CN115721716A - Mdh2抑制剂在雄激素性脱发治疗中的应用 - Google Patents
Mdh2抑制剂在雄激素性脱发治疗中的应用 Download PDFInfo
- Publication number
- CN115721716A CN115721716A CN202210818009.8A CN202210818009A CN115721716A CN 115721716 A CN115721716 A CN 115721716A CN 202210818009 A CN202210818009 A CN 202210818009A CN 115721716 A CN115721716 A CN 115721716A
- Authority
- CN
- China
- Prior art keywords
- mdh2
- androgenetic alopecia
- inhibitor
- alopecia
- sirna
- 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.)
- Granted
Links
- 201000004384 Alopecia Diseases 0.000 title claims abstract description 89
- 101001033820 Homo sapiens Malate dehydrogenase, mitochondrial Proteins 0.000 title claims abstract description 71
- 201000002996 androgenic alopecia Diseases 0.000 title claims abstract description 71
- 102100039742 Malate dehydrogenase, mitochondrial Human genes 0.000 title claims abstract description 70
- 206010068168 androgenetic alopecia Diseases 0.000 title claims abstract description 68
- 239000003112 inhibitor Substances 0.000 title claims abstract description 32
- 238000011282 treatment Methods 0.000 title description 14
- 108020004459 Small interfering RNA Proteins 0.000 claims abstract description 33
- 230000014509 gene expression Effects 0.000 claims abstract description 24
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 17
- 239000004055 small Interfering RNA Substances 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 12
- 101150075558 CHGA gene Proteins 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 210000004761 scalp Anatomy 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 8
- 238000003753 real-time PCR Methods 0.000 claims description 8
- -1 prrx1 Proteins 0.000 claims description 7
- 239000000523 sample Substances 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 238000001262 western blot Methods 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000012502 risk assessment Methods 0.000 claims description 3
- 238000012360 testing method Methods 0.000 claims description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 2
- 238000013115 immunohistochemical detection Methods 0.000 claims description 2
- 231100000360 alopecia Toxicity 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 11
- 238000010172 mouse model Methods 0.000 abstract description 11
- 206010061218 Inflammation Diseases 0.000 abstract description 5
- 230000004054 inflammatory process Effects 0.000 abstract description 5
- 230000003779 hair growth Effects 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 210000004209 hair Anatomy 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 16
- 210000001519 tissue Anatomy 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 108010080146 androgen receptors Proteins 0.000 description 8
- 210000003780 hair follicle Anatomy 0.000 description 8
- 229960003604 testosterone Drugs 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 7
- 102100032187 Androgen receptor Human genes 0.000 description 7
- 239000003098 androgen Substances 0.000 description 7
- 230000003676 hair loss Effects 0.000 description 7
- 210000003491 skin Anatomy 0.000 description 7
- 229960003473 androstanolone Drugs 0.000 description 6
- 238000005119 centrifugation Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 208000024963 hair loss Diseases 0.000 description 5
- 210000001732 sebaceous gland Anatomy 0.000 description 5
- 101150101095 Mmp12 gene Proteins 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000008506 pathogenesis Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 101150019925 MDH2 gene Proteins 0.000 description 3
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 3
- 229940030486 androgens Drugs 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960004039 finasteride Drugs 0.000 description 3
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229960003632 minoxidil Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 2
- 102100037579 D-3-phosphoglycerate dehydrogenase Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000004125 Interleukin-1alpha Human genes 0.000 description 2
- 108010082786 Interleukin-1alpha Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 108010026217 Malate Dehydrogenase Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000002951 depilatory effect Effects 0.000 description 2
- 230000037149 energy metabolism Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004630 mental health Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 210000002374 sebum Anatomy 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 102100033875 3-oxo-5-alpha-steroid 4-dehydrogenase 2 Human genes 0.000 description 1
- 229940113178 5 Alpha reductase inhibitor Drugs 0.000 description 1
- 239000002677 5-alpha reductase inhibitor Substances 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241001248531 Euchloe <genus> Species 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 101000640851 Homo sapiens 3-oxo-5-alpha-steroid 4-dehydrogenase 2 Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 108091081021 Sense strand Proteins 0.000 description 1
- 239000006180 TBST buffer Substances 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 230000004156 Wnt signaling pathway Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000003778 catagen phase Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000032677 cell aging Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 238000011841 epidemiological investigation Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 208000028329 epileptic seizure Diseases 0.000 description 1
- 239000005452 food preservative Substances 0.000 description 1
- 235000019249 food preservative Nutrition 0.000 description 1
- 210000001061 forehead Anatomy 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 230000001295 genetical effect Effects 0.000 description 1
- 210000000442 hair follicle cell Anatomy 0.000 description 1
- 230000003781 hair follicle cycle Effects 0.000 description 1
- 210000004919 hair shaft Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002955 secretory cell Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000003797 telogen phase Effects 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
Abstract
本发明公开了新型雄激素性脱发的治疗靶点MDH2,以及公开了MDH2抑制剂在制备治疗雄激素性脱发药物中的应用。MDH2抑制剂在雄激素性脱发小鼠模型中可以抑制脱发及炎症相关基因(Mmp12、Sfrp2、Chga、Prrx1、Vim)的表达,进而促进毛发生长。本发明公开的MDH2抑制剂选自化合物16c,AMB5965675或小干扰RNA中的一种或多种。MDH2抑制剂具有成本低,毒副作用小,疗效显著的优点,为雄激素性脱发的治疗提供了新策略。
Description
技术领域
本发明属于雄激素性脱发治疗技术领域,具体涉及MDH2抑制剂在制备治疗雄激素性脱发药物中的应用。
背景技术
脱发是与细胞衰老有关的常见临床表现,主要分为瘢痕性脱发和非瘢痕性脱发,其中雄激素性脱发(androgenetic alopecia,AGA)是最为常见的一种脱发类型,为非瘢痕性脱发,分为男性型AGA与女性型AGA。AGA的病理特征性改变主要为毛囊微型化和毛囊周期改变,退行期、休止期毛囊增多,生长期毛囊减少,毛干粗细不均、毳毛的数目增加。流行病学调查显示,我国AGA的男性患病率为21.3%,女性为6.0%。男性AGA主要表现为前发际线后移或顶部进行性脱发,最终发展为头皮明显外露,并伴有头皮油腻。女性AGA临床表现主要为头顶弥漫性稀疏,保留前额发际线。AGA虽然对患者身体健康无明显影响,但直接影响患者的外观,对患者的个人形象、心理健康、工作学习及社会认同感有着极大的影响,甚至可出现生活质量下降,女性尤其明显。
AGA的具体发病机制目前尚未明确,其是多因素共同作用的结果。雄激素在AGA的发病中起着重要的作用,在具有遗传易感性的个体中,即使血液中雄激素浓度正常,也会发病。睾酮在5-α还原酶的作用下代谢为二氢睾酮。这种代谢物与雄激素受体(AR)更有亲和力,被认为是AGA患者头皮中雄激素介导效应的重要原因。在雄激素的作用下,毛囊毛乳头细胞分泌多种细胞因子,如转化生长因子-β(TGF-β)、白细胞介素-1α(IL-1α)和肿瘤坏死因子-α(TNF-α),可诱导毛囊生长期提前终止。不仅如此,遗传基因、前列腺素、Wnt信号通路和铁储备等都参与了AGA的发病过程。
目前,正式被美国FDA批准用于临床治疗雄激素脱发的药物包括米诺地尔(minoxidil)和非那雄胺(finasteride)。米诺地尔的治疗机制尚不完全明确,可能包含了多条途径,如开放细胞膜上ATP依赖的K+通道、影响雄激素受体(AR)活性及稳定性等。非那雄胺是一种II型5α-还原酶抑制剂,能够阻断睾酮(Testosterone,T)转变为活性更强的双氢睾酮(DHT)从而减弱雄激素对毛囊的抑制作用。目前二者虽广泛应用于临床,但均不能完全阻断病程进展,且都存在不同程度的不良反应。当下新药研发的主要靶点集中在AR,针对AR开发的新药较多。但这些药物均存在一定局限性,特别是对于AGA机制尚不明确的疾病。
因此,探索新的AGA治疗靶点具有广阔的市场前景。
发明内容
为了解决上述技术问题,本发明提供了一种新型AGA治疗靶点MDH2并验证了MDH2抑制剂对AGA的治疗用途。
本发明第一方面提供了MDH2抑制剂在制备治疗雄激素性脱发药物中的应用。所述MDH2抑制剂能够有效抑制雄激素性脱发。
在某些实施方式中,所述MDH2抑制剂对雄激素性脱发的治疗作用表现为抑制头皮中炎症相关基因的表达。
在某些实施方式中,所述炎症相关基因选自Mmp12、Sfrp2、Chga、Prrx1、Vim中一种或多种基因的表达。
在某些实施方式中,所述MDH2抑制剂选自化合物抑制剂或小干扰RNA。
在某些实施方式中,所述化合物抑制剂选自16c或AMB5965675。
所述AMB5965675结构为:
在某些实施方式中,所述小干扰RNA选自siRNA#1或siRNA#2;所述siRNA#1包含SEQID NO:1的正义链和SEQ ID NO:2的反义链;所述siRNA#2包含SEQ ID NO:3的正义链和SEQID NO:4的反义链。
本发明第二方面提供了MDH2检测试剂在制备雄激素性脱发风险评估试剂盒中的用途。
在某些实施方式中,所述MDH2检测试剂包括用于MDH2蛋白印迹检测的抗体、用于免疫组化检测的抗体或用于定量PCR的引物和探针。
在某些实施方式中,所述MDH2检测试剂或所述雄激素性脱发风险评估试剂盒的检测对象为受试者头皮组织。
本发明相对于现有技术具有的效果:
1)本发明通过对正常人和雄激素性脱发患者进行头皮活检,检测出差异表达基因MDH2,通过该差异表达因子的检测可以预测雄激素性脱发的发生风险。
2)本发明发现MDH2抑制剂通过有效抑制MDH2在雄激素性脱发小鼠模型中,阻止相关基因(Mmp12、Sfrp2、Chga、Prrx1、Vim)的转录,使得相关基因的表达量发生改变,相关基因表达的降低会促进雄激素性脱发模式小鼠的毛发生长,进而能够作为雄激素性脱发的一个治疗药物。
3)本发明提供的采用MDH2抑制剂制备雄激素性脱发的药物,具有成本低,毒副作用小,疗效显著的优点,为雄激素性脱发的治疗提供了新策略。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式描述中所需要使用的附图作简单地介绍。
图1显示雄激素性脱发患者以及正常志愿者头皮样本中MDH2的表达情况。
图2A为构建的小鼠雄激素性脱发模型中,各种MDH2抑制剂药物的治疗效果。图2B为构建的小鼠雄激素性脱发模型中,剃下的新生毛发重量统计图。
图2C为构建的小鼠雄激素性脱发模型中,MDH2在皮肤组织中的相对表达量。
图3A-3E分别显示抑制剂16c,AMB5965675,MDH2小干扰RNA,siRNA#1,siRNA#2对基因Mmp12(图3A)、Sfrp2(图3B)、Chga(图3C)、Prrx1(图3D)、Vim(图3E)的表达水平的影响。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施案例所描述的内容仅用于说明和解释本发明,并不用于限制权利要求书中所详细描述的本发明。除非特别说明,本发明采用的试剂、方法和设备如无特别说明,均为常规方法,所使用的试验材料如无特别说明,均可从商业公司获取。
如本文所用,术语“MDH2”,苹果酸脱氢酶(malate dehydrogenase,MDH)2,是三羧酸循环的重要氧化还原酶,MDH2主要被用来研究某些动物的遗传学特性和形态学特性。MDH2可通过影响mRNA的稳定性参与调节癫痫发作相关基因的表达,而MDH2的突变会导致三羧酸循环的破坏,进而影响细胞能量代谢,引发早发性线粒体表型性疾病。MDH2的上调可以增加细胞能量代谢,敲低MDH2会显著降低细胞ATP水平,升高细胞内活性氧浓度,同时降低DNA的合成效率。已有报道(Aimee Flores et.al,Experimental Dermatology.2021;30:448–456)称抑制TCA循环的原料—丙酮酸进入线粒体可以治疗脱发,而MDH2作为TCA循环的关键酶在TCA循环中发挥了关键作用。
如本文所用,术语“MDH2抑制剂”,指能够用于抑制MDH2活性和/或表达的化合物或者组合物。包括但不限于,16c,AMB5965675,根据序列合成的MDH2小干扰RNA,如siRNA#1,siRNA#2等等。化合物16c,结构式为(Ravi Naik et.al,J.Med.Chem.2017,60,8631-8646);化合物AMB5965675结构式为(Hyun Seung Ban et.al,PLOS ONE|DOI:10.1371/journal.pone.0162568September 9,2016)。
如本文所用,术语“MDH2小干扰RNA”,指能够用于诱导的转录后MDH2基因沉默的小干扰RNA。
如本文所用,术语“雄激素性脱发(AGA)”,androgenetic alopecia,是皮肤科的常见病与多发病,是一种具有遗传因素参与的且依赖雄激素作用的特征性秃发,往往会对病人的身体形象及心理健康产生不利的影响。AGA产生的原因主要是由于皮肤内的睾酮含量过多时,在5-α还原酶的催化下,睾酮能够生成双氢睾酮,双氢睾酮与睾酮竞争毛囊靶标细胞内的雄激素受体。由于双氢睾酮的活性明显高于睾酮,因此,双氢睾酮结合雄激素受体的能力强于睾酮。一旦双氢睾酮进入细胞核内,就能抑制毛囊细胞的生长,促使毛囊提前进入休止期,导致毛发的脱落。雄激素还能作用于皮脂腺,激活皮脂腺细胞中的SREBP通路,促进皮脂腺细胞外层的幼稚细胞发育分化为成熟的分泌细胞,使皮脂腺腺体肥大,分泌功能增强,产生过多的皮脂。当皮脂腺分泌亢进时,过多的皮脂会堵塞或者压迫毛孔,阻碍毛发的正常生长甚至诱发炎症,导致毛发枯萎、脱落。
实施例1雄激素性脱发中MDH2表达量检测
如Aimee Flores等人所报道,抑制TCA循环的原料—丙酮酸进入线粒体可以治疗脱发,而MDH2作为TCA循环的关键酶在TCA循环中发挥了关键作用。因此,我们设计实施例1,通过蛋白质印迹法检测MDH2在雄激素性脱发患者和正常志愿者头皮组织样本中的表达量情况,以验证MDH2表达与雄激素性脱发的相关性。
头皮组织样本是通过头皮活检技术搜集而来,一共搜集了30例雄激素性脱发患者以及30例正常志愿者头皮组织样本。随后使用RIPA组织/细胞裂解液与PMSF试剂进行蛋白质提取,将提取而来的蛋白进行下一步蛋白质印迹实验。
蛋白质印迹实验具体步骤如下:首先,按照配方配制10%SDS分离胶与浓缩胶,样品与加样缓冲液混合,100℃冰浴煮沸5min,冰浴、离心后用微量加样器等量加入各泳道进行电泳分离,通过SDS-PAGE分离蛋白质,转移至PVDF膜(Merck Millipore,MA,USA)并在5%BSA中孵育1小时。将膜在4℃条件下用1:400稀释MDH2一抗(abcam,#ab181873)和β-actin一抗(abcam,#ab115777)温育过夜,用TBST洗涤3次后与山羊抗兔二抗(abcam,#ab6721)温育1小时。室温下PBS缓冲液洗涤3次,每次5min。将膜浸入ECL反应液中,室温1min。移除液体后,将膜用食品保鲜膜覆盖,于阴暗室中环境下通过线片曝光,显影、定影后观察结果。
分析结果如图1显示,MDH2在雄激素性脱发患者样本中存在差异表达,脱发患者中的表达量显著高于正常对照。
实施例2MDH2抑制剂对雄激素性脱发小鼠模型表型的影响
基于实施例1的发现,发明人推测MDH2的差异表达影响了TCA循环进而导致脱发,基于此,发明人构建雄激素性脱发小鼠模型,探究抑制MDH2对雄激素性脱发的治疗效果。发明人采取两个方式抑制MDH2:1.使用MDH2抑制剂(16c,AMB5965675)直接抑制MDH2;2.使用MDH2小干扰RNA(Small interfering RNA;siRNA)特异沉默MDH2.
MDH2小干扰RNA(siRNA#1,siRNA#2)则根据下表1给出的序列由广州市锐博生物科技有限公司合成。
表1MDH2 siRNA序列
雄激素性脱发小鼠模型的构建:选取6-8周龄、体重18-22g的雄性C57BL/6小鼠进行模型制备,适应性饲养1周后,按体质量编号并用Excel根据体质量随机分为6组,每组5只,先用剃毛刀剃下小鼠毛发,再使用脱毛膏在其背部脱除约2×3cm2,脱毛5-10min后用温水将脱毛膏擦净,每只小鼠均以脊柱为分界线,在其背部对称部位取面积2×3cm2大小的皮肤,作为实验区,实验中所有给药组的药物溶剂均为无毒无害的玉米油,实验动物随机分为以下组别,见下表2:
表2雄激素性脱发小鼠模型的处理方式
其中空白组小鼠除剃毛不做任何处理,其余组小鼠经5%水合氯醛轻度麻醉后,按照5mg/kg剂量每日皮下注射丙酸睾酮建立雄激素性脱发小鼠模型,连续30天。建模组以及给药组于造模处理30min后,按照上述方案给药处理,每日拍照记录小鼠新生毛发情况,连续30天后,处死小鼠,用剃毛刀剃下小鼠新生毛发,统计小鼠新生毛发重量。图2A为构建的小鼠雄激素性脱发模型中,各类药物的治疗效果图。图2B为构建的小鼠雄激素性脱发模型中,剃下的5只小鼠新生毛发平均重量统计图。图2C为构建的小鼠雄激素性脱发模型中,小鼠皮肤组织中Mdh2的表达量。由图2A,2B可以看建模组经历30天的毛发生长,新生毛发稀疏,脱发面积大,小鼠背部仍有大片裸露无毛区域且新生毛发平均重量轻,而MDH2抑制剂处理组、空白组经历30天的毛发生长后,新生毛发浓密,脱发面积小,小鼠背部肉眼可见覆盖大片新生毛发且几乎没有裸露无毛区域,新生毛发平均重量远超建模组。MDH2小干扰RNA处理组,背部可见有大片新生毛发且新生毛发平均重量远超建模组。由图2C可知,MDH2小干扰RNA处理组的Mdh2表达量相较建模组降低。
实施例3 MDH2抑制剂对雄激素性脱发小鼠模型基因表达的影响
之前就有研究报道雄激素性脱发患者的头皮活检样本中炎症相关基因显著上调。为进一步探究MDH2抑制剂在雄激素性脱发治疗中的作用机制,发明人检测了MDH2抑制剂处理后脱发相关基因(Mmp12、Sfrp2、Chga、Prrx1、Vim)的转录情况。
将上述构建雄激素性脱发模型小鼠处死后,取下小鼠皮肤样本消化。随后使用TRIZOL提取组织RNA,将提取下来的RNA进行反转录为cDNA,最后通过实时荧光定量PCR(qPCR)检测相关基因的表达水平。用于Mmp12、Sfrp2、Chga、Prrx1、Vim qPCR检测的引物序列如下表3所示。
表3脱发相关基因qPCR引物
具体的操作步骤如下:将组织样本切成2-4毫米的薄片。然后将其转移到gentleMACS的C管当中,加入适量的TRIzol后盖紧C管的盖子,并将其倒置于gentleMACS组织离解器上,持续旋转孵育组织样本30分钟,反应结束后,可将其中的液体转移到离心管中,12000rpm,进行10分钟离心。离心完成后,然后将所有吸出的上清转移到新的离心管当中,然后向其中再加入200mL三氯甲烷,使用涡旋振荡器震动摇晃离心管15秒左右,然后将其静止放置在离心管架上5-8分钟后,12000rpm的10分钟离心。完成上步离心之后,可观察到此时离心管的液体分为三层,提取最上层的水相层的RNA,向其中加入500μL异丙醇,静止放置10分钟后12000rpm离心10分钟。弃上清,向离心管中加入之前预备好的使用DEPC水配制的75%乙醇1mL,盖紧离心管的管盖,上下混匀后将离心管放入离心机中,转8000rpm,5分钟离心。弃上清,此时可以观察到离心管底部有少许白色沉淀物,将离心管倒置于滤纸上,使其水分被吸尽,加入20-30μL DEPC水溶解其中的白色沉淀物。待溶解好了以后,可以使用NANODROP 2000仪器检测提取好的RNA浓度,并在离心管外壁进行标注。使用5XAll-In-OneRT MasterMix逆转录试剂盒将RNA逆转录为cDNA,使用中国近岸蛋白公司生产的SYBRSuperMix Plus qPCR试剂盒来完成实时荧光定量PCR实验。
实验结果如图3A-3E所示,相较于建模组,使用MDH2抑制剂(16c,AMB5965675)MDH2小干扰RNA(siRNA#1,siRNA#2)处理小鼠的皮肤样本中,相关基因Mmp12(图3A)、Sfrp2(图3B)、Chga(图3C)、Prrx1(图3D)、Vim(图3E)的表达水平下降,接近于空白对照组。
由实施例3可知,使用了MDH2抑制剂和MDH2小干扰RNA会导致小鼠皮肤样本中的相关基因(Mmp12、Sfrp2、Chga、Prrx1、Vim)的表达水平下降,发明人认为这些基因是调控脱发的关键基因,它们的表达下调最终改善了雄激素性脱发小鼠模型的毛发脱落的情况。
以上所述,仅是本发明的较佳实施例,并非对本发明作任何限制,凡是根据本发明技术实质对以上实施例所作的任何简单修改、变更以及等效结构变化,均仍属于本发明技术方案的保护范围内。
Claims (10)
1.MDH2抑制剂在制备治疗雄激素性脱发药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述MDH2抑制剂能够有效抑制雄激素性脱发。
3.根据权利要求2所述的应用,其特征在于,所述MDH2抑制剂对雄激素性脱发的治疗作用表现为抑制选自Mmp12、Sfrp2、Chga、Prrx1、Vim中一种或多种基因的表达。
4.根据权利要求1所述的应用,其特征在于,所述MDH2抑制剂选自化合物16c,AMB5965675以及MDH2小干扰RNA中一种或多种。
7.根据权利要求4所述的应用,其特征在于,所述小干扰RNA选自siRNA#1或siRNA#2;所述siRNA#1包含SEQ ID NO:1的正义链和SEQ ID NO:2的反义链;所述siRNA#2包含SEQ IDNO:3的正义链和SEQ ID NO:4的反义链。
8.MDH2检测试剂在制备雄激素性脱发风险评估试剂盒中的用途。
9.根据权利要求8所述的用途,其特征在于,所述MDH2检测试剂包括用于MDH2蛋白印迹检测的抗体、用于免疫组化检测的抗体或用于定量PCR的引物和探针。
10.根据权利要求9所述的用途,其特征在于,所述MDH2检测试剂或所述雄激素性脱发风险评估试剂盒的检测对象为受试者头皮组织。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210818009.8A CN115721716B (zh) | 2022-07-13 | 2022-07-13 | Mdh2抑制剂在雄激素性脱发治疗中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210818009.8A CN115721716B (zh) | 2022-07-13 | 2022-07-13 | Mdh2抑制剂在雄激素性脱发治疗中的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115721716A true CN115721716A (zh) | 2023-03-03 |
CN115721716B CN115721716B (zh) | 2024-06-14 |
Family
ID=85292649
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210818009.8A Active CN115721716B (zh) | 2022-07-13 | 2022-07-13 | Mdh2抑制剂在雄激素性脱发治疗中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115721716B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116173063A (zh) * | 2023-04-12 | 2023-05-30 | 中南大学湘雅三医院 | Mlkl抑制剂在制备促进毛发生长或改善雄激素性脱发制剂中的应用 |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5994319A (en) * | 1996-04-15 | 1999-11-30 | Dyad Pharmaceutical Corporation | Combination therapy for androgenic alopecia with antisense oligonucleotides and minoxidil |
WO2004078916A2 (en) * | 2003-03-03 | 2004-09-16 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | In vitro micro-organs, and uses related thereto |
FR2854243A1 (fr) * | 2003-04-24 | 2004-10-29 | Oreal | Procede de determination d'etats pre-alopeciques et/ou d'atteintes cutanees au moyen d'un marqueur predictif: hif-1(hypoxia inducible factor-1) |
CN1670198A (zh) * | 2005-02-22 | 2005-09-21 | 中山大学 | 华支睾吸虫热稳定型胞浆苹果酸脱氢酶,其编码核酸及其应用 |
US20060009429A1 (en) * | 2003-09-26 | 2006-01-12 | Kerner Nestor A | Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders relating to androgen metabolism, their pharmaceutical compositions, their uses and treatment method |
US20090197954A1 (en) * | 2008-02-01 | 2009-08-06 | Mcdaniel William Robert | Linoleic acid preparations for the topical treatment of male and female pattern androgenetic alopecia, age-related alopecia, and keratosis pilaris |
KR20130117260A (ko) * | 2012-04-18 | 2013-10-25 | 경북대학교 산학협력단 | 남성형 탈모 진단용 바이오마커 조성물 및 이를 이용한 진단 방법 |
CN107429284A (zh) * | 2016-03-25 | 2017-12-01 | 花王株式会社 | 皮脂腺或毛囊选择性雄激素受体活性控制剂的评价或选择方法 |
KR20210129565A (ko) * | 2020-04-20 | 2021-10-28 | 주식회사 뷰렌코리아 | 전립선 비대증 또는 안드로겐성 탈모증 예방, 개선 또는 치료용 조성물 |
CN113876955A (zh) * | 2020-07-01 | 2022-01-04 | 陈敏 | Pcsk9抑制剂在制备促进毛发生长产品中的应用 |
-
2022
- 2022-07-13 CN CN202210818009.8A patent/CN115721716B/zh active Active
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5994319A (en) * | 1996-04-15 | 1999-11-30 | Dyad Pharmaceutical Corporation | Combination therapy for androgenic alopecia with antisense oligonucleotides and minoxidil |
WO2004078916A2 (en) * | 2003-03-03 | 2004-09-16 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | In vitro micro-organs, and uses related thereto |
FR2854243A1 (fr) * | 2003-04-24 | 2004-10-29 | Oreal | Procede de determination d'etats pre-alopeciques et/ou d'atteintes cutanees au moyen d'un marqueur predictif: hif-1(hypoxia inducible factor-1) |
US20060009429A1 (en) * | 2003-09-26 | 2006-01-12 | Kerner Nestor A | Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders relating to androgen metabolism, their pharmaceutical compositions, their uses and treatment method |
CN1670198A (zh) * | 2005-02-22 | 2005-09-21 | 中山大学 | 华支睾吸虫热稳定型胞浆苹果酸脱氢酶,其编码核酸及其应用 |
US20090197954A1 (en) * | 2008-02-01 | 2009-08-06 | Mcdaniel William Robert | Linoleic acid preparations for the topical treatment of male and female pattern androgenetic alopecia, age-related alopecia, and keratosis pilaris |
KR20130117260A (ko) * | 2012-04-18 | 2013-10-25 | 경북대학교 산학협력단 | 남성형 탈모 진단용 바이오마커 조성물 및 이를 이용한 진단 방법 |
CN107429284A (zh) * | 2016-03-25 | 2017-12-01 | 花王株式会社 | 皮脂腺或毛囊选择性雄激素受体活性控制剂的评价或选择方法 |
KR20210129565A (ko) * | 2020-04-20 | 2021-10-28 | 주식회사 뷰렌코리아 | 전립선 비대증 또는 안드로겐성 탈모증 예방, 개선 또는 치료용 조성물 |
CN113876955A (zh) * | 2020-07-01 | 2022-01-04 | 陈敏 | Pcsk9抑制剂在制备促进毛发生长产品中的应用 |
Non-Patent Citations (5)
Title |
---|
BAN, HYUN SEUNG等: "A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration", 《PLOS ONE》, vol. 11, no. 9, pages 1 - 14 * |
NAIK, RAVI等: "Methyl 3-(3-(4-(2, 4, 4-Trimethylpentan-2-yl)phenoxy)-propanamido)benzoate as a Novel and Dual Malate Dehydrogenase (MDH) 1/2 Inhibitor Targeting Cancer Metabolism", 《2017-11-19》, vol. 60, no. 20, pages 8631 - 8646, XP055606289, DOI: 10.1021/acs.jmedchem.7b01231 * |
ROMEO, G等: "Hair root versus red cell individual phenotype in Sardinian heterozygotes for G6PD deficiency (Mediterranean type)", 《AMERICAN JOURNAL OF HUMAN GENETICS》, vol. 28, no. 5, pages 506 * |
候圣祥等: "基于加权基因共表达网络分析识别雄激素性脱发的枢纽基因", 《实用皮肤病学杂志》, vol. 15, no. 1, pages 9 - 13 * |
吴巍等: "雄激素性脱发的药物研究进展", 《中国美容整形外科杂志》, vol. 33, no. 05, pages 308 - 311 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116173063A (zh) * | 2023-04-12 | 2023-05-30 | 中南大学湘雅三医院 | Mlkl抑制剂在制备促进毛发生长或改善雄激素性脱发制剂中的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN115721716B (zh) | 2024-06-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Fu et al. | Dihydrotestosterone-induced hair regrowth inhibition by activating androgen receptor in C57BL6 mice simulates androgenetic alopecia | |
Ellis et al. | Androgenetic alopecia: pathogenesis and potential for therapy | |
Garza et al. | Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia | |
EP2889384B1 (en) | Method for identifying active agents for improving the aesthetic appearance of human skin | |
EP3403673B1 (en) | Composition for preventing or ameliorating loss of hair and graying of hair, and use thereof | |
EP2827952B1 (en) | Composition for stimulating hair growth | |
CN111184773B (zh) | 一种女贞子提取物及其在制备5α-还原酶抑制剂中的应用 | |
Wu et al. | 5-HT1A/1B receptors as targets for optimizing pigmentary responses in C57BL/6 mouse skin to stress | |
CN115721716B (zh) | Mdh2抑制剂在雄激素性脱发治疗中的应用 | |
WO2023208013A1 (zh) | HIF-1α抑制剂在雄激素性脱发治疗中的应用 | |
Wolf et al. | Nitric oxide in the human hair follicle: constitutive and dihydrotestosterone-induced nitric oxide synthase expression and NO production in dermal papilla cells | |
CN109550051B (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 | |
EP3003308B1 (en) | New drug for the treatment and/or prevention of depressive disorders | |
Guo et al. | Cucurbitacin promotes hair growth in mice by inhibiting the expression of fibroblast growth factor 18 | |
Jeong et al. | Rab25 deficiency perturbs epidermal differentiation and skin barrier function in mice | |
Prugsakij et al. | Mechanistic synergy of hair growth promotion by the Avicennia marina extract and its active constituent (avicequinone C) in dermal papilla cells isolated from androgenic alopecia patients | |
Thianthanyakij et al. | Salvianolic Acid B Reduces Oxidative Stress to Promote Hair-Growth in Mice, Human Hair Follicles and Dermal Papilla Cells | |
EP2033968A1 (en) | Target of rapamycin modulators of and use thereof | |
JP2018027920A (ja) | 色素幹細胞の分化抑制剤、白髪予防剤、及び白髪評価方法 | |
US20210000801A1 (en) | Composition for prevention and treatment of hair growth disorders | |
He et al. | Amygdalin ameliorates alopecia areata on C3H/HeJ mice by inhibiting inflammation through JAK2/STAT3 pathway | |
US11931325B2 (en) | Hair-growth promoting composition and usage thereof | |
CN117257958B (zh) | Trps1抑制剂的新用途及用于治疗和/或预防雄激素性秃发的药物 | |
LU505470B1 (en) | An application of taurine in the preparation of products for the prevention and treatment of androgenetic alopecia | |
Yilmaz et al. | Prospects of integrated multi-omics-driven biomarkers for efficient hair loss therapy from systems biology perspective |
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 |