{"id":4156,"date":"2024-08-04T08:37:17","date_gmt":"2024-08-04T08:37:17","guid":{"rendered":"https:\/\/longchangextracts.com\/?p=4156"},"modified":"2024-08-04T08:37:17","modified_gmt":"2024-08-04T08:37:17","slug":"sophoridine","status":"publish","type":"post","link":"https:\/\/longchangextracts.com\/tr\/sophoridine\/","title":{"rendered":"Prostat kanseri tedavisinde sofokarpinin etki mekanizmas\u0131n\u0131n in vitro h\u00fccre deneyleri ve a\u011f farmakolojisine dayal\u0131 olarak ara\u015ft\u0131r\u0131lmas\u0131"},"content":{"rendered":"

Prostat kanseri tedavisinde sofokarpinin etki mekanizmas\u0131n\u0131n in vitro h\u00fccre deneyleri ve a\u011f farmakolojisine dayal\u0131 olarak ara\u015ft\u0131r\u0131lmas\u0131
\nProstat kanseri (PCa), d\u00fcnya \u00e7ap\u0131nda orta ya\u015fl\u0131 ve ya\u015fl\u0131 erkeklerin \u00fcriner sisteminde en s\u0131k g\u00f6r\u00fclen malign t\u00fcm\u00f6rlerden biridir. 2020 y\u0131l\u0131nda, 1,41 milyon yeni PCa vakas\u0131 ve 380000 \u00f6l\u00fcm dahil olmak \u00fczere d\u00fcnya \u00e7ap\u0131nda 10,06 milyon yeni erkek kanseri vakas\u0131 ve 5,53 milyon \u00f6l\u00fcm ger\u00e7ekle\u015fmi\u015ftir ve \u00f6l\u00fcm oran\u0131 insidansa oran\u0131 27%'dir. \u00c7in'de 120000 yeni PCa vakas\u0131 ve 50000 \u00f6l\u00fcm ger\u00e7ekle\u015fmi\u015f olup, PCa mortalitesinin insidansa oran\u0131 41.7%'dir. Amerikan Kanser Derne\u011fi'nin 2023 y\u0131l\u0131 ara\u015ft\u0131rma verilerine g\u00f6re, PCa insidans\u0131 yakla\u015f\u0131k 29% ile erkek k\u00f6t\u00fc huylu t\u00fcm\u00f6rler aras\u0131nda ilk s\u0131rada yer almaktad\u0131r. \u015eu anda, klinik uygulamada PCa i\u00e7in ana tedavi se\u00e7enekleri androjen yoksunlu\u011fu tedavisi, radikal prostatektomi, radyoterapi, kemoterapi ve molek\u00fcler hedefli tedaviyi i\u00e7ermektedir. Bununla birlikte, bu tedavi y\u00f6ntemlerinin bir\u00e7ok yan etkisi vard\u0131r ve ila\u00e7 direncine e\u011filimlidir, bu da baz\u0131 hastalarda k\u00f6t\u00fc prognoz ve n\u00fcks veya progresyonla sonu\u00e7lan\u0131r. Bu nedenle, PCa tedavisi i\u00e7in g\u00fcvenli ve etkili yeni ila\u00e7lar\u0131n ara\u015ft\u0131r\u0131lmas\u0131 b\u00fcy\u00fck \u00f6nem ta\u015f\u0131maktad\u0131r.
\nSophoridin (SRI), esas olarak Sophora alopecuroides L'den izole edilen tetrasiklik bir kinolin alkaloididir. Ara\u015ft\u0131rmalar, SRI'nin anti-enflamatuar, antiviral ve anti-t\u00fcm\u00f6r etkileri dahil olmak \u00fczere bir\u00e7ok farmakolojik etkiye sahip oldu\u011funu g\u00f6stermi\u015ftir. 2005 y\u0131l\u0131nda, sophocarpine hidroklor\u00fcr enjeksiyonu, malign trofoblastik t\u00fcm\u00f6rlerin klinik tedavisi i\u00e7in Devlet G\u0131da ve \u0130la\u00e7 \u0130daresi taraf\u0131ndan onaylanm\u0131\u015ft\u0131r. \u015eu anda, SRI gastrointestinal t\u00fcm\u00f6rlerin karaci\u011fer metastaz\u0131 tedavisinde denenmektedir. Ayn\u0131 zamanda, \u00e7ok say\u0131da rapor SRI'n\u0131n kolorektal kanser, akci\u011fer kanseri, pankreas kanseri ve di\u011fer t\u00fcm\u00f6rler \u00fczerinde iyi bir inhibit\u00f6r etkiye sahip oldu\u011funu do\u011frulam\u0131\u015ft\u0131r. Bununla birlikte, SRI'n\u0131n PCa \u00fczerindeki etkisi ve olas\u0131 etki mekanizmas\u0131 hala belirsizdir.
\nA\u011f farmakolojisi, klasik farmakoloji, biyoinformatik ve bilgisayar bilimi teorilerine dayanan, ila\u00e7 geli\u015ftirme ve ila\u00e7 etki mekanizmalar\u0131 ara\u015ft\u0131rmalar\u0131nda yayg\u0131n olarak kullan\u0131lan yeni bir disiplindir. Bu makale, SRI'nin DU-145 h\u00fccrelerinin proliferasyonu ve apoptozu \u00fczerindeki etkilerini in vitro h\u00fccre deneyleri yoluyla ara\u015ft\u0131rmakta ve PCa'n\u0131n SRI ile klinik tedavisi i\u00e7in teorik temel ve veri deste\u011fi sa\u011flamak amac\u0131yla olas\u0131 etki mekanizmas\u0131n\u0131 ke\u015ffetmek i\u00e7in a\u011f farmakolojisi ve molek\u00fcler yerle\u015ftirme tekniklerini birle\u015ftirmektedir.<\/p>\n

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PCa, orta ya\u015fl\u0131 ve ya\u015fl\u0131 erkekler aras\u0131nda en s\u0131k g\u00f6r\u00fclen malign t\u00fcm\u00f6rd\u00fcr ve ila\u00e7 direnci ve metastaza yatk\u0131nd\u0131r, bu da k\u00f6t\u00fc prognoza ve y\u00fcksek n\u00fcks oran\u0131na yol a\u00e7ar. Bu nedenle, PCa tedavisi i\u00e7in yeni terapiler aramak \u00e7ok acil hale gelmi\u015ftir. Geleneksel \u00c7in t\u0131bb\u0131n\u0131n do\u011fal kimyasal aktif bile\u015fenleri, malign t\u00fcm\u00f6rlerin \u00f6nlenmesi ve tedavisinde \u00f6nemli bir rol oynamaktad\u0131r. SRI esas olarak geleneksel \u00c7in t\u0131bb\u0131 Sophora alopecuroides'ten izole edilen aktif bir alkaloiddir ve aralar\u0131nda anti-t\u00fcm\u00f6r aktivitesinin \u00f6zellikle \u00f6ne \u00e7\u0131kt\u0131\u011f\u0131 \u00e7e\u015fitli farmakolojik aktivitelere sahiptir. 2005 y\u0131l\u0131nda, sophocarpine hidroklor\u00fcr enjeksiyonu \u00c7in G\u0131da ve \u0130la\u00e7 \u0130daresi taraf\u0131ndan bir anti-kanser ilac\u0131 olarak onaylanm\u0131\u015ft\u0131r. SRI, mide kanseri, karaci\u011fer kanseri, akci\u011fer kanseri, kolon kanseri, pankreas kanseri ve di\u011fer t\u00fcm\u00f6rler \u00fczerinde in vivo ve in vitro olarak iyi anti-t\u00fcm\u00f6r etkiler g\u00f6stermi\u015ftir. SRI, \u00e7e\u015fitli t\u00fcm\u00f6r h\u00fccrelerinin proliferasyonunu ve invazyonunu inhibe edebilir, kanser h\u00fccrelerinin apoptozunu ve otofajisini te\u015fvik edebilir. \u0130\u015flevi PI3K\/AKT, Wnt\/B-catenin, MAPK\/ERK ve h\u00fccre d\u00f6ng\u00fcs\u00fc gibi yolaklarla ili\u015fkilidir. Mevcut ara\u015ft\u0131rmalar s\u00f6z konusu oldu\u011funda, SRI'n\u0131n PCa \u00fczerindeki rol\u00fc ve kesin mekanizmas\u0131 hala tam olarak anla\u015f\u0131lamam\u0131\u015ft\u0131r. Bu \u00e7al\u0131\u015fma, in vitro h\u00fccre deneyleri, a\u011f farmakolojisi ve molek\u00fcler yerle\u015ftirme teknikleri arac\u0131l\u0131\u011f\u0131yla PCa i\u00e7in SRI tedavisinin molek\u00fcler mekanizmas\u0131n\u0131 ara\u015ft\u0131rmakta ve klinik uygulamas\u0131 i\u00e7in belirli bir ara\u015ft\u0131rma temeli ve teorik temel sa\u011flamaktad\u0131r.
\nY\u00fcksek proliferasyon oran\u0131, malign t\u00fcm\u00f6r h\u00fccrelerinin sonsuz b\u00fcy\u00fcmesinin \u00f6nemli bir \u00f6zelli\u011fidir, bu nedenle h\u00fccre proliferasyonunu inhibe etmek kanser tedavisinde etkili bir stratejidir. Bu \u00e7al\u0131\u015fmada, SRI konsantrasyonunun artmas\u0131yla, DU-145 h\u00fccrelerinin b\u00fcy\u00fcmesinin, h\u00fccre canl\u0131l\u0131\u011f\u0131 ve h\u00fccre klon olu\u015fumu tespit edilerek \u00f6nemli \u00f6l\u00e7\u00fcde inhibe edildi\u011fi bulunmu\u015ftur, bu da SRI'n\u0131n DU-145 h\u00fccrelerinin \u00e7o\u011falmas\u0131n\u0131 inhibe etme yetene\u011fine sahip oldu\u011funu g\u00f6stermektedir. \u00c7o\u011falan h\u00fccre n\u00fckleer proteinleri Ki67 ve PCNA, h\u00fccre \u00e7o\u011falmas\u0131 i\u00e7in belirte\u00e7 proteinlerdir ve genellikle kanser te\u015fhisi ve tedavisi i\u00e7in \u00f6ng\u00f6r\u00fcc\u00fc ve prognostik belirte\u00e7ler olarak kullan\u0131l\u0131rlar. Bu \u00e7al\u0131\u015fma, DU-145 h\u00fccrelerinde Ki67 ekspresyonunu imm\u00fcnofloresan ve qPCR yoluyla tespit etmi\u015f ve SRI'nin Ki67 ekspresyonunu \u00f6nemli \u00f6l\u00e7\u00fcde inhibe edebilece\u011fini bulmu\u015ftur. qPCR ve Western blot analizi, SRI'nin DU-145 h\u00fccrelerinde PCNA ekspresyonunu \u00f6nemli \u00f6l\u00e7\u00fcde azaltabilece\u011fini g\u00f6stermi\u015f ve SRI'nin DU-145 h\u00fccrelerinin proliferasyonunu inhibe etme yetene\u011fine sahip oldu\u011funu kan\u0131tlam\u0131\u015ft\u0131r.
\nApoptoz, t\u00fcm\u00f6r h\u00fccresi \u00f6l\u00fcm\u00fcn\u00fcn ana nedenidir, bu nedenle apoptozdan ka\u00e7\u0131nmak t\u00fcm\u00f6r tedavisinde dirence yol a\u00e7abilir. Bir apoptoz inhibit\u00f6r\u00fc olarak Bcl-2, h\u00fccre apoptozunun d\u00fczenlenmesinde belirleyici bir rol oynar. Bax, Bcl-2'nin homolog bir konjugat\u0131 ve pro apoptotik bir proteindir. Bcl-2'nin Bax'a oran\u0131, h\u00fccre apoptozunun etkisini \u00f6l\u00e7mek i\u00e7in \u00f6nemli bir g\u00f6stergedir. Caspase-3 ve Caspase-7 h\u00fccre apoptozunun y\u00fcr\u00fct\u00fcc\u00fcleridir. Apoptoz meydana geldi\u011finde, Caspase-3 ve Caspase-7, yukar\u0131 ak\u0131\u015f Caspase proteinleri taraf\u0131ndan s\u0131rayla b\u00f6l\u00fcn\u00fcr ve aktive edilir. Ard\u0131ndan, aktive edilmi\u015f Kaspaz-3 ve Kaspaz-7, birden fazla a\u015fa\u011f\u0131 ak\u0131\u015f substrat\u0131n\u0131 par\u00e7alayacak ve sonu\u00e7ta apoptotik bir kaskad reaksiyonunu tetikleyecektir. Bu \u00e7al\u0131\u015fma, ak\u0131\u015f sitometrisi deneyleri yoluyla 48 saatlik SRI tedavisinden sonra DU-145 h\u00fccrelerinin apoptozunu tespit etti ve sonu\u00e7lar, SRI'nin DU-145 h\u00fccrelerinin apoptozunu \u00f6nemli \u00f6l\u00e7\u00fcde te\u015fvik edebilece\u011fini g\u00f6sterdi. Bu nedenle, apoptozla ilgili fakt\u00f6rlerin ekspresyonunu daha fazla inceledik. QPCR sonu\u00e7lar\u0131, SRI'nin Kaspaz-3 ve Kaspaz-7'nin mRNA ekspresyonunu yukar\u0131, Bcl-2'nin mRNA ekspresyonunu a\u015fa\u011f\u0131 ve Bax'\u0131n mRNA ekspresyon seviyesini a\u015fa\u011f\u0131 d\u00fczenleyebilece\u011fini, ancak Bcl-2\/Bax oran\u0131n\u0131n \u00f6nemli \u00f6l\u00e7\u00fcde azald\u0131\u011f\u0131n\u0131 g\u00f6sterdi (P<0.05). Ek olarak, Western blot sonu\u00e7lar\u0131 SRI'n\u0131n temizlenmi\u015f-Caspase-3 proteininin ekspresyonunu art\u0131rabildi\u011fini ve Bcl-2 proteininin ekspresyonunu azaltabildi\u011fini g\u00f6stermi\u015ftir. Bax protein ekspresyonunun yukar\u0131 reg\u00fclasyonunda anlaml\u0131 bir fark olmamas\u0131na ra\u011fmen, Bcl-2\/Bax protein ekspresyon oran\u0131 \u00f6nemli \u00f6l\u00e7\u00fcde azalm\u0131\u015ft\u0131r (P<0.05). Bu sonu\u00e7lar, SRI'n\u0131n apoptozla ilgili fakt\u00f6rlerin ekspresyonunu d\u00fczenleyebilece\u011fini, apoptoz sinyal yolaklar\u0131n\u0131 aktive edebilece\u011fini ve DU-145 h\u00fccrelerinde apoptozu ind\u00fckleyebilece\u011fini g\u00f6stermektedir.
\nAyr\u0131ca, DU-145 h\u00fccrelerinin proliferasyonunu ve apoptozunu etkileyen SRI mekanizmas\u0131n\u0131 ara\u015ft\u0131rmak i\u00e7in, bu \u00e7al\u0131\u015fma a\u011f farmakolojisi ara\u015ft\u0131rma y\u00f6ntemleri ile analiz etmi\u015ftir. HERB, TCMSP, Pharm Mapper ve Swiss Target Prediction veritabanlar\u0131 arac\u0131l\u0131\u011f\u0131yla toplam 127 SRI hedefi toplad\u0131k ve Venny 2.1.0 \u00e7evrimi\u00e7i arac\u0131 arac\u0131l\u0131\u011f\u0131yla PCa \u00fczerinde etkili olan 60 ortak SRI hedefi elde ettik. PPI a\u011f analizi yoluyla, ALB, TNF, IL6, CASP3, MAPK1, PPARG, MDM2, PGR, MAPK8, NR3C1, ABL1, MAPK14, PARP1, HDAC2, CDK2, GSK3B, vb. dahil olmak \u00fczere 16 \u00e7ekirdek hedef (ilk 10 derece de\u011feri) belirledik. MAPK8, CASP3, MAPK1, MAPK14 ve TNF \u00e7ekirdek hedefleri MAPK sinyal yolunda zenginle\u015ftirilmi\u015ftir. GO zenginle\u015ftirme analizi 158 girdi sa\u011flam\u0131\u015ft\u0131r (P<0.01), bu da SRI'n\u0131n PCa \u00fczerinde esas olarak gen ekspresyonu, apoptoz s\u00fcreci, protein fosforilasyonu ve protein serin\/treonin\/tirozin kinaz aktivitesini d\u00fczenleyerek terap\u00f6tik etkiler g\u00f6sterebilece\u011fini g\u00f6stermektedir. KEGG yolu zenginle\u015ftirme analizi sonu\u00e7lar\u0131, kanser sinyal yolu, kanserde proteoglikanlar, MAPK sinyal yolu, kemokarsinogenez reaktif oksijen t\u00fcrleri, PI3K-AKT sinyal yolu, apoptoz vb. dahil olmak \u00fczere 84 sinyal yolu g\u00f6stermi\u015ftir (P<0.01). En endi\u015fe verici husus, MAPK sinyal yolunun SRI'n\u0131n anti PCa s\u00fcrecindeki rol\u00fcd\u00fcr. Mitojenle aktive olan protein kinaz (MAPK) h\u00fccre d\u0131\u015f\u0131 bilgiyi \u00e7ekirde\u011fe iletebilir ve fizyolojik ve patolojik s\u00fcre\u00e7lerde \u00f6nemli bir rol oynar. Memeli h\u00fccrelerinde \u00fc\u00e7 tip MAPK ailesi \u00fcyesi vard\u0131r: h\u00fccre d\u0131\u015f\u0131 sinyalle d\u00fczenlenen kinaz (ERK), c-JunN-terminal protein kinaz\/stresle aktive edilen protein kinaz (JNK\/SAPK) ve p38 mitojenle aktive edilen protein kinaz (p38MAPK, MAPK14 olarak da bilinir).
\nP38MAPK, h\u00fccre \u00e7o\u011falmas\u0131, farkl\u0131la\u015fmas\u0131 ve apoptoz gibi \u00e7ok say\u0131da biyolojik s\u00fcrece kat\u0131lan aktif bir protein kinazd\u0131r. Aktivasyonu h\u00fccre proliferasyonunu inhibe edebilir ve apoptozu te\u015fvik edebilir. Ara\u015ft\u0131rmalar, p38 yola\u011f\u0131n\u0131n aktivasyonunun BGC-823 mide kanseri h\u00fccrelerinin proliferasyon aktivitesini azaltabilece\u011fini ve onlar\u0131 G2\/M faz\u0131nda bloke edebilece\u011fini bulmu\u015ftur. P38MAPK'nin aktivasyonu SMMC-7721 h\u00fccrelerinin proliferasyonunu inhibe edebilir ve h\u00fccre i\u00e7i Caspase sinyal kaskad\u0131n\u0131 ba\u015flatarak sonu\u00e7ta apoptozu ind\u00fckleyebilir. Buna ek olarak, \u00e7al\u0131\u015fmalar geleneksel \u00c7in t\u0131bb\u0131 ekstrelerinin p38MAPK'yi aktive edebildi\u011fini, Caspase arac\u0131l\u0131 apoptotik kaskad reaksiyonlar\u0131n\u0131 tetikleyebildi\u011fini ve Lewis akci\u011fer kanseri h\u00fccrelerinin yan\u0131 s\u0131ra HSC-3 ve SCC-9 a\u011f\u0131z kanseri h\u00fccrelerinde apoptozu ind\u00fckleyebildi\u011fini g\u00f6stermi\u015ftir. P38MAPK kinaz, PCa'n\u0131n olu\u015fumu ve geli\u015fiminde de \u00f6nemli bir rol oynamaktad\u0131r. Ara\u015ft\u0131rmalar, p38MAPK aktivasyonunun h\u00fccre \u00e7o\u011falmas\u0131na direnebilece\u011fini, apoptozu te\u015fvik edebilece\u011fini ve prostat epitelinin veya kemik metastatik prostat kanserinin malign transformasyonunda t\u00fcm\u00f6r dormansisini ind\u00fckleyebilece\u011fini bulmu\u015ftur. Bu arada, di\u011fer \u00e7al\u0131\u015fmalar dosetaksel ve ursolik asit gibi bile\u015fenlerin p38MAPK fosforilasyon seviyesini art\u0131rabildi\u011fini, PCa h\u00fccrelerinin ya\u015flanmas\u0131n\u0131 ind\u00fckleyebildi\u011fini, PC-3 ve 22Rv1 gibi \u00e7e\u015fitli PCa h\u00fccrelerinin \u00e7o\u011falmas\u0131n\u0131 engelledi\u011fini ve apoptozunu te\u015fvik etti\u011fini g\u00f6stermi\u015ftir. Bu nedenle, bu \u00e7al\u0131\u015fma p38MAPK protein kinaz\u0131n SRI anti PCa'daki rol\u00fcne odaklanmaktad\u0131r. SRI'nin p38MAPK proteinine ba\u011flanmas\u0131n\u0131 do\u011frulamak i\u00e7in molek\u00fcler yerle\u015ftirme teknolojisi kullan\u0131larak, sonu\u00e7lar SRI'nin -6.83 kcal\/mol ba\u011flanma enerjisi ile p38MAPK proteinine kararl\u0131 bir \u015fekilde ba\u011flanabilece\u011fini g\u00f6stermi\u015ftir. P-p38MAPK ve p38MAPK protein ekspresyon seviyelerinin tespit sonu\u00e7lar\u0131, SRI'n\u0131n p38MAPK proteinini aktive edebilece\u011fini ve p38MAPK proteininin fosforilasyon seviyesinin y\u00fckseldi\u011fini g\u00f6stermektedir; bu da SRI'n\u0131n p38MAPK proteinini aktive ederek ve apoptoz yolunu ind\u00fckleyerek PCa kar\u015f\u0131t\u0131 etkiler g\u00f6sterebilece\u011fini d\u00fc\u015f\u00fcnd\u00fcrmektedir.
\n\u00d6zetle, SRI DU-145 h\u00fccrelerinin proliferasyonunu inhibe edebilir ve apoptozlar\u0131n\u0131 te\u015fvik edebilir, bu da p38MAPK aktivasyonu ile ili\u015fkili olabilir. Ancak, bu \u00e7al\u0131\u015fma sadece SRI'nin DU-145 h\u00fccreleri \u00fczerindeki etkisini in vitro olarak ara\u015ft\u0131rm\u0131\u015ft\u0131r. Bir sonraki ad\u0131m, SRI'n\u0131n PCa kar\u015f\u0131t\u0131 etkisinin mekanizmas\u0131n\u0131 daha fazla ara\u015ft\u0131rmak i\u00e7in in vivo hayvan deneyleri yapmak olacakt\u0131r.<\/p>","protected":false},"excerpt":{"rendered":"

Exploring the mechanism of action of sophocarpine in the treatment of prostate cancer based on in vitro cell experiments and network pharmacology Prostate cancer (PCa) is one of the most common malignant tumors in the urinary system of middle-aged and elderly men worldwide. 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