Objective: Alzheimer’s disease is a neurodegenerative sickness and increasing with age throughout the world. A substantial body of evidence suggests the role of exosomal noncoding ribonucleic acids in the development of Alzheimer’s disease, but the regulatory mechanisms mediated by these noncoding ribonucleic acids remain extensively unknown. Using plasma samples from Alzheimer’s disease patients, this study explored the exosomal circular ribonucleic acid–microribonucleic acid profiles. Materials and Methods: The ArrayExpress platform was used to convey data from 3 samples from each group (healthy, mild cognitive impairment, and Alzheimer’s disease). Using plasma exosomes, differentially expressed microribonucleic acids and differentially expressed circular ribonucleic acids were compared between the Alzheimer’s disease and mild cognitive impairment groups. Afterward, to define pathways, gene ontologies, and networks, differentially expressed microribonucleic acids and differentially expressed circular ribonucleic acids common to both mild cognitive impairment and Alzheimer’s disease groups were analyzed. Eventually, the selection of hub genes and protein–protein interaction network was analyzed. Results: A total of common 19 (7 upregulated and 12 downregulated) differentially expressed microribonucleic acids and 24 differentially expressed circular ribonucleic acids were recognized. A total of 4559 target genes were predicted for upregulated differentially expressed microribonucleic acids, while 6504 target genes were identified for downregulated differentially expressed microribonucleic acids, and most of the target genes involved in the phosphoinositide 3-kinases-Akt pathway and that were mostly regulated by hsa-mir-374a-3p, mir-196a-5p, let-205-5p, mir-185-3p, mir-374a-5p, mir-615-3p, let-7c-5p, mir-185-5p. Additionally, 9 hub genes (HSP90AA, ACTB, MAPK1, GSK3B, CCNE2, CDK6, AKT1, IGF1R, CCND1) were revealed as the genes considerably related to Alzheimer’s disease by a protein–protein interaction network using the cytohubba in Cytoscape software. Conclusion: Our findings provide a new perspective on how microribonucleic acids could connect with circular ribonucleic acids in the pathogenesis of Alzheimer’s disease. Cite this article as: Besli N, Sarikamis B, Kalkan Cakmak R, Kilic U. Exosomal circular ribonucleic acid–microribonucleic acid expression profile from plasma in Alzheimer’s disease patients by bioinformatics and integrative analysis. Eurasian J Med., 2023;55(3):218-227.

Background/Objectives: Cancer-associated fibroblasts (CAFs) are key stromal mediators of breast tumor progression and therapy resistance. Carvacrol, a dietary monoterpenic phenol, exhibits antiproliferative activity in cancer cells, but its effects on primary human breast CAFs remain unclear. This study aimed to determine whether carvacrol selectively induces mitochondria-related apoptotic signaling in breast CAFs while sparing normal fibroblasts (NFs). Methods: Primary fibroblast cultures were established from invasive ductal carcinoma tissues (CAFs, n = 9) and nonmalignant breast tissues (NFs, n = 5) and validated by α-SMA and FAP immunofluorescence. Cells were exposed to 400 μM carvacrol. Apoptosis was assessed by TUNEL assay and BAX/BCL-XL Western blotting. Changes in signaling pathways were evaluated by analyzing PPARα/NF-κB, sirtuin (SIRT1, SIRT3), autophagy-related markers (LAMP2A, p62), and matrix metalloproteinases (MMP-2, MMP-3). In silico molecular docking and 100-ns molecular dynamics simulations were performed to examine interactions between carvacrol and caspase-3 and caspase-9. Results: Carvacrol induced a pronounced, time-dependent apoptotic response in CAFs, with TUNEL-based viability declining to approximately 10% of control levels by 12 h and a marked increase in the BAX/BCL-XL ratio. In contrast, NFs exhibited minimal TUNEL positivity and no significant change in BAX/BCL-XL. In CAFs, but not NFs, carvacrol reduced PPARα expression and NF-κB nuclear localization, increased SIRT1 and SIRT3 levels, selectively suppressed MMP-3 while partially normalizing MMP-2, and altered autophagy-related markers (decreased LAMP2A and accumulation of p62), consistent with autophagic stress and possible impairment of autophagic flux. Computational analyses revealed stable carvacrol binding to caspase-3 and caspase-9 with modest stabilization of active-site loops, supporting caspase-dependent, mitochondria-related apoptosis. Conclusions: Carvacrol selectively targets breast cancer-associated fibroblasts by inducing mitochondria-related apoptotic signaling while largely sparing normal fibroblasts. This effect is accompanied by coordinated modulation of PPARα/NF-κB, sirtuin, autophagy, and MMP pathways. These findings support further evaluation of carvacrol as a microenvironment-directed adjunct in breast cancer therapy.

Understanding the mechanism behind Alzheimer’s disease is imperative due to the critical role of the autophagy pathway in protein homeostasis and neuronal survival. Autophagy pathway irregularities in neurons may increase exosome-mediated toxic protein transport, which can spread neurodegenerative diseases. Compelling evidence hints that acacetin (ACA) is a naturally occurring biocomponent exhibiting neuroprotective pharmacological properties. However, further molecular investigations are pressing to uncover the therapeutic potential of ACA. The present investigation endeavors to scrutinize the impact of ACA on the autophagy pathway and exosome release in an amyloid beta (Aβ) peptide-induced toxicity model. Herein, first, molecular modeling was performed between ACA and autophagy-related proteins. Afterward, the Aβ peptide-induced toxicity model cells were treated with ACA, and total and exosomal protein isolation was carried out and analyzed. Considering the findings, our molecular dynamics simulation of the ACA-protein complexes, spanning 100 ns, conclusively demonstrated stable protein–ligand interactions. Additionally, ACA was determined to regulate LC3II, Beclin-1, p62, and Lamp2a protein levels and reduce amyloid-β and Alix protein levels. In conclusion, our study highlights the significant in vitro neuroprotective effect of ACA against Aβ toxicity through autophagy. Moving forward, future studies may seek to elucidate the specific neuroprotective, therapeutic effects and mechanisms of ACA via autophagy in in vivo models. Addressing the identified limitations and capitalizing on the outlined future prospects are essential steps towards harnessing the therapeutic potential of ACA in combating neurodegenerative diseases, offering renewed hope for patients and caregivers alike.