Browsing by Author "Arga, Kazim Yalcin"

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Citation Count: 5
Cancer Drug Repositioning by Comparison of Gene Expression in Humans and Axolotl (Ambystoma mexicanum) During Wound Healing
(Mary Ann Liebert, inc, 2019) Oktem, Elif Kubat; Yazar, Metin; Gulfidan, Gizem; Arga, Kazim Yalcin; Genetik ve Biyomühendislik / Genetic and Bio-Engineering
Urodele amphibians such as the axolotl (Ambystoma mexicanum) display a large capacity for tissue regeneration and remarkable resistance to cancer. As a model organism, axolotl thus offers a unique opportunity for cancer research and anticancer drug discovery, not to mention the discerning mechanisms that underpin controlled cellular growth and regeneration versus cancer. To the best of our knowledge, little is known on comparative gene expression changes during regeneration events such as wound healing in axolotl and humans. Using publicly available transcriptomics data and bioinformatics analyses, we examined the differential gene expression signatures in skin wound samples from axolotl and humans after skin biopsy punch injury, in comparison with intact (uninjured) control skin samples. We identified 95 genes exhibiting a reversal expression pattern between humans and axolotl during the wound healing/regeneration period. These genes were significantly associated with collagen biosynthesis, extracellular matrix organization, PI3K-Akt signaling pathway, immune system response, and apoptotic process. Furthermore, this new gene set exhibited high prognostic performance in discriminating the survival risk in skin-related cancers, including melanoma (hazard ratio [HR] = 8.14, p < 10(-30)), oral cancer (HR >100, p < 10(-12)), and head and neck carcinoma (HR = 5.29, p < 10(-30)). Moreover, considering these gene signatures, we repositioned 11 small molecules as potential anticancer drug candidates indicating reversal effects on upregulated human genes and downregulated axolotl genes or mimicking downregulated human genes and upregulated axolotl genes. We anticipate that this study offers new insights on gene signatures bridging regeneration mechanisms with tumorigenesis and cancer drug repositioning.
Citation Count: 5
Integrative Analysis of Motor Neuron and Microglial Transcriptomes from SOD1^G93A Mice Models Uncover Potential Drug Treatments for ALS
(Springernature, 2022) Oktem, Elif Kubat; Yazar, Metin; Yazar, Metin; Arga, Kazim Yalcin; Genetik ve Biyomühendislik / Genetic and Bio-Engineering
Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neurons that mainly affects the motor cortex, brainstem, and spinal cord. Under disease conditions, microglia could possess two distinct profiles, M1 (toxic) and M2 (protective), with the M2 profile observed at disease onset. SOD1 (superoxide dismutase 1) gene mutations account for up to 20% of familial ALS cases. Comparative gene expression differences in M2-protective (early) stage SOD1(G93A) microglia and age-matched SOD1(G93A) motor neurons are poorly understood. We evaluated the differential gene expression profiles in SOD1(G93A) microglia and SOD1(G93A) motor neurons utilizing publicly available transcriptomics data and bioinformatics analyses, constructed biomolecular networks around them, and identified gene clusters as potential drug targets. Following a drug repositioning strategy, 5 small compounds (belinostat, auranofin, BRD-K78930611, AZD-8055, and COT-10b) were repositioned as potential ALS therapeutic candidates that mimic the protective state of microglia and reverse the toxic state of motor neurons. We anticipate that this study will provide new insights into the ALS pathophysiology linking the M2 state of microglia and drug repositioning.
Citation Count: 0
Three candidate anticancer drugs were repositioned by integrative analysis of the transcriptomes of species with different regenerative abilities after injury
(Elsevier Sci Ltd, 2023) Oktem, Elif Kubat; Yazar, Metin; Yazar, Metin; Arga, Kazim Yalcin; Genetik ve Biyomühendislik / Genetic and Bio-Engineering
Regeneration is a homeostatic process that involves the restoration of cells and body parts. Most of the molecular mechanisms and signalling pathways involved in wound healing, such as proliferation, have also been associated with cancer cell growth, suggesting that cancer is an over/unhealed wound. In this study, we examined differentially expressed genes in spinal cord samples from regenerative organisms (axolotl and zebrafish) and nonregenerative organisms (mouse and rat) compared to intact control spinal cord samples using publicly available transcriptomics data and bioinformatics analyses. Based on these gene signatures, we investigated 3 small compounds, namely cucurbitacin I, BMS-754807, and PHA-793887 as potential candidates for the treatment of cancer. The predicted target genes of the repositioned compounds were mainly enriched with the greatest number of genes in cancer pathways. The molecular docking results on the binding affinity between the repositioned compounds and their target genes are also reported. The repositioned 3 small compounds showed anticancer effect both in 2D and 3D cell cultures using the prostate cancer cell line as a model. We propose cucurbitacin I, BMS-754807, and PHA-793887 as potential anticancer drug candidates. Future studies on the mechanisms associated with the revealed gene signatures and anticancer effects of these three small compunds would allow scientists to develop therapeutic approaches to combat cancer. This research contributes to the evaluation of mechanisms and gene signatures that either limit or cause cancer, and to the development of new cancer therapies by establishing a link between regeneration and carcinogenesis.