CN115590844B - 中康酸在制备用于预防或治疗代谢综合征的药物中的应用 - Google Patents
中康酸在制备用于预防或治疗代谢综合征的药物中的应用 Download PDFInfo
- Publication number
- CN115590844B CN115590844B CN202211246070.6A CN202211246070A CN115590844B CN 115590844 B CN115590844 B CN 115590844B CN 202211246070 A CN202211246070 A CN 202211246070A CN 115590844 B CN115590844 B CN 115590844B
- Authority
- CN
- China
- Prior art keywords
- mesaconic acid
- group
- mice
- preventing
- hfd
- 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.)
- Active
Links
- HNEGQIOMVPPMNR-NSCUHMNNSA-N mesaconic acid Chemical compound OC(=O)C(/C)=C/C(O)=O HNEGQIOMVPPMNR-NSCUHMNNSA-N 0.000 title claims abstract description 58
- HNEGQIOMVPPMNR-UHFFFAOYSA-N methylfumaric acid Natural products OC(=O)C(C)=CC(O)=O HNEGQIOMVPPMNR-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 239000003814 drug Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 208000001145 Metabolic Syndrome Diseases 0.000 title abstract description 10
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 title abstract description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 20
- 208000004930 Fatty Liver Diseases 0.000 claims abstract description 13
- 206010019708 Hepatic steatosis Diseases 0.000 claims abstract description 13
- 208000010706 fatty liver disease Diseases 0.000 claims abstract description 13
- 231100000240 steatosis hepatitis Toxicity 0.000 claims abstract description 13
- 102000007330 LDL Lipoproteins Human genes 0.000 claims abstract description 12
- 108010007622 LDL Lipoproteins Proteins 0.000 claims abstract description 12
- 102000015779 HDL Lipoproteins Human genes 0.000 claims abstract description 11
- 108010010234 HDL Lipoproteins Proteins 0.000 claims abstract description 11
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 159000000007 calcium salts Chemical class 0.000 claims description 4
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- 150000003626 triacylglycerols Chemical class 0.000 claims 1
- 208000008589 Obesity Diseases 0.000 abstract description 23
- 235000020824 obesity Nutrition 0.000 abstract description 23
- 210000004369 blood Anatomy 0.000 abstract description 15
- 239000008280 blood Substances 0.000 abstract description 15
- 108090000623 proteins and genes Proteins 0.000 abstract description 15
- 230000037149 energy metabolism Effects 0.000 abstract description 13
- 102000015494 Mitochondrial Uncoupling Proteins Human genes 0.000 abstract description 11
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 abstract description 11
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 10
- 210000003486 adipose tissue brown Anatomy 0.000 abstract description 7
- 230000004060 metabolic process Effects 0.000 abstract description 6
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 4
- 230000000476 thermogenic effect Effects 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 230000003213 activating effect Effects 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 48
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 15
- 239000008103 glucose Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 12
- 210000000577 adipose tissue Anatomy 0.000 description 10
- 238000013218 HFD mouse model Methods 0.000 description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 9
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 229910021642 ultra pure water Inorganic materials 0.000 description 7
- 239000012498 ultrapure water Substances 0.000 description 7
- 206010022489 Insulin Resistance Diseases 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 235000009200 high fat diet Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 4
- 238000011047 acute toxicity test Methods 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000002224 dissection Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 208000030159 metabolic disease Diseases 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 230000010627 oxidative phosphorylation Effects 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000031648 Body Weight Changes Diseases 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 241000581650 Ivesia Species 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 230000004579 body weight change Effects 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000035924 thermogenesis Effects 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102100039441 Cytochrome b-c1 complex subunit 2, mitochondrial Human genes 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 1
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 101000746756 Homo sapiens Cytochrome b-c1 complex subunit 2, mitochondrial Proteins 0.000 description 1
- 101000874160 Homo sapiens Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 1
- 108010019598 Liraglutide Proteins 0.000 description 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 1
- 108050002686 Mitochondrial brown fat uncoupling protein 1 Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 238000009004 PCR Kit Methods 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000007683 Pediatric Obesity Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 206010041969 Steatorrhoea Diseases 0.000 description 1
- 102100035726 Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial Human genes 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000000593 adipose tissue white Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 238000007446 glucose tolerance test Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000037308 hair color Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229960002701 liraglutide Drugs 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 230000006705 mitochondrial oxidative phosphorylation Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000015816 nutrient absorption Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000005813 organ abnormality Effects 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 208000001162 steatorrhea Diseases 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Child & Adolescent Psychology (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明属于生物医药技术领域,具体涉及中康酸在制备用于预防或治疗代谢综合征的药物中的应用。本发明提供的应用,为中康酸或其药学上可接受的制剂在制备用于预防或治疗代谢综合征的药物中的应用。本发明研究证实,中康酸能够调节机体能量代谢,还能通过激活棕色脂肪的UCP1及产热基因以起到白色脂肪棕色化的效果,并且能够促进机体血糖的代谢水平加快,降低机体内总胆固醇、甘油三酯和低密度脂蛋白的含量,并提高高密度脂蛋白的含量。因此中康酸在制备改善肥胖症、脂肪肝或糖尿病的药物中具有应用前景,本发明能够为上述疾病的防治提供一条新途径。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种中康酸在制备用于预防或治疗代谢综合征的药物中的应用。
背景技术
肥胖被定义为由体内脂肪积聚过多或分布异常而造成的慢性代谢性疾病。肥胖首先引起胰岛素抵抗,进而导致肥胖症、糖尿病、高血压、高脂血症、动脉粥样硬化、心脑血管疾病等一系列代谢紊乱症状的发生。近年来,肥胖在世界范围内呈现出爆发增长的趋势,尽管人们花费了大量时间和经济成本在饮食控制和体质改善上,但其发生率仍持续上升。据估计,全世界有4.0亿人存在肥胖问题。我国的肥胖症患病率近年来也呈上升趋势。据统计,我国目前拥有超重者至少2.7亿人次。近年来,我国投入到肥胖及其相关疾病的防治费用飞速上涨。不仅如此,肥胖尤其是儿童型肥胖的迅猛发展也必然会对全民的身体素质和整个社会的和谐发展产生无法估量的影响。
目前,临床上用作肥胖治疗剂的处方药主要是用来控制食欲和抑制营养吸收,但它们均具有一定的毒副作用。例如,奥利司他是获美国食品药品管理局(FDA)批准的第一个减肥处方药。它能够特异性抑制人体胃肠道中负责消化脂肪的酶,阻止脂肪在消化道的吸收,从而减少热量摄入,进而控制体重。但是,未消化的脂肪沿着胃肠道移动的同时会引发腹泻、脂肪泻等副作用。这些副作用会导致患者需穿着成人纸尿裤,难以进行正常社会生活。此外,作为GLP-1受体的激动剂,利拉鲁肽能够调节胰岛素分泌、抑制食欲、延缓胃排空、增加饱胀感。但是它同时会引发胰腺炎、恶心、呕吐等副作用,并且尤其对髓样甲状腺癌和2型多发内分泌腺瘤患者禁用。因此,鉴于现有的肥胖治疗剂通常具有毒副作用的现状,亟需寻找一种安全有效的方法来控制肥胖的发展。
中康酸,即反式-2-甲基-2-丁烯二酸。现有最新研究证实中康酸具有抗炎作用,可以降低巨噬细胞的炎症因子分泌,降低巨噬细胞的T细胞招募能力。然而,目前尚未见中康酸在肥胖症防治方面的应用以及作用效果的相关报道。
发明内容
为了解决上述问题,本发明的目的在于提供中康酸或其药学上可接受的制剂在制备用于预防或治疗代谢综合征的药物中的应用,代谢综合征具体为肥胖症、脂肪肝或II型糖尿病中的一种。
同时,本发明的另一目的在于提供中康酸或其药学上可接受的制剂在制备改善机体能量代谢的药物中的应用。
为实现本发明目的,本发明采用的技术方案是:
中康酸或其药学上可接受的制剂在制备用于预防或治疗代谢综合征的药物中的应用,所述代谢综合征为肥胖症、脂肪肝或II型糖尿病中的一种。
进一步优选地,中康酸药学上可接受的制剂为药学上可接受的盐或药学上可接受的酯;所述药学上可接受的盐为钠盐、钾盐、钙盐中的一种或多种。
优选地,所述预防或治疗代谢综合征的药物由中康酸或其药学上可接受的制剂与药用辅料组成。作为进一步优选的方案,药用辅料为淀粉和/或用于促进吸收或缓释的纳米颗粒。
本发明还提供中康酸或其药学上可接受的制剂在制备改善机体能量代谢的药物中的应用。
优选地,中康酸药学上可接受的制剂为药学上可接受的盐或药学上可接受的酯;所述药学上可接受的盐为钠盐、钾盐、钙盐中的一种或多种。
优选地,所述改善机体能量代谢的药物由中康酸或其药学上可接受的制剂与药用辅料组成。作为进一步优选的方案,药用辅料为淀粉和/或用于促进吸收或缓释的纳米颗粒。
本发明的有益效果在于:
本发明通过动物试验首次发现并证实,中康酸能够激活高脂饮食诱导小鼠机体的脂肪产热活性来消耗机体内多余的能量,进而可以有效地调节机体能量代谢。并且,中康酸能够通过激活棕色脂肪的UCP1及产热基因以起到白色脂肪棕色化的效果,从而达到抗肥胖及改善脂肪肝的效果。因此中康酸具有开发作为改善机体能量代谢或肥胖症药物的潜力。并且,中康酸能够促进小鼠体内血糖的代谢水平加快,降低机体内总胆固醇、甘油三酯和低密度脂蛋白的含量,并提高高密度脂蛋白的含量,因此中康酸在制备改善脂肪肝或糖尿病的药物中同样具有应用前景。
本发明针对目前对于能量代谢综合征例如肥胖症、脂肪肝、糖尿病的药物研究现状,提供一种通过改善机体能量代谢而用于预防和/或治疗代谢综合征的新型药物,能够为预防和/或治疗代谢综合征开辟一条新颖的途径。
附图说明
图1为本发明中NC组、HFD组和HFD+MA组三组小鼠体重变化的检测结果;
图2为本发明中NC组、HFD组和HFD+MA组三组小鼠各脂肪组织重量变化的结果;
图3为本发明中NC组、HFD组和HFD+MA组三组小鼠各脂肪组织HE染色的结果;
图4为本发明中NC组、HFD组和HFD+MA组三组小鼠的葡萄糖耐量的检测结果;
图5为本发明中NC组、HFD组和HFD+MA组三组小鼠的胰岛素耐量的检测结果;
图6为本发明中NC组、HFD组和HFD+MA组三组小鼠血清中TCHO(总胆固醇)、TG(甘油三酯)、LDL(低密度脂蛋白)和HDL(高密度脂蛋白)含量的检测结果;
图7为本发明中NC组、HFD组和HFD+MA组三组小鼠的UCP1蛋白及氧化磷酸化相关蛋白的表达结果;
图8为本发明中NC组、HFD组和HFD+MA组三组小鼠的UCP1的mRNA相对表达量的检测结果;
以上附图中,NC组表示灌喂等体积无菌超纯水的普通饲料小鼠组,HFD组表示灌喂等体积无菌超纯水的高脂诱导的HFD小鼠组,HFD+MA组表示以2mg/kg/天的剂量灌喂中康酸的高脂诱导的HFD小鼠组。
具体实施方式
以下结合附图以及具体实施方式,对本发明做进一步描述。应当理解,下述实施例仅是对本发明的进一步阐明,而非对本发明的限制。
除非特别指明,以下实施例中所用的试剂均可从商业渠道获得。以下实施例和试验例中,所用的昆明小鼠购自河南省实验动物中心,所用的C57BL/6小鼠购自北京维通利华实验动物技术有限公司。中康酸购自上海麦克林生化科技有限公司。中康酸溶液的配制方法为:将中康酸粉末溶于无菌超纯水,得到终浓度的中康酸溶液。
实施例1
中康酸用于制备预防或治疗肥胖症的药物。
实施例2
中康酸用于制备预防或治疗脂肪肝的药物。
实施例3
中康酸用于制备预防或治疗II型糖尿病的药物。
实施例4
中康酸用于制备改善机体能量代谢的药物。
在其他的实施例中,可采用中康酸药学上可接受的制剂进行上述药物的制备,中康酸药学上可接受的制剂可选择药学上可选自接受的盐或药学上可接受的酯。药学上可接受的盐可选自钠盐、钾盐、钙盐中的一种或多种。上述药物可由中康酸或其药学上可接受的制剂与药用辅料混合来制备,可以使用制剂领域常用辅料,采用常规方法来制备上述药物。例如药用辅料可采用淀粉和/或用于促进吸收或缓释的纳米颗粒。
试验例1中康酸急性毒性试验
取20只昆明(KM)小鼠,分为对照组和给药组,每组雌雄各5只。检疫后一周进行中康酸急性毒性实验。对照组给予无菌超纯水,给药组给予500mg/kg中康酸(药效学剂量的250倍)。给药后,分别于5分钟、15分钟、30分钟、1小时、2小时、4小时、6小时各观察1次动物的毒性反应情况,于次日开始每日观察记录小鼠的一般状况,包括行为状态、粪、尿、毛色及眼、口、鼻和肛门等有无异常分泌物,连续观察14天。在给药当天及给药后的1、3、7及14天对小鼠进行称重(其中,给药当天计为0天体重,数据用平均数±标准差表示,增加量表明是第14天和第0天之间的增量)。在给药14天后,对所有小鼠进行解剖,观察小鼠各个脏器是否发生病变并进行记录。结果如表1和表2所示。
表1中康酸在急性毒性试验中对小鼠体质量变化检测结果
表2中康酸在急性毒性试验中对动物存活的影响以及尸检结果
表1数据的统计学分析结果表明,给药前,两组小鼠的体质量无明显差异(P>0.05)。从给药后第2天开始,两组小鼠的体质量逐天呈均衡上升趋势,统计结果显示四组小鼠在相应天数的质量增长均无显著性差异(P值均>0.05)。
由表2可知,给药后14天内,小鼠均未出现异常反应及死亡情况。对小鼠进行剖检后未发现脏器异常。
以上试验结果表明,中康酸以25mg/mL的浓度和20mL/kg体积对小鼠灌胃给药,最大单次给药量达500mg/kg,相当于临床用药量250倍。给药后小鼠均未出现异常状况,给药14天内小鼠未出现死亡现象。这表明中康酸口服给药具有良好的安全性。
试验例2中康酸药效学试验
试验分组:“NC”组表示灌喂等体积无菌超纯水的普通饲料小鼠组,“HFD”组表示灌喂等体积无菌超纯水的高脂诱导的HFD小鼠组,“HFD+MA”组表示以2mg/kg/天的剂量灌喂中康酸的高脂诱导的HFD小鼠组。
小鼠模型的构建:取4周龄C57BL/6小鼠30只,随机分为三组,其中,NC组(10只)、HFD组(10只)和HFD+MA(10只),构建高脂饮食诱导肥胖模型。
试验过程:每日用中康酸溶液灌喂HFD+MA组小鼠,剂量为2mg/kg/天,同时灌喂NC组、HFD组小鼠等体积的无菌超纯水。灌胃8周,在此期间,每周称重并于第8周检测葡萄糖耐量、胰岛素耐量等指标。8周后取材,进行后续指标分析。具体指标和测试结果如下所示。
一、体重变化测试
体重测试采用常规称重方式进行,NC组、HFD组和HFD+MA组三组小鼠每周体重变化的检测结果如图1所示。
由图1可知,相较于HFD组,高脂诱导的HFD小鼠每天饲喂中康酸可以有效抑制体重增加,饲喂第3周开始,体重出现显著差异,到第8周体重差异有2.26克(其中第3-4周是“*”,第5-7周是“**”,第8周是“***”,分别表示p<0.05、p<0.01和p<0.001,“*”表示HFD+MA组与HFD组比较)。
二、脂肪组织重量变化以及H&E染色
8周后对所有动物进行解剖,对脂肪组织进行称重以及脂肪组织的H&E染色实验。H&E染色的实验过程为:将脂肪组织固定于4%多聚甲醛中,固定24小时后即可进行后续试验。首先将组织进行脱水及包埋,然后将包埋好的组织切成4μm的切片。之后将切片进行脱蜡处理,然后用苏木素及伊红染色,最后进行脱水并用中性树胶封片。
其中,NC组、HFD组和HFD+MA组小鼠解剖后各脂肪组织重量变化的结果如图2所示。NC组、HFD组和HFD+MA组三组小鼠解剖后各脂肪组织的H&E染色结果如图3所示。
由图2可知,高脂诱导的HFD小鼠饲喂中康酸后,棕色脂肪(BAT)、皮下脂肪(sWAT)和附睾脂肪(eWAT)组织的重量均显著降低。说明中康酸具有有效降低机体脂肪含量的作用。
由图3可知,与高脂诱导的HFD小鼠相比,饲喂中康酸后,小鼠各脂肪组织中脂肪细胞体积明显变小,脂滴含量明显降低。
三、葡萄糖耐量及胰岛素耐量检测
葡萄糖耐量测定过程为:在实验结束前一周内进行葡萄糖耐量的测定,在测定前将小鼠禁食不禁水12小时。测定禁食后小鼠尾尖血液的血糖值,并记作0min血糖值。随后取0.15g/mL葡萄糖溶液按10mL/kg的量给小鼠进行腹腔注射,并在注射后15、30、60、90和120分钟测量血糖。
胰岛素耐量测定过程为:在实验结束前一周内进行胰岛素耐量的测定,在测定前将小鼠禁食不禁水4小时。测定禁食后小鼠尾尖血液的血糖值,并记作0min血糖值。随后取0.075U/mL胰岛素溶液按10mL/kg的量给小鼠进行腹腔注射,并在注射后15、30、60、90和120分钟测量血糖。
NC组、HFD组和HFD+MA组小鼠的葡萄糖耐量及胰岛素耐量的检测结果如图4、5所示。
由图4可知,葡萄糖耐量结果表明,高脂诱导的HFD小鼠饲喂中康酸后,各个时间点的血糖较高脂饮食组相比均有所降低,且曲线下面积(AUC)也显著降低。
由图5可知,胰岛素耐量结果表明,在腹腔注射胰岛素后,HFD+MA组的血糖水平下降较快,并能较快恢复,且显著降低了曲线下面积(AUC)。
四、总胆固醇、甘油三酯、低密度脂蛋白量及高密度脂蛋白检测
上述指标检测的过程为:小鼠禁食不禁水12小时后,将小鼠进行麻醉并采血。将小鼠血液以3000rpm/min离心15min后,吸取上清液即得待测血清。总胆固醇、甘油三酯、低密度脂蛋白量及高密度脂蛋白检测试剂盒购自南京建成生物工程研究所,具体操作程序遵循制造商产品说明书的说明,在此不再赘述。
NC组、HFD组和HFD+MA组三组小鼠血清中总胆固醇(TCHO)、甘油三酯(TG)、低密度脂蛋白(LDL)和高密度脂蛋白(HDL)含量的检测结果如图6所示。
由图6可知,在饲喂中康酸后,高脂诱导的HFD小鼠血清中的总胆固醇、甘油三酯和低密度脂蛋白含量显著降低,并在一定程度上升高了高密度脂蛋白的浓度。说明中康酸对机体内总胆固醇、甘油三酯以及低密度脂蛋白的代谢具有促进作用。
五、UCP1蛋白及氧化磷酸化相关蛋白的表达结果
测试过程为:用含有蛋白酶抑制剂的RIPA裂解缓冲液从冷冻的棕色脂肪组织中提取总蛋白,离心,取上清液。使用BCA蛋白质测定试剂盒测量上清液中的蛋白质浓度。用SDS加载缓冲液加热变性蛋白质之后,将含有蛋白质的样品加载到12% SDS–PAGE凝胶上电泳分离。电泳后,将蛋白质转移到PVDF膜上,在室温下用5%脱脂牛奶封闭1h,之后与anti-UCP1、anti-OXPHOS和anti-Actin在4℃孵育过夜。将膜与相应的二级抗体在室温下孵育2小时。采用化学发光技术检测蛋白的表达水平。结果如图7所示。
由图7可知,中康酸饲喂后,高脂诱导的HFD小鼠的UCP1、氧化磷酸化相关蛋白(ATP5A、UQCRC2、SDHB、NDUFB8)的蛋白表达水平显著增加。UCP1位于线粒体内膜中,主要与控制体温和能量代谢有关。增加棕色脂肪组织中UCP1的活性和线粒体氧化磷酸化蛋白的表达可以改善线粒体的功能,增加产热,改善能量代谢,并有助于对抗肥胖和代谢紊乱。
六、UCP1的mRNA相对表达水平结果
使用Trizon从棕色脂肪组织中提取总RNA,并用cDNA逆转录试剂盒进行逆转录,然后用Green PCR试剂盒对目的基因进行定量分析。NC组、HFD组和HFD+MA组三组小鼠的UCP1的mRNA相对表达水平见图8所示。
由图8可知,相较于对照组和高脂诱导组,中康酸饲喂后,高脂诱导的HFD小鼠的UCP1的mRNA相对表达水平显著增加。此结果与蛋白表达水平结果一致,表明中康酸能够通过上调产热基因UCP1的表达,改善机体能量代谢,增加机体产热,改善高脂饮食诱导的小鼠肥胖。
综上所述,本发明研究证实,中康酸能够激活高脂饮食诱导小鼠的脂肪产热活性来消耗机体内多余的能量,进而可以有效地调节机体能量代谢,改善高脂饮食诱导的小鼠的肥胖症。并且,中康酸能够促进小鼠体内血糖的代谢水平加快,因而在制备防治糖尿病的药物方面具有应用前景。此外,本发明证实,中康酸能够降低机体内总胆固醇、甘油三酯和低密度脂蛋白的含量,并提高高密度脂蛋白的含量,说明中康酸在制备防治脂肪肝的药物中具有应用前景。因此,本发明能够为预防和/或治疗上述代谢综合征开辟一条新的途径。
Claims (3)
1.中康酸或其药学上可接受的盐在制备用于预防或治疗脂肪肝的药物中的应用,其特征在于,中康酸通过降低机体内总胆固醇、甘油三酯和低密度脂蛋白的含量,并提高高密度脂蛋白的含量,从而预防或治疗脂肪肝。
2.如权利要求1所述的中康酸或其药学上可接受的盐在制备用于预防或治疗脂肪肝的药物中的应用,其特征在于,所述药学上可接受的盐为钠盐、钾盐、钙盐中的一种或多种。
3.如权利要求1或2所述的中康酸或其药学上可接受的盐在制备用于预防或治疗脂肪肝的药物中的应用,其特征在于,所述用于预防或治疗脂肪肝的药物由中康酸或其药学上可接受的盐与药用辅料组成。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211246070.6A CN115590844B (zh) | 2022-10-12 | 2022-10-12 | 中康酸在制备用于预防或治疗代谢综合征的药物中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211246070.6A CN115590844B (zh) | 2022-10-12 | 2022-10-12 | 中康酸在制备用于预防或治疗代谢综合征的药物中的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115590844A CN115590844A (zh) | 2023-01-13 |
CN115590844B true CN115590844B (zh) | 2024-03-15 |
Family
ID=84846720
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211246070.6A Active CN115590844B (zh) | 2022-10-12 | 2022-10-12 | 中康酸在制备用于预防或治疗代谢综合征的药物中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115590844B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10041903A1 (de) * | 2000-08-25 | 2002-03-07 | Bayer Ag | Fluoreszenzaktive Aconitsäurederivate |
US6620424B1 (en) * | 1998-10-27 | 2003-09-16 | Suntory Limited | Process for producing glycolytic metabolism regulators |
CN114209684A (zh) * | 2021-12-24 | 2022-03-22 | 北京谷海天目生物医学科技有限公司 | 衣康酸在制备预防和/或治疗超重或肥胖药物或预防超重或肥胖的保健品中的应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017142855A1 (en) * | 2016-02-15 | 2017-08-24 | Artyomov Maxim | Immunomodulatory agents and methods of use thereof |
-
2022
- 2022-10-12 CN CN202211246070.6A patent/CN115590844B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6620424B1 (en) * | 1998-10-27 | 2003-09-16 | Suntory Limited | Process for producing glycolytic metabolism regulators |
DE10041903A1 (de) * | 2000-08-25 | 2002-03-07 | Bayer Ag | Fluoreszenzaktive Aconitsäurederivate |
CN114209684A (zh) * | 2021-12-24 | 2022-03-22 | 北京谷海天目生物医学科技有限公司 | 衣康酸在制备预防和/或治疗超重或肥胖药物或预防超重或肥胖的保健品中的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN115590844A (zh) | 2023-01-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Wan et al. | Gastrodin improves nonalcoholic fatty liver disease through activation of the adenosine monophosphate–activated protein kinase signaling pathway | |
WO2019105060A1 (zh) | 锰型高稳定性超氧化物歧化酶的应用 | |
Fang et al. | Crocin improves insulin sensitivity and ameliorates adiposity by regulating AMPK-CDK5-PPARγ signaling | |
CN116077536B (zh) | 一种用于改善肥胖相关代谢疾病的微生态活菌制剂及其制备方法和应用 | |
Lu et al. | Bifidobacterium animalis F1-7 in combination with konjac glucomannan improves constipation in mice via humoral transport | |
Hou et al. | Taurine transporter regulates adipogenic differentiation of human adipose-derived stem cells through affecting Wnt/β-catenin signaling pathway | |
CN116531410B (zh) | 白色葡萄球菌在制备组合物中的应用 | |
Sun et al. | Early oral nutrition improves postoperative ileus through the TRPA1/CCK1-R-mediated mast cell-nerve axis | |
KR102397916B1 (ko) | 건강한 임산부 모유 유래 혐기성 인체 균주 및 이를 이용한 대사성 질환의 예방 또는 치료방법 | |
CN115590844B (zh) | 中康酸在制备用于预防或治疗代谢综合征的药物中的应用 | |
Yi et al. | Intervention effects of lotus leaf flavonoids on gastric mucosal lesions in mice infected with Helicobacter pylori | |
Han et al. | The roles and mechanisms of miR-26 derived from exosomes of adipose-derived stem cells in the formation of carotid atherosclerotic plaque | |
CN116004481A (zh) | 一种肠道菌株及其应用 | |
Chen et al. | Hibiscus manihot L improves obesity in mice induced by a high-fat diet | |
CN109550051A (zh) | 组蛋白去甲基化酶kdm6a抑制剂在制备肥胖症治疗药物的用途 | |
CN116585329A (zh) | 阿伦酸在制备治疗肝炎和肺纤维化药物中的用途 | |
Zhu et al. | Probiotic yogurt regulates gut microbiota homeostasis and alleviates hepatic steatosis and liver injury induced by high‐fat diet in golden hamsters | |
US20230226018A1 (en) | Application of compound using intra-cyclic peroxo-bridged sesquiterpenes as parent nucleus in metabolism-related fatty liver diseases | |
US20230106742A1 (en) | Composition for inducing browning, containing milk exosomes | |
Li et al. | MiRNA‐100 ameliorates diabetes mellitus‐induced erectile dysfunction by modulating autophagy, anti‐inflammatory, and antifibrotic effects | |
CN109939122B (zh) | 调控一碳代谢影响肿瘤干细胞干性的物质的应用 | |
Wen et al. | Effects of dandelion tea on type II collagen induced arthritis in mice by regulation of ROR-γt/Foxp3 signaling | |
CN115990194B (zh) | 植物乳杆菌hnu082在制备缓解肝脏炎症药品的应用 | |
CN111544455B (zh) | 益生菌株或其代谢产物用于制备降胆固醇的组合物的用途 | |
Ren et al. | Red Raspberry Extracts Inhibit A549 Lung Cancer Cell Migration, Invasion, and Epithelial-Mesenchymal Transition Through the Epidermal Growth Factor Receptor/Signal Transducer and Activator of Transcription-3 Signaling Pathway |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |