse parapsoriasis model process
1,5-anhydroglucitol is given, after 5 days modeling phases terminated, is compared with injection PBS control groups, the thickness of skin scurf and epidermis is equal
Significantly reduce.Experimental result shows that 2- deoxyglucoses have certain treatment/prevention effect to intravital mouse psoriasis.
In embodiment 2, by observing influence of the 1,5-anhydroglucitol to Hacat cell growths it can be found that through 2- deoxidations
The treated Hacat cell proliferation speed of glucose is remarkably decreased, and the doubling time is approximately 4.7 times of control group doubling time, and
Hacat cells are mainly used to replace the research normal keratinocyte of people, it can be considered that 1,5-anhydroglucitol is normal to people
The excessive and too fast increment of keratinocyte has certain therapeutic action.Further it is believed that 2- deoxyglucoses
Sugar has certain therapeutic action to people's psoriasis.
The effect of embodiment and effect
It can be reasoned out by the interpretation of result to intravital mouse parapsoriasis model and Hacat cell growth assays,
1,5-anhydroglucitol has certain suppression and therapeutic effect to mouse and people's parapsoriasis.Further it is considered that 2- takes off
Oxygen glucose has curative effect to mammal psoriasis, may apply in the treatment of mammal psoriasis and has well
Curative effect.
Above-mentioned embodiment is the preferred case of the present invention, is not intended to limit the scope of protection of the utility model.
Claims (6)
- Application of the 1.2- deoxyglucoses as treatment mammal psoriasis.
- 2. application of the 1,5-anhydroglucitol according to claim 1 as treatment mammal psoriasis, its feature It is：Wherein, the mammal is mouse or the mankind.
- A kind of 3. medicine for being used to treat psoriasis containing 1,5-anhydroglucitol.
- 4. medicine according to claim 3, it is characterised in that：Wherein, the formulation of the medicine for treating psoriasis is injection or oral agents.
- A kind of 5. medicine for being used to treat the mankind or mouse psoriasis containing 1,5-anhydroglucitol.
- 6. medicine according to claim 5, it is characterised in that：Wherein, the formulation of the medicine for treating the mankind or mouse psoriasis is injection or oral agents.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653736A (en) * | 2018-04-28 | 2018-10-16 | 中国人民解放军第二军医大学 | Application of the M2 types pyruvate kinase as drug target in the drug for preparing prevention psoriasis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106309458A (en) * | 2016-07-28 | 2017-01-11 | 中南大学湘雅医院 | Application of 2-deoxy-D-glucose and pharmaceutically acceptable salt thereof in preparation of psoriasis treatment drug |
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2017
- 2017-07-25 CN CN201710610363.0A patent/CN107468699A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106309458A (en) * | 2016-07-28 | 2017-01-11 | 中南大学湘雅医院 | Application of 2-deoxy-D-glucose and pharmaceutically acceptable salt thereof in preparation of psoriasis treatment drug |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653736A (en) * | 2018-04-28 | 2018-10-16 | 中国人民解放军第二军医大学 | Application of the M2 types pyruvate kinase as drug target in the drug for preparing prevention psoriasis |
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