Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside

Advancements in our comprehension of tumor biology and chemoresistance have spurred the development of treatments that precisely target specific molecules within the body. Despite the expanding landscape of therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA therapeutics have emerged as a promising frontier in this realm, offering novel avenues for intervention such as RNA interference and the utilization of antisense oligonucleotides (ASOs). ASOs represent a versatile class of therapeutics capable of selectively targeting messenger RNAs (mRNAs) and silencing disease-associated proteins, thereby disrupting pathogenic processes at the molecular level. Recent advancements in chemical modification and carrier molecule design have significantly enhanced the stability, biodistribution, and intracellular uptake of ASOs, thereby bolstering their therapeutic potential. While ASO therapy holds promise across various disease domains, including oncology, coronary angioplasty, neurological disorders, viral, and parasitic diseases, our review manuscript focuses specifically on the application of ASOs in targeted cancer therapies. Through a comprehensive examination of the latest research findings and clinical developments, we delve into the intricacies of ASO-based approaches to cancer treatment, shedding light on their mechanisms of action, therapeutic efficacy, and prospects

Archaeogenetic analysis of Neolithic sheep from Anatolia suggests a complex demographic history since domestication

Sheep were among the first domesticated animals, but their demographic history is little understood. Here we analyzed nuclear polymorphism and mitochondrial data (mtDNA) from ancient central and west Anatolian sheep dating from Epipaleolithic to late Neolithic, comparatively with modern-day breeds and central Asian Neolithic/Bronze Age sheep (OBI). Analyzing ancient nuclear data, we found that Anatolian Neolithic sheep (ANS) are genetically closest to present-day European breeds relative to Asian breeds, a conclusion supported by mtDNA haplogroup frequencies. In contrast, OBI showed higher genetic affinity to present-day Asian breeds. These results suggest that the east-west genetic structure observed in present-day breeds had already emerged by 6000 BCE, hinting at multiple sheep domestication episodes or early wild introgression in southwest Asia. Furthermore, we found that ANS are genetically distinct from all modern breeds. Our results suggest that European and Anatolian domestic sheep gene pools have been strongly remolded since the Neolithic

Siçan testi?si?ndeki?i?skemi?-reperfüzyon hasari sonucu oluşan oksi?dati?f stres ve hi?stopatoloj?ik değ?işi?kli?kler üzeri?ne ketoprofeni?n koruyucu etk?i?i

Introduction: Testicular torsion is a common surgical emergency affecting newborns, children and adolescents. A possible cause of testicular injury is ischemia-reperfusion (I/R) injury. In this study we evaluated the effect of ketoprofen, a non-steroidal anti-inflammatory drug, on I/R injury due to testicular torsion-detorsion (T/D). Materials and Methods: Twenty-eight prepubertal male Wistar rats were divided into four groups each containing 7 rats: Group 1, control; Group 2, sham; Group 3, T/D; and Group 4, T/D+ketoprofen. Group 3 and 4 underwent 2 hours of left testicular torsion and 4 hours of detorsion. In Group 4, ketoprofen (5 mg/kg) was administrated intraperitoneally 60 minutes before detorsion. At the end of the study, bilateral orchiectomies were performed for measurement of MDA and NO levels and histopathologic examination. Results: Testicular torsion-detorsion significantly induced oxidative stress and tissue damage in both ipsilateral and contralateral testes. Administration of ketoprofen significantly lowered MDA level and improved histologic parameters of spermatogenesis in both testes. Conclusion: Ketoprofen has a protective effect on testicular ischemia-reperfusion injury due to testicular torsion/detorsion

EPR studies of intermolecular interactions and competitive binding of drugs in a drug-BSA binding model

Understanding intermolecular interactions between drugs and proteins is very important in drug delivery studies. Here, we studied different binding interactions between salicylic acid and bovine serum albumin (BSA) using electron paramagnetic resonance (EPR) spectroscopy. Salicylic acid was labeled with a stable radical (spin label) in order to monitor its mobilized (free) or immobilized (bound to BSA) states. In addition to spin labeled salicylic acid (SL-salicylic acid), its derivatives including SL-benzoic acid, SL-phenol, SL-benzene, SL-cyclohexane and SL-hexane were synthesized to reveal the effects of various drug binding interactions. EPR results of these SL-molecules showed that hydrophobic interaction is the main driving force. Whereas each of the two functional groups (-COOH and -OH) on the benzene ring has a minute but detectable effect on the drug-protein complex formation. In order to investigate the effect of electrostatic interaction on drug binding, cationic BSA (cBSA) was synthesized, altering the negative net charge of BSA to positive. The salicylic acid loading capacity of cBSA is significantly higher compared to that of BSA, indicating the importance of electrostatic interaction in drug binding. Moreover, the competitive binding properties of salicylic acid, ibuprofen and aspirin to BSA were studied. The combined EPR results of SL-salicylic acid/ibuprofen and SL-ibuprofen/salicylic acid showed that ibuprofen is able to replace up to similar to 83% of bound SL-salicylic acid, and salicylic acid can replace only similar to 14% of the bound SL-ibuprofen. This indicates that similar to 97% of all salicylic acid and ibuprofen binding sites are shared. On the other hand, aspirin replaces only similar to 23% of bound SL-salicylic acid, and salicylic acid replaces similar to 50% of bound SL-aspirin, indicating that similar to 73% of all salicylic acid and aspirin binding sites are shared. These results show that EPR spectroscopy in combination with the spin labeling technique is a very powerful method to investigate drug binding dynamics in detail