Akademik Veri Yönetim Sistemi
11th International Drug Chemistry Conference, Antalya, Türkiye, 9 - 12 Mart 2023
Circadian rhythms regulate biochemical and behavioral outputs in line with 24 hours cycle [1-3]. Circadian rhythm is controlled by a molecular clock mechanism composed of transcription and translational feedback loops. In mammals, CLOCK and BMAL1 generate a heterodimer and bind to the promoter of genes having the E-box sequences. They initiate the transcription of clock-controlled genes including the Crys and Pers [4-6]. Later, PER and CRY accumulate in the cytosol and translocate into the nucleus and inhibit BMAL1/CLOCK-dependent transcription [2, 4, 7]. Posttranscriptional and posttranslational regulations help precise ticking of the clock [8]. The clock mechanism governs a variety of physiological processes, including the sleep-wake cycle, blood pressure, mood, and the release of certain hormones [9, 10]. Disrupted or perturbed clock is associated with several metabolic diseases and sleep disorders [11, 12]. Several studies suggest that malfunctioned clock accelerates aging and drives diseases linked with it [13]. In a recent study, in mice models it has been shown that the number of rhythmically expressed genes and their amplitude decreases with age, indicating a weaker circadian regulation [14]. Furthermore, in elderly people, the reduced amplitude of the circadian rhythm has been reported [15]. Previously we reported a small molecule, CLK8, that modulates CLOCK-BMAL1 interaction and enhances the amplitude of the circadian rhythm in various cell lines [16]. Here, we studied how CLK8 affects the amplitude of the circadian rhythm in aged cells. CLK8 helped to maintain amplitude during the aging of cells. We utilized genome-wide transcriptome analysis to determine the genes and pathways to elucidate the mechanism behind the amplitude maintenance. Our results suggest that CLK8 reprograms the rhythmic expression of more than 3000 genes compared to the control. KEGG pathway analysis of CLK8-only-rhythmic genes showed that several pathways including cellular senescence were maintained. These genes directly or indirectly control the causes of senescence such as DNA damage, cell cycle arrest, and oxidative stress. Hence, CLK8 delayed the senescence phenotype. We will further test the effect of CLK8 on the amplitude of the locomotor activity of aged mice. However, the toxicity and pharmacokinetic profile of the molecule should be determined before the efficacy studies. Hence we determined the toxicity profile of the molecule and will continue with the pharmacokinetic studies.