Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Review Citation - WoS: 6Citation - Scopus: 8Molecular Trojan Horses for Treating Lysosomal Storage Diseases(Academic Press, 2023) Leal, Andres Felipe; Rintz, Estera; Çelik, Betül; Ago, Yasuhiko; León, Daniel; İnci, Orhan Kerim; Seyrantepe, VolkanLysosomal storage diseases (LSDs) are caused by monogenic mutations in genes encoding for proteins related to the lysosomal function. Lysosome plays critical roles in molecule degradation and cell signaling through interplay with many other cell organelles, such as mitochondria, endoplasmic reticulum, and peroxisomes. Even though several strategies (i.e., protein replacement and gene therapy) have been attempted for LSDs with promising results, there are still some challenges when hard-to-treat tissues such as bone (i.e., cartilages, ligaments, meniscus, etc.), the central nervous system (mostly neurons), and the eye (i.e., cornea, retina) are affected. Consistently, searching for novel strategies to reach those tissues remains a priority. Molecular Trojan Horses have been well-recognized as a potential alternative in several pathological scenarios for drug delivery, including LSDs. Even though molecular Trojan Horses refer to genetically engineered proteins to overcome the blood-brain barrier, such strategy can be extended to strategies able to transport and deliver drugs to specific tissues or cells using cell-penetrating peptides, monoclonal antibodies, vesicles, extracellular vesicles, and patient-derived cells. Only some of those platforms have been attempted in LSDs. In this paper, we review the most recent efforts to develop molecular Trojan Horses and discuss how this strategy could be implemented to enhance the current efficacy of strategies such as protein replacement and gene therapy in the context of LSDs. © 2023Article Citation - WoS: 2Citation - Scopus: 2Novel 2 '-alkoxymethyl Substituted Klavuzon Derivatives as Inhibitors of Topo I and Crm1(Academic Press, 2020) Çetinkaya, Hakkı; Yıldız, Mehmet Salih; Kutluer, Meltem; Alkan, Aylin; Otaş, Hasan Ozan; Çağır, AliIn this work, 2'-alkoxymethyl substituted klavuzon derivatives were prepared starting from 2-methyl-1-naphthoic acid in eight steps. Anticancer potencies of the synthesized compounds were evaluated by performing MTT cell viability test over cancerous and healthy pancreatic cell lines, along with CRM1 inhibitory properties in HeLa cells by immunostaining and Topo I inhibition properties by supercoiled DNA relaxation assay. Their cytotoxic activities were also presented in hepatocellular carcinoma cells (HuH-7) derived 3D spheroids. Among the tested klavuzon derivatives, isobutoxymethyl substituted klavuzon showed the highest selectivity of cytotoxic activity against pancreatic cancer cell line. They showed potent Topo I inhibition while their CRM1 inhibitory properties somehow diminished compared to 4'-alkylsubstituted klavuzons. The most cytotoxic 2'-methoxymethyl derivative inhibited the growth of the spheroids derived from HuH-7 cell lines and PI staining exhibited time and concentration dependent cell death in 3D spheroids.Conference Object Alteration in Redox Homeostasis in Early-Onset Tay-Sachs Disease Mouse Model(Academic Press, 2020) Seyrantepe, Volkan; Ateş, Nurselin; Başırlı, Hatice Hande; Demir, Seçil Akyıldız; Dağalp, Berkay; Nalbant, Ayten; Çalışkan, Tufan UtkuTay-Sachs disease is an autosomal recessively inherited lysosomal disorder. It is caused by mutations on the HEXA gene encoding α-subunit of β-Hexosaminidase A enzyme. The enzyme normally catalyzes GM2 to GM3 conversion but when it is absent or dysfunctional the GM2 degradation is interrupted. The undegraded GM2 ganglioside is progressively accumulated especially in neurons and causes neurodegenaration at the end. The Hexa−/− mice generated as Tay-Sachs model was nearly normal and a bypass mechanism mediated by a sialidase was suggested. Recently we determined that Neu3 sialidase involves in ganglioside degradation in the Tay-Sachs disease pathology and the Hexa−/-Neu3−/− mice mimic the neuropathologic and clinical phenotype of the disease. It was reported that oxidative stress is triggered in neurodegenerative diseases and several lysosomal disorders. It is caused by the imbalance between antioxidant defence mechanism and production of reactive oxygen species (ROS). ROS have high chemical reactivity which react and damage DNA, protein, carbohydrates and lipids.