| Abstract | Kod kroničnih plućnih bolesti postoje nakupine senescentnih stanica. Senoterapeutici djeluju na sam uzrok bolesti i time se sprječava progresija plućnih bolesti. Senolitici su lijekovi koji potiču apoptozu senescentnih stanica. Prirodni senolitici su kvercetin, fisetin, piperlongumin, kurkumin i kardiotonični glikozidi. Nedostatak im je slaba bioraspoloživost, a prednost im je niska toksičnost. Sintetizirani su sintetski senolitici, ali dosta njih ima nuspojave. Senolitici onemogućavaju SCAP antiapoptozne putove kojima se senescentna stanica štiti od apoptoze. Time se potiče apoptoza senescentnih stanica. Postoje galaktoza-konjugirani senolitički prolijekovi, inhibitori Hsp90, dasatinib, panobinostat, A1331852, A1155463, navitoklaks (ABT263), sintetski peptid FOXO4-DRI te imunosna terapija CAR T stanicama. S druge strane, postoje senostatici koji sprječavaju stanice da postanu senescentne blokirajući signalne putove koji vode u senescenciju. Kombinacijom senolitika sa senostaticima se može djelovati na različite mehanizme istovremeno. Senostatici blokiraju PI3K-mTOR signalni put. Senostatici su rapamicin, metformin, AICAR, biljni polifenol resveratrol, STAC, antagomiri miR-34a/miR-570 te antioksidansi, uključujući melatonin. Sprječavanjem oksidacijskog stresa se sprječava oštećenje DNA, a time i senescencija. Zbog nuspojava rapamicina razvijeni su manje toksični lijekovi rapalogs. Zbog slabe bioraspoloživosti resveratrola razvijeni su sintetski STAC lijekovi. Većinom su sva ispitivanja provedena na miševima pa je potrebno još puno istraživanja provesti da bi se dokazala učinkovitost i sigurnost ovakvih lijekova na ljudima. Jedino ispitivanje na ljudima je provedeno s kombinacijom dasatinib i kvercetin čime se dokazala učinkovitost uz prihvatljive nuspojave. |
| Abstract (english) | In chronic lung diseases, there are clusters of senescent cells. Senotherapeutics act on the cause of the disease and thus prevent the progression of lung diseases. Senolytics are drugs that promote apoptosis of senescent cells. Natural senolytics are quercetin, fisetin, piperlongumin, curcumin and cardiotonic glycosides. Their disadvantage is poor bioavailability, and their advantage is low toxicity. Synthetic senolytics have been synthesized, but many have side effects. Senolytics disable SCAP antiapoptotic pathways that protect the senescent cell from apoptosis. This promotes apoptosis of senescent cells. There are galactose-conjugated senolytic prodrugs, Hsp90 inhibitors, dasatinib, panobinostat, A1331852, A1155463, navitoclax (ABT263), the synthetic peptide FOXO4-DRI, and CAR T cell immune therapy. On the other hand, there are senostatics that prevent cells from becoming senescent by blocking signaling pathways leading to senescence. By combining senolytics with senostatics, different mechanisms can be acted upon simultaneously. Senostatics block the PI3K-mTOR signaling pathway. Senostatics include rapamycin, metformin, AICAR, plant polyphenol resveratrol, STAC, miR-34a / miR-570 antagonists, and antioxidants including melatonin. Preventing oxidative stress prevents DNA damage and thus senescence. Due to the side effects of rapamycin, less toxic drugs rapalogs have been developed. Due to the poor bioavailability of resveratrol, synthetic STAC drugs have been developed. Most of the tests have been performed on mice, so much more research is needed to prove the effectiveness and safety of such drugs in humans. The only human study was performed with a combination of dasatinib and quercetin to demonstrate efficacy with acceptable side effects. |
