Hu rau: jerry.he@wecistanche.com

Mikhail v Blagosklonny

Cell Stress Biology; Roswell Park Cancer lub koom haum; Buffalo, NY, USA

Hot Tags: mob cancer, laus, geroconversion, gerosuppression, rapamycin, rapalogs, mTOR

Cov kev tshawb pom tsis ntev los no tau nthuav tawm tias iGF- 1, Ras, MeK, AMPK, TSC1/2, FOXO, Pi3K, mTOR, S6K, thiab NFκB koom nrog txoj kev laus. Qhov no yog qhov zoo tshaj plaws vim tias tib lub teeb liab molecules, oncoproteins thiab cov qog nqaij hlav, yog lub hom phiaj paub zoo rau kev kho mob qog noj ntshav. Tsis tas li ntawd, cov tshuaj tiv thaiv kabmob kheesxaws tsom rau qee lub hom phiaj no twb tau tsim lawm. Cov arsenal no tuaj yeem ua haujlwm rauanti-agingkev cuam tshuam (vim tias qhov zoo sib xws ntawm cov cim molecules koom nrog hauv kev mob qog noj ntshav thiab kev laus). nyob rau hauv mob qog noj ntshav, intrinsic thiab acquired resistance, qog heterogeneity, adaptation, thiab genetic instability ntawm cov qog nqaij hlav cancer txhua yam cuam tshuam txoj kev kho mob cancer. Tab sis rauanti-agingkev siv, cov teeb meem no tsis cuam tshuam. Piv txwv li, txij li thaumanti-agingCov kev cuam tshuam yuav tsum yog tsom rau cov hlwb postmitotic ib txwm, tsis muaj kev xaiv rau kev tawm tsam. Ntawm cov koob tshuaj tsawg, qee cov neeg ua haujlwm tuaj yeem txo qis kev laus thiab cov kab mob muaj hnub nyoog. Qhov tseem ceeb, kev txo qis ntawm kev laus tuaj yeem ua rau ncua kev mob qog noj ntshav, uas yog kab mob ntsig txog hnub nyoog.

Cistanche muaj cov nyhuv anti-aging

Taw qhia

Hauv peb lub xyoos dhau los, ntau pua lub hom phiaj muaj feem cuam tshuam txog kev mob qog noj ntshav (oncotargets) tau raug txheeb xyuas thiab kho tau tsim. Qee cov tshuaj tiv thaiv kab mob no tau pom zoo rau kev kho mob qog noj ntshav. Thawj thiab tseem yog ib qho piv txwv zoo tshaj plaws yog imatinib (Gleevec), lub hom phiaj Bcr-Abl, PDGFR, thiab c-kit (Ref).1-5 Kev kho mob siv imatinib qhia txog kev txwv ntawm kev kho mob xws li xaiv rau kev tiv thaiv, 1,2,6 uas yog qhov tseeb kwv yees ntawm qhov theoretical grounds.7 Tsis tas li ntawd, qhov kev tiv thaiv rau cov tshuaj oncotargeted feem ntau ua ke nrog kev mob qog noj ntshav thiab mob qog noj ntshav.8,9 Qhov no yog nrog los ntawm kev mob qog noj ntshav. Muaj ntau lub tswv yim los kov yeej qee qhov teeb meem no 4,10,11 thiab txawm siv los siv lawv.12,13 Ntawm no kuv tham txog tias cov tshuaj oncotargeted tuaj yeem tshawb xyuas rau kev tawm tsam ntawm cov txheej txheem kev laus (zero suppression). Piv txwv li, xaiv cov tshuaj tiv thaiv kab mob ua kom ntev lub neej nyob rau hauv Drosophila.14 Thaum xub thawj siab ib muag, qhov no yuav zoo li paradoxical, muab hais tias (a) classic tshuaj tiv thaiv kab mob ua rau DNA thiab protein puas tsuaj thiab (b) kev laus yog ntseeg tau tias yog tsav los ntawm lub kev puas tsuaj. Txawm li cas los xij, oncotargeted cov neeg ua haujlwm tsis ua rau DNA lossis cov protein puas tsuaj tab sis es tsis txhob cuam tshuam cov teeb liab. Qhov thib ob, cov pov thawj tshwm sim tias kev laus tsis yog tsav los ntawm kev puas tsuaj tab sis hloov pauv los ntawm kev hnov ​​​​cov cim qhia txoj hauv kev tswj hwm cellular metabolism thiab kev loj hlob.15-17 Thiab cov kev taw qhia no zoo ib yam rau txoj kev oncogenic uas ua rau mob qog noj ntshav.18 Oncotargets koom nrog. cellular seroconversion, organismal longevity, thiab cov kab mob uas muaj hnub nyoog.

Cellular Geroconversion

Cov khoom noj khoom haus, kev loj hlob, inflammatory cytokines, insulin, thiab lwm yam tshuaj hormones ua rau txoj kev mTOR (mammalian hom phiaj ntawm rapamycin) txoj hauv kev. ib tug senescent phenotype.24 Lub senescent phenotype yog tus yam ntxwv los ntawm ib tug loj, ca cell morphology (hyper-trophy), cellular hyperfunctions xws li hypersecretion thiab proinflammation, thiab muaj zog lysosomal kev ua ub no thiab lipid tsub zuj zuj ntawm lub hlwb. 24-33 Senescent hlwb tau nce qib ntawm cyclin D1. Txawm hais tias hypermitogenic tsav, qhov kev rov ua dua tshiab (regenerative) muaj peev xwm qis.24,34 Kev hloov pauv los ntawm quiescence lossis thim rov qab lub voj voog ntawm tes raug ntes mus rau senescence yog hu ua gerogenic conversion (geroconversion).18,35 Inhibitors ntawm PI-3K / mTOR txoj kev suppress geroconversion.34-42 Yog li, overstimulation ntawm quiescent hlwb tsav geroconversion. Nyob rau hauv lub cev, geroconversion yog txuam nrog kev hloov pauv ntawm homeostasis, uas ua rau cov kab mob muaj hnub nyoog, ua rau cov kab mob tuag taus.

Ib zaug lub hom phiaj thiab Longevity

Ntau cov noob caj noob ces cuam tshuam rau kev laus hauv cov poov xab, cab, yoov, thiab tsiaj txhu. Inactivation ntawm Ras, PI-3K, TOR, thiab S6K nce lub neej. Pro-aging txoj kev yog antagonized los ntawm gerosuppressors xws li PTEN, AMPK, TSC1/2, sirtuins, thiab p53, uas tseem hu ua qog suppressors.47-63 IGF-1/PI3K/mTOR/ S6K txoj kev muaj feem xyuam rau cov kab mob uas muaj hnub nyoog xws li atherosclerosis, organ hypertrophy, mob ntshav qab zib, thiab neurodegeneration.64-72

Hom Hom Phiaj hauv Cancer thiab Kev Laus

Ntau tus neeg ua haujlwm tsom mus rau mTOR, PI-3K, kev loj hlob zoo receptors, thiab muaj feem xyuam nrog tyrosine kinases, Ras, Raf, thiab B-Raf, S6K, MEK1/2 tau raug sim los kho mob qog noj ntshav.73-86 Lub mTOR txoj kev yuav luag ua kom muaj mob cancer.18 Thaum lub voj voog ntawm tes raug thaiv, ces mTOR tsav geroconversion. Thaum lub voj voog ntawm tes qhib, mTOR tsav kev loj hlob thiab koom nrog hauv malignant phenotype. Yog li ntawd, hauv kev mob qog noj ntshav, kev tswj lub voj voog ntawm tes yuav tsum tau ua tsis taus, piv txwv li, vim qhov poob ntawm p53, p16, p27, lossis Rb. Qhov tseem ceeb, p53 inhibits ob lub voj voog ntawm tes thiab txoj hauv kev mTOR.18,36,87-90 Rapalogs (rapamycin thiab nws cov analogues), uas tsis yog tsuas yog inhibit mTOR tab sis kuj qeeb lub voj voog ntawm tes, ib nrab hloov pauv rau p53.18.

Rapalogs

Rapamycin (sirolimus) thiab lawv cov analogues (everolimus, tem- sirolimus, thiab deforolimus) khi FKBP12 thiab yog li inhibit mTOR complex 1 (mTORC1). Rapamycin (sirolimus) thiab everolimus txo qis kev mob qog noj ntshav hauv cov neeg mob raum hloov pauv hauv lub raum.104-107

Temsirolimus thiab everolimus tau pom zoo rau kev kho mob raum cell carcinoma, mob qog noj ntshav mis, mob qog nqaij hlav neuroendocrine ntawm pancreatic keeb kwm, thiab subependymal giant cell astrocytoma thiab raug tshawb xyuas rau ntau lwm yam malignancies.94-111 Tsis tas li ntawd, ATP-kev sib tw inhibitors ntawm cov TOR kinase raug kev sim tshuaj. Tsis zoo li rapalogs, lawv inhibit ob qho tib si mTOR complex 1 thiab mTOR complex 2 thiab kuj rapamycin- ywj siab ua haujlwm ntawm mTORC1.79, 112-121

Akt thiab PI3K Inhibitors

Knockout ntawm PI3K ncua lub neej ntawm C. elegans yuav luag 10-fold.122 Thiab PI3K yog ib qho kev cog lus tshaj plaws ntawm oncotargets123-131 Kev hloov hauv PI3K pab txhawb kev ntxeem tau thiab metastasis. Me me molecule inhibitors ntawm PI3K tiv thaiv metastasis tsim nyob rau hauv nas tab sis tsis xenografts los yog thawj intra-abdominal qog.132 Perifosine, ib tug Akt inhibitor, yuav siv tau yam xyuam xim, tab sis nws tsis muaj txaus anti-cancer kev ua tau zoo nyob rau hauv cov neeg mob qog noj ntshav.133-135

MEK thiab Raf Inhibitors

Trametinib, ib qho MEK inhibitor, tau pom zoo rau kev kho mob ntawm melanoma.136 Trametinib, piv nrog cov kws khomob, kev txhim kho tus nqi ntawm kev loj hlob-dawb thiab tag nrho cov ciaj sia nyob ntawm cov neeg mob uas muaj metastatic melanoma nrog ib tug BRAF (V600E los yog V600K) mutation.137 MEK inhibitors kuj tau txais ntau qhov kev sim tshuaj ib leeg thiab hauv kev sib xyaw ua ke. Lwm cov MEK inhibitors hauv kev txhim kho kev kho mob suav nrog selumetinib, pimasertib, trametinib, PD-0325901, TAK733, MEK162, RO5126766, WX-554, RO4987655, GDC-0973, thiab AZD83313,816 inhibitors Tsis tas li ntawd. tuaj yeem ua ke nrog cov neeg sawv cev ntawm oncotargeted.140,141 Kev tiv thaiv thiab kev tiv thaiv kev sib tw yog ib txwm muaj142-144

Txawm hais tias BRAF thiab MEK inhibitors tau ua pov thawj cov txiaj ntsig kho mob hauv melanoma, cov neeg mob feem ntau txhim kho. Kev tiv thaiv kev kho mob nrog BRAF kinase inhibitors yog txuam nrog kev rov ua haujlwm ntawm MAPKpathway. Ua ke kev kho mob nrog dabrafenib, BRAF inhibitor, thiab trametinib, MEK inhibitor, tuaj yeem txhim kho kev vam meej tsis muaj sia nyob.145 Txawm li cas los xij, BRAF-inhibitor resistance mechanisms kuj tseem tuaj yeem cuam tshuam rau MEK-inhibitor thiab kev kho ua ke.142,146,147 Cov tshuaj tiv thaiv tuaj yeem cuam tshuam nrog MAPK thiab S6 kinase activation. Kev sib xyaw ua ke ntawm dabrafenib, trametinib, thiab PI3K / mTOR inhibitor GSK2126458 tuaj yeem cuam tshuam cov qog loj hlob.143 Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias monotherapy nrog RAF inhibitors vemurafenib thiab sorafenib tuaj yeem ua rau cov kab mob epithelial proliferation (keratosis pilaris, seborrheic keratis, seborrheic keratosis, seborrheic keratosis, seborrheic keratosis, seborrheic keratosis. . Inhibition ntawm MEK ua ke nrog RAF tiv thaiv kev tsim ntawm cov qog.149 Yog li, vim muaj peev xwm xaiv rau Ras-mutant hlwb, Raf inhibitors tsis zoo li yuav siv tau rauanti-agingdaim ntawv thov.

Cistanche muaj ib qhoanti-agingnyhuv

Kev Tiv Thaiv Kab Mob

Cov lus qhia tias cov tshuaj tiv thaiv tuaj yeem siv los tiv thaiv qog noj ntshav tsis yog qhov tshiab. Txawm li cas los xij, nws tau xav tias cov tshuaj qog nqaij hlav tshwj xeeb no yuav tsum tsom tshwj xeeb ua ntej cov qog nqaij hlav thiab cov qog nqaij hlav. Ntawm no kuv tham txog kev sib txawv heev. Nyob rau hauv txoj kev xav, qee tus neeg sawv cev ntawm oncotargeted tuaj yeem tiv thaiv qog noj ntshav, yog tias lawv ua rau cov txheej txheem kev laus qeeb thiab txo qis geroconversion. Qhov tseem ceeb, txoj hauv kev no tsis tas yuav tsom mus rau cov qog nqaij hlav ncaj qha. Chemoprevention vim gerosuppression tsis nyob ntawm kev hloov pauv ntawm cov qog nqaij hlav qog noj ntshav lossis ntawm cov yam ntxwv ntawm cov qog nqaij hlav cancer. Piv txwv li, yog tias rapamycin inhibits kev laus, nws yuav tiv thaiv kev mob qog noj ntshav nrog rau cov uas muaj p53 thiab Rb hloov pauv lossis ua kom ErbB. Qhov tseeb, rapamycin tiv thaiv kev mob qog noj ntshav hauv p53-cov nas tsis muaj peev xwm thiab Rb-tsis muaj peev xwm150-153 nrog rau cov qog nqaij hlav hauv cov nas ib txwm muaj. 154-160 Metformin, uas cuam tshuam rau mTOR txoj hauv kev thiab qeeb kev laus. , kuj tiv thaiv ntau yam mob qog noj ntshav.

Calorie Restriction (CR) decelerates aging. CR ncua kev mob qog noj ntshav hauv tib neeg thiab lwm yam tsiaj. Txhua yam uas txo qis kev laus (piv txwv li kev txwv calories thiab kev siv caj ces) kuj ncua kev mob qog noj ntshav.