Kusala ndi Khansa: Njira Zamagetsi Ndi Kugwiritsa Ntchito Zachipatala

by Dr Alex Jimenez | Kusala kudya

Alessio Nencioni, Irene Caffa, Salvatore Cortellino ndi Valter D. Longo

Chidule | Kusatetezeka kwa ma cell a khansa ku kusowa kwa michere komanso kudalira kwawo pa metabolites inayake ndizizindikiro za khansa. Kusala kudya kapena kusala kudya-kutsanzira zakudya (FMDs) kumabweretsa kusintha kwakukulu kwa kukula kwa zinthu ndi misinkhu ya metabolite, kupanga malo omwe angachepetse mphamvu ya maselo a khansa kuti azitha kusintha ndikukhala ndi moyo komanso kupititsa patsogolo zotsatira za mankhwala a khansa. Kuonjezera apo, kusala kudya kapena ma FMD kumawonjezera kukana mankhwala a chemotherapy mwachibadwa koma osati maselo a khansa ndikulimbikitsa kusinthika m'magulu abwino, zomwe zingathandize kupewa zotsatira zowononga komanso zomwe zingawononge moyo wa mankhwala. Ngakhale kuti kusala kudya sikuloledwa ndi odwala, maphunziro a zinyama ndi zachipatala amasonyeza kuti ma FMD otsika kwambiri ndi otheka komanso otetezeka. Mayesero angapo azachipatala omwe amayesa kusala kudya kapena ma FMD pazochitika zovuta zachipatala komanso zotsatira zake zikupitirirabe. Tikukulimbikitsani kuti kuphatikiza kwa ma FMD ndi chemotherapy, immunotherapy kapena mankhwala ena kumayimira njira yodalirika yowonjezera chithandizo chamankhwala, kupewa kukana komanso kuchepetsa zotsatirapo.

Zinthu zokhudzana ndi zakudya komanso moyo ndizomwe zimayambitsa chiopsezo chokhala ndi khansa, ndi makhansa ena omwe amadalira kwambiri zakudya kuposa ena1�9. Mogwirizana ndi lingaliro ili, kunenepa kwambiri kukuyembekezeka kuchititsa 14% mpaka 20% yaimfa zonse zokhudzana ndi khansa ku United States. States7, kutsogolera ku malangizo okhudza zakudya ndi masewera olimbitsa thupi pofuna kuchepetsa chiopsezo chokhala ndi matenda khansa 6. Kuonjezera apo, chifukwa cha kukula kwa maselo a khansa, koma osati amtundu wamba, kuti asamvere zizindikiro zotsutsana ndi kukula (chifukwa cha kusintha kwa oncogenic) 10 komanso kulephera kwawo kuti agwirizane ndi kusala kudya11,12, pali chidwi chochuluka kuti mwina zakudya zina zokhala ndi ma calorie ochepa zimathanso kukhala gawo lofunikira kwambiri popewa khansa komanso, mwina, chithandizo cha khansa ngati njira yowonjezerera mphamvu komanso kulekerera kwa anticancer agents11�13.

Ngakhale m'zaka khumi zapitazi tawona kusintha kosaneneka komanso kupita patsogolo kodabwitsa kwa chithandizo cha khansa14,15, pakufunikabe kufunikira kogwira ntchito komanso, mwina, njira zochizira chifukwa zotupa komanso, komanso kofunika kwambiri, njira zochepetsera zotsatira za mankhwala a khansa15,16. Nkhani ya zochitika zowopsa zamankhwala (TEAEs) ndi imodzi mwazovuta zazikulu mu oncology yachipatala15,16. M'malo mwake, odwala ambiri omwe ali ndi khansa amakumana ndi zovuta komanso / kapena zotsatira zanthawi yayitali za chithandizo cha khansa, zomwe zingafunike kugonekedwa m'chipatala komanso chithandizo chaukali (monga maantibayotiki, matenda a hematopoietic zinthu zokula ndi kuikidwa magazi) ndipo zimakhudza kwambiri moyo wawo (mwachitsanzo, mankhwala a chemotherapy peripheral neuropathy) 16. Choncho, njira zothandizira kuchepetsa poizoni ndizoyenera komanso zikuyembekezeka kukhala ndi zotsatira zazikulu zachipatala, zamagulu ndi zachuma15,16.

Kusala kudya kumakakamiza maselo athanzi kuti alowe pang'onopang'ono ndikutetezedwa kwambiri komwe kumawateteza ku chipongwe chowopsa chochokera kumankhwala oletsa khansa kwinaku akudziwitsa mitundu yosiyanasiyana ya ma cell a khansa ku mankhwalawa11,12,17. Kupeza uku kukutanthauza kuti kulowererapo kamodzi kokhako kungathandize kuthana ndi zinthu zosiyanasiyana komanso zofunika kwambiri pamankhwala a khansa.

M'nkhani ino ya Malingaliro, tikambirana zachilengedwe chogwiritsa ntchito kusala kudya kapena kusala kudya motsanzira zakudya (FMDs) kuti tisokoneze ma TEAE komanso kupewa ndi kuchiza khansa. Tikuwonetsanso machenjezo a njira yoyeserayi18,19 ndi maphunziro ofalitsidwa komanso opitilira azachipatala omwe kusala kudya kapena ma FMD agwiritsidwa ntchito kwa odwala khansa.

Mayankho a Systemic & Cellular Fasting

Kusala kudya kumabweretsa kusintha kwa machitidwe a njira zambiri za kagayidwe kachakudya zomwe zimagwirizanitsidwa ndi kusinthana munjira yomwe imatha kupanga mphamvu ndi metabolites pogwiritsa ntchito magwero a kaboni otulutsidwa makamaka kuchokera ku minofu ya adipose komanso mbali ina ya minofu. Kusintha kwa ma hormoni ozungulira ndi metabolites kumapangitsa kuchepa kwa magawano a cell ndi ntchito ya metabolic a maselo abwinobwino ndipo pamapeto pake amawateteza ku chipongwe chamankhwala11,12. Maselo a khansa, mwa kusamvera malamulo oletsa kukula omwe amawunikidwa ndi njala imeneyi, amatha kukhala ndi mayankho otsutsana ndi maselo abwinobwino, motero amalimbikitsidwa ndi mankhwala a chemotherapy ndi machiritso ena a khansa.

Kuyankha Mwadongosolo Kusala kudya

Yankho la kusala kudya limapangidwa mbali imodzi ndi kuchuluka kwa shuga, insulini, glucagon, kukula kwa hormone (GH), IGF1, glucocorticoids. ndi adrenaline. Pa gawo loyambirira la kuyamwa, lomwe nthawi zambiri limatenga maola 6-24, milingo ya insulin imayamba kutsika, ndipo kuchuluka kwa glucagon kumakwera, zomwe zimalimbikitsa kuwonongeka kwa masitolo a glycogen m'chiwindi (omwe amatha pakatha pafupifupi maola 24) ndi kutulutsa kwa shuga kuti apange mphamvu.

Glucagon ndi kuchepa kwa insulin kumapangitsanso kuwonongeka kwa triglycerides (omwe nthawi zambiri amasungidwa mu minofu ya adipose) kukhala glycerol ndi mafuta acids aulere. Panthawi yosala kudya, minofu yambiri imagwiritsa ntchito mafuta acids kukhala mphamvu, pamene ubongo umadalira shuga ndi matupi a ketone opangidwa ndi hepatocytes (matupi a ketone amatha kupangidwa kuchokera ku acetyl-CoA yopangidwa kuchokera ku fatty acid ?-oxidation kapena ketogenic amino acid). Mu gawo la ketogenic la kusala kudya, matupi a ketone amafika pamlingo wa millimolar, makamaka kuyambira patatha masiku 2-3 kuyambira chiyambi cha kusala kudya. Pamodzi ndi glycerol yopangidwa ndi mafuta ndi ma amino acid, matupi a ketone amathandizira gluconeogenesis, yomwe imasunga milingo ya shuga pamlingo wa pafupifupi 4mM (70mg pa dl), yomwe imagwiritsidwa ntchito kwambiri ndi ubongo.

Glucocorticoids ndi adrenaline zimathandizira kuwongolera kagayidwe kachakudya kusala, kuthandiza kukhalabe ndi shuga m'magazi ndikulimbikitsa lipolysis20,21. Makamaka, ngakhale kusala kudya kumatha kukulitsa kwakanthawi milingo ya GH (kuwonjezera gluconeogenesis ndi lipolysis komanso kuchepetsa kutengeka kwa glucose), kusala kumachepetsa milingo ya IGF1. Kuonjezera apo, pansi pa kusala kudya, ntchito ya IGF1 yachilengedwe imalepheretsedwa mwa gawo limodzi ndi kuwonjezeka kwa insulini-monga kukula kwa chinthu chomwe chimamanga mapuloteni 1 (IGFBP1), omwe amamangiriza ku IGF1 yozungulira ndikulepheretsa kuyanjana kwake ndi selo lofanana ndi receptor22.

Pomaliza, kusala kudya kumachepetsa kuchuluka kwa leptin, timadzi timene timapangidwa ndi adipocytes omwe amalepheretsa njala, ndikuwonjezera kuchuluka kwa adiponectin, komwe kumawonjezera kuwonongeka kwa mafuta23,24. Choncho, pomaliza, zizindikiro za mammalian systemic reaction kusala kudya ndizochepa kwambiri za shuga ndi insulini, glucagon ndi matupi a ketone, otsika kwambiri a IGF1 ndi leptin ndi adiponectin.

Mayankho a Mafoni Pakusala Kudya

Kuyankha kwa ma cell athanzi pakusala kudya kumasungidwa mwachisinthiko ndipo kumapereka chitetezo cha ma cell, ndipo osachepera muzamoyo zachitsanzo, zawonetsedwa kuti zimawonjezera moyo ndi thanzi12,22,25�31. Chithunzi cha IGF1 kusonyeza cascade ndi kiyi kusonyeza njira yolumikizirana ndi kusala kudya pamlingo wa ma cell. Pazakudya zabwinobwino, kudya kwamafuta ndi kuchuluka kwa ma amino acid kumawonjezera milingo ya IGF1 ndikulimbikitsa ntchito ya AKT ndi mTOR, potero kumakulitsa kaphatikizidwe ka mapuloteni. Mosiyana ndi zimenezi, panthawi ya kusala kudya, milingo ya IGF1 ndi kuchepa kwa zizindikiro zapansi, kuchepetsa kuletsa kwa AKT-mediated kwa mammalian FOXO zolemba zolemba ndi kulola kuti zinthu zolembera izi zisinthe majini, zomwe zimapangitsa kuti ma enzyme monga haem oxygenase 1 (HO1), superoxide dismutase (HO32) ayambe kugwira ntchito. SOD) ndi catalase yokhala ndi antioxidant ntchito ndi zoteteza34�XNUMX. Kuchuluka kwa glucose kumalimbikitsa protein kinase A (PKA) kusonyeza, yomwe imayang'anira molakwika mphamvu yamphamvu yamphamvu ya AMP-activated protein kinase (AMPK)35, yomwe imalepheretsanso kufotokozera za kupanikizika kwapang'onopang'ono kutsekemera koyambirira kwa mapuloteni 1 (EGR1) (Msn2 ndi / kapena Msn4 mu yisiti) 26,36 ,XNUMX .

Kusala kudya komanso kuletsa kwa glucose kumalepheretsa ntchito ya PKA, kuonjezera ntchito ya AMPK ndikuyambitsa EGR1 ndipo potero kumapeza zotsatira zoteteza maselo, kuphatikizapo omwe ali mu myocardium22,25,26. Potsirizira pake, kusala kudya ndi ma FMD (onani m'munsimu chifukwa cha mapangidwe awo) ali ndi mphamvu zolimbikitsa kukonzanso (Bokosi 1) ndi njira za maselo, zina zomwe zakhala zikukhudzidwa ndi khansa, monga kuwonjezeka kwa autophagy kapena induction of sirtuin activity22,37�49 .

Njira Zakudya mu Cancer FMDs

Njira zazakudya zozikidwa pa kusala kudya zomwe zafufuzidwa mozama mu oncology, ponseponse komanso mwachipatala, zimaphatikizapo kusala kudya kwamadzi (kupewa zakudya zonse ndi zakumwa kupatula madzi) ndi ma FMDs11,12,17,25,26,50�60 (Table 1). Zambiri zakuchipatala zikuwonetsa kuti kusala kudya kwa maola 48 kungafunike kuti mukwaniritse zotsatira zachipatala pazamankhwala, monga kupewa kuwonongeka kwa DNA komwe kumachitika chifukwa cha chemotherapy pamatenda athanzi ndikuthandiza kusungabe. wodwala Ubwino wa moyo pa chemotherapy52,53,61.

Komabe, odwala ambiri amakana kapena amavutika kuti amalize kusala kudya kwamadzi, ndipo zoopsa zomwe zingakhalepo za calorie yowonjezereka ndi kuchepa kwa micronutrient zomwe zimagwirizanitsidwa nazo zimakhala zovuta kufotokoza. Ma FMD ndi zakudya zomwe zimapangidwa ndi mankhwala otsika kwambiri m'ma calories (ndiko kuti, pakati pa 300 ndi 1,100kcal patsiku), shuga ndi mapuloteni omwe amabwezeretsanso zotsatira zambiri za kusala kudya kwa madzi koma ndi kutsata bwino kwa odwala komanso kuchepetsa chiopsezo cha zakudya22,61,62, 3 . Panthawi ya FMD, odwala nthawi zambiri amalandira madzi opanda malire, magawo ang'onoang'ono, ovomerezeka a masamba a masamba, supu, timadziti, mipiringidzo ya mtedza, ndi tiyi wa zitsamba, komanso zowonjezera za micronutrients. Pakafukufuku wachipatala wa 5 mwezi uliwonse wa FMD wa 1-day mu maphunziro omwe ali ndi thanzi labwino, zakudyazo zinali zolekerera bwino komanso kuchepetsa thunthu ndi mafuta onse a thupi, kuthamanga kwa magazi ndi IGF62 levels3. M'mayesero am'mbuyomu komanso opitilira azachipatala a oncological, kusala kudya kapena ma FMD nthawi zambiri amaperekedwa masabata onse a 4�1, mwachitsanzo, kuphatikiza ndi mankhwala a chemotherapy, ndipo nthawi yawo yakhala pakati pa 5 ndi 52,53,58,61,63 masiku68�3. . Chofunika kwambiri, palibe zovuta zoyipa (level G52,53,58,61 kapena pamwambapa, malinga ndi Common Terminology Criteria for Adverse Events) zomwe zidanenedwa m'maphunzirowaXNUMX.

Zakudya za Ketogenic

Zakudya za Ketogenic (KDs) ndi zakudya zomwe zimakhala ndi calorie yokhazikika, mafuta ochulukirapo komanso otsika kwambiri amafuta69,70. Mu classical KD, chiŵerengero cha pakati pa kulemera kwa mafuta ndi kulemera kophatikizana kwa carbohydrate ndi mapuloteni ndi 4: 1. Zindikirani, ma FMD ndi ketogenic chifukwa ali ndi mafuta ambiri ndipo amatha kuchititsa kukwera kwakukulu (? 0.5mmol pa lita) m'magulu ozungulira matupi a ketone. Kwa anthu, KD ikhozanso kuchepetsa IGF1 ndi insulini (ndi oposa 20% kuchokera kuzinthu zoyambira), ngakhale kuti zotsatirazi zimakhudzidwa ndi magulu ndi mitundu ya chakudya ndi mapuloteni mu zakudya71. Ma KD amatha kuchepetsa kuchuluka kwa shuga m'magazi, koma nthawi zambiri amakhala mkati mwanthawi yake (ndiko kuti,> 4.4mmol pa lita) 71.

Makamaka, ma KD atha kukhala othandiza poletsa kuchuluka kwa shuga ndi insulini zomwe zimachitika poyankha ma PI3K inhibitors, omwe adafunsidwa kuti achepetse mphamvu zawo72. Mwachikhalidwe, ma KD akhala akugwiritsidwa ntchito pochiza khunyu, makamaka mwa ana69. M'mitundu ya mbewa, ma KD amapangitsa zotsatira za anticancer, makamaka glioblastoma70,72�86. Kafukufuku wazachipatala akuwonetsa kuti ma KD mwina alibe chithandizo chambiri chothandizira akagwiritsidwa ntchito ngati othandizira okha kwa odwala khansa ndipo akuwonetsa kuti phindu lazakudyazi liyenera kufunidwa limodzi ndi njira zina, monga chemotherapy, radiotherapy, antiangiogenic therapy, PI3K inhibitors. ndi FMDs72,73.

Ma KD adanenedwa kukhala ndi zotsatira za neuroprotective m'mitsempha yozungulira komanso mu hippocampus87,88. Komabe, ziyenera kutsimikiziridwa ngati ma KD alinso ndi zotsatira zoberekera zofanana ndi kusala kudya kapena ma FMD (Bokosi 1) komanso ngati KDs angagwiritsidwe ntchito kuteteza zinyama zamoyo ku poizoni wa chemotherapy. Mwachidziwitso, zotsatira zotsitsimutsa za kusala kudya kapena ma FMD akuwoneka kuti akuchulukitsidwa ndi kusintha kwa njira yoyankhira njala, yomwe imaphatikizapo kuwonongeka kwa zigawo za ma cellular ndi imfa ya maselo ambiri, ndi nthawi yodyetsanso, momwe maselo ndi minofu zimayendera. kumanganso22. Chifukwa ma KD samakakamiza kulowa munjira ya njala, musalimbikitse kuwonongeka kwakukulu kwa zigawo za intracellular ndi minyewa ndipo sizimaphatikizapo nthawi yodyetsera, sizingatheke kuchititsa mtundu wa kusinthika kogwirizana komwe kunachitika panthawi ya FMD refeeding.

Kuletsa Kalori

Ngakhale kuletsa kwapang'onopang'ono kwa calorie (CR) ndi zakudya zopanda ma amino acids ndizosiyana kwambiri ndi kusala kudya nthawi ndi nthawi, amagawana ndi kusala kudya ndi ma FMDs choletsa chochepa chosankha m'zakudya, ndipo amakhala ndi zotsatira za anticancer81,89�112. CR nthawi zambiri imaphatikizapo kuchepetsa 20-30% kuchepetsa mphamvu yamagetsi kuchokera ku zakudya zopatsa mphamvu zomwe zingalole munthu kukhalabe ndi kulemera kwabwino113,114. Ndiwothandiza kwambiri kuchepetsa chiopsezo cha mtima ndi matenda a khansa mu zamoyo zachitsanzo, kuphatikizapo primates108,109,114.

Komabe, CR ingayambitse zotsatira zake, monga kusintha kwa maonekedwe a thupi, kuwonjezeka kwa kutentha kwa thupi, kuchepa kwa mphamvu, kusokonezeka kwa msambo, kusabereka, kutaya libido, osteoporosis, kuchira kwachilonda pang'onopang'ono, kudya kwambiri, kukwiya, ndi kuvutika maganizo. Odwala omwe ali ndi khansa, pali zodetsa nkhawa kuti zitha kukulitsa kusowa kwa zakudya m'thupi komanso kuti zitha kuchititsa kutaya thupi kwambiri18,113�116. CR imachepetsa kusala kudya kwa shuga m'magazi, ngakhale amakhalabe mumtundu wamba114. Mwa anthu, matenda a CR samakhudza milingo ya IGF1 pokhapokha ngati kuletsa kwapakatikati kwa mapuloteni kumakhazikitsidwa117.

Kafukufuku amasonyeza kuti pochepetsa zizindikiro za mTORC1 m'maselo a Paneth, CR imawonjezera ntchito yawo ya stem cell komanso imatetezanso maselo osungira matumbo a m'mimba kuchokera ku DNA kuwonongeka118,119, koma sizikudziwika ngati zotsatira zobwezeretsanso ziwalo zina zimaperekedwanso ndi CR. Choncho, deta yomwe ilipo imasonyeza kuti kusala kudya ndi ma FMD kumapanga kagayidwe kachakudya kamene kamayambitsa kagayidwe kachakudya, kamene kamatsitsimutsa komanso koteteza kamene kamakhala kosiyana komanso kamene kamakhala kolimba kwambiri kuposa kamene kamapangidwa ndi KD kapena CR.

Kusala kudya & ma FMD mu Therapy: Zotsatira za mahomoni ndi metabolite

Zambiri mwa kusintha kwa ma hormone ozungulira ndi ma metabolites omwe nthawi zambiri amawonedwa poyankha kusala kudya amatha kukhala ndi zotsatira zotsutsana ndi zotupa (ndiko kuti, kuchepa kwa shuga, IGF1, insulini ndi leptin ndi kuchuluka kwa adiponectin) 23,120,121 ndi / kapena kupeza chitetezo cha minofu yathanzi ku zotsatira zoyipa (ndiko kuti, kuchepa kwa IGF1 ndi shuga). Chifukwa matupi a ketone amatha kuletsa histone deacetylases (HDACs), kuwonjezereka kofulumira kwa matupi a ketone kungathandize kuchepetsa kukula kwa chotupa ndikulimbikitsa kusiyanitsa kudzera mu njira za epigenetic122.

Komabe, ketone body acetoacetate yawonetsedwa kuti imathandizira, m'malo mochepetsa, kukula kwa zotupa zina, monga melanomas ndi mutated BRAF123. Kusintha kumeneku komwe kuli umboni wamphamvu kwambiri wokhudza zotsatira zopindulitsa za kusala kudya ndi ma FMD motsutsana ndi khansa ndi kuchepetsa milingo ya IGF1 ndi shuga. Pa mlingo wa maselo, kusala kudya kapena FMD kumachepetsa ma intracellular signing cascades kuphatikizapo IGF1R�AKT�mTOR�S6K ndi cAMP�PKA signing, kumawonjezera autophagy, kumathandiza maselo abwino kupirira kupsinjika ndikulimbikitsa chitetezo cha anticancer25,29,56,124

Kusiyana Kwa Kupsinjika Maganizo: Kuchulukitsa Kupirira Kwa Chemotherapy

Ena yisiti oncogene orthologues, monga Ras ndi Sch9 (yogwira ntchito orthologue ya mammalian S6K), amatha kuchepetsa kupsinjika kwa zamoyo zamitundu27,28. Kuphatikiza apo, masinthidwe omwe amayambitsa IGF1R, RAS, PI3KCA kapena AKT, kapena omwe amaletsa PTEN, amapezeka m'makhansa ambiri amunthu10. Pamodzi, izi zidatsogolera ku lingaliro lakuti njala ingayambitse zotsutsana ndi khansa motsutsana ndi maselo abwinobwino malinga ndi kuthekera kwawo kolimbana ndi zovuta zama cell, kuphatikiza ma chemotherapeutics. M'mawu ena, njala ingayambitse kusiyana kukana kupsinjika (DSR) pakati pa maselo abwinobwino ndi a khansa.

Malinga ndi lingaliro la DSR, maselo abwinobwino amayankha njala mwa kuchepetsa kuchulukana komwe kumakhudzana ndi ribosome biogenesis ndi / kapena majini ophatikizira, omwe amakakamiza maselo kuti alowe m'njira yodzisamalira komanso kuwateteza ku kuwonongeka komwe kumachitika chifukwa cha chemotherapy, radiotherapy ndi mankhwala ena oopsa. Mosiyana ndi zimenezi, m'maselo a khansa, njira yodzisamalira yokha imatetezedwa kupyolera mu kusintha kwa oncogenic, zomwe zimayambitsa kuletsa kwapang'onopang'ono kwa njira zothetsera nkhawa12 (mkuyu 1). Mogwirizana ndi chitsanzo cha DSR, njala yaifupi kapena kuchotsedwa kwa proto-oncogene homologues (ndiko kuti, Sch9 kapena Sch9 ndi Ras2) yowonjezera chitetezo cha Saccharomyces cerevisiae ku nkhawa ya okosijeni kapena mankhwala a chemotherapy mpaka kuwirikiza ka 100 poyerekeza ndi ma cell a yisiti omwe amawonetsa mphamvu ya oncogene yogwira ntchito. azimuthandiza Ras2val19.

Zotsatira zofananira zidapezekanso m'maselo amtundu wa mammalian: kukhudzana ndi ma cell a glucose otsika kumateteza ma cell a mbewa a glia ku kawopsedwe kuchokera ku hydrogen peroxide kapena cyclophosphamide (prooxidant chemotherapeutic) koma sikunateteze mbewa, makoswe ndi glioma yamunthu ndi ma cell a khansa ya neuroblastoma. Mogwirizana ndi zowonera izi, ndi masiku 2 kusala kudya kunachulukitsa kupulumuka kwa mbewa zothandizidwa ndi mlingo waukulu wa etoposide poyerekeza ndi mbewa zosasala kudya ndikuwonjezera kupulumuka kwa neuroblastoma. alllograftbearing mbewa poyerekeza ndi mbewa zosasala chotupa12.

Kafukufuku wotsatira adapeza kuti kuchepetsedwa kwa chizindikiro cha IGF1 poyankha kusala kumateteza glia ndi ma neuroblastoma oyambirira, koma osati ma cell a glioma ndi neuroblastoma, kuchokera ku cyclophosphamide komanso ku mankhwala oletsa okosijeni komanso amateteza ma embryonic fibroblasts kuchokera ku doxorubicin29. Chiwindi cha IGF1-deficient (LID) mbewa, nyama za transgenic zokhala ndi chiwopsezo cha chiwindi cha Igf1 chomwe chikuwonetsa kutsika kwa 70&80% pamayendedwe a IGF1 (milingo yofanana ndi yomwe idakwaniritsidwa ndi mbewa za maola 72) 29,125, idatetezedwa mankhwala atatu mwa anayi omwe adayesedwa, kuphatikiza doxorubicin.

Kafukufuku wa histology adawonetsa zizindikiro za doxorubicin-induced cardiac myopathy mu mbewa zowongolera zothandizidwa ndi doxorubicin koma osati mu LID mbewa. Poyesa nyama zokhala ndi melanoma zomwe zimathandizidwa ndi doxorubicin, palibe kusiyana pakati pa kuwongolera ndi mbewa za LID zomwe zidawonedwa, zomwe zikuwonetsa kuti maselo a khansa sanatetezedwe ku chemotherapy pochepetsa milingo ya IGF1. Komabe, kachiwiri, mbewa zokhala ndi chotupa LID zidawonetsa mwayi wopulumuka poyerekeza ndi nyama zowongolera chifukwa chakutha kupirira toxicity ya doxorubicin29. Choncho, ponseponse, zotsatirazi zatsimikizira kuti IGF1 downregulation ndi njira yofunika kwambiri yomwe kusala kudya kumawonjezera kupirira kwa chemotherapy.

Dexamethasone ndi mTOR inhibitors amagwiritsidwa ntchito kwambiri pochiza khansa, mwina chifukwa cha mphamvu yawo ngati anti-emetics ndi anti-allergens (ndiko kuti, corticosteroids) kapena awo antitumor katundu (ndiko kuti, corticosteroids ndi mTOR inhibitors). Komabe, chimodzi mwazotsatira zawo zazikulu komanso zomwe nthawi zambiri zimalepheretsa mlingo ndi hyperglycemia. Mogwirizana ndi lingaliro lakuti kuchuluka kwa glucose "cAMP" PKA kusonyeza amachepetsa kukana kwa poizoni wa mankhwala a chemotherapeutic12,26,126, onse dexamethasone ndi rapamycin amawonjezera kawopsedwe wa doxorubicin mu mbewa cardiomyocytes ndi mbewa26. Chochititsa chidwi chinali kotheka kusintha kawopsedwe kotereku pochepetsa kuchuluka kwa shuga m'magazi kudzera m'majakisoni osala kudya kapena a insulin26.

Izi zimachepetsa ntchito za PKA pamene zikukulitsa ntchito za AMPK ndikuyambitsa EGR1, kusonyeza kuti cAMP� PKA siginecha imayimira DSR yofulumira kusala kudzera pa EGR1 (ref. 26). EGR1 imalimbikitsanso mawu a cardioprotective peptides, monga atrial natriuretic peptide (ANP) ndi B-mtundu wa natriuretic peptide (BNP) mu minofu ya mtima, yomwe imathandizira kukana doxorubicin. Kuphatikiza apo, kusala kudya ndi/kapena FMD kumatha kuteteza mbewa ku cardiomyopathy yopangidwa ndi doxorubicin mwa kulimbikitsa autophagy, yomwe ingalimbikitse thanzi la ma cell pochepetsa kupanga kwamtundu wa okosijeni (ROS) pochotsa mitochondria yosokonekera komanso kuchotsa zophatikizira zapoizoni.

Kuphatikiza pa kuchepetsa kuopsa kwa mankhwala a chemotherapy m'maselo ndi kuonjezera kupulumuka kwa mbewa zothandizidwa ndi mankhwala a chemotherapy, kusala kudya kumapangitsa kuti mafupa apangidwenso komanso kuteteza chitetezo chamthupi chomwe chimayambitsidwa ndi cyclophosphamide mu PKA-yokhudzana ndi IGF1. Choncho, zotsatira zokakamiza zowonongeka zimasonyeza kuthekera kwa kusala kudya ndi ma FMD kuti awonjezere kulekerera kwa mankhwala a chemotherapy komanso kupewa zotsatira zazikulu. Chifukwa chakuti deta yoyambirira yachipatala imapereka chithandizo chowonjezereka ku izi, maphunziro oyambirirawa amapanga zifukwa zomveka zowunika ma FMD m'mayesero achipatala osadziwika bwino ndi TEAEs monga mapeto oyambirira.

Kusiyanitsa Kupsinjika Maganizo: Kuchulukitsa Imfa Ya Maselo a Khansa

Ngati agwiritsidwa ntchito okha, njira zambiri za zakudya, kuphatikizapo kusala kudya ndi ma FMD, zimakhala ndi zotsatira zochepa zotsutsana ndi kukula kwa khansa. Malingana ndi lingaliro la kusiyana kwa maganizo (DSS), kuphatikiza kusala kudya kapena ma FMD ndi chithandizo chachiwiri ndikulonjeza kwambiri11,12. Lingaliro ili limaneneratu kuti, ngakhale maselo a khansa amatha kutengera mpweya wochepa komanso kuchuluka kwa michere, mitundu yambiri ya maselo a khansa sangathe kuchita zosintha zomwe zingalole kupulumuka m'malo osowa michere komanso poizoni wopangidwa ndi kuphatikiza kusala kudya ndi chemotherapy. , Mwachitsanzo. Kuyesa koyambirira kwa khansa ya m'mawere, melanoma ndi ma cell a glioma adapeza kuwonjezereka kodabwitsa kwa kufotokozera kwa majini okhudzana ndi kuchulukana kapena ma ribosome biogenesis ndi ma gene a msonkhano poyankha kusala kudya11,12. Zosintha zotere zidatsagana ndi kuyambitsa kosayembekezereka kwa AKT ndi S6K, chizolowezi chopanga kuwonongeka kwa ROS ndi DNA ndi kuchititsa chidwi kupita ku mankhwala owononga DNA (kudzera ku DSS)11.

Timawona kuyankha kosayenera kwa maselo a khansa kuzinthu zosinthidwa kuphatikizapo kuchepetsa IGF1 ndi milingo ya shuga chifukwa cha kusala kudya kapena ma FMD ngati njira yofunika kwambiri yomwe imayambitsa antitumor Zomwe zimagwiritsidwa ntchito pazakudyazi komanso zothandiza zake pakulekanitsa zotsatira za mankhwala oletsa khansa pazabwinobwino motsutsana ndi maselo owopsa11,12 (mkuyu 1). Mogwirizana ndi lingaliro la DSS, kusala kudya nthawi ndi nthawi kapena ma FMD ndikokwanira kuchepetsa kukula kwa mitundu yambiri ya matenda. chotupa ma cell, kuyambira ma cell olimba a chotupa kupita ku ma lymphoid leukemia cell, mu mbewa ndipo, chofunikira kwambiri, kudziwitsa maselo a khansa ku chemotherapeutics, radiotherapy ndi tyrosine kinase inhibitors (TKIs) 11,17,22,25,50,54.

Pochepetsa kupezeka kwa shuga ndikuwonjezera mafuta acid ?-oxidation, kusala kudya kapena ma FMD amathanso kulimbikitsa kusintha kuchokera ku aerobic glycolysis (Warburg effect) kupita ku mitochondrial oxidative phosphorylation m'maselo a khansa, zomwe ndizofunikira kuti maselo a khansa apitirire kukula m'malo osauka kwambiri50 (mkuyu 2). Kusinthaku kumabweretsa kuchulukira kwa ROS kupanga11 chifukwa chakuchulukira kwa kupuma kwa mitochondrial komanso kungaphatikizepo kuchepetsa kuthekera kwa ma cell redox chifukwa cha kuchepa kwa kaphatikizidwe ka glutathione kuchokera ku glycolysis ndi pentose phosphate pathway50. Kuphatikizika kwa ROS augmentation ndikuchepetsa chitetezo cha antioxidant kumawonjezera kupsinjika kwa okosijeni m'maselo a khansa ndikukulitsa ntchito ya chemotherapeutics. Makamaka, chifukwa ntchito yapamwamba ya glycolytic yomwe ikuwonetsedwa ndi kupanga kwa lactate yapamwamba ikuwonetseratu zaukali ndi metastatic propensity mu mitundu ingapo ya khansa129, zotsatira za anti-Warburg za kusala kudya kapena FMD zimatha kukhala zogwira mtima kwambiri polimbana ndi khansa yaukali ndi metastatic.

Kupatula kusintha kwa metabolism, kusala kudya kapena ma FMD kumapangitsa kusintha kwina komwe kungalimbikitse DSS m'maselo a khansa ya pancreatic. Kusala kudya kumawonjezera kuchuluka kwa mawu wofanana nucleoside transporter 1 (ENT1), wonyamula gemcitabine kudutsa membrane ya plasma, zomwe zimatsogolera ku ntchito yabwino ya mankhwalawa128. M'maselo a khansa ya m'mawere, kusala kudya kumayambitsa SUMO2-mediated ndi/kapena SUMO3-mediated kusinthidwa kwa REV1, DNA polymerase ndi p53-binding protein127. Kusintha kumeneku kumachepetsa mphamvu ya REV1 kuletsa p53, zomwe zimapangitsa kuti p53-mediated transcript ya pro-apoptotic gene ndipo, potsirizira pake, ku imfa ya maselo a khansa (mkuyu 2). Kusala kudya kumawonjezeranso kuthekera kwa ma TKI omwe amaperekedwa nthawi zambiri kuti aletse kukula kwa maselo a khansa ndi/kapena kufa mwa kulimbikitsa kuletsa kusaina kwa MAPK ndipo, potero, kutsekereza mafotokozedwe a jini otengera E2F komanso kuchepetsa kuchuluka kwa shuga17,54.

Pomaliza, kusala kudya kumatha kukweza cholandilira cha leptin ndi kutsika kwake kusonyeza kudzera mu protein PR/SET domain 1 (PRDM1) ndipo potero amalepheretsa kuyambika ndikusintha kupita patsogolo kwa B cell ndi T cell acute lymphoblastic. khansa ya m'magazi (Zonse), koma osati za myeloid yovuta khansa ya m'magazi (AML) 55. Chochititsa chidwi n'chakuti, kafukufuku wodziimira yekha adawonetsa kuti B cell precursors amasonyeza kuti ali ndi malire osatha mu shuga ndi mphamvu zamagetsi zomwe zimaperekedwa ndi zolemba za PAX5 ndi IKZF1 (ref. 130). Kusintha kwa majini omwe amasunga mapuloteni awiriwa, omwe amapezeka muzochitika zoposa 80% za pre-B cell ALL, adawonetsedwa kuti akuwonjezera kutengeka kwa shuga ndi ma ATP. Komabe, kukonzanso PAX5 ndi IKZF1 m'maselo a preB-ALL kumabweretsa vuto lamphamvu komanso kuwonongeka kwa maselo. Kutengedwa pamodzi ndi phunziro lapitalo, ntchitoyi ikuwonetsa kuti ONSE akhoza kukhala okhudzidwa ndi zoletsa zomanga thupi ndi mphamvu zomwe zimaperekedwa ndi kusala kudya, mwinamwake kuimira munthu wabwino wachipatala kuti ayese kusala kudya kapena FMD.

Mwachidziwitso, zikutheka kuti mitundu yambiri ya maselo a khansa, kuphatikizapo AML29, imatha kukana poletsa kusintha kwa kagayidwe kachakudya komwe kumadza chifukwa cha kusala kudya kapena ma FMD, mwayi womwe umakulitsidwanso chifukwa cha metabolic heterogeneity yomwe imakhala ndi khansa zambiri129. Choncho, cholinga chachikulu cha posachedwapa chidzakhala kuzindikira mitundu ya khansa yomwe imakhala yovuta kwambiri kumagulu a zakudya izi pogwiritsa ntchito biomarkers. Kumbali ina, akaphatikizidwa ndi mankhwala ochiritsira, kusala kudya kapena ma FMD sikunayambitse kupeza kukana mu zitsanzo za mbewa za khansa, ndipo kukana kusala kudya pamodzi ndi mankhwala amphamvu a chemotherapy kumakhalanso kwachilendo m'maphunziro a m'mimba, kutsindika kufunika kozindikira mankhwala omwe, zikaphatikizidwa ndi ma FMD, zimapangitsa kuti pakhale zowopsa zolimbana ndi ma cell a khansa omwe ali ndi kawopsedwe kakang'ono ku maselo wamba ndi minofu11,17,50,55�57,59,124.

Antitumour Immunity Kupititsa patsogolo Mwa Kusala kapena FMD

Deta yaposachedwa ikuwonetsa kuti kusala kudya kapena ma FMD okha, komanso mokulirapo akaphatikizidwa ndi chemotherapy, kumayambitsa kufalikira kwa ma lymphoid progenitors ndikulimbikitsa. chotupa chitetezo chamthupi kudzera munjira zosiyanasiyana25,56,60,124. FMD inachepetsa mawu a HO1, puloteni yomwe imapereka chitetezo ku kuwonongeka kwa okosijeni ndi apoptosis, m'maselo a khansa mu vivo koma kufotokozera HO1 m'maselo abwinobwino124,131. Kutsika kwa HO1 m'maselo a khansa kumagwirizanitsa ndi FMD-induced chemosensitization poonjezera CD8 + chotupa-infiltrating lymphocyte-dependent cytotoxicity, yomwe ingathe kuthandizidwa ndi kutsika kwa maselo T olamulira124 (Mkuyu 2). Kafukufuku wina, womwe unatsimikizira kuthekera kwa kusala kudya kapena ma FMD ndi ma CR mimetics kuti apititse patsogolo chitetezo chamthupi cha anticancer, amatanthauza kuti zotsatira za anticancer za kusala kudya kapena ma FMD zingagwiritsidwe ntchito kwa autophagy oyenerera, koma osati autophagy-deficient, khansa56. Pomaliza, kafukufuku waposachedwa wa kusala kudya kwamasiku awiri kwa milungu iwiri mu mtundu wa khansa ya m'matumbo a mbewa adawonetsa kuti, poyambitsa autophagy m'maselo a khansa, kusala kumachepetsa mawu a CD2 ndipo chifukwa chake kumachepetsa kupanga kwa immunosuppressive adenosine ndi ma cell a khansa73. Pamapeto pake, kutsika kwa CD60 mwa kusala kudya kunasonyezedwa kuteteza kusintha kwa macrophage ku M73 immunosuppressive phenotype (Mkuyu 2). Pamaziko a maphunzirowa, ndizosangalatsa kunena kuti ma FMD atha kukhala othandiza kwambiri m'malo mwake kapena kuphatikiza ndi immune checkpoint inhibitors2, katemera wa khansa kapena mankhwala ena omwe amathandizira. antitumor chitetezo chokwanira, kuphatikizapo mankhwala ochiritsira ochiritsira133.

Zakudya za Anticancer mu Ma Mouse Models

Ponseponse, zotsatira za kafukufuku woyambirira wa kusala kudya kapena ma FMD mumitundu ya khansa ya nyama, kuphatikiza mitundu ya khansa ya metastatic (Table 2), zikuwonetsa kuti kusala kudya nthawi ndi nthawi kapena ma FMD amakwaniritsa zotsatira za pleiotropic anticancer ndikuwonjezera ntchito ya chemotherapeutics ndi TKIs pomwe akugwira ntchito zoteteza komanso zosinthika. mu ziwalo zambiri22,25. Kupeza zotsatira zomwezo popanda kusala kudya ndi / kapena ma FMD kungafunike choyamba chizindikiritso ndiyeno kugwiritsa ntchito mankhwala ambiri ogwira mtima, okwera mtengo komanso omwe nthawi zambiri amawotcha ndipo mwina angakhale opanda mwayi wopangitsa chitetezo cha maselo athanzi. Ndizofunikira kudziwa kuti m'maphunziro osachepera awiri kusala kudya kophatikizana ndi chemotherapy kunatsimikizira kukhala njira yokhayo yomwe ingathe kuthetseratu chotupa kapena kupulumuka kwanthawi yayitali mu gawo losasinthika la nyama zochiritsidwa11,59

Ma KD osatha amawonetsanso a chotupa Kuchedwetsa kukula kukagwiritsidwa ntchito ngati monotherapy, makamaka mumitundu ya mbewa za khansa ya muubongo77,78,80�82,84,134. Gliomas mu mbewa zomwe zimasungidwa pa KD zosatha zachepetsa kuwonetsetsa kwa hypoxia marker carbonic anhydrase 9 ndi hypoxia-inducible factor 1?, kuchepa kwa nyukiliya factor-?B activation ndi kuchepetsedwa kwa vascular marker expression (ndiko kuti, vascular endothelial growth factor receptor 2, matrix metalloproteinase 2 ndi vimentin)86. Mu mtundu wa mbewa wa intracranial wa glioma, mbewa zodyetsera KD zowonetsedwa zidakwera chotupa-zotakasika Mayankho obadwa nawo komanso osinthika a chitetezo chamthupi omwe amalumikizidwa makamaka ndi CD8+ T cell79. Ma KD adawonetsedwa kuti apititse patsogolo ntchito ya carboplatin, cyclophosphamide ndi radiotherapy mu glioma, khansa ya m'mapapo. ndi Mitundu ya mbewa ya neuroblastoma73�75,135. Kuphatikiza apo, kafukufuku waposachedwa akuwonetsa kuti KD ikhoza kukhala yothandiza kwambiri kuphatikiza ndi PI3K inhibitors72. Poletsa insulin kusonyezaMankhwalawa amathandizira kusweka kwa glycogen m'chiwindi ndikuletsa kuyamwa kwa shuga m'mitsempha ya chigoba, zomwe zimabweretsa kusakhalitsa. hyperglycemia ndi kubweza kwa insulin kuchokera ku kapamba (chodabwitsa chotchedwa "insulin feedback"). M'malo mwake, izi kwezani mumilingo ya insulin, yomwe imatha kukhala yayitali, makamaka kwa odwala omwe ali ndi insulin kukana, imayambiranso PI3KMTOR. kusonyeza in zotupa, motero kuchepetsa kwambiri phindu la PI3K inhibitors. KD idawonetsedwa kuti ndiyothandiza kwambiri poletsa kuyankha kwa insulin poyankha mankhwalawa komanso kuwongolera mwamphamvu zochita zawo zolimbana ndi khansa mu mbewa. Pomaliza, malinga ndi kafukufuku wamtundu wa cachexia wopangidwa ndi murine chotupa (MAC16 zotupa), KDs zingathandize kuteteza kutaya kwa mafuta ndi osakhala mafuta a thupi kwa odwala khansa85.

CR yachepetsa tumorigenesis mumitundu ya khansa ya mbewa, mitundu ya mbewa yokhala ndi tumorigenesis yokhayokha komanso mitundu ya mbewa ya khansa, komanso anyani91,92,97,98,101,102,104�106,108,109,136�138. Mosiyana ndi zimenezi, kafukufuku anapeza kuti CR kuyambira zaka zapakati kwenikweni imawonjezera chiwerengero cha ma neoplasms a plasma mu C57Bl / 6 mice139. Komabe, mu kafukufuku womwewo, CR idakulitsanso moyo wautali ndi pafupifupi 15%, ndipo kuchulukitsidwa kwachiwopsezo cha khansa kunayamba chifukwa cha kuchuluka kwa moyo wautali wa mbewa zomwe zimakumana ndi CR, zaka zomwe. chotupa mbewa zomwe zikukumana ndi CR zidafa komanso kuchuluka kwa chotupa mbewa zomwe zidamwalira ndi CR. Chifukwa chake, olembawo adatsimikiza kuti CR mwina imalepheretsa kukwezedwa komanso / kapena kupitilira kwa khansa ya lymphoid yomwe ilipo. Kuwunika kwa meta kuyerekeza CR yosatha ndi CR yapakatikati malinga ndi kuthekera kwawo popewa khansa mu makoswe kunawona kuti CR yokhazikika ndiyothandiza kwambiri pamachitidwe a mbewa opangidwa ndi majini, koma siyothandiza kwambiri pamakoswe opangidwa ndi mankhwala90. CR idawonetsedwa kuti ikuchedwa chotupa kukula ndi/kapena kukulitsa kupulumuka kwa mbewa m'mitundu yosiyanasiyana ya mbewa za khansa, kuphatikiza khansa ya ovarian ndi pancreatic140,94 ndi neuroblastoma81.

Chofunika kwambiri, CR inapititsa patsogolo ntchito ya mankhwala oletsa khansa m'mitundu ingapo ya khansa, kuphatikizapo zochita za antiIGF1R antibody (ganitumab) motsutsana ndi khansa ya prostate141, cyclophosphamide motsutsana ndi ma cell a neuroblastoma135 ndi autophagy inhibition mu xenografts ya HRAS-G12Vtransformed immortal baby mouse cell epitheli. Komabe, CR kapena KD kuphatikiza ndi mankhwala ochizira khansa akuwoneka kuti alibe mphamvu kuposa kusala kudya. Kafukufuku wa mbewa adapeza kuti, mosiyana ndi kusala kudya kokha, CR yokha sinathe kuchepetsa kukula kwa GL100 mouse gliomas yomwe ikukula pang'onopang'ono komanso kuti, mosiyana ndi kusala kudya kwakanthawi kochepa, CR sinawonjezere ntchito ya cisplatin motsutsana ndi mawere a subcutaneous 26T4. zotupa1. Mu phunziro lomwelo, kusala kudya kunakhalanso kothandiza kwambiri kuposa CR ndi KD pakukulitsa kulekerera kwa doxorubicin51. Ngakhale kusala kudya kapena FMD, CR ndi KD atha kuchitapo kanthu ndikuwongolera kuphatikizika kusonyeza Njira, kusala kudya kapena FMD mwina imakhudza njira zotere movutikira kwambiri panthawi yovuta kwambiri kwa masiku angapo.

Gawo la refeeding akanakhoza ndiye chisomo kuchira kwa homeostasis ya chamoyo chonse komanso kuyambitsa ndi kulimbikitsa njira zomwe zingathandize kuzindikira ndikuchotsa chotupa ndi kukonzanso maselo athanzi. CR ndi KD ndi njira zosatha zomwe zimatha kupondereza pang'onopang'ono njira yowonongeka kwa michere, mwinamwake popanda kufika pazigawo zina zofunika kuti athetse zotsatira za mankhwala oletsa khansa, pamene amabweretsa kulemetsa kwakukulu ndipo nthawi zambiri kuchepetsa thupi. CR ndi KD monga zakudya zosatha kwa odwala omwe ali ndi khansa zimakhala zovuta kuzitsatira ndipo zimakhala ndi chiopsezo cha thanzi. CR ikhoza kuchititsa kuti thupi likhale lochepa kwambiri komanso kuchepetsa mahomoni a steroid komanso mwina chitetezo cha mthupi142. Ma KD osatha amalumikizidwanso ndi zotsatira zofanana ngakhale zochepa kwambiri143. Choncho, kusala kudya nthawi ndi nthawi komanso maulendo a FMD osapitirira masiku a 5 omwe amagwiritsidwa ntchito pamodzi ndi mankhwala ochiritsira ali ndi mwayi wopititsa patsogolo chithandizo cha khansa pamene amachepetsa zotsatira zake. Makamaka, zikhala zofunikira kuphunzira momwe kuphatikizidwira kwa ma FMD nthawi zonse, ma KD osatha ndi njira zochiritsira zokhazikika, makamaka zochizira makhansa owopsa monga glioma.

Kusala ndi ma FMD mu Kupewa Khansa

Maphunziro a Epidemiological ndi maphunziro a zinyama, kuphatikizapo anyani108,109,144, ndi anthu amapereka chithandizo ku lingaliro lakuti CR yosatha ndi kusala kudya nthawi ndi nthawi komanso / kapena FMD ikhoza kukhala ndi zotsatira zopewera khansa mwa anthu. Komabe, CR sangathe kukhazikitsidwa mwa anthu ambiri chifukwa cha kutsata malamulo komanso zovuta zomwe zingatheke115. Chifukwa chake, ngakhale malingaliro ozikidwa paumboni azakudya zomwe mungakonde (kapena kupewa) komanso malingaliro amoyo kuti achepetse chiopsezo cha khansa akukhazikitsidwa6,8,9,15, cholinga chake tsopano ndikuzindikira, mwina, kukhazikika bwino, kulekerera, pafupipafupi. zakudya zomwe zili ndi zotsatira zochepa kapena zopanda pake ndikuwunika mphamvu zawo zopewera khansa m'maphunziro azachipatala.

Monga tafotokozera kale, maulendo a FMD amachititsa kutsika kwa IGF1 ndi shuga ndi kuwongolera kwa IGFBP1 ndi matupi a ketone, omwe amasintha mofanana ndi omwe amayamba chifukwa cha kusala kudya ndipo ndi biomarkers ya kusala kudya22. Pamene C57Bl/6 mbewa (zomwe zimangopanga zokha zotupa, makamaka ma lymphoma, pamene akukalamba) amadyetsedwa ndi FMD kwa masiku 4 kawiri pamwezi kuyambira zaka zapakati ndi ad libitum zakudya pakati pa nthawi ya FMD, chiwerengero cha ma neoplasms chinachepetsedwa kuchokera pafupifupi 70% mu mbewa zomwe zimayendetsa. zakudya pafupifupi 40% mu mbewa mu gulu la FMD (kuchepetsa kwa 43%)22. Kuonjezera apo, FMD inaimitsidwa ndi miyezi yoposa 3 kuchitika kwa imfa zokhudzana ndi neoplasm, ndipo chiwerengero cha nyama zomwe zimakhala ndi zotupa zambiri zachilendo zinali zoposa katatu mu gulu lolamulira kusiyana ndi mbewa za FMD, kusonyeza kuti ambiri zotupa mu mbewa za FMD sizinali zaukali kapena zopanda pake.

Kafukufuku wam'mbuyomu wa kusala kudya kwamasiku ena, komwe kunachitika pa mbewa zazaka zapakati kwa miyezi yonse ya 4, adapezanso kuti kusala kudya kumachepetsa kuchuluka kwa lymphoma, kubweretsa kuchokera ku 33% (kwa mbewa zowongolera) mpaka 0% (mosala kudya). nyama) 145, ngakhale chifukwa cha nthawi yochepa ya kafukufuku sizikudziwika ngati ndondomeko yosala kudyayi inalepheretsa kapena kuchedwetsa chotupa chiyambi. Kuphatikiza apo, kusala kudya kwamasiku ena kumapangitsa masiku a 15 pamwezi kusala kudya kwamadzi okha, pomwe kuyesa kwa FMD komwe kufotokozedwa pamwambapa mbewa zinayikidwa pazakudya zomwe zimapatsa chakudya chochepa kwa masiku 8 okha pamwezi. Kwa anthu, maulendo a 3 a masiku a 5 a FMD kamodzi pamwezi adawonetsedwa kuti achepetse kunenepa kwambiri m'mimba ndi zizindikiro za kutupa komanso IGF1 ndi milingo ya shuga m'mitu yomwe ili ndi milingo yokwera yazizindikiro62, zomwe zikuwonetsa kuti kugwiritsa ntchito nthawi ndi nthawi kwa FMD kumatha kukhala nako. zodzitetezera zokhudzana ndi kunenepa kwambiri kapena zokhudzana ndi kutupa, komanso zina, khansa mwa anthu, monga zasonyezedwera mbewa22.

Choncho, zotsatira zodalirika za maphunziro a preclinical pamodzi ndi deta yachipatala pa zotsatira za FMD pazochitika zoopsa za zokhudzana ndi ukalamba matenda, kuphatikizapo khansa62, amapereka chithandizo ku maphunziro amtsogolo mwachisawawa a FMDs ngati chida chothandizira kupewa khansa, komanso zina. zokhudzana ndi ukalamba matenda aakulu, mwa anthu.

Kugwiritsidwa Ntchito Kwachipatala mu Oncology

Maphunziro anayi otheka kusala kudya ndi ma FMD kwa odwala omwe akudwala chemotherapy adasindikizidwa kuyambira lero52,53,58,61. Pankhani ya odwala 10 omwe adapezeka ndi mitundu yosiyanasiyana ya khansa, kuphatikiza bere, prostate, ovarian, chiberekero, khansa ya m'mapapo ndi esophageal, omwe adasala kudya modzifunira mpaka 140hours isanachitike komanso / kapena mpaka 56hours kutsatira chemotherapy, palibe zotsatirapo zazikulu zomwe zidachitika. mwa kusala kudya kwina kupatula njala ndi kupepuka mutu zinanenedwa58. Odwala (asanu ndi mmodzi) omwe adalandira mankhwala a chemotherapy ndi osasala kudya adanenanso kuchepa kwakukulu kwa kutopa, kufooka ndi zochitika za m'mimba pamene akusala kudya. Kuphatikiza apo, mwa odwala omwe kukula kwa khansa kungayesedwe, kusala kudya sikunalepheretse kuchepetsedwa kwa chemotherapy-kuchepetsa kuchuluka kwa chotupa kapena zolembera zotupa. Mu kafukufuku wina, amayi 13 omwe ali ndi HER2 (omwe amadziwikanso kuti ERBB2) alibe, khansa ya m'mawere ya II/III omwe amalandila neo-adjuvant taxotere, adriamycin ndi cyclophosphamide (TAC) chemotherapy adasinthidwa mwachisawawa kuti azitha kudya (madzi okha) maola 24 asanayambe kapena atangoyamba mankhwala a chemotherapy kapena ku zakudya molingana ndi malangizo okhazikika52.

Kusala kudya kwakanthawi kochepa kunaloledwa bwino ndikuchepetsa kuchepa kwa erythrocyte ndi thrombocyte masiku 7 pambuyo pa chemotherapy. Chochititsa chidwi n'chakuti, mu phunziroli, milingo ya ?-H2AX (chizindikiro cha kuwonongeka kwa DNA) inawonjezeka 30minutes pambuyo pa chemotherapy mu leukocytes kuchokera kwa odwala osasala kudya koma osati odwala omwe anasala kudya. Pakuchulukirachulukira kwa kusala kudya kwa odwala omwe amalandila mankhwala a chemotherapy opangidwa ndi platinamu, odwala 20 (omwe adalandira chithandizo cha khansa ya urothelial, ovarian kapena khansa ya m'mawere) adasinthidwa mwachisawawa kuti asala kudya kwa 24, 48 kapena 72hours (ogawidwa ngati 48hours isanachitike chemotherapy ndi 24hours pambuyo pa chemotherapy. ) 53. Zomwe zingatheke (zomwe zimatanthauzidwa ngati maphunziro atatu kapena kuposerapo mwa asanu ndi limodzi pamagulu onse omwe amadya? 200kcal patsiku panthawi yofulumira popanda poizoni wochuluka) adakumana. Zowopsa zokhudzana ndi kusala kudya anali giredi nthawi zonse 2 kapena pansi, chofala kwambiri ndi kutopa, kupweteka mutu ndi chizungulire. Monga momwe taphunzirira kale, kuchepetsa kuwonongeka kwa DNA (monga kuzindikiridwa ndi comet assay) mu leukocytes kuchokera kwa anthu omwe anasala kudya kwa maola osachepera a 48 (poyerekeza ndi anthu omwe anasala kudya kwa 24hours okha) amathanso kudziwika muyeso laling'ono ili. Kuonjezera apo, chizolowezi chopanda chigawo chochepa cha 3 kapena 4 neutropenia kwa odwala omwe amasala kudya kwa 48 ndi 72hours motsutsana ndi omwe amasala kudya kwa 24hours okha adalembedwanso.

Posachedwapa, kuyesedwa kwachipatala kwachindunji kunachitika poyesa zotsatira za FMD pa umoyo wa moyo ndi zotsatira za mankhwala a chemotherapy mwa odwala 34 omwe ali ndi khansa ya m'mawere kapena yamchiberekero61. FMD inali ndi tsiku lililonse kudya kwa caloric <400kcal, makamaka ndi timadziti ndi msuzi, kuyambira 36-48hours isanayambike chemotherapy ndipo imatha mpaka 24hours pambuyo pa kutha kwa chemotherapy. Mu phunziro ili, FMD inalepheretsa chemotherapy kuti ichepetse khalidwe la moyo komanso kuchepetsa kutopa. Apanso, palibe zovuta zoyipa za FMD zomwe zidanenedwa. Mayesero ena angapo azachipatala a ma FMD ophatikizana ndi chemotherapy kapena mitundu ina yamankhwala ochiritsira akupitilirabe ku US ndi zipatala zaku Europe, makamaka mwa odwala omwe amapezeka ndi khansa ya m'mawere kapena ya prostate63,65�68. Awa ndi maphunziro azachipatala a mkono umodzi kuti awone chitetezo ndi kuthekera kwa FMD kapena maphunziro azachipatala osasinthika omwe amayang'ana kwambiri momwe FMD imakhudzira kawopsedwe ka chemotherapy kapena moyo wa odwala panthawi ya chemotherapy yokha. Zonsezi, maphunzirowa adalembetsa odwala opitilira 300, ndipo zotsatira zawo zoyambirira zikuyembekezeka kupezeka mu 2019.

Mavuto mu Clinic

Kuphunzira kusala kudya nthawi ndi nthawi kapena ma FMD mu oncology sikukhala ndi nkhawa, makamaka pokhudzana ndi kuthekera kuti mtundu uwu wa zakudya ukhoza kuyambitsa kuperewera kwa zakudya m'thupi, sarcopenia, ndi cachexia mwa odwala omwe ali ndi chiopsezo kapena ofooka (mwachitsanzo, odwala omwe amadwala anorexia chifukwa cha chemotherapy) 18,19. Komabe, palibe zochitika za kuchepa thupi (pamwamba pa giredi 3) kapena kuperewera kwa zakudya m'thupi zomwe zidanenedwapo m'maphunziro azachipatala okhudzana ndi kusala kudya limodzi ndi mankhwala amphamvu omwe adasindikizidwa masiku ano, ndipo odwala omwe adachepetsa thupi pakusala kudya adachira asanafike. kuzungulira kotsatira popanda kuvulaza. Komabe, timalimbikitsa kuti nthawi ndi nthawi kuyesedwa kwa anorexia ndi zakudya zopatsa thanzi pogwiritsa ntchito njira za golidi18,19,146�150 ziyenera kukhala gawo lofunika kwambiri la maphunzirowa komanso kuti kuwonongeka kulikonse kwa zakudya kwa odwala omwe akusala kudya ndi / kapena ma FMD kumakonzedwa mofulumira.

Mawuwo

Kusala kudya kwanthawi ndi nthawi kapena ma FMD nthawi zonse amawonetsa zotsatira zamphamvu zolimbana ndi khansa mumitundu ya khansa ya mbewa kuphatikiza kuthekera kopanga chemoradiotherapy ndi TKIs komanso kuyambitsa chitetezo chamthupi. Matenda a FMD ndi otheka kusiyana ndi zakudya zowonongeka chifukwa amalola odwala kudya chakudya nthawi zonse panthawi ya FMD, kukhala ndi zakudya zoyenera pakati pa zozungulira ndipo sizimapangitsa kuti thupi likhale lolemera kwambiri ndipo mwina zotsatira zowononga chitetezo cha mthupi ndi endocrine. Makamaka, monga njira zochiritsira zodziyimira pawokha, kusala kudya nthawi ndi nthawi kapena kuzungulira kwa FMD kumatha kuwonetsa mphamvu zochepa zolimbana ndi zotupa zokhazikika. Ndipotu, mu mbewa, kusala kudya kapena ma FMD zimakhudza kukula kwa khansa zingapo mofanana ndi chemotherapy, koma zokhazokha, sizimagwirizana ndi zotsatira zomwe zimapezeka pamodzi ndi mankhwala a khansa omwe angapangitse kuti apulumuke opanda khansa11,59. Choncho, tikupempha kuti ndiphatikizepo maulendo a nthawi ndi nthawi a FMD ndi mankhwala ochiritsira omwe ali ndi mwayi wapamwamba kwambiri wopititsa patsogolo kupulumuka kwa khansa kwa odwala, monga momwe ma mbewa amachitira11,59 (Mkuyu 3).

Kuphatikizika kumeneku kungakhale kothandiza kwambiri pazifukwa zingapo: choyamba, mankhwala a khansa ndi machiritso ena amatha kukhala othandiza, koma gawo lina la odwala samayankha chifukwa maselo a khansa amatengera njira zina za metabolic zomwe zimatsogolera kupulumuka. Mitundu ina ya kagayidwe kagayidwe kachakudya imakhala yovuta kwambiri kuti ipitirire pansi pa kusala kudya kapena FMD chifukwa cha zofooka kapena kusintha kwa shuga, ma amino acid ena, mahomoni, ndi kukula, komanso njira zina zosadziwika zomwe zimatsogolera ku imfa ya selo. Chachiwiri, kusala kudya kapena ma FMD kumatha kuletsa kapena kuchepetsa kukana. Chachitatu, kusala kudya kapena ma FMD amateteza maselo abwinobwino ndi ziwalo ku zotsatira zoyipa zomwe zimayambitsidwa ndi mankhwala osiyanasiyana a khansa. Pamaziko a umboni wotsimikizirika komanso wachipatala wotheka, chitetezo ndi mphamvu (pa kuchepetsa IGF1, mafuta a visceral ndi zowopsa za mtima), ma FMD amawonekeranso ngati njira yabwino yophunzirira popewa khansa. Vuto lalikulu lamtsogolo lidzakhala kuzindikira iwo zotupa omwe ndi omwe akuyenera kupindula ndi kusala kudya kapena ma FMD. Ngakhale mu mitundu ya khansa yomwe ikuwoneka kuti siimakhudzidwa ndi kusala kudya kapena ma FMD, zingakhale zotheka kuzindikira njira zodzitetezera ndikulowererapo ndi mankhwala omwe amatha kubwezeretsa kukana kumeneko. Kumbali ina, kusamala kwambiri kuyenera kutsatiridwa ndi mitundu ina yazakudya, makamaka ngati ili ndi zopatsa mphamvu zambiri, chifukwa zingayambitse kuchulukirachulukira komanso osaletsa. kukula za khansa zina. Mwachitsanzo, KD ikuwonjezeka kukula ya mtundu wa melanoma wokhala ndi mutated BRAF mu mice123, ndipo idanenedwanso kuti imathandizira kukula kwa matenda mu mbewa ya AML model72.

Kuphatikiza apo, ndikofunikira kugwiritsa ntchito ma FMD ndikumvetsetsa njira zogwirira ntchito, popeza mphamvu zawo ngati atagwiritsidwa ntchito molakwika zitha kubweretsa zotsatira zoyipa. Mwachitsanzo, makoswe akasala kudya ndikuthandizidwa ndi carcinogen yamphamvu asanayamwitse, izi zidapangitsa kuti chiwopsezo cha chiwindi, m'matumbo chikule. ndi rectum poyerekeza ndi makoswe osasala kudya151,152. Ngakhale njira zomwe zimakhudzidwa ndi izi sizikumveka, ndipo foci izi mwina sizinachitike zotupa, maphunzirowa amasonyeza kuti nthawi yochepa ya 24�48hours pakati pa mankhwala a chemotherapy ndi kubwereranso ku zakudya zoyenera ndizofunikira kuti tisaphatikize zizindikiro za regrowth zomwe zilipo panthawi ya refeeding pambuyo posala kudya ndi mankhwala oopsa kwambiri monga chemotherapy. Maphunziro azachipatala a kusala kudya kapena FMD kwa odwala omwe akudwala chemotherapy amathandizira kuthekera kwake komanso chitetezo chonse52,53,58,61. M'mayesero ang'onoang'ono omwe analembetsa odwala 34, FMD inathandiza odwala kukhala ndi moyo wabwino panthawi ya chemotherapy komanso kuchepetsa kutopa61. Kuonjezera apo, deta yoyambirira imasonyeza kuthekera kwa kusala kudya kapena ma FMD kuti achepetse mankhwala a chemotherapy Kuwonongeka kwa DNA m'maselo athanzi mwa odwala52,53.

Maphunziro opitilira azachipatala a ma FMD kwa odwala omwe ali ndi khansa63,65�68 adzapereka mayankho olimba ngati kufotokozera ma FMD nthawi ndi nthawi kuphatikiza ndi mankhwala ochiritsira ochiritsira kumathandizira kuwongolera kulolerana ndi zochitika zomaliza. Ndikofunika kulingalira kuti ma FMD sangakhale othandiza kuchepetsa zotsatira za chithandizo cha khansa kwa odwala onse komanso sangagwire ntchito kuti athetsere chithandizo chamankhwala onse, koma ali ndi kuthekera kwakukulu kochita zimenezo pang'onopang'ono ndipo mwinamwake. kwa gawo lalikulu la odwala ndi mankhwala. Odwala ofooka kapena osowa zakudya m'thupi kapena odwala omwe ali pachiopsezo cha kuperewera kwa zakudya m'thupi sayenera kulembedwa m'maphunziro a zachipatala a kusala kudya kapena ma FMD, ndipo odwala matenda a matenda a anorexia ayenera kuyang'aniridwa mosamala panthawi yonse ya mayesero a zachipatala. Choyenera kudya mapuloteni, mafuta ofunikira, mavitamini ndi mchere pamodzi, ngati n'kotheka, ndi kuwala ndi / kapena zolimbitsa thupi zolimbitsa cholinga kuonjezera minofu Unyinji ziyenera kugwiritsidwa ntchito pakati pa kusala kudya kapena kuyendayenda kwa FMD kuti odwala azikhala ndi thupi lochepa thupi18,19. Njira iyi yazakudya zambiri idzakulitsa phindu la kusala kudya kapena ma FMD pomwe nthawi yomweyo kuteteza odwala ku kusowa kwa zakudya m'thupi.

Zothandizira: