CN112891368A - Pharmaceutical use of hydrogen sulfide donor - Google Patents
Pharmaceutical use of hydrogen sulfide donor Download PDFInfo
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- CN112891368A CN112891368A CN202110103087.5A CN202110103087A CN112891368A CN 112891368 A CN112891368 A CN 112891368A CN 202110103087 A CN202110103087 A CN 202110103087A CN 112891368 A CN112891368 A CN 112891368A
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- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229910000037 hydrogen sulfide Inorganic materials 0.000 title claims abstract description 44
- 208000007474 aortic aneurysm Diseases 0.000 claims abstract description 50
- 208000002251 Dissecting Aneurysm Diseases 0.000 claims abstract description 43
- 206010002895 aortic dissection Diseases 0.000 claims abstract description 32
- UBAXRAHSPKWNCX-UHFFFAOYSA-N diallyl trisulfide Chemical compound C=CCSSSCC=C UBAXRAHSPKWNCX-UHFFFAOYSA-N 0.000 claims abstract description 12
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- YZMHNNLDUWRZFW-UHFFFAOYSA-N (4-methoxyphenyl)-morpholin-4-yl-sulfanyl-sulfanylidene-$l^{5}-phosphane;morpholine Chemical compound C1COCC[NH2+]1.C1=CC(OC)=CC=C1P([S-])(=S)N1CCOCC1 YZMHNNLDUWRZFW-UHFFFAOYSA-N 0.000 claims abstract description 6
- IWBBKLMHAILHAR-UHFFFAOYSA-N chembl402341 Chemical compound C1=CC(O)=CC=C1C1=CC(=S)SS1 IWBBKLMHAILHAR-UHFFFAOYSA-N 0.000 claims abstract description 6
- RMKCQUWJDRTEHE-UHFFFAOYSA-N diallyl tetrasulfane Natural products C=CCSSSSCC=C RMKCQUWJDRTEHE-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000004201 L-cysteine Substances 0.000 claims abstract description 5
- 235000013878 L-cysteine Nutrition 0.000 claims abstract description 5
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 claims abstract description 5
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- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
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- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
-
- 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/105—Persulfides
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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Abstract
The application of hydrogen sulfide donor in preparing medicine for treating aortic aneurysm and aortic dissection is disclosed. In particular to the application of hydrogen sulfide donor sodium hydrosulfide, DATS, L-cysteine and analogues thereof, GYY4137, ADT-OH and analogues thereof, and Gem-dithiol and analogues thereof in preparing medicaments for treating aortic aneurysm and aortic dissection. According to the invention, through an integral animal model, the hydrogen sulfide and the donor thereof are determined to be capable of reducing the incidence rate and the death rate of aortic aneurysm and aortic dissection, increasing the hydrogen sulfide content in circulating blood, inhibiting the expression of inflammatory factors in the aortic aneurysm and aortic dissection process and improving the loss of smooth muscle cells in the aortic aneurysm and aortic dissection process. Can be used as therapeutic medicine for improving aortic aneurysm and aortic dissection.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of a hydrogen sulfide donor in preparation of a medicine for treating aortic aneurysm and aortic dissection.
Background
Aortic aneurysms (AoA) and aortic dissections (AoD) are potentially fatal vascular diseases with genetic predisposition induced by a variety of factors. Aortic aneurysms are manifested as a tumor-like dilatation of the aorta, defined as an arterial dilatation of more than 1.5 times the normal arterial diameter. Aortic dissection is characterized by aortic wall intimal tear, and circulating blood enters the middle layer of the aortic wall through intimal lacerations, so that the middle layer tears widely and forms a dissection. More than 80% of patients with AoA and AoD have hypertension as their etiology. The percentage of deaths between AoA and AoD in adult males aged 65-85 years in developed countries is statistically between 1% and 3%. The pathological mechanism of AoA and AoD is not known at present, and besides known genetic factors such as Marfan syndrome caused by FBN1 mutation, Loeys-Dietz syndrome caused by TGFBR2 mutation, etc., changes in the structure and function of vascular constitutive cells play an important role in AoA and AoD. The aortic dissection is emergent and has high fatality rate after onset, but the current aortic aneurysm and aortic dissection have high missed diagnosis and misdiagnosis rate, and no specific medicine for treating the aortic dissection is clinically available. Therefore, finding new means for diagnosis and treatment of aortic aneurysms and aortic dissections is of great importance.
Aortic aneurysm and aortic dissection are the result of the combined action of multiple cell functional injuries, and researches have found that dysfunction of medial smooth muscle cells in blood vessels, such as smooth muscle cell apoptosis and matrix adhesion capacity reduction, are involved in AoA and AoD. Furthermore, monocyte activation and enhanced vascular inflammatory responses can also promote the development of AoA and AoD. Vascular endothelial cells play a key role in vasoconstriction, morphological and functional regulation, suggesting that endothelial dysfunction may also contribute to the development of AoA and AoD. Therefore, a treatment that can improve the endothelial function of smooth muscle, inflammatory nuclei in combination may be an effective means for treating AoA and AoD.
In the cardiovascular system H2S exerts a variety of biological effects including vasodilation, regulation of blood pressure, antagonism of oxidative stress, inhibition of smooth muscle cell proliferation, mitochondrial protection, and anti-inflammatory, to maintain cardiovascular function. The hydrogen sulfide as the 3 rd gas signal molecule can activate an ATP sensitive potassium channel of endothelial cells, relax blood vessels, inhibit the adhesion between the endothelial cells and white blood cells, and directly and indirectly reduce the oxidative stress state of the endothelial cells, thereby reducing the inflammation level, maintaining the functions of the endothelial cells of the blood vessels and relieving the vascular remodeling after the endothelial cells are damaged. However, it has not been reported whether hydrogen sulfide changes during occurrence of aortic aneurysm and aortic dissection and whether it participates in inflammatory injury and loss of smooth muscle in aortic aneurysm and aortic dissection. In addition, whether the hydrogen sulfide donor has a therapeutic effect on the occurrence and development of aortic aneurysm and aortic dissection or not is not researched at present.
Disclosure of Invention
The technical problem to be solved is as follows: the invention provides a pharmaceutical application of a hydrogen sulfide donor, and particularly relates to an application of the hydrogen sulfide donor in treating aortic aneurysm and aortic dissection.
The technical scheme is as follows: use of a hydrogen sulfide donor in the manufacture of a medicament for the treatment of aortic aneurysm and aortic dissection.
The hydrogen sulfide donors of the present invention include DATS, L-cysteine and its analogs, GYY4137, ADT-OH and its analogs, and Gem-dithiol and its analogs.
Has the advantages that: the applicant finds that the hydrogen sulfide level in the blood plasma of the aortic dissection patient is reduced compared with that of a normal person through high performance liquid phase analysis. In an animal model, a subcutaneous embedded angiotensin II (AngII) micro-osmotic pump is used for inducing a mouse aortic aneurysm model, sodium hydrosulfide, DATS, L-cysteine, GYY4137, ADT-OH and Gem-dithiol are given for intervention, and a hydrogen sulfide donor is found to be capable of remarkably improving the plasma hydrogen sulfide level of a model mouse, reducing the IL-1 beta inflammatory factor level and reducing the ROS level in vascular tissues. In addition, the hydrogen sulfide donor can remarkably improve the rupture of elastic fibers of the aorta of a mouse caused by an AngII micro-osmotic pump, reduce the incidence rate of aortic aneurysm and aortic dissection and reduce the death rate. The hydrogen sulfide donor can be used as a therapeutic drug for treating aortic aneurysm and aortic dissection.
Drawings
FIG. 1 shows H in plasma of normal and aortic dissection patients2S expression level: extracting blood plasma of normal person and aortic dissection patient, and detecting H by chemiluminescence method2And (4) expressing S. P<0.05。
Figure 2 hydrogen sulfide donor restoration of AngII micro-osmotic pump induced aortic aneurysm mouse plasma hydrogen sulfide levels. Apoe-/-An Ang II osmotic pump is implanted subcutaneously in a mouse to construct a mouse aortic aneurysm model, a hydrogen sulfide donor is used for intervention treatment, and the level of plasma hydrogen sulfide is detected after 28 days. P<0.05。
Figure 3 hydrogen sulfide donor reduced AngII micro-osmotic pump induced vascular tissue inflammatory factor expression in mice with aortic aneurysm. Apoe-/-An Ang II osmotic pump is implanted subcutaneously in a mouse to construct a mouse aortic aneurysm model, a hydrogen sulfide donor is given for intervention treatment, the mouse aortic aneurysm model is killed after 28 days, RNA is extracted from aortic vascular tissues of the mouse, and the IL-1 beta expression level is detected. P<0.05，**P<0.01，***P<0.001。
Figure 4 hydrogen sulfide donors reduced angioplastic injury in aortic aneurysm mice induced by AngII micro-osmotic pump. Apoe-/-The mouse aortic aneurysm model is constructed by subcutaneously implanting Ang II osmotic pumps in mice, a hydrogen sulfide donor is given every day for intervention treatment, the mice are killed after 28 days, the aortic vascular tissues of the mice are subjected to OCT embedding, frozen sections are stained, and then the ROS level of the aortic tissues is detected by a DHE probe. P<0.05，**P<0.01。
Figure 5 hydrogen sulfide donors reduce aortic aneurysm incidence and mouse mortality. Apoe-/-The mice are subcutaneously implanted with Ang II osmotic pumps to construct a mouse aortic aneurysm model, hydrogen sulfide donors are given every day for intervention treatment, the mice are sacrificed after 28 days, and the blood vessels of the mice are separated and photographed. Aortic aneurysm incidence and mortality were calculated simultaneously. The A diagram is the aorta general picture, in whichAneurysms occur primarily in the abdominal aorta; panel B is a statistics of incidence, hydrogen sulfide donor can significantly reduce aortic aneurysm incidence; and the C picture is a survival rate curve, and the hydrogen sulfide donor can obviously improve the survival rate.
Figure 6 hydrogen sulfide donor reduces spandex breakage. Apoe-/-The method comprises the steps of embedding an Ang II osmotic pump in a mouse under the skin to construct a mouse aortic aneurysm model, providing a hydrogen sulfide donor for intervention treatment every day, killing the mouse after 28 days, separating a mouse blood vessel for paraffin embedding, slicing the mouse blood vessel for HE staining, and detecting the rupture condition of elastic fibers.
Detailed Description
The following examples are given to enable those skilled in the art to fully understand the present invention, but are not intended to limit the present invention in any manner.
Example 1
RNA extraction and Q-PCR
Extraction of Total RNA
(1) After washing the vascular tissue by ice PBS, adding 1mL of Trizol, blowing cells, transferring the cells to an Eppendorf centrifuge tube without RNase, and placing the cells on ice for 5 min;
(2) adding 200 mu L of chloroform, shaking vigorously and mixing uniformly, and then freezing for 2-3 minutes;
(3)12000rcf, 4 ℃, 15 minutes;
(4) sucking 400 mu L of the supernatant, transferring the supernatant into a new Eppendorf centrifuge tube, adding isopropanol with the same volume, reversing, uniformly mixing, and freezing for 10 minutes;
(5)12000rcf, 4 ℃, 10 minutes, abandoning the supernatant;
(6) adding 75% ethanol diluted by DEPC water, 7500rcf, 4 ℃, 5 minutes;
(7) taking the supernatant, drying at room temperature, adding 20 mu L DEPC water for dissolving, and measuring the concentration of RNA by using an ultraviolet spectrophotometer;
(8) the purified RNA samples were stored at-80 ℃.
Reverse transcription
Use of
II SuperMix kit was used for reverse transcription with a total reaction volume of 20. mu.L, and the specific composition was as followsShown in the figure:
the reaction was carried out on a Bio-Rad semiquantitative PCR instrument under the following specific reaction conditions:
95 ℃ for 50 seconds
5 minutes at 4 DEG C
Real-time PCR
In the experiment, AceQ qPCR SYBR Green Master Mix is adopted to carry out relative quantitative detection on the gene of the cardiac fibroblast, and the PCR reaction system is as follows:
the reaction is carried out on a Bio-Rad 480I type quantitative PCR instrument, and the specific reaction conditions are as follows:
2. plasma H2And (3) S expression detection:
(1) blood samples were collected, centrifuged, 4 ℃, 3000rpm, 10min, and the supernatant carefully pipetted (around 500 μ L) to a new EP tube.
(2) 1% O in anoxic Chamber2Add 200mM ice in sulfosalicylic acid solution and seal, incubate 30min at 37 ℃.
(3) Vortex, centrifuge, 4 ℃, 12000rpm, 5min, 100 μ L of supernatant was transferred to an HPLC vial containing 200 μ L of insert.
(4) Detection of H by high performance liquid chromatography2S content, acetonitrile and water gradient elution, 0.08% acetic acid was added.
3. Detection of Reactive Oxygen Species (ROS) levels
(1) And separating mouse vascular tissues, and carrying out frozen sections after OCT embedding.
(3) Adding dropwise PBS containing 2 μmol/L of Dihydroethidium (DHE), incubating at 37 deg.C for 30min in dark,
(4) after incubation, the tissue sections were washed with PBS. The red fluorescence was observed under an inverted fluorescence microscope and the fluorescence intensity was counted.
The hydrogen sulfide donor structure:
4. establishment and administration of animal aortic dissection model
After 8-week-old ApoE-/-mice were anesthetized, Micro-ecological pump 2004(Alzet, USA) was subcutaneously implanted in the abdomen of the mice, Ang II (200ng/kg/min) was administered to the experimental group, physiological saline was administered to the Sham group, and sodium hydrosulfide (100mg/kg/day), DATS (50mg/kg/day), GYY4137(50mg/kg/day), L-cysteine (300mg/kg/day) were intraperitoneally injected daily to the treatment groups. Or gavage ADT-OH (40mg/kg) and Gem-dithiol (75mg/kg) every other day. The subcutaneous embedding time was 28 days.
5. Aortic vascular HE staining
(1) The paraffin sections were put into a 65 ℃ oven and baked for 30 min.
(2) Dewaxing: xylene for 5min, 3 times in total. 100% ethanol for 1 min. 95% ethanol for 1 min. 70% ethanol for 1 min.
(3) Washing with distilled water until water drops are not hung on the slide, throwing off water on the slide, and staining with hematoxylin for 5 min.
(4) Washing with tap water to remove floating color on the slices.
(5) 1% hydrochloric acid ethanol for 1-3 s. Tap water was washed several times.
(6) Scott solution for 1min, tap water washed several times. Water was drained off, eosin stained, blood vessels 10 s.
(7) After several times of washing with distilled water, the chips were washed off to remove floating color. 70% ethanol was quickly washed with water. The solution was quickly washed with 95% ethanol. 100% ethanol 30s, 3 times in total.
(8) Xylene for 2min, 3 times in total. Sealing the tablet with neutral gum when the xylene is not dry.
Results of the experiment
In order to explore whether hydrogen sulfide participates in the pathological changes of the aorta in the aorta tissues of normal people and the aorta of an aortic dissection patient, plasma of the aortic dissection patient and the normal people is collected, and the hydrogen sulfide level in the plasma is detected by HPLC. H was found in plasma of aortic dissection patients compared to normal persons2The level of S was significantly reduced (fig. 1).
To clarify the role of hydrogen sulfide and its donor in aortic aneurysm and aortic dissection, we constructed an aortic aneurysm animal model. In Apoe-/-Embedding a normal saline micro-osmotic pump in a control group on a mouse; the model group is embedded with Ang II (1 mug/min/kg) micro-osmotic pump; the administration group was implanted with Ang II (1. mu.g/min/kg) micro osmotic pump and injected intraperitoneally with sodium hydrosulfide (100mg/kg/day), DATS (50mg/kg/day), GYY4137(50mg/kg/day), and L-cysteine (300mg/kg/day) daily. Or gavage ADT-OH (40mg/kg) and Gem-dithiol (75mg/kg) every other day. After 4 weeks, collecting blood plasma of mice to detect hydrogen sulfide level (figure 2), extracting aortic vascular tissues of mice, separating RNA to detect inflammatory factor level (figure 3), performing frozen section to observe vascular oxidative damage (figure 4), observing general morphology of blood vessels and calculating incidence and death rate of aortic aneurysm (figure 5), and performing paraffin section HE staining to observe rupture of elastic fibers (figure 6). The results show that H is administered2The S donor is effective in reducing the formation of aortic aneurysms. The above experimental results can further prove that: h2S can effectively inhibit the occurrence of aortic aneurysm and aortic dissection.
The above experimental results fully demonstrate that hydrogen sulfide participates in the process of aortic aneurysm and aortic dissection. The development of aortic aneurysm and aortic dissection can be effectively inhibited by exogenously administering hydrogen sulfide donor. Therefore, the hydrogen sulfide donor is considered to be a medicament for clinically treating aortic aneurysm and aortic dissection.
The above examples are only for illustrating the technical idea and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (2)
1. Application of hydrogen sulfide donor and its analogs in preparing medicine for treating aortic aneurysm and aortic dissection is provided.
2. Use according to claim 1, wherein the hydrogen sulfide donor is one of: sodium hydrosulfide, DATS, L-cysteine and its analogs, GYY4137, ADT-OH and its analogs, Gem-dithiol and its analogs.
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| CN114177169A (en) * | 2021-10-30 | 2022-03-15 | 南京吉芮康生物科技研究院有限公司 | Method for inhibiting melanoma metastasis by using hydrogen sulfide sustained-release donor ADT-OH and application thereof |
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| CN114177169A (en) * | 2021-10-30 | 2022-03-15 | 南京吉芮康生物科技研究院有限公司 | Method for inhibiting melanoma metastasis by using hydrogen sulfide sustained-release donor ADT-OH and application thereof |
| CN114177169B (en) * | 2021-10-30 | 2024-01-26 | 南京吉芮康生物科技研究院有限公司 | Method for inhibiting melanoma metastasis by using hydrogen sulfide slow-release donor ADT-OH and application thereof |
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