CN107157977A - Glycine betaine treats the pharmaceutical applications of pulmonary hypertension - Google Patents
Glycine betaine treats the pharmaceutical applications of pulmonary hypertension Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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Abstract
The invention discloses purposes of the glycine betaine (Bataine) in treatment pulmonary hypertension medicine is prepared.The present invention test result indicates that when being used in safe-dosaging limits, dosage can significantly improve rat mean pulmonary arterial pressure, right ventricular systolic pressure for 400mg/kg glycine betaine, reduce right ventricle and the reconstruct of lung arteriolar, improve the inflammatory reaction in lung tissue, it was demonstrated that glycine betaine has therapeutic action to pulmonary hypertension.
Description
Technical field
The present invention relates to the application of glycine betaine, more particularly to glycine betaine is used as the purposes for treating pulmonary hypertension medicine.
Background technology
Pulmonary hypertension (pulmonary arterial hypertension, PAH) be one group by heterologous disease and not
With continuing to increase caused by pathogenesis with pulmonary vascular resistance, and cause right ventricle failure and the dead pulmonary artery remodeling being characterized
Property disease, with high incidence, high disability rate, high mortality, it is considered to be " false malignant tumour ".Lung blood caused by inflammatory reaction
Vascular smooth muscle cell proliferation and pulmonary artery remodeling, lung artery occlusion are considered as pulmonary hypertension hair caused by endothelial tube damage
The principal character of interpretation of the cause, onset and process of an illness system and pathological change.Due to the increase of pulmonary vascular resistance and increasing for right ventricular afterload, cause the right heart
Room is reconstructed, and ultimately results in right ventricle failure.With going deep into Pulmonary Artery Hypertension and Pathological Physiology research, and
The clinical practice of newtype drug, oneself has taken on a new look for the prognosis of patients with pulmonary hypertension, but long-term effectiveness is limited, 5 annual survival rates
Only 49%.Therefore, find to have and suppress even reversing pulmonary vascular reconstruct, suppress cell propagation, for right ventricular function and valency
The cheap medicine of lattice, it will help clinical early intervention and treatment, with far-reaching Research Significance.
Matrimony vine (Lyciumbarbarum L) is the rare resource that Ningxia characteristic returns medicinal material and important medicine-food two-purpose, in having
The good reputation of state northwest " red gold ".Its nature and flavor is sweet, tepor, Return liver, kidney, lung channel, function tonification liver kidney, improving eyesight, moistening lung, cures mainly liver
Deficiency of the kidney is empty, has a dizzy spell, visually unclear, cough due to consumptive disease, quenches one's thirst and draws the card such as drink.Glycine betaine (Betaine) also known as the sweet ammonia of trimethyl
Acid, is isolated first a kind of amino acid derivativges from matrimony vine, safe, belongs to actual non-toxic type medicine.It is domestic
Outer research shows that glycine betaine can promote fat metabolism, reduces internal homocysteine；With anti-fatty liver, protection kidney, drop blood
Pressure, antitumor, mitigation stress wait pharmacological action, but on it to the current rarely seen document report of pulmonary hypertension inhibitory action.
The content of the invention
The purpose of the present invention is to be used as to treat pulmonary hypertension there is provided glycine betaine by the pharmacological research to glycine betaine
Medicine purposes.
The present invention is achieved through the following technical solutions goal of the invention：
The present invention provides glycine betaine as the purposes for the treatment of pulmonary hypertension medicine, the structural formula such as formula of the glycine betaine
(1) shown in：
Specifically, the pulmonary hypertension is that subcutaneously disposably injection monocrotaline is lured rat abdomen after 50mg/kg21 days
Lead the pulmonary hypertension to be formed.
Further, the glycine betaine single application dosage is 100~400mg/kg.
Preferably, the glycine betaine single application dosage is 200~400mg/kg.
Preferably, the glycine betaine single application dosage is 300~400mg/kg.
Preferably, the glycine betaine single application dosage is 400mg/kg.
Specifically, the glycine betaine single application dosage is the dosage for not causing CNS inhibition.
Specifically, the formulation of the medicine is the peroral dosage form or injection type allowed in pharmacy.
The glycine betaine that the present invention is provided has the advantages that as the purposes for the treatment of pulmonary hypertension medicine：
(1) glycine betaine can significantly reduce mean pulmonary arterial pressure and right ventricular systolic pressure, reduce in Right ventricular hypertrophy index and lung
Parteriole is reconstructed；
(2) glycine betaine can suppress inflammatory effect, significantly suppress NF- κ B in Rats of Pulmonary Hypertension lung tissue, TNF-α,
The expression of IL-1 β albumen.
Test result indicates that glycine betaine has treatment pulmonary hypertension effect, available for the curative for preparing pulmonary hypertension
Thing.
Brief description of the drawings
Fig. 1：Glycine betaine significantly reduces Rats of Pulmonary Hypertension mean pulmonary arterial pressure (mPAP) figure；
Fig. 2：Glycine betaine significantly reduces Rats of Pulmonary Hypertension right ventricular systolic pressure (RVSP) figure；Fig. 3：Glycine betaine significantly drops
Low Rats of Pulmonary Hypertension Right ventricular hypertrophy index (RVHI) figure；
Fig. 4：Glycine betaine significantly reduces Rats of Pulmonary Hypertension pipe thickness percentage (WT%) figure；
Fig. 5：Glycine betaine significantly reduces Rats of Pulmonary Hypertension tube wall area percentage (WA%) figure；
Fig. 6：Glycine betaine changes the HE colored graphs (× 400) of influence on Rats of Pulmonary Hypertension pathologic；
Fig. 7：HE colored graphs that glycine betaine influences on Rats of Pulmonary Hypertension right ventricular apex histopathologic change (×
400)；
Fig. 8：Glycine betaine significantly reduces Rats of Pulmonary Hypertension diameter of myocytes (AD) figure；
Fig. 9：Glycine betaine significantly reduces Rats of Pulmonary Hypertension cardiac muscle cell cuclear density (MND) figure；
Figure 10：Glycine betaine on Rats of Pulmonary Hypertension expression of collagen in lung fiber change influence Masson colored graphs (×
400)；
Figure 11：The influence SABC figure (× 400) that glycine betaine is expressed MCP-1 in Rats of Pulmonary Hypertension lung tissue；
Figure 12：The influence SABC figure (× 400) that glycine betaine is expressed ET-1 in Rats of Pulmonary Hypertension lung tissue；
Figure 13：Influence of the glycine betaine to NF- kB protein expressions in Rats of Pulmonary Hypertension lung tissue is (with normal group ratio
Compared with：##P<0.01, compared with model group：*P<0.05,*P<0.01(N=6))；
Figure 14：Influence of the glycine betaine to TNF-α protein expression level in Rats of Pulmonary Hypertension lung tissue is (with normal group ratio
Compared with：##P<0.01, compared with model group：*P<0.05,*P<0.01(N=6))；
Figure 15：Influence of the glycine betaine to IL-1 β protein expression levels in Rats of Pulmonary Hypertension lung tissue is (with normal group ratio
Compared with：##P<0.01, compared with model group：*P<0.05,*P<0.01(N=6))；
Embodiment
With reference to embodiment, the present invention is further detailed explanation, and glycine betaine used is foregoing in embodiment
Formula (1) shown in compound.
Embodiment 1
Glycine betaine as treatment pulmonary hypertension medicine purposes, wherein, glycine betaine single application dosage be rat
100mg/kg, the formulation of medicine is solution dosage.
Embodiment 2
Glycine betaine as treatment pulmonary hypertension medicine purposes, wherein, glycine betaine single application dosage be rat
200mg/kg, the formulation of medicine is powder-injection type.
Embodiment 3
Glycine betaine as treatment pulmonary hypertension medicine purposes, wherein, glycine betaine single application dosage be rat
400mg/kg, the formulation of medicine is powder-injection type.
Following zoopery further illustrates the effect of above-described embodiment 1 to 3：
First, experiment material
1.1 animals are handled
Adult male SD rats, 260-300g, purchased from Ningxia Medical University's Experimental Animal Center, animal productiong licensing
Number：NCXK (peaceful) 2016-0005.Feeding conditions include standard feed, and running water, room temperature is maintained at (24 ± 2) DEG C, humidity 50-
60%, daily illumination and interlunation each 12h.Before experiment, animal is placed in experimental situation and adapted to 3 days.
1.2 experimental drugs and instrument
Glycine betaine (sigma companies of the U.S.), with normal saline, concentration be respectively 100mg/mL, 200mg/mL,
400mg/mL, it is now with the current.Masson dyeing liquors (build up Bioengineering Research Institute) purchased from Nanjing, rabbit-anti NF- κ B, TNF-α,
IL-1 β, MCP-1, ET-1 polyclonal antibody (are purchased from Abcam companies), ELIASA (1510, Thermo Fisher companies), electrophoresis
Instrument, electroporation (Powerpac basic, Bio-Rad companies of the U.S.), (JS-860B, Shanghai training is clear public for gel image analyser
Department).
1.3 experimental animals are grouped and are administered
SD rats are randomly divided into Normal group, model group, positive drug silaenafil group, glycine betaine various dose group.
Normal group abdominal part hypodermic physiological saline, remaining each group rat disposably injects monocrotaline 50mg/ in subcutaneous abdomen
Kg, the 22nd day after modeling starts by the daily gastric infusion of 100mg/kg, 200mg/kg, 400mg/kg dosage.Normal group
The physiological saline of equivalent is given with method with model group.The 22nd day after successive administration carry out haemodynamics, histopathology with
The pharmacodynamic evaluations such as morphological change, molecular biology expression change.
1.4SD Pulmonary Hypertensions (PAH) model is set up
Weigh and be placed in after monocrotaline in 15ml centrifuge tubes, adjusted after being dissolved with HCL (1mol/L) with NaOH (1mol/L)
PH value is saved to 7.0~7.2, then with distilled water polishing volume.Take 280g or so rat, disposable abdominal part hypodermic open country hundred
Close alkali 50mg/kg, selection abdominal part hypodermic mode be it is documented that：Abdominal part hypodermic can form typically " inflammatory " lung
Arterial hypertension.Normally raised after injection, diet is free, pulmonary hypertension was formed at the 3rd week.
2nd, experimentation
(1) Hemodynamic Changes
1.1 experimental method：
Test after last dose 24h, urethane intraperitoneal injection of anesthesia rat, separate right vena jugularis externa, ligature distal end,
Proximal part tilts 45 ° and cuts an osculum, and the special right heart catheter of rat for being connected with pressure transducer and be full of heparin is inserted into right
Vena jugularis externa, left-handed and push ahead and enter right ventricle, record right ventricular systolic pressure (RVSP) turns to pulmonary artery, and record is average
Pulmonary arterial pressure (MPAP).
1.2 experimental result：
The 42nd day after injection monocrotaline is can be seen that by Fig. 1,2, compared with control rats, model group rats are put down
Equal pulmonary arterial pressure and right ventricular systolic pressure significantly rise (P ＜ 0.01).Compared with model group, the rat for giving glycine betaine treatment is put down
Equal pulmonary arterial pressure and right ventricular systolic pressure are significantly reduced (P ＜ 0.01, P ＜ 0.05).Point out glycine betaine (100mg/kg, 200mg/
Kg, 400mg/kg) Pulmonary Hypertension of monocrotaline induction can be improved.
(2) Right ventricular hypertrophy index is detected
2.1 experimental method
After hemodynamics Indexs measure terminates, thoracic cavity is opened, the syringe needle for connecting device for casting is inserted through right ventricle
Enter to pulmonary artery, use normal saline flushing lung.Heart is taken out, separation right ventricle, left ventricle add interventricular septum, weighed respectively, calculate
Right ventricle plumpness index (RVHI)=right ventricle (RV)/left ventricle+interventricular septum (LV+S).
2.2 experimental result：
As seen from Figure 3 injection monocrotaline after the 42nd day, compared with control rats, the right heart of model group rats
Plump index significantly rises (P ＜ 0.01).Compared with model group, the rat Right ventricular hypertrophy index for giving glycine betaine treatment significantly drops
Low (P ＜ 0.01, P ＜ 0.05), right ventricle remodeling is improved.Point out glycine betaine (100mg/kg, 200mg/kg, 400mg/kg)
The Pulmonary Hypertension of monocrotaline induction can be improved.
(3) lung arteriolar reconstruct Indexs measure
3.1 experimental method
Bottom right lung is taken, 10% formaldehyde fixes 48h, and routine paraffin wax embedding takes the thick serial section of 5um, Yihong-haematoxylin (HE)
Dyeing, resinene mounting, test under microscope is simultaneously taken a picture.Caliber is randomly selected each 10 in 50-100um lung parterioles, is used
Microscope carries out taking the photograph piece, and Image-Pro Plus image analysis softwares system carries out graphical analysis, calculates lung parteriole thickness of pipe wall
Degree (wall thickness, WT) accounts for the percentage WT% of caliber, tube wall area (wall area, WA) and accounts for the blood vessel gross area
Percentage WA%, using WT% and WA% as pulmonary artery remodeling index.
3.2 experimental result
The 42nd day after injection monocrotaline, compared with control rats, model group rats lung are can be seen that by Fig. 4,5
Percentage WT%, the tube wall area that parteriole pipe thickness accounts for caliber account for the percentage WA% of the blood vessel gross area and significantly rise (P ＜
0.01).Compared with model group, the Pulmonary Arterioles of Rat Exposed pipe thickness for giving glycine betaine treatment accounts for the percentage WT% of caliber, pipe
The percentage WA% that wall area accounts for the blood vessel gross area is significantly reduced (P ＜ 0.01, P ＜ 0.05), and the reconstruct of lung arteriolar is changed
It is kind.The rat pulmonary artery that prompting glycine betaine (100mg/kg, 200mg/kg, 400mg/kg) can improve monocrotaline induction is high
Pressure.
(4) pathologic change HE colored graphs
4.1 experimental method
Bottom right lung is taken, 10% formaldehyde fixes 48h, and serial dehydration, dimethylbenzene is transparent, waxdip 2 hours, routine paraffin wax embedding,
The thick serial section of 5um is taken, Yihong-haematoxylin (HE) is dyed,
4.2 experimental result
Visible in light Microscopic observation as seen from Figure 6, control rats PA endothelium cells are continuously flat, carefully
Born of the same parents' distribution uniform, lumen of vessels is complete, and alveolar mucosal structure is complete, has no inflammatory cell infiltration；Model group rats pulmonary artery blood
Endothelial cell swelling, come off, the obvious hyperplasia of vascular smooth muscle cells, hypertrophy, tube chamber irregular thickening, luminal stenosis, even
Occlusion, Endovascular, which is remained in a large amount of red blood cells, alveolar space, sees massive inflammatory cells infiltrated；Treatment group's rat pulmonary artery tube chamber
Thickness is thickened between control group and model group, hyperplasia also occur in endothelial cell partial exfoliation, vascular smooth muscle cells, but gently
In also visible inflammatory cell infiltration, but inflammatory cell infiltration lesser extent in model group, alveolar space.Point out glycine betaine (100mg/
Kg, 200mg/kg, 400mg/kg) Pulmonary Hypertension of monocrotaline induction can be improved.
(5) right ventricle pathological change HE colored graphs
5.1 experimental method
Right ventricular apex tissue is taken, 10% formaldehyde fixes 48h, and serial dehydration, dimethylbenzene is transparent, waxdip 2 hours, conventional stone
Wax is embedded, and takes the thick serial section of 5um, Yihong-haematoxylin (HE) dyeing.
5.2 experimental result
Fig. 7 results show that observing cardiac muscle cell under an optical microscope finds, control rats cardiac muscle cell's marshalling,
Cell continuity is good and space between cells is smaller；Compared with control group, substantially arrangement is substantially disorderly by model group rats cardiac muscle cell, the heart
Myocyte is substantially loose, gap turn narrow between cardiac muscle cell, is consistent with when dissected with visually observing the plump situation of right ventricle.And it is western
Rat myocardial cell diameter after ground that non-sum glycine betaine treatment generally reduces, and cardiac muscle cell's arrangement also slightly shows neat.Reflect
There is the effect for being relieved cardiac myocyte hypertrophy, right ventricular hypertrophy, Right Ventricular Remodeling after glycine betaine treatment.Point out glycine betaine
(100mg/kg, 200mg/kg, 400mg/kg) can improve the Pulmonary Hypertension of monocrotaline induction.
(6) influence of the glycine betaine to myocardium of right ventricle cell
6.1 experimental method
Right ventricular apex tissue is taken, 10% formaldehyde fixes 48h, and serial dehydration, dimethylbenzene is transparent, waxdip 2 hours, conventional stone
Wax is embedded, and takes the thick serial section of 5um, Yihong-haematoxylin (HE) dyeing.Image-Pro Plus image analysis softwares system is carried out
Graphical analysis, calculating myocardium cell dia (AD), cardiac muscle cell's cuclear density (MND), using AD and MND as pulmonary artery remodeling finger
Mark.
6.2 experimental result
Fig. 8, influence of 9. glycine betaines to Rats of Pulmonary Hypertension myocardium of right ventricle cell dia and cardiac muscle cell's cuclear density.
By measurement it was found that, MCT group rat myocardial cell average diameters (AD) and cardiac muscle cell's cuclear density (MND) are bright
It is aobvious to be higher than control rats, and Tet groups rat also shows also myocyte's diameter (AD) and diminished, also muscle corpuscle density (MND)
Reduction, the effect of cardiac myocyte hypertrophy, right ventricular hypertrophy, Right Ventricular Remodeling can be relieved after reflecting glycine betaine treatment, and is measured
As a result equally illustrate that its effect produced is treated similar to silaenafil.Prompting glycine betaine (100mg/kg, 200mg/kg,
It can 400mg/kg) improve the Pulmonary Hypertension of monocrotaline induction.
(7) lung tissue Masson colored graphs
7.1 experimental method
Bottom right lung tissue is taken, 10% formaldehyde fixes 48h, and serial dehydration, dimethylbenzene is transparent, waxdip 2 hours, routine paraffin wax bag
Bury, take the thick serial section of 5um, row Masson dyeing.
7.2 experimental result
Figure 10：Glycine betaine on Rats of Pulmonary Hypertension expression of collagen in lung fiber change influence Masson colored graphs (×
400)。
Control rats lung tissue section Masson dyes visible arteriolar vascular wall collagen fiber structure clearly, arrangement
Neatly, alveolar structure is clear, and model group rats arteriolar vascular wall and surrounding tissue then see a large amount of collagenous fibres propagation, knot
Structure is disorderly, and the obvious atrophy of alveolar is even blocked, and glycine betaine treatment group lung tissue of rats situation has clear improvement compared with model group, collagen
Fibroplasia is reduced, and alveolar structure is also more visible, close with silaenafil group rat situation.Prompting glycine betaine (100mg/kg,
200mg/kg, 400mg/kg) Pulmonary Hypertension of monocrotaline induction can be improved.
(8) lung tissue immunohistochemical experiment
8.1 experimental method
Bottom right lung tissue is taken, 10% formaldehyde fixes 48h, and serial dehydration, dimethylbenzene is transparent, waxdip 2 hours, routine paraffin wax bag
Bury, take the thick serial section of 5um, immunohistochemical experiment is carried out by step, primary antibody concentration is MCP-1 (1:200), ET-1 (1:
1000)。
8.2 experimental result
By Figure 11,12 as can be seen that compared with control group, MCP-1 in model group rats lung tissue, ET-1 expression significantly increases
Plus, and give glycine betaine and treat MCP-1 in lung tissue of rats later, ET-1 expression reductions are as a result similar to silaenafil group.Carry
Show that glycine betaine (100mg/kg, 200mg/kg, 400mg/kg) can improve the Pulmonary Hypertension of monocrotaline induction.
(9) lung tissue Western blot are tested
9.1 experimental method
Take and freeze lung tissue in right amount, after liquid nitrogen grinding, add full histone extract and extract histone, determine egg
10min is boiled after Bai Hanliang, and unified dilution in boiling water, after room temperature cooling, -82 DEG C of refrigerators are saved backup；According to testing protein
Bulk of molecule prepares the sds gel of suitable concentration, adds protein sample and standard protein mark, and protein is separated by electrophoresis
Afterwards, transfer albumen is in nitrocellulose filter.
The nitrocellulose filter of albumen is loaded with after the closing of 5% skim milk, NF- κ B, TNF-α, IL-1 β and internal reference is added
Stayed overnight for 4 DEG C according to primary antibodies such as β-actin, after being changed clothes through PBS, plus corresponding secondary antibody is incubated, then changes clothes post-exposure through PBS, determines each egg
Informal voucher band OD value simultaneously calculates corresponding Reinhoit Zahl.
9.2 experimental result
It is can be seen that by Figure 13,14,15 compared with rats in normal control group, NF- κ B in model group rats lung tissue,
TNF-α, IL-1 β expressing quantity significantly rises (P ＜ 0.01), and carries out NF- κ B in glycine betaine treatment group lung tissue of rats,
TNF-α, IL-1 β expressing quantity is significantly reduced (P ＜ 0.01).Point out glycine betaine (100mg/kg, 200mg/kg, 400mg/
Kg the Pulmonary Hypertension of monocrotaline induction can) be improved.
Above-described is only some embodiments of the present invention.For the person of ordinary skill of the art, not
On the premise of departing from the invention design, various modifications and improvements can be made, these belong to the protection model of the present invention
Enclose.
Claims (11)
1. purposes of the glycine betaine in the medicine for preparing treatment pulmonary hypertension, it is characterised in that：The structural formula of the glycine betaine
As shown in formula (1)：
Formula (1).
2. purposes according to claim 1, it is characterised in that：Glycine betaine single application dosage is not cause CNS inhibition
Dosage.
3. purposes according to claim 2, it is characterised in that：Glycine betaine single application dosage is 100~400mg/kg.
4. purposes according to claim 3, it is characterised in that：Glycine betaine single application dosage is 100mg/kg.
5. purposes according to claim 3, it is characterised in that：Glycine betaine single application dosage is 200mg/kg.
6. purposes according to claim 3, it is characterised in that：Glycine betaine single application dosage is 400mg/kg.
7. purposes according to claim 1, it is characterised in that：Glycine betaine single application dosage be rat 100mg/kg~
400mg/kg, standard weight people the 70kg amount of being intended for single use are 16mg/kg~64mg/kg.
8. the purposes according to claim any one of 1-7, it is characterised in that：Medicine is configured to by intestines and stomach or stomach
The formulation given outside.
9. purposes according to claim 8, it is characterised in that：The formulation of the medicine is the oral agents allowed in pharmacy
Type, parenteral solution formulation or powder-injection.
10. use of the glycine betaine in the test instrument medicine or reagent of the Pulmonary Hypertension induced for monocrotaline is prepared
On the way.
11. purposes according to claim 10, it is characterised in that：The pulmonary hypertension is that subcutaneous abdomen is disposably injected
The pulmonary hypertension of monocrotaline induced rat formation after 50mg/kg21 days.
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| CN201710470446.4A CN107157977A (en) | 2017-06-20 | 2017-06-20 | Glycine betaine treats the pharmaceutical applications of pulmonary hypertension |
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| CN201710470446.4A CN107157977A (en) | 2017-06-20 | 2017-06-20 | Glycine betaine treats the pharmaceutical applications of pulmonary hypertension |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110898048A (en) * | 2019-09-16 | 2020-03-24 | 宁夏医科大学 | Use of betaine in preparation of pulmonary vasodilator |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006050581A2 (en) * | 2004-11-10 | 2006-05-18 | Jallal Messadek | Betaine as agent against arthropod - or mosquito -borne diseases |
| WO2008009071A2 (en) * | 2006-07-20 | 2008-01-24 | Jallal Messadek | Combination therapy using betaine and endothelin antagonists |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006050581A2 (en) * | 2004-11-10 | 2006-05-18 | Jallal Messadek | Betaine as agent against arthropod - or mosquito -borne diseases |
| WO2006050585A2 (en) * | 2004-11-10 | 2006-05-18 | Jallal Messadek | Modulation of nitric oxide synthases by betaines |
| WO2008009071A2 (en) * | 2006-07-20 | 2008-01-24 | Jallal Messadek | Combination therapy using betaine and endothelin antagonists |
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| Title |
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| I.D. KALMAR, ET AL.: "Dietary N,N-dimethylglycine supplementation improves nutrient digestibility and attenuates pulmonary hypertension syndrome in broilers", 《JOURNAL OF ANIMAL PHYSIOLOGY AND ANIMAL NUTRITION》 * |
| TAIJIE LIN, ET AL.: "1H NMR-Based Analysis of Serum Metabolites in Monocrotaline-Induced Pulmonary Arterial Hypertensive Rats", 《DISEASE MARKERS》 * |
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| CN110898048A (en) * | 2019-09-16 | 2020-03-24 | 宁夏医科大学 | Use of betaine in preparation of pulmonary vasodilator |
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Application publication date: 20170915 |