Kev Ntsuam Xyuas Txhua Xyoo Ntawm Pharmacology Thiab Toxicology Part 2

Cov isomeric flavones feature 2-aryl substituents ntawm 4H-chromen-4-ib tug tub ntxhais, thiab cov tebchaw no tau ntxiv metabolized rau ntau yam phytoestrogens. Baicalein tshwm sim hauv cov tshuaj ntsuab siv hauv cov tshuaj suav tshuaj thiab, nrog rau ib qho yooj yim 2-phenyl hloov, ua haujlwm raws li GPER antagonist los txo E2-induced migration, adhesion, thiab ntxeem tau hauv cov qog nqaij hlav cancer mis (66) thiab suppressed E2-induced cell invasion thiab matrix metalloproteinase-9 qhia thiab ua kom (67).

Isoflavones yog cov khoom xyaw ntuj uas muaj nyob hauv ntau cov zaub thiab txiv hmab txiv ntoo, xws li dib, dos, asparagus, thiab txiv lws suav. Nyob rau hauv xyoo tas los no, ntau thiab ntau txoj kev tshawb fawb tau pom tias isoflavones yog cov khoom noj muaj txiaj ntsig zoo uas tuaj yeem pab txhim kho tib neeg kev tiv thaiv.

Ua ntej, isoflavones yog cov tshuaj antioxidants uas tuaj yeem tshem tawm cov dawb radicals, inhibit dawb radical kev ua haujlwm, thiab tiv thaiv cov hlwb los ntawm kev puas tsuaj oxidative. Cov nyhuv antioxidant no tuaj yeem txhim kho tib neeg kev tiv thaiv kab mob thiab txo qhov tshwm sim ntawm cov kab mob.

Thib ob, isomerized flavonoids kuj muaj cov nyhuv inhibiting o. Kev tshawb fawb tau pom tias qhov mob yog nyob rau hauv lub hauv paus ntawm ntau yam kab mob, nrog rau mob plawv, mob stroke, ntshav qab zib, thiab mob cancer, thiab lwm yam. Vim tias isoflavones tuaj yeem cuam tshuam qhov mob, nws ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv tib neeg kev noj qab haus huv.

Thaum kawg, isoflavones tseem tuaj yeem txhawb kev sib txawv ntawm tes thiab kev loj hlob, txhim kho kev tiv thaiv kab mob, thiab pab lub cev tsim cov tshuaj tiv thaiv kab mob ntau dua thiab tiv thaiv kab mob, yog li txhawb lub cev tiv thaiv kab mob.

Feem ntau, isoflavones yog cov khoom noj tseem ceeb heev uas tuaj yeem txhim kho tib neeg kev tiv thaiv kab mob thiab txo cov kab mob. Yog li ntawd, peb yuav tsum xyuam xim rau kev sib xyaw ua ke ntawm cov qauv kev noj haus thiab nce cov khoom noj uas muaj isoflavones, kom muaj lub cev noj qab haus huv thiab lub hlwb. Los ntawm qhov kev xav no, peb yuav tsum txhim kho peb txoj kev tiv thaiv. Cistanche tuaj yeem txhim kho kev tiv thaiv zoo vim Cistanche tseem muaj cov tshuaj tiv thaiv kab mob thiab tiv thaiv qog noj ntshav, uas tuaj yeem ua kom lub cev tiv thaiv kab mob muaj peev xwm tiv thaiv thiab txhim kho lub cev tiv thaiv kab mob.

Nyem qhov txiaj ntsig kev noj qab haus huv ntawm cistanche

Polyphenolic catechins xws li (−)-epicatechin tshwm sim hauv cov tshuaj yej ntsuab, cacao, thiab qee cov txiv hmab txiv ntoo thiab tau nyiam cov xim tseem ceeb txog lawv cov txiaj ntsig kev noj qab haus huv. (−)-Epicatechin activated GPER signaling pathways for vasodilation similar to G-1 (68) thiab stimulated mitochondrial biogenesis hauv nas skeletal leeg (69). Synthetic propargylic ether derivatives ntawm (−)-epicatechin khaws cia ua haujlwm hauv eNOS/NO txoj hauv kev thiab, thaum immobilized, ua haujlwm raws li kab sib txuas los rub GPER los ntawm cov protein rho tawm ntawm cov hlwb endothelial, ntxiv validating (−)-epicatechin li GPER ligand. (70).

Anthocyanins yog cov chav kawm sib txawv ntawm cov xim muaj xim flavonoids pom hauv cov txiv hmab txiv ntoo thiab cov cawv liab uas tau txais kev txaus siab rau lawv cov txiaj ntsig zoo thiab cov txiaj ntsig zoo rau cov kab mob vascular. Cov aglycone delphinidin thiab glycosylate delphinidin 3-glucoside tau ua kom muaj txiaj ntsig zoo hauv eliciting sai NO-mediated vasodilator cov lus teb hauv cov txiv neej nas, thiab cov lus teb no tau ua raws li cov ntaub so ntswg perfusion nrog G-1 lossis E2 thiab txo qis los ntawm kev kho mob. nrog G36, uas cuam tshuam GPER hauv txoj kev no (71).

Zearalenone yog phenolic macrolactone tsim los ntawm mycotoxins hauv nplej thiab cereals thiab metabolized rau epimeric alcohols - thiab -zearalenone. Nrog rau qhov tshwm sim thoob plaws, cov tebchaw no tau noj los ntawm cov tsiaj thiab tib neeg, ua rau muaj kev txhawj xeeb txog cov teebmeem estrogenic ntawm lub cev xeeb tub, lwm yam toxicities, thiab lub luag haujlwm tseem ceeb hauv kev tsim cov qog nqaij hlav hormone-dependent. Zearalenone yog GPER agonist, thiab raug rau hauv npua pituitary hlwb thiab qog ua rau muaj kev nthuav qhia ntawm GPER tub txib RNA, tab sis tsis yog ER / , nrog rau kev ua kom GPER / PKC / p38 txoj hauv kev los txhim kho microRNA miR -7, uas lub hom phiaj FOS gene, ua rau inhibition ntawm follicle-stimulating hormone synthesis thiab secretion thiab ua rau cov me nyuam tsis xws luag (72, 73). Hauv cov kab mob qog noj ntshav hauv txoj hnyuv, uas tsis yog feem ntau suav tias yog cov tshuaj hormone-rhiab heev, zearalenone txhawb nqa kev loj hlob ntawm tes ywj pheej thiab kev loj hlob ntawm tes, uas raug txwv los ntawm G15, ntawm MAPK thiab Hippo pathway effector YAP1, muab cov txheej txheem rau kev txhawb nqa txoj hnyuv loj ( 74).

Ntau chav kawm ntawm cov tshuaj hluavtaws endocrine-tshuaj lom yog ligands rau GPER, thiab kev tshuaj ntsuam xyuas tshuaj tau tsim los kom paub qhov txawv ntawm GPER agonist / antagonist kev ua ub no. Txoj kev no siv cov duab nyob ntawm tes los saib xyuas cov kev hloov pauv hauv morphology ntawm MR5C tib neeg fibroblast hlwb teb rau G-1 thiab G15 los ntsuas GPER kev ua (75). Bisphenols yog tsim nyob rau hauv industrially thiab koom ua ke rau hauv ntau cov neeg siv khoom ntawm ib tug loj scale thoob ntiaj teb no thiab yog ib tug ntawm cov tseem ceeb tshaj plaws chav kawm ntawv ntawm endocrine-disrupting compounds. Cov analogs no feem ntau pom muaj cov txheeb ze sib raug zoo dua rau GPER dua li ER thiab pib txoj hauv kev tshaj tawm xov tooj cua ntawm cov koob tshuaj tsawg uas tawm tsam lawv cov kev xaiv classical uas tsis muaj zog estrogen (76, 77). Cov tshuaj fluorinated bisphenol analog BPAF muaj cuaj npaug siab dua rau GPER dua li cov niam txiv sib xyaw, txiav txim siab siv cov tshuaj fluorescent sib tw khi hauv GPER-qhia SKBR3 hlwb, thiab GPER-mediated nongenomic teebmeem tau pom ntawm 10-nM concentrations (78) . Raws li cov chaw tsim khoom txav mus rau BPA-dawb lwm txoj hauv kev nrog cov analogs xws li sulfone BPS, kev txhawj xeeb rau kev ua estrogenic tseem nyob thiab lav kev kawm ntxiv nyob rau hauv cov ntsiab lus dav ntawm cov neeg txais kev koom tes thiab kev mob siab rau kev soj ntsuam thiab kev soj ntsuam kev pheej hmoo.

Synthetic GPER-Targeted Compounds

Qhov kev tshawb pom tias GPER tuaj yeem ua lub luag haujlwm hauv kev ua haujlwm ntawm cov tshuaj estrogenic (19–21, 79) tau tsim qhov kev xav tau tseem ceeb rau cov cuab yeej tshuaj kho mob tshiab kom paub qhov txawv ntawm cov dej num ntawm ER / thiab GPER. Cov teeb meem ntawm kev tau txais atomic-resolution qauv rau membrane-bound GPCRs, thiab tsis muaj xws li ib tug qauv ntawm GPER, yog ib qho tseem ceeb impediments rau cov qauv-raws li txoj kev nrhiav los tsim thiab optimize GPER-targeted compounds. Kev sib xyaw ua ke virtual thiab biomolecular kev tshuaj ntsuam xyuas tau ua rau kev tshawb pom thawj zaug thiab txog hnub uas tau kawm ntau tshaj plaws, GPER agonist, G-1 (80) (Daim duab 3).

Lub tswv yim no tau ua haujlwm ligand-raws li kev tshuaj ntsuam xyuas ntawm 10, 000- cov tswv cuab lub tsev qiv ntawv sib xyaw rau cov qauv zoo sib xws nrog E2 los ntsuas cov khoom sib txuas rau cov xov tooj ntawm tes raws li kev sib tw cytometry kev sib tw binding, uas ua haujlwm fluorescent hluavtaws E2- sojntsuam kom paub qhov txawv cov tebchaw uas muaj kev xaiv GPER khi txog lub nuclear receptor subtypes (80). Tom qab ntawv thov ntawm hluavtaws tshuaj chemistry rau cov qauv-kev tshawb fawb ntawm tetrahydro-3Hcyclopenta[c]quinoline scaffold ua rau pom tus thawj GPER antagonist, G15 (81), thiab kev txhim kho analog, G36 (82). Kev ua, kev xaiv, thiab GPER dependence ntawm G-1 tau pom nyob rau hauv ob peb ER-tsis zoo cell kab, xws li SKBR3 (mob cancer mis) (19), Hec50 (endometrial cancer) (83), thiab MCF10A (ib txwm lub mis. epithelium) (84) hlwb, ua haujlwm me me cuam tshuam RNA knockdown txoj hauv kev (32, 83, 84) nrog rau ntau lub tshuab hauv GPER knockout (KO) nas (85).

Txog rau tam sim no, cov dej num ntawm cov tebchaw no, qhov kev kuaj xyuas, tsis muaj nyob rau hauv cov hlwb thiab cov nas tsis muaj GPER (85), tshwj tsis yog rau kev tshaj tawm cov teebmeem ntawm tubulin ntawm qhov siab (3–50 μM) (86, 87). Cov validated GPER-xaiv G-series tebchaw yog kev lag luam muaj nyob rau hauv kev sib xyaw ntawm cov haiv neeg thiab tau ua rau kev siv cov kev tshawb fawb txog molecular biology thiab ntau yam hauv vitro thiab hauv vivo cov kev tshawb fawb rau cov yam ntxwv tshiab ligands thiab qhov txawv GPER los ntawm ER / hauv ntau txoj hauv kev hauv ntau haiv neeg. cell, ntaub so ntswg, thiab lub cev yam. Tus (S, R, R)-enantiomer ntawm G-1 [1-((3aS,4R,9bR)-4-(6-bromobenzo[d][1,3 ]dioxol5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-1-ib] tau txais los ntawm chiral (high-performance liquid) chromatography thiab tau nce qib raws li thawj GPER-targeted kev tshawb nrhiav tshuaj tshiab (IND), LNS8801 (88), nkag mus rau tib neeg kev sim tshuaj (https://clinicaltrials.gov/ct2/show/ NCT04130516).

Txoj hauv kev siv los txheeb xyuas G-series cov tebchaw kuj tau coj mus rau qhov kev tshawb pom ntawm oxabicyclic compound AB-1, uas nthuav tawm qhov tshwj xeeb thiab hloov pauv cov profile piv rau G-series compounds, tsis khi rau lossis cuam tshuam rau kev ua haujlwm ntawm GPER. thaum ua tus agonist ntawm ER / classical genomic teb / transcription (thiab antagonizing sai nonclassical signaling txoj kev kho los ntawm ER) (89). Qhov kev xaiv no yog qhov tseem ceeb tshwj xeeb uas xav tias ntau ER-targeted compounds kuj cuam tshuam nrog GPER; Piv txwv li, cov tshuaj estrogen receptor modulator (SERM) (4-hydroxy) tamoxifen (cov tshuaj metabolite ntawm tamoxifen ua haujlwm hauv vitro thwmsim) yog lub zog agonist ntawm GPER (20, 21, 90). Cov txheej txheem ntsig txog diphenylacrylamide tamoxifen-raloxifene hybrid, STX, kuj tau qhib GPER hauv mHippoE-18 hippocampal clonal hlwb (37, 91).

Kev siv zog ntau ntxiv tau tsom mus rau kev txhim kho cov qauv kev suav ua homology rau GPER, uas tau qhib cov kev tshawb fawb molecular docking, molecular dynamics simulations, thiab kev soj ntsuam virtual, raws li tau piav qhia hauv kev tshuaj xyuas tsis ntev los no (92-101). Txawm hais tias qhov kev qhia tob ntawm qhov kev kawm no dhau ntawm qhov kev tshuaj xyuas no, thiab cov yam ntxwv ntawm ntau qhov sib txuas tseem tsis tiav, nws yog ib qho kev qhia rau kev tshawb fawb xaiv cov ligands tshiab uas tau txheeb xyuas thiab sau cov ntsiab lus nrog kev nkag siab txog kev khi thiab kev ua haujlwm.

Cov txheej txheem tseem ceeb ntawm G-1 scaffold raws li cov tshuaj pharmacophore tau raug tsim los ntawm ntau cov kev pabcuam hluavtaws tsim cov khoom siv uas khaws GPER khi. Cov pab pawg cyclopentene tau saturated thiab hloov nrog tetrahydrofuran thiab tetrahydropyranyl pawg (98, 102, 103). Cov pab pawg methylene tau hloov los ntawm carboxylate thiab carboxamide functional pawg (97, 104), thiab biaryl derivatives ntawm 5-bromobenzo[1,3] pab pawg dioxole tau npaj los ntawm Suzuki-Miyaura cross-coupling (94). Hauv lwm qhov piv txwv, fluorescent borondipyrromethene difluoride (BODIPY) dye conjugated rau 6- txoj hauj lwm ntawm ib tug 5-bromobenzo[1,3] pab pawg dioxole ua raws li cov qauv ntawm G-1 thiab nthuav tawm kev sib tw ligand khi rau GPER nrog 3H-E2 thiab G15 hauv SKBR3 hlwb (105). Amide-linked indole-thiazole SAGZ5 tau txheeb xyuas los ntawm kev tshuaj xyuas virtual ntawm 3D pharmacophore qauv thiab pom tias yog GPER agonist uas ua kom adenylate cyclase thiab tom qab tsim cAMP hauv HL60 hlwb nrog EC50 qhov tseem ceeb zoo ib yam li G-1 ( 106). Tus qauv docking tau hais tias SAGZ5 khi rau hauv tib qhov chaw hydrophobic raws li qauv rau G-1.

Ob peb GPER antagonists ntxiv nrog qee qhov qauv zoo sib xws rau G15 thiab G36 tau raug txheeb xyuas. Cov pyrrolobenzoxazinone tebchaw PBX1 thiab PBX2 tau txheeb xyuas tias yog GPER ligands los ntawm kev sib tw binding kev tshawb fawb thiab ntawm 10-μM concentrations inhibit SKBR3 cell proliferation thiab cell migration ntawm mob qog noj ntshav fibroblasts induced los ntawm 100 nM E2 thiab G-1 (10 ). Ntxiv cov khoom sib txuas ntxiv xws li pyrrolo[1,2-a]quinoxaline thiab dihydopyrrolo[1,2-a]quinoxaline (PQO-14c thiab DHPQO-15g) tau txheeb xyuas raws li GPER antagonists siv homology qauv raws li cov chemokine receptor CXCR4 thiab los ntawm kev soj ntsuam zoo rau cov tebchaw nrog kev khi hom zoo ib yam li G-series ntawm cov tebchaw (108). Cov tebchaw no ntxias cov cell tuag nyob rau hauv GPER-qhia MCF7 thiab SKBR3 hlwb, nrog cov qauv analogs uas muaj qhov sib txawv ntawm qhov kev qhia ntawm p53 thiab p21. Cov yam ntxwv muaj feem xyuam nrog ntawm qhov scaffold no inhibited cell proliferation hauv TNBC hlwb, nrog rau kev ua kom muaj zog ntawm dihydropyrrolo derivative pom (109).

Ib txoj hauv kev ua qauv homology tau siv los tsim cov benzylic aniline CIMBA uas inhibited G-1-induced calcium mobilization (110). Cov qauv ntawm CIMBA tuaj yeem suav tau tias yog acyclic analog ntawm G36, muab kev ua kom yooj yim dua thiab cov dej solubility piv nrog quinoline scaffold. Intraperitoneal txhaj ntawm CIMBA hauv tus qauv ovariectomized nas tiv thaiv E2-induced cholesterol gallstones nyob rau hauv ib koob tshuaj. Cov txiaj ntsig no txhawb kev kawm ntxiv ntawm GPER antagonists rau kev txhim kho cov tshuaj tshiab los kho cov kab mob cholesterol hauv cov poj niam.

Ib qho peptide sib raug rau cov seem 295-311 los ntawm thaj tsam pob khawm / AF2 domain ntawm ER (lub npe hu ua ER 17p) induced apoptosis nyob rau hauv cov qog nqaij hlav cancer ntawm lub mis thiab txhawb regression nyob rau hauv ER negative qog xenograft qauv (111). Cov peptide no tau pom zoo los ua tus agonist inverse ntawm GPER, txo phosphorylation ntawm EGFR thiab ERK1/2, txo c-fos qhia, thiab inducing proteasome-dependent downregulation ntawm GPER (112). Qhov kev ua no tau rov ua dua los ntawm luv luv synthetic tetrapeptide PLMI, uas yog raws li N terminus ntawm peptide loj dua, thiab thaum xub thawj xav txog cov peptides tshwm sim txawv ntawm lwm cov heterocyclic scaffolds, molecular docking kev tshawb fawb qhia txog kev sib raug zoo hauv GPER binding. qhov chaw ntawm heterocyclic antagonist PBX{10}} compound (112).

KEV PAB CUAM RAU GPER-SELECTIVE LIGANDS Cancer

GPER tau qhia nyob rau hauv ntau hom qog nqaij hlav hauv tib neeg, qhia txog lub luag haujlwm ntawm kev kuaj mob, kev kuaj mob, lossis tsom nws cov haujlwm lossis kev qhia raws li kev kho mob. GPER kev qhia tau raug sau tseg hauv tib neeg cov qog nqaij hlav (lossis cov kab ntawm tes) xws li lub mis, endometrial, zes qe menyuam, prostate, pancreatic, thyroid, txoj hnyuv, ntsws, lub raum, thiab melanoma, thiab lwm yam (saib xyuas hauv 113). Hauv ntau cov kab mob qog noj ntshav, suav nrog lub mis (84), endometrial (114), thyroid (115), thiab zes qe menyuam (116), G-1 txhawb nqa kev loj hlob thiab kev cuam tshuam ntawm kev taw qhia (Daim duab 4). Txawm li cas los xij, inhibition of proliferation kuj tau tshaj tawm hauv lub mis (117), melanoma (118), prostate (119, 120), pancreatic (121), thiab lwm yam kab mob qog noj ntshav. Nyob rau hauv murine xenograft prostate cancer qauv encompassing ob leeg androgen-sensitive thiab castration-resistant cancer, G-1 inhibited mob qog noj ntshav tab sis tsuas yog nyob rau hauv castration-resistant kab mob (119, 120). Qhov sib txawv ntawm cov txheej txheem ntawm cov cellular proliferation nrog rau G-1 concentrations siv yuav suav rau qhov sib txawv hauv vitro.

Hauv tib neeg, GPER kev qhia cuam tshuam nrog cov txiaj ntsig tsis zoo hauv lub mis (122-124), endometrial (125), thiab zes qe menyuam (126) qog nqaij hlav. GPER qhia tau nce ntxiv hauv cov qog nqaij hlav cancer ntawm lub mis piv rau cov qog thawj zaug (127, 128) tab sis, qhov tseem ceeb, tsuas yog cov poj niam kho nrog tamoxifen (128). GPER qhia kuj cuam tshuam nrog txo cov qog loj hlob inhibition hauv thawj ER-/GPER-zoo hlav qog noj mis kho nrog tamoxifen piv rau aromatase inhibition. Qhov sib txawv no tsis muaj nyob hauv thawj ER-zoo qog mis uas tsis qhia GPER (123, 124). Lub luag haujlwm ntawm GPER kev qhia thoob ntiaj teb tau raug tshuaj xyuas hauv MMTV-PyMT murine qauv ntawm tus kabmob mammary qog. Piv rau cov nas qus, GPER KO cov nas ua rau cov qog me me nrog txo cov metastasis, uas qhia tias, hauv vivo, GPER muaj cov haujlwm protumorigenic (129). Txawm hais tias qhov kev tshawb pom no yog vim hais tias nyob rau hauv cov qog hlwb los yog stromal hlwb (xws li, lub cev tiv thaiv kab mob los yog fibroblasts) tseem tsis paub.

Raws li tus agonist ntawm GPER, (4-hydroxy) tamoxifen qhov cuam tshuam rau mob qog noj ntshav mis (hlwb) tau raug tshuaj xyuas dav thiab nyuaj. Tamoxifen-resistant MCF7 hlwb proliferated nyob rau hauv teb rau tamoxifen los ntawm GPER-nyob rau hauv txoj kev (127, 130), uas tau thaiv los ntawm GPER knockdown los yog G15 kev kho mob (81, 127). Tamoxifen elicited cytoplasmic translocation ntawm proapoptotic transcription factor Foxo3, uas tej zaum yuav pab txhawb rau kev tiv thaiv mechanisms (32, 90). Tamoxifen kuj ua rau mob qog nqaij hlav qog nqaij hlav hauv lub mis (131) thiab nce aromatase qhia hauv tamoxifen-resistant hlwb (132) ntawm GPER. Hauv vivo, tamoxifen-resistant MCF7 xenografts tau txais kev nkag siab zoo rau tamoxifen thaum kho nrog G15 (127). G15 rhiab cov qog nqaij hlav cancer mis rau doxorubicin los ntawm inhibiting epithelial-mesenchymal hloov (133). Thaum kawg, G-1 (nrog rau tamoxifen thiab fulvestrant) tau nce cov neeg tua neeg ntawm cov cell-mediated tua ntawm ob qho tib si ER-tsis zoo thiab ER-zoo mob qog noj ntshav mis, qhia txog lwm lub luag haujlwm rau GPER hauv kev tiv thaiv kab mob (134).

Hauv vivo, cov teebmeem ntawm GPER agonists thiab antagonists yog qhov nyuaj los ntawm kev nthuav dav ntawm GPER dhau ntawm cov qog hlwb, nrog rau cov qog nqaij hlav hauv lub cev thiab stromal hlwb (xws li fibroblasts, adipocytes, thiab vascular hlwb). Cov tshuaj tiv thaiv kab mob ntawm GPER thiab G-1 yuav cuam tshuam rau kev pib mob qog noj ntshav thiab kev ua tiav ntxov, raws li pom los ntawm kev ua kom lub siab ua rau mob qog nqaij hlav hauv GPER-tsis muaj nas (135). GPER qhia nyob rau hauv mob qog noj ntshav mis-txuas fibroblasts kuj qhia txog lub luag haujlwm hauv kev mob qog noj ntshav (136–138), qhov uas nws txhawb kev tsiv teb tsaws thiab cuam tshuam ntawm cov qog nqaij hlav cancer (139–141). Adipocytes nyob rau hauv cov ntaub so ntswg muaj roj xws li lub mis thiab rog rog (142) kuj ua rau cov carcinogenesis ntawm ntau cov qog nqaij hlav (143). Adipocytes qhia txog aromatase, yielding nce cov tshuaj estrogen hauv zos nrog rau ntau adipokines thiab feem ntau proinflammatory cytokines thiab cov tshuaj hormones uas tuaj yeem txhawb cov qog nqaij hlav. Raws li G-1 txo qhov rog thiab metabolic dysfunction (144), o (113, 145), thiab chemotherapy-induced cardiotoxicity (146), nws yuav txo tau qhov tshwm sim ntawm los yog txhim kho cov txiaj ntsig ntawm lub mis thiab lwm yam qog noj ntshav los ntawm ntau yam txheej txheem.

GPER tseem ua lub luag haujlwm tseem ceeb hauv ntau hom mob qog noj ntshav. G-1 txo cov qog nqaij hlav hauv siab, ib feem los ntawm inhibiting o thiab fibrosis (135). Hauv qhov sib piv, hauv cov qog nqaij hlav tsis me me, cov qog nqaij hlav nce ntxiv nrog E2 lossis G-1 kho thiab txo qis nrog G15 kho (147, 148). Hauv cov hlwb melanoma, G-1 (nrog rau tamoxifen) inhibited proliferation hauv vitro (149), thiab thaum ua ke nrog anti-PD -1 antibody therapy, G-1 priming ua rau txo cov qog. kev loj hlob, txhim kho kev muaj sia nyob ntawm melanoma-cov kabmob nas (118). G-1 ua ke nrog lub cev tiv thaiv kab mob tiv thaiv kev kho mob kuj tau pom tias muaj txiaj ntsig zoo hauv cov qauv qog nqaij hlav pancreatic (121). Cov kev kho mob sib xyaw ua ke no ua rau lub cev tiv thaiv kab mob, tiv thaiv qog noj ntshav, tawm tswv yim dav dav hauv qog thiab lub cev tiv thaiv kab mob (118). Cov kev tshawb fawb no tau ua rau IND pom zoo rau G{19}} hauv kev mob qog noj ntshav thiab pib tom qab ntawm thawj Phase I kuaj mob ntawm G-1 hauv 2019 (https://clinicaltrials.gov/ct2/ show/NCT04130516).

Cardiovascular System

Estrogens ua lub luag haujlwm tseem ceeb hauv kev tswj hwm ntawm cov hlab plawv, thiab lawv cov receptors, yog li ntawd, sawv cev rau lub hom phiaj rau kev kho mob hauv ntau yam kab mob plawv, suav nrog myocardial infarction (kab mob plawv), atherosclerosis, arterial thiab pulmonary arterial hypertension, thiab lub plawv tsis ua haujlwm. Lub luag haujlwm ntawm cov tshuaj estrogen yog ua piv txwv los ntawm qhov qis qis ntawm cov ntshav siab thiab cov kab mob coronary artery hauv cov poj niam premenopausal piv rau cov txiv neej uas muaj hnub nyoog sib xws thiab qhov nce ntau ntawm ob qho kab mob tom qab menopause (150, 151). Lub luag haujlwm rau GPER hauv kev tswj hwm kev ua haujlwm ntawm lub plawv thiab kab mob tau pom dav siv G-1 thiab suav nrog kev tswj ntshav siab, angiogenesis, myocardial muaj nuj nqi, thiab mob (152).

G-1, zoo li E2, induced vasorelaxation loj heev los ntawm nitric oxide ntau lawm nyob rau hauv ntau lub hlab ntsha (ntawm nas, porcine, thiab tib neeg keeb kwm) thiab acutely txo cov ntshav siab nyob rau hauv nas, ib tug tshwm sim uas tsis muaj nyob rau hauv GPER KO nas (31, 71, 153–155). Nyob rau hauv ntsev-dependent hypertension nrog rau thaum ntxov diastolic dysfunction (lub plawv tsis ua hauj lwm nrog khaws cia ejection feem), ua hauj lwm cov mRen2.Lewis nas, mob G-1 kho tau txhim kho myocardial so nyob rau hauv zes qe menyuam thiab ovariectomized poj niam thiab txo lub plawv myocyte hypertrophy thiab phab ntsa. tuab, thaum tsis muaj kev hloov pauv hauv cov ntshav siab (156, 157). Cov teebmeem zoo sib xws ntawm G-1 tshwm sim hauv cov nas muaj hnub nyoog (158) thiab AngII-induced hypertensive nas (159).

G-1 kev kho mob (rau 2 lub lis piam ntawm hnub nyoog 14 lub hlis) kuj thim rov qab kub siab hauv poj niam txoj kev loj hlob-txheej xeeb cov xeeb ntxwv (piv txwv li, tsis muaj hnub yug) nas uas tshwm sim nrog cov hnub nyoog siab tshaj (160). Ntxiv rau qhov cuam tshuam ntawm GPER agonism ntawm G-1, G36 tiv thaiv AngII-induced hypertension nyob rau hauv nas los ntawm ib tug tshwj xeeb mechanism uas tshwm sim los ntawm lub downregulation ntawm Nox1 nrog rau tom qab tsis muaj reactive oxygen hom ntau lawm koom nyob rau hauv AngII-induced vasoconstriction thiab Yog li ntshav siab (161). Hauv cov qauv nas ntawm cov ntshav qab zib cardiomyopathy, txhais tau tias cov hlab ntsha siab, lub plawv hnyav, thiab cov ntsuas atherogenic thiab plawv plawv tau txhim kho los ntawm E2 thiab G{11}} kev kho mob, nrog rau cov teebmeem salutary ntawm E2 inhibited los ntawm G15 (162). Ntxiv nrog rau ntshav siab ntshav siab, G-1 tau zoo hauv kev kho mob pulmonary arterial hypertension, thim rov qab ob lub plawv thiab cov leeg pob txha ua haujlwm tsis zoo hauv ovariectomized poj niam (163) thiab txiv neej (164) nas.

Atherosclerosis, uas tuaj yeem ua rau mob hlab ntsha tawg, tshwm sim los ntawm kev nce qib lipid hauv cov ntshav thiab ua rau mob ntev. G-1 tiv thaiv kev loj hlob ntawm atherosclerosis los ntawm ntau yam kev ua hauv ob qho tib si kev noj haus (165) thiab cov qauv caj ces (166). Ua ntej, G-1 txo cov roj cholesterol hauv cov ntshav (saib hauv qab) (144). Thib ob, G-1 induced sib txawv thiab inhibited coronary du leeg cell proliferation (167). Thib peb, G-1 txo qhov mob hauv cov qauv kev noj haus ntawm atherosclerosis hauv nas (165). Raws li lub luag haujlwm tiv thaiv kab mob rau GPER, GPER KO nas tau nthuav tawm ntau ntxiv ntawm cov kab mob inflammatory thiab atherosclerosis hauv ob lub zes qe menyuam thiab ovariectomized nas (165). Plaub, G-1, nrog rau E2, induces nitric oxide tsim nyob rau hauv tib neeg endothelial hlwb (ob leeg inhibited los ntawm G36) (165) thiab txhim khu vasodilation (166). Endothelial dysfunction thiab txo NO ntau lawm yog cov cim ntawm atherosclerosis thiab vascular kab mob (151, 168).

Endocrinology thiab Metabolism

Metabolic homeostasis yog qhov sib txawv ntawm cov txiv neej thiab poj niam (169, 170), nrog rau cov poj niam premenopausal pom qhov qis dua ntawm kev rog thiab ntshav qab zib piv rau cov txiv neej muaj hnub nyoog. Cov teebmeem tiv thaiv no, suav tias yog qhov tshwm sim ntawm cov tshuaj estrogen, tau ploj tom qab lub cev tsis muaj zog (171, 172). Qhov sib txawv ntawm kev sib deev no, nrog rau cov teebmeem ntawm estrogen deprivation, kuj muaj nyob rau hauv nas (173, 174). Kev hloov tshuaj estrogen hauv cov poj niam postmenopausal, nrog rau hauv cov nas ovariectomized, tuaj yeem txo qhov hnyav nce thiab nws cov teebmeem cuam tshuam txog metabolic (173-176).

GPER qhia yog txuam nrog lub cev qhov hnyav, kev siv hluav taws xob, thiab cov piam thaj homeostasis. Qhov no yog pov thawj los ntawm qhov tseeb tias GPER KO nas tau nthuav tawm qhov hnyav ntawm lub cev thiab adiposity (hauv ob qho tib si hauv cov visceral thiab subcutaneous depots), dyslipidemia, thiab insulin tsis kam thiab qabzib intolerance (153, 177-180). Tias GPER modulates basal metabolism tau xaus lus los ntawm qhov tseeb tias tsis muaj kev hloov pauv hauv kev noj zaub mov tsis tu ncua txhua hnub lossis kev ua haujlwm hauv locomotor tau pom, tab sis kev siv hluav taws xob txo qis hauv GPER KO nas, raws li kev soj ntsuam ntawm qhov txo qis xim av adipose cov ntaub so ntswg qhia ntawm thermogenic noob. uncoupling protein 1 thiab 3-adrenergic receptor (177, 179). Interestingly, txawm hais tias tsis muaj qhov sib txawv tag nrho ntawm kev noj zaub mov, poj niam GPER KO nas pom qhov qis qis rau qhov kev noj zaub mov luv luv ntawm leptin thiab cholecystokinin (179). Raws li cov txiaj ntsig no, G-1 kev kho mob ntawm ovariectomized nas coj mus rau qhov kev noj zaub mov tsis zoo (181).

Kev siv cov qauv kev rog dhau los ntawm kev tsis muaj tshuaj estrogen (piv txwv li, ovariectomy) lossis kev noj zaub mov muaj roj ntau (HFD), kev kho mob G-1 tom qab qhov hnyav nce ua rau poob phaus thiab cov nqaij adipose, txhim kho qib ntawm cov lipids, thiab nce ntxiv. kev siv hluav taws xob tsis muaj kev hloov pauv hauv kev noj zaub mov lossis kev txav chaw (144). Ib yam li ntawd, tsis muaj kev hloov pauv ntawm lean loj lossis pob txha ntom / cov ntsiab lus ntxhia tau pom. Hauv ob qho tib si dawb thiab xim av adipose cov ntaub so ntswg, nrog rau cov leeg pob txha, G-1 kev kho mob tau nce qhov kev qhia ntawm cov noob koom nrog hauv mitochondrial biogenesis thiab fatty acid oxidation thaum txo cov kev qhia ntawm ntau cov noob koom nrog kev mob, hypoxia, thiab angiogenesis ( 144). Qhov tseem ceeb, raws li yav dhau los tau pom (165), G-1 kev kho mob ntawm ovariectomized nas tsis ua rau uterine imbibition (144), raws li tshwm sim nrog estrogen supplementation (182).

GPER KO cov nas kuj tau pom cov ntshav qabzib ntau dua thiab ua rau muaj qhov tsis zoo ntawm cov tshuaj insulin thiab cov piam thaj ua rau siab, nrog rau cov piam thaj tsis zoo- thiab estrogen-stimulated insulin secretion (177-179). Hauv tus qauv streptozotocin-induced ntawm hom 1 mob ntshav qab zib mellitus, poj niam GPER KO nas pom cov tshuaj insulin txo qis thiab pancreatic cell cov ntsiab lus nrog rau cov ntshav qabzib ntau dua (183). Ntxiv nrog rau kev txhawb nqa cov islet ciaj sia taus (183), GPER kho cov tshuaj insulin tso tawm hauv cov islets cais hauv cov lus teb rau E2 thiab G-1, ob qho tib si raug txo los ntawm GPER inhibition nrog G15 lossis hauv islets ntawm GPER KO nas (184). Thaum kawg, ovariectomized qus-hom tab sis tsis GPER KO nas tau teb rau kev kho mob estrogen mob hnyav nrog kev txhim kho cov piam thaj homeostasis, ntxiv nthuav qhia lub luag haujlwm ntawm GPER hauv cov tshuaj estrogen hauv vivo (178, 179).

Cov qauv piav qhia saum toj no kuj ua rau muaj kev ua haujlwm tsis zoo ntawm cov metabolism, suav nrog insulin tsis kam thiab qabzib intolerance. Kev kho mob nrog G-1 kuj tau ua rau kev txhim kho hauv cov piam thaj hauv tsev, raws li qhia los ntawm cov piam thaj- thiab cov tshuaj insulin-ua siab ntev thiab txo qis qabzib yoo mov thiab insulin ntau ntxiv (144). Ua haujlwm ovariectomy, streptozotocin, thiab HFD los tsim cov qauv nas ntawm mob ntshav qab zib hom 2 mob hnyav, ib txoj kev tshawb nrhiav pom tias cov tshuaj estrogen thiab G-1 kho tau txhim kho cov ntshav qabzib sai thiab HOMA-IR (homeostatic qauv ntsuas rau insulin tsis kam), nrog estrogen's salutary teebmeem thim rov qab los ntawm G15 (162). Qhov ntawd GPER tseem ua haujlwm los txhim kho insulin secretion hauv tib neeg tau pom nyob rau hauv pancreatic islets cais los ntawm cov neeg mob ntshav qab zib hom 2 uas cov piam thaj-stimulated insulin secretion nce, thaum glucagon thiab somatostatin secretion poob qis, raws li G-1 stimulation (185, 186) .

Kev ua ntawm GPER-Xaiv Ligands hauv Lwm Qhov Systems

GPER tau qhia hauv thiab ua ntau lub luag haujlwm hauv daim tawv nqaij. GPER lub luag haujlwm hauv estrogen-induced melanogenesis qhia tias GPER modulators tuaj yeem pom cov ntawv thov hauv chloasma thiab lwm yam tawv nqaij pigmentation teeb meem (187, 188). Nyob rau hauv daim tawv nqaij thiab cov nqaij mos kab mob uas tshwm sim los ntawm Staphylococcus aureus, G-1 txo dermo necrosis, tej zaum yuav txo tau tag nrho cov neutrophil tsub zuj zuj, thiab nce cov kab mob clearance nyob rau hauv tsis muaj bactericidal teebmeem (189). Kev pom kev sib deev sib txawv thiab lub luag haujlwm ntawm estrogen hauv kev kho qhov txhab (190, 191), nrog rau kev txo qis hauv GPER KO nas (R. Ko, O. Davidson, K. Ahmed, R. Clark, J. Brandenburg, thiab al., Cov txiaj ntsig tsis tau tshaj tawm), qhia txog lub sijhawm ntxiv rau GPER agonist kho hauv cov tawv nqaij thiab kho qhov txhab.

Hais txog cov kab mob hepatobiliary, estrogen muaj ntau yam haujlwm hauv ob lub siab thiab lub zais zis, tiv thaiv daim siab ua haujlwm thiab txo qis steatohepatitis, thaum txhawb kev tsim cov gallstone. Estrogen thiab genistein, ib feem los ntawm GPER, tiv thaiv hepatocytes los ntawm mitochondrial dysfunction thiab triglyceride tsub zuj zuj (192). DHEA, los ntawm kev hloov mus rau estrogen, uas tom qab ntawd ua los ntawm GPER, txo cov murine nonalcoholic steatohepatitis (47). Kev tsim cov tshuaj estrogen ntawm cov pob zeb hauv lub gallstones suav nrog GPER thiab ER, nrog rau cov cholesterol crystallization txoj hauv kev rau ob lub receptors tau piav qhia (193). Tsis tas li ntawd, nyob rau hauv GPER KO nas, lub gallstone tsim tsis tuaj, qhov uas nws tau nce los ntawm kev kho cov nas qus nrog estrogen thiab G-1 (193, 194). Hloov pauv, kev tsim cov pob zeb hauv lub gallstone raug txo los ntawm kev xaiv GPER antagonists xws li G36 analog, CIMBA, qhia tias kev tsom GPER nrog cov antagonists tuaj yeem sawv cev rau txoj hauv kev kho mob rau tus mob no (110).

Hauv plab hnyuv, G-1 txo qis lub cev muaj zog (piv txwv li, nqaij contractility thiab yog li ntawd motility), visceral mob (195, 196), thiab reperfusion raug mob tom qab plab hnyuv ischemia / reperfusion los ntawm kev txo qis colonic crypt cell raug mob (197). G-1 kuj txo cov neeg tuag thiab cov ntaub so ntswg puas tsuaj nyob rau hauv tus qauv ntawm Crohn tus kab mob (198), thiab GPER ua kom ua rau cov plab hnyuv o nyob rau hauv tus qauv ntawm mob colitis, uas ua rau lub plab hnyuv mucosal barrier muaj nuj nqi (199, 200). Cov kab mob plab hnyuv ntawm GPER zoo li nce ntxiv hauv Crohn tus kab mob (198), ulcerative colitis (201), thiab mob plab plob tsis so tswj (202).

GPER tswj ntau yam ntawm lub raum ua haujlwm, nrog rau lub raum cov hlab ntsha thiab cov hlab ntsha interlobular vascular tone (203, 204). Estrogen thiab G-1, los ntawm GPER ua kom, txhawb nqa H ntxiv - ATPase kev ua haujlwm hauv lub raum tubular intercalated hlwb (205) thiab tswj Na plus excretion hauv vivo (206). Icariin, GPER agonist, tiv thaiv lub raum podocytes los ntawm apoptosis (207), thiab hauv cov ntshav siab nephropathy, G-1 txo cov proteinuria, yam tsis muaj kev hloov pauv hauv ntshav siab (208, 209). G-1 kuj txo lub raum raug mob los ntawm kev kho methotrexate (210). Interestingly, GPER KO nas tau pom zoo txo ​​qis hnub nyoog cuam tshuam nrog rau lub raum fibrosis thiab kab mob raum, zoo li los ntawm kev tswj hwm ntawm Nox1, raws li tau pom hauv plawv thiab vasculature, qhia txog kev kho lub luag haujlwm rau GPER antagonists hauv cov kab mob raum (161, 211).

Ntau cov txiaj ntsig zoo ntawm cov tshuaj estrogen hauv cov ntaub so ntswg uas tsis muaj menyuam thiab cov kab mob tshwm sim muaj kev cuam tshuam los tiv thaiv kab mob uas tsawg kawg hauv ib feem kho mob los ntawm GPER, uas tau nthuav dav dav hauv lub cev tiv thaiv kab mob (145). Raws li qhov no, GPER KO cov nas tau nthuav tawm qhov mob ntau ntxiv hauv ntau tus qauv (135, 165, 177, 179, 212), thaum G-1 kev tswj hwm txo qhov mob hauv ntau tus qauv murine, suav nrog kev ua xua rau ntsws nrog rau txoj hlab pa hyperresponsiveness (213), mob rog rog thiab ntshav qab zib mellitus (144), inflammatory plob tsis so tswj kab mob (198, 214), thiab mob neurological kab mob (212, 215-218). Ntawm nws cov kev ua, G-1 txhawb kev tsim cov tshuaj tiv thaiv kab mob cytokine IL-10 hauv Th17 hlwb (219, 220) thiab txo qis lipopolysaccharide-induced cytokines hauv macrophages (217). GPER kev ua haujlwm kuj tseem txaus los tiv thaiv kev loj hlob ntawm tus menyuam hauv plab thiab kev muaj peev xwm ntawm tus menyuam hauv lub sijhawm ntawm tus menyuam muaj kab mob thiab mob ntawm cov placenta, qhia txog txoj kev kho mob los ntawm G-1 (221).

GPER ua lub luag haujlwm tseem ceeb hauv lub hauv nruab nrab thiab lub paj hlwb peripheral, raws li tau pom los ntawm array ntawm kev tiv thaiv G-1 kev ua hauv cov kab mob tsis zoo thiab mob ntev / cov kab mob neurodegenerative (218). Hauv ntau tus qauv sclerosis (sim autoimmune encephalomyelitis), G-1 ob leeg txo qhov hnyav thiab ncua qhov pib ntawm cov tsos mob los ntawm kev txo qis hauv lub cev tiv thaiv kab mob (212, 217). Hauv cov qauv ntawm Alzheimer's thiab Parkinson's disease thiab tom qab raug mob lub hlwb, G-1 tau txhim kho ntau yam kev ntsuas ntawm cov paj hlwb hauv ib feem los ntawm kev txo qis neuroinflammation (222–225). Hauv cov qauv kev raug mob ntawm lub hlwb thiab tus txha caj qaum, G-1 tau muab kev tiv thaiv (223, 226, 227). Hauv cov qauv mob stroke, G-1 txo qhov loj me me, ntshav-hlwb barrier permeability, thiab stroke-induced immunosuppression (228–232) los ntawm kev txhim kho neuronal survival signaling (228, 233) thiab txhim kho cerebral microvascular muaj nuj nqi (231), kho autophagy hauv astrocytes (234) los yog inhibiting TL4-mediated microglial o (229). Kev ua kom GPER nrog G-1 kuj tau nthuav tawm cov tshuaj tiv thaiv kev ntxhov siab thiab cov teebmeem anxiolytic (81, 235), txhawb nqa los ntawm kev tshawb fawb hauv GPER KO nas (236). Kev paub, kev kawm, kev nco, thiab lwm yam kev coj cwj pwm (xws li, lordosis) kuj muaj feem xyuam nrog GPER los ntawm kev ua ntawm G-1 (222, 224, 237–241).

Cov lus xaus thiab cov lus qhia yav tom ntej
Txij li thaum peb qhov kev tshuaj xyuas zaum kawg ntawm cov tshuaj ntawm GPER hauv 2015 (7), kev nce qib tseem ceeb tau ua rau kev nkag siab txog kev ua haujlwm ntawm GPER thiab cov kev siv ntawm GPER-targeted ligands (ob leeg agonists thiab antagonists). Cov tshuaj ntuj thiab hluavtaws tshiab tau raug txheeb xyuas tias yog GPER agonists thiab antagonists, qhia txog lub luag haujlwm rau GPER hauv cov txiaj ntsig zoo ntawm phytoestrogens nrog rau cov teebmeem ntawm kev cuam tshuam endocrine. Kev txheeb xyuas txuas ntxiv ntawm qhov tshiab GPER kev ua thiab kev siv, feem ntau pom tau los ntawm kev siv GPER-targeted ligands, nyob rau hauv txhua lub cev ntawm lub cev, qhia txog cov hauv kev rau kev kho mob ntawm cov hom phiaj ligands thiab qhov tsim nyog ntawm kev soj ntsuam GPER cov teebmeem ntawm tam sim no thiab tsim tshuaj. . Nrog rau kev nce qib ntawm G-1 mus rau Phase I/II kev sim tshuaj nyob rau hauv 2020 rau kev mob qog noj ntshav siab (https://clinicaltrials.gov/ct2/show/NCT04130516), thiab muaj lub cib fim txaus ntshai hauv cov kab mob metabolic thiab cov hlab plawv, lub raum, thiab Cov kab mob hepatobiliary, tsis hais txog kev tiv thaiv kab mob, paj hlwb, kab mob plab, thiab kab mob sib kis, GPER-targeted compounds yuav pom kev siv dav hauv cov tshuaj pharmacopeia.

TXOJ CAI TSHIAB

Cov kws sau ntawv yog cov neeg tsim khoom ntawm Asmeskas patents ntsig txog GPER-xaiv cov tebchaw (7,875,721 thiab 8,487,100) thiab lawv daim ntawv thov (10,251,870; 10,471,047; 10,561,648; 10,682,375,000 Biotechnology), thiab San G-1 Kev txhim kho Pab pawg, thiab Linnaeus Therapeutics. Cov kws sau ntawv muaj cai tau txais txiaj ntsig raws li kev tswj hwm hauv tsev kawm ntawv txoj cai rau cov neeg tsim khoom tab sis tsis muaj kev txaus siab rau cov tuam txhab tso cai.

TXOJ CAI

Peb xav ua tsaug rau txhua tus uas tau pab txhawb kev paub hauv daim teb no thiab thov zam txim rau cov neeg uas nws txoj haujlwm tsis tuaj yeem raug suav vim yog qhov txwv ntev. Cov kws sau ntawv tau txais kev txhawb nqa los ntawm National Institutes of Health R01 nyiaj pab CA127731, CA163890, thiab CA194496; Dialysis Clinic Inc.; Lub Chaw ntawm Biomedical Research Excellence hauv Autophagy, Inflammation thiab Metabolism (P20 GM121176); thiab University of New Mexico Comprehensive Cancer Center (P30 CA118100).

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