CN111544459B - 一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用 - Google Patents
一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用 Download PDFInfo
- Publication number
- CN111544459B CN111544459B CN202010525304.5A CN202010525304A CN111544459B CN 111544459 B CN111544459 B CN 111544459B CN 202010525304 A CN202010525304 A CN 202010525304A CN 111544459 B CN111544459 B CN 111544459B
- Authority
- CN
- China
- Prior art keywords
- chemotherapy
- radiotherapy
- ovarian
- seed oil
- application
- 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
- 230000002611 ovarian Effects 0.000 title claims abstract description 66
- 230000006378 damage Effects 0.000 title claims abstract description 50
- 238000001959 radiotherapy Methods 0.000 title claims abstract description 49
- 238000002512 chemotherapy Methods 0.000 title claims abstract description 48
- 208000027418 Wounds and injury Diseases 0.000 title claims abstract description 31
- 208000014674 injury Diseases 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 title claims abstract description 21
- 235000013399 edible fruits Nutrition 0.000 title claims abstract description 20
- 235000013402 health food Nutrition 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 241000229143 Hippophae Species 0.000 claims abstract description 57
- 235000003145 Hippophae rhamnoides Nutrition 0.000 claims abstract description 50
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 45
- 241000196324 Embryophyta Species 0.000 claims abstract description 18
- 235000019198 oils Nutrition 0.000 claims abstract description 18
- 239000000839 emulsion Substances 0.000 claims description 6
- 239000000865 liniment Substances 0.000 claims description 6
- 229940040145 liniment Drugs 0.000 claims description 6
- 239000006210 lotion Substances 0.000 claims description 6
- 239000002674 ointment Substances 0.000 claims description 6
- 239000006187 pill Substances 0.000 claims description 6
- 239000007901 soft capsule Substances 0.000 claims description 6
- 239000000829 suppository Substances 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 210000001672 ovary Anatomy 0.000 abstract description 30
- 230000012173 estrus Effects 0.000 abstract description 23
- 230000000694 effects Effects 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 235000013305 food Nutrition 0.000 abstract description 5
- 241000699670 Mus sp. Species 0.000 description 31
- 230000006870 function Effects 0.000 description 29
- 108010005853 Anti-Mullerian Hormone Proteins 0.000 description 24
- 102100030173 Muellerian-inhibiting factor Human genes 0.000 description 24
- 239000000868 anti-mullerian hormone Substances 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 11
- 229940011871 estrogen Drugs 0.000 description 11
- 239000000262 estrogen Substances 0.000 description 11
- 230000009467 reduction Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 7
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 7
- 235000003935 Hippophae Nutrition 0.000 description 7
- 229960002092 busulfan Drugs 0.000 description 7
- 229960004397 cyclophosphamide Drugs 0.000 description 7
- 210000000287 oocyte Anatomy 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 229940044683 chemotherapy drug Drugs 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 230000035558 fertility Effects 0.000 description 5
- 229940088597 hormone Drugs 0.000 description 5
- 239000005556 hormone Substances 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 206010016654 Fibrosis Diseases 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 210000002919 epithelial cell Anatomy 0.000 description 4
- 230000004761 fibrosis Effects 0.000 description 4
- 210000002503 granulosa cell Anatomy 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 230000016087 ovulation Effects 0.000 description 4
- 230000027758 ovulation cycle Effects 0.000 description 4
- 230000001850 reproductive effect Effects 0.000 description 4
- 230000001568 sexual effect Effects 0.000 description 4
- 201000000736 Amenorrhea Diseases 0.000 description 3
- 206010001928 Amenorrhoea Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 231100000540 amenorrhea Toxicity 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000003163 gonadal steroid hormone Substances 0.000 description 3
- 231100000535 infertility Toxicity 0.000 description 3
- 208000000509 infertility Diseases 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 230000000737 periodic effect Effects 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 210000003756 cervix mucus Anatomy 0.000 description 2
- 210000004246 corpus luteum Anatomy 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 231100000502 fertility decrease Toxicity 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000002055 immunohistochemical effect Effects 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 230000005906 menstruation Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 231100000377 ovarian toxicity Toxicity 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 235000013619 trace mineral Nutrition 0.000 description 2
- 239000011573 trace mineral Substances 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- HBOQXIRUPVQLKX-UHFFFAOYSA-N 2,3-di(octadeca-9,12-dienoyloxy)propyl octadeca-9,12-dienoate Chemical compound CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC HBOQXIRUPVQLKX-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 230000005971 DNA damage repair Effects 0.000 description 1
- 206010012205 Delayed puberty Diseases 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000008238 LHRH Receptors Human genes 0.000 description 1
- 108010021290 LHRH Receptors Proteins 0.000 description 1
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- 101100460719 Mus musculus Noto gene Proteins 0.000 description 1
- 206010033266 Ovarian Hyperstimulation Syndrome Diseases 0.000 description 1
- 206010033122 Ovarian atrophy Diseases 0.000 description 1
- 206010036590 Premature baby Diseases 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000031016 anaphase Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 235000005473 carotenes Nutrition 0.000 description 1
- 150000001746 carotenes Chemical class 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 235000019804 chlorophyll Nutrition 0.000 description 1
- 229930002875 chlorophyll Natural products 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000007368 endocrine function Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001667 episodic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000035611 feeding Effects 0.000 description 1
- 210000005002 female reproductive tract Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002212 flavone derivatives Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical class C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000021121 meiosis Effects 0.000 description 1
- 231100000551 menstrual abnormality Toxicity 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 231100001043 ovarian atrophy Toxicity 0.000 description 1
- 208000015124 ovarian disease Diseases 0.000 description 1
- 201000004535 ovarian dysfunction Diseases 0.000 description 1
- 231100000543 ovarian dysfunction Toxicity 0.000 description 1
- 210000002394 ovarian follicle Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000031877 prophase Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009933 reproductive health Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 230000035946 sexual desire Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000004085 squamous epithelial cell Anatomy 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Veterinary Medicine (AREA)
- Reproductive Health (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Botany (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Mycology (AREA)
- Organic Chemistry (AREA)
- Medical Informatics (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Alternative & Traditional Medicine (AREA)
- Epidemiology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Medicinal Preparation (AREA)
Abstract
本申请公开了一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用，所述植物果油为沙棘籽油。本申请发现沙棘籽油对放化疗引起卵巢损伤有很好的治疗作用。沙棘籽油不仅可以治疗放化疗引起的小鼠卵巢损伤、动情周期的紊乱，还可以有效改善卵巢储备功能等。该发明对于直接利用沙棘籽油治疗放化疗引起的卵巢损伤提供了依据。
Description
技术领域
本申请涉及植物果油用途技术领域，特别涉及一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用。
背景技术
化疗和放疗是治疗恶性肿瘤以及防止肿瘤复发的主要方法，但放化疗不仅会带来骨髓造血和免疫功能抑制等严重不良反应，还会对性腺造成损害，导致不孕不育及性激素紊乱。在女性表现为卵巢损伤，卵巢萎缩，间质纤维化，原始卵泡减少，出现卵巢功能的损伤。卵巢损伤是目前导致女性生育力降低的主要原因，由卵巢损伤发展成的卵巢功能减退成为女性不孕的主要疾病。近年来，随着肿瘤发病人群趋于年轻化，放化疗导致卵巢功能损伤的发生率也逐步增加，育龄期妇女的生育力受到严重威胁。
卵巢储备功能是指卵巢内存留的可募集卵泡的数量和质量，反应女性的生育潜能和生殖内分泌功能。卵巢产生的卵母细胞数量减少，卵泡质量下降，导致生育能力下降和性激素的缺乏，称为卵巢储备功能下降。卵母细胞凋亡是放化疗致原始卵泡丢失、卵巢储备功能减退的主要原因。原始卵泡中的卵母细胞长期处于第一次减数分裂前期,对毒性物质所致的遗传性损伤很敏感,特别在DNA损伤修复失败时极易积累损伤,且多数情况下受损卵母细胞修复失败,进而凋亡。因此放化疗是导致卵巢储备功能降低的主要原因之一。目前对于放化疗引起卵巢损伤及卵巢损伤的修复治疗无特异性方法，对于确诊的卵巢损伤患者，也无明确的治疗方法和有效药物，只能对症治疗。因此积极寻找应对卵巢损伤的有效药物，成为临床亟待解决的问题。
中药沙棘在国具有悠久的药用历史，《四部医典》记载了沙棘有止咳、平喘、活血化瘀等作用。沙棘的活性成份有400多种，主要包括：黄酮类、粗纤维、多糖类、氨基酸、维生素、微量元素、胡萝卜素、蛋白质、有机酸、叶绿素等营养及活性成分；可以广泛应用于食品、医药、轻工、航天、农牧渔业等国民经济的许多领域。沙棘籽油是沙棘的主要成分，沙棘籽油营养丰富，据测定其中含有多种维生素、脂肪酸、微量元素、植物甾醇、亚油素、沙棘黄酮、α-生育酚、超氧化物等100多种活性物质和人体所需的各种氨基酸。沙棘籽油具有抗炎生肌、修复溃疡、抑瘤抗癌的功效，尤其对脑动脉硬化、心绞痛、高血脂等有显著疗效。迄今为止，尚没有报道沙棘籽油对放化疗引起卵巢损伤有治疗作用。
发明内容
本申请公开一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用，即沙棘籽油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用。
根据本申请的实施例，提供一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物中的应用，所述植物果油为沙棘籽油。
根据本申请的实施例，本申请提供一种植物果油在制备治疗由放化疗引起的卵巢损伤的保健食品中的应用，所述植物果油为沙棘籽油。
进一步地，所述药物的剂型包括汤剂、软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
进一步地，所述保健食品的剂型包括汤剂、软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
本申请首次证实沙棘籽油具有完全不同于以上所述的新功能：沙棘籽油对放化疗引起卵巢损伤有很好的治疗作用。沙棘籽油不仅可以治疗放化疗引起的小鼠卵巢损伤、动情周期的紊乱，还可以有效改善卵巢储备功能等。该发明对于直接利用沙棘籽油治疗放化疗引起的卵巢损伤提供了依据。
附图说明
为了更清楚地说明本申请实施例或现有技术中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本申请的实验设计图；
图2为本申请的技术路线图；
图3为各组小鼠卵巢组织石蜡切片H&E染色结果；
图4为各组小鼠阴道分泌物观察结果；
图5为各组小鼠雌激素E2水平的变化；
图6为各组小鼠卵巢组织免疫组化AMH表达结果；
图7为各组小鼠血清AMH含量的变化。
具体实施方式
本申请提供一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物中的应用，所述植物果油为沙棘籽油。
本申请提供一种植物果油在制备治疗由放化疗引起的卵巢损伤的保健食品中的应用，所述植物果油为沙棘籽油。
进一步地，所述药物的剂型包括汤剂、软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
进一步地，所述保健食品的剂型包括汤剂、软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
本申请证实沙棘籽油具有完全不同于以上所述的新功能：沙棘籽油对放化疗引起卵巢损伤有很好的治疗作用。沙棘籽油不仅可以治疗放化疗引起的小鼠卵巢损伤、动情周期的紊乱，还可以有效改善卵巢生殖内分泌激素水平以及卵巢储备功能等。该发明对于直接利用沙棘籽油治疗放化疗引起卵巢损伤提供了依据。
本申请旨在探讨沙棘籽油的治疗性应用对放化疗引起的卵巢组织损伤的治疗作用，为临床肿瘤治疗中应用大剂量的放化疗药物时所导致的卵巢损伤，提供有效的治疗方法和科学依据。
为了证实沙棘籽油具有上述新功能，做了如下实验。
1.技术方案
(1)建立放化疗药引起卵巢损伤的动物模型：
实验设计图如图1所示。
环磷酰胺(CY)和白消安(BUS)为临床常用抗癌药物，也是代表性的卵巢毒性药物。本申请通过成年雌性小鼠一次性腹腔注射120mg/kg环磷酰胺和10mg/kg白消安建立卵巢损伤小鼠模型。
(2)对化疗药引起卵巢损伤动物模型给予干预：
本实验采用12周龄雌性ICR小鼠，分为正常对照组、模型组、沙棘籽油治疗组、阳性对照组(GnRha组)，每组8只。
正常组给予生理盐水对照；
模型组给予一次性腹腔注射120mg/kg环磷酰胺和10mg/kg白消安建立卵巢损伤小鼠模型，后用生理盐水0.2ml持续灌胃天(每天灌胃是为了与模型组和沙棘籽油治疗组一致，规避灌胃操作带来的差异)。
沙棘籽油治疗组，从造模第1天起，每天沙棘籽油2.5ml/kg连续灌胃给药，第60天取材；
阳性对照组(GnRha组)，于造模第1天一次性皮下注射给予促性腺激素释放激素类似物(GnRha)38mg/kg，后生理盐水0.2ml每天持续灌胃至第60天取材。
所有组小鼠，在灌胃60天取材，观察卵巢的组织形态学改变，计数卵巢组织中各级卵泡数量，检测血清雌激素E2和抗苗勒氏管激素(AMH)水平，用免疫组化检测AMH蛋白的表达水平。
(3)实验结果监测及数据收集
所有小鼠，从12周龄开始，每4天检测并记录各组小鼠体重、摄食及动情周期变化，直至取材。取材后通过石蜡包埋剂切片染色技术，观察卵巢形态学改变。通过免疫组化技术检测AMH改变。
2.技术路线图
技术路线图如图2所示。
3.主要技术
1)建立化疗药引起卵巢损伤的动物模型
环磷酰胺(CY)和白消安(BUS)为临床常用抗癌药物，也是代表性的卵巢毒性药物。本研究通过成年雌性小鼠一次性腹腔注射120mg/kg环磷酰胺和10mg/kg白消安建立卵巢损伤小鼠模型
2)阴道脱落细胞冲洗液涂片法检测动情周期
用滴管吸取适量生理盐水，每隔4天，在同一时间点冲洗、吸取阴道分泌物于载玻片上，迅速于显微镜下观察细胞形态，判断动情周期。
4.实验结果
4.1沙棘籽油可以治疗放化疗引起小鼠卵巢组织病变。
放化疗对卵巢有短期和长期作用。短期作用发生在治疗过程中，是由于破坏了生长过程中的卵泡导致的短暂性的闭经，而长期的作用是破坏了原始卵泡所导致。多数的化疗药物优先作用于增殖快的细胞，从而抑制细胞的增生，而处于静止状态的原始卵泡并不是化疗药物的自然靶细胞，而烷化剂为细胞周期非特异性药物，及时细胞处于休眠状态也会受到影响，从而使原始卵泡的数量减少。
研究发现，化疗药会造成卵巢明显萎缩，组织严重纤维化，皮质增厚、结构混乱。如图3所示，正常组小鼠的卵巢在HE染色下可见多个不同发育阶段的卵泡及黄体，颗粒细胞形态完整且排列整齐紧密，形态完整；模型组小鼠的卵巢皮质增厚，结构混乱，间质纤维化，颗粒细胞掉落，皮质区原始卵泡数量明显减少；阳性对照组的卵巢虽然也出现部分损伤，如皮质纤维化、颗粒细胞减少等，但相对于模型组有很大改善；沙棘籽油治疗组小鼠卵巢组织形态良好，皮质区内原始卵泡数、初级卵泡数、成熟卵泡数以及卵泡总数均有明显增高，且形态接近正常对照组。
4.2沙棘籽油可以治疗放化疗引起的小鼠动情周期紊乱。
动情周期主要是指哺乳动物性成熟后，性功能衰退前，在性行为和生殖系统结构与功能上出现的周期性变化。雌性小鼠性成熟后，生殖器官发生增生、退化的周期性变化称为动情周期，具体指的是雌性哺乳动物从上一次发情开始至下一次发情开始，或指上一次排卵至下一次排卵之间的时间间隔。通常根据动物的精神状态、雌性动物对雄性动物产生的性欲表现、卵巢内卵泡的生长发育、排卵和黄体形成的情况及雌性生殖道(子宫、阴道等)的生理变化等几个主要方面，将发情周期划分为动情前期(前情期)、动情期、动情后期(后情期)及间情期(间期)，拥有规律的动情周期是哺乳动物性成熟的标志，意味着卵巢开始发挥功能。在临床中，接受放化疗的女性患者会出现月经失调的临床表现，表现为月经稀发、月经量少甚至闭经。表现在小鼠上，则为动情周期紊乱，即持续的间期。
如图4所示，动情前期(阳性对照组)可见成群或单独出现的梭形上皮细胞，白细胞较少。动情期(正常对照组)见大量鳞状上皮细胞，形状大而不规则，无核，白细胞消失；动情后期(沙棘籽油治疗组)可见多种细胞类型，白细胞，无核的上皮细胞及梭形上皮细胞；动情间期(模型组)可见大量白细胞，极少量梭形上皮细胞。经过造模后每天的连续动情周期观察发现：模型组小鼠在造模后的几天就出现动情周期紊乱，表现为持续的间期，提示卵巢功能严重损害；沙棘籽油治疗组小鼠在造模后也出现动情周期紊乱的现象，但随着持续的沙棘籽油的治疗，小鼠逐渐恢复了规律的动情周期；因此可证明，沙棘籽油对维持正常的动情周期有很好的作用。
4.3沙棘籽油可以治疗放化疗引起小鼠雌激素E2水平减退。
雌激素主导女性第二性征的发育和维持，并调控女性体内环境的稳定，控制女性的生命周期，同时周期性的月经、生育能力、丰满体态等均离不开雌激素的作用。雌激素与卵巢、输卵管、子宫以及阴道粘膜上靶细胞受体结合，引起细胞DNA、RNA和蛋白质合成增加，促进细胞分裂与生长，从而使上述这些靶器官生长发育，并维持其正常功能。E2是雌性激素中活性最强的一种，主要产自卵巢的卵泡和胎盘，少量产自肾上腺和睾丸。血清E2测定对评价各种月经异常是非常有用的指标：如女孩青春期提前或延迟、原发性或继发性闭经、卵巢损伤和功能减退等。
如图5所示，模型组小鼠血清雌激素E2水平明显降低，这表明放化疗可严重影响卵巢雌激素的分泌，进而影响其他激素使内分泌紊乱；而沙棘籽油组和GnRHa对照组小鼠血清雌激素E2水平与正常组接近。这说明沙棘籽油可治疗放化疗引起卵巢雌激素分泌减退。
4.4沙棘籽油可以逆转由放化疗引起小鼠卵巢储备功能的损伤。
卵巢储备功能反映卵巢皮质区卵泡生长发育形成优质卵母细胞的能力，指的是卵巢内存留卵泡的数量和质量，反映了女性的生育潜能。卵巢储备功能下降是指卵巢产生优质卵母细胞的能力减弱,导致生育能力下降,同时伴随性激素的异常。卵巢储备功能下降约占不孕症的10％,且呈现不断上升趋势,严重影响着广大妇女的生殖健康和生活质量。抗缪勒管激素(AMH)是由卵巢窦前卵泡和小窦卵泡的颗粒细胞分泌的蛋白，能够反映整个生命周期的卵巢储备功能。由于AMH参与小卵泡变成大卵泡，到卵泡成熟以及排卵、受孕的过程，因此AMH与卵巢储备功能息息相关。近年来，AMH在卵巢储备功能评估、女性辅助生殖诊疗中的重要价值日益凸显。
本申请用免疫组织化学法检测卵巢组织中AMH的表达情况。如图6所示，正常组小鼠卵巢颗粒细胞间有均匀的黄染部分，证明AMH在这些部位有表达；模型组小鼠的卵巢不但结构出现改变，而且颗粒细胞间黄染部分明显降低；阳性对照GnRHa组和沙棘籽油治疗组小鼠卵巢颗粒细胞间出现均匀的强度很高的黄染区，且沙棘籽油治疗组黄染比GnRHa组还要高，这说明沙棘籽油不但能增强受损卵巢的储备功能，而且作用强于促性腺激素释放激素类受体激动药，是用于治疗卵巢储备功能减退很好的药物。
4.5沙棘籽油可以治疗放化疗引起小鼠AMH激素含量降低。
AMH是一种卵巢颗粒细胞分泌的细胞因子，其对募集始基卵泡及生长发育与卵母细胞成熟等方面有重要的作用。AMH不会受到月经周期的控制，正常月经周期的患者其AMH水平基本保持稳定，且AMH能够反映卵巢窦卵泡的数量的大小，进而可预测卵巢储备及超排卵卵巢反应的相关指标。研究表明，AMH浓度水平与卵泡数呈正相关，说明AMH可作为放化疗所致卵巢损伤患者卵巢反应重要预测指标。
本申请应用酶联免疫吸附方法(ELISA)测定血清AMH水平。如图7所示，与模型组相比，沙棘籽油组和GnRHa对照组小鼠血清中，AMH含量与正常组接近，均高于模型组，这表明沙棘籽油明显能提高放化疗所致小鼠损伤卵巢中AMH的表达，更进一步证明，沙棘籽油对放化疗药引起的卵巢储备功能减低有很好的治疗作用。
由以上实验结果可知，
(1)沙棘籽油可以治疗放化疗引起小鼠卵巢组织改变，改善卵巢组织形态
(2)沙棘籽油可以治疗放化疗引起小鼠的动情周期紊乱，维持小鼠的正常生理周期
(3)沙棘籽油可以治疗放化疗引起小鼠雌激素水平减退
(4)沙棘籽油可以治疗放化疗引起小鼠卵巢储备功能的损伤
(5)沙棘籽油可以治疗放化疗引起小鼠AMH激素含量降低
(6)放疗和化疗对小鼠卵巢损伤的相似性，沙棘籽油对放化疗引起的卵巢功能异常的治疗均有保护作用。
本领域技术人员在考虑说明书及实践这里公开的申请后，将容易想到本申请的其它实施方案。本申请旨在涵盖本申请的任何变型、用途或者适应性变化，这些变型、用途或者适应性变化遵循本申请的一般性原理并包括本申请未公开的本技术领域中的公知常识或惯用技术手段。说明书和实施例仅被视为示例性的，本申请的真正范围和精神由下面的权利要求指出。
应当理解的是，本申请并不局限于上面已经描述的内容，并且可以在不脱离其范围进行各种修改和改变。本申请的范围仅由所附的权利要求来限制。
Claims (4)
1.一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物中的应用，所述植物果油为沙棘籽油。
2.一种植物果油在制备改善由放化疗引起的卵巢损伤的保健食品中的应用，所述植物果油为沙棘籽油。
3.根据权利要求1所述的应用，其特征在于，所述药物的剂型包括汤剂、软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
4.根据权利要求2所述的应用，其特征在于，所述保健食品的剂型包括汤剂、软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010525304.5A CN111544459B (zh) | 2020-06-10 | 2020-06-10 | 一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用 |
| US17/344,008 US11911426B2 (en) | 2020-06-10 | 2021-06-10 | Use of a plant in preparation of medicines and health products for preventing and treating ovarian injury |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010525304.5A CN111544459B (zh) | 2020-06-10 | 2020-06-10 | 一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111544459A CN111544459A (zh) | 2020-08-18 |
| CN111544459B true CN111544459B (zh) | 2021-12-07 |
Family
ID=71997739
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010525304.5A Active CN111544459B (zh) | 2020-06-10 | 2020-06-10 | 一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111544459B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112370446B (zh) * | 2020-12-03 | 2023-03-24 | 华中科技大学同济医学院附属同济医院 | Egcg药物组合物及其制备方法和在卵巢功能保护中的应用 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110075139B (zh) * | 2019-05-29 | 2021-07-30 | 宁夏医科大学 | 沙棘籽油在预防多囊卵巢综合征药物中的应用 |
-
2020
- 2020-06-10 CN CN202010525304.5A patent/CN111544459B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111544459A (zh) | 2020-08-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Malik et al. | Why leiomyomas are called fibroids: the central role of extracellular matrix in symptomatic women | |
| Giugliano et al. | The adjuvant use of N-palmitoylethanolamine and transpolydatin in the treatment of endometriotic pain | |
| Murdoch et al. | Preovulatory changes in prostaglandins E2 and F2α in ovine follicles | |
| CN110075139B (zh) | 沙棘籽油在预防多囊卵巢综合征药物中的应用 | |
| CN111544459B (zh) | 一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用 | |
| CN111686101A (zh) | 萝卜硫素在提高哺乳动物繁殖性能中的应用 | |
| Li et al. | Protective effect of Clinopodium chinense (Benth.) O. Kuntze against abnormal uterine bleeding in female rats | |
| EP0020649A1 (en) | CHORIONIC GONADOTROPINE COMPOSITIONS AND METHOD FOR USE THEREOF. | |
| TW201945024A (zh) | 用於經控制之卵巢刺激的組成物 | |
| CN110123851B (zh) | 沙棘籽油在治疗多囊卵巢综合征药物中的应用 | |
| CN111481579B (zh) | 一种植物果浆在制备预防由放化疗引起的卵巢损伤的药物和保健食品中的应用 | |
| Anderson et al. | Biological actions of relaxin in pigs and beef cattle | |
| Oehninger et al. | 9 Induction of ovulation for assisted reproduction programmes | |
| Luo et al. | Effect of GnRH-antagonist, mifepristone and letrozole on preventing ovarian hyperstimulation syndrome in rat model | |
| CN115300566B (zh) | 一种药物组合物在治疗桥本氏甲状腺炎的药物中的新用途 | |
| KR20020081273A (ko) | 불임치료용 ｆｓｈ의 용도 | |
| CN111643532B (zh) | 一种植物果浆在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用 | |
| CN114984028A (zh) | 黄芪甲苷的用途 | |
| Allen et al. | The induction of breeding activity in lactating ewes during anoestrus | |
| CN117883549B (zh) | 枸杞糖肽在制备改善卵巢功能不全的产品中的应用 | |
| CN111529557B (zh) | 一种植物果油在制备预防由放化疗引起的卵巢损伤的药物和保健食品中的应用 | |
| KR101582734B1 (ko) | 플라보피리돌을 유효성분으로 함유하는 자궁근종 예방 또는 치료용 조성물 | |
| CN107334786B (zh) | 双歧杆菌活菌胶囊及其在制备预防卵巢早衰药物中的应用 | |
| Chauhan et al. | Responses of different doses of prostaglandin F2 alpha on estrus induction, fertility and progesterone levels in subestrous buffaloes | |
| Rosenberg | Cystic ovaries in dairy cattle |
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 |