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Öğe Circular RNAs, miRNAs, and Exosomes: Their Roles and Importance in Amyloid-Beta and Tau Pathologies in Alzheimer's Disease(Wiley, 2025) Pala, Mukaddes; Yilmaz, Senay GorucuAlzheimer's disease (AD) is a devastating neurodegenerative disorder. The pathology of this disease is based on two basic mechanisms: amyloid-beta (A beta) and tau fibrillation. Many genes and mechanisms have been identified as the primary causes of AD in clinical settings, and there have been exciting developments in drug treatments. Several molecules and biological structures regulate the genome outside of the standard DNA function. As in many diseases, circular RNAs (circRNAs), microRNAs (miRNAs), and exosomes (EXOs), investigated from different aspects of AD, are useful for treatment and diagnosis. This review examines two biological elements regarding their roles in the A beta-tau pathology of AD and their potential as treatment targets. Importantly, the activities of miRNAs that play a role in these processes were evaluated.Trial Registration: ClinicalTrials.gov identifiers: NCT04120493, NCT04969172, NCT04388982Öğe Deep phenotyping of miRNAs in exercise-induced cardiac hypertrophy and fibrosis(Indian Acad Sciences, 2023) Pala, Mukaddes; Yilmaz, Senay Gorucu; Altan, Mehmet; Sonmez, Osman Fuat; Dincer, Sensu; Mengi, Murat; Metin, GokhanCardiac hypertrophy (CH) is an adaptational enlargement of the myocardium, in exposure to altered stress conditions or in case of injury which can lead to heart failure and death. MicroRNAs (miRNAs) are non-coding RNAs that play a significant role in modulating gene expression. Here, we aimed to identify new miRNAs effective in an experimental CH model and to find an epigenetic biomarker that could demonstrate therapeutic targets responsible for the pathology of heart tissue and serum. In this study, Sprague-Dawley male rats were divided into the training group (TG, n=9) and the control group (CG, n=6). Systolic and diastolic dimensions of the left ventricle and myocardial wall thickness were measured by echocardiography to assess CH. After the exercise program of the rats, miRNA expression measurements and histological analyses were performed. The 25,000 genes in the rat genome were searched using microarray analysis. A total of 128 miRNAs were selected according to the fold change rates, and nine miRNAs were validated for expression analysis. The terminal deoxynucleotidyl transferase dUTP nick (TUNEL) method was used to detect apoptotic cells. Cell proliferation was evaluated by the proliferative cell nuclear antigen (PCNA) method. Necrosis, bleeding, and intercellular edema were detected in TG. The mean histopathological score was higher in TG (p=0.03). There were rarely positive cells for apoptosis of both groups in cardiomyocytes. In the receiver characteristic curve analysis (ROC), the heart tissue rno-miR-290 had an area under the curve (AUC) of 0.920 with 100% sensitivity and 89.90% specificity (p=0.045), rno-miR-194-5p had AUC of 0.940 with 83.33% sensitivity and 100% specificity (p=0.003), and the serum rno-miR-132-3p AUC was 0.880 with 66.67% sensitivity and 100% specificity (p=0.004) in TG. miR-194-5p was used as a therapeutic target for remodeling the cardiac process. While miR-290 contributes to CH as a negative regulator, miR-132 in serum is effective in the pathological and physiological cardiac remodeling process and is a candidate biomarker.Öğe Downregulatory effect of miR-342-3p on epileptogenesis in the PTZ-kindling model(Springer, 2022) Pala, Mukaddes; Meral, Ismail; Acikgoz, Nilgun Pala; Yilmaz, Senay Gorucu; Okur, Semra Karaca; Acar, Seyma; Akbas, FahriBackground Epileptogenesis is a process that results in neurons firing abnormally, causing seizures. Increasing evidence has shown that miRNAs expressed in the epileptic hippocampus are involved in epileptogenesis. We demonstrated the expression changes of miRNAs that may be effective in epileptogenesis in silico analysis in the kindling model created with Pentylenetetrazole (PTZ). Thus, we aimed to identify the target genes responsible for epileptogenesis. Methods and results Fifteen male Wistar-albino rats (200-230 g) were randomly divided into two groups control (n = 6) and PTZ (n = 9). The control group received 0.5 ml saline, and the PTZ group (35 mg/kg i.p.) intraperitoneally (i.p.) (11 times, every other day) to induce tonic-clonic seizures. Seizures were observed and scored 30 min after PTZ injection. After the last dose of PTZ (75 mg/kg) administration, the hippocampus tissues of the rats were removed by anesthesia. Analysis of miRNAs was performed with the Affymetrix gene chip miRNA sequence (728 miRNA) and confirmed by the Real-Time Polymerase Chain Reaction (Real-Time PCR) method (29 miRNAs). We evaluated the expression change of the target gene of miRNA, whose expression change was detected using in silico analysis, by q-RT PCR. Eight miRNAs with changes in expression were detected. Of these miRNAs, miR-342-p was downregulated in the PTZ group and was statistically significant (p < 0.005). Ultimately, we determined that the target gene of miR-342-p is a metabotropic glutamate receptor 2 (GRM2) and that GRM2 expression is upregulated. Conclusions Downregulation of miR-342-3p in the PTZ kindling model may result in the upregulation of GRM2.Öğe Evaluation of hypoxia pathway genes and serum parameters in new coronavirus pneumonia (COVID-19)(Elsevier, 2025) Oterkus, Mesut; Pala, Mukaddes; Yilmaz, Senay Gorucu; Tanriverdi, Elif Seren; Gunduz, Ayten; Delen, Leman Acun; Doger, CihanBackground: Coronavirus disease-2019 (COVID-19) causes severe hypoxemia. Unlike normal pneumonia, pneumonia due to COVID-19 causes oxygen deprivation without breathing difficulties (i.e., silent hypoxia). We evaluated the relationship between COVID-19 and hypoxemia and examined possible mechanisms of pneumonia from the perspective of gene expression (HIF1A, vascular endothelial growth factor [VEGF], NF-kB, MEKK1, and EGFR) using real-time PCR and ELISA for serum parameters. Methods: We evaluated 100 individuals (50 patients and 50 controls). The patients were individuals with respiratory symptoms and pneumonia who were (COVID)-D-center dot-19 positive. The relative quantification of standardized samples wa s calculated according to the formula 2-Delta Delta CT. Receiver operating curve (ROC) analysis was made to define the diagnostic power of the genes. The expression changes of four genes in the hypoxia pathway were significant (excluding VEGF) and upregulated in the patients' serums. Results: The fold change values of the HIF1A, VEGF, NF-kB, MEKK1, and EGFR genes were 0.048, 0.688, 0.168, 0.207, and 0.171, respectively, in the cases checked against to the controls. The areas under the ROC values indicating the diagnostic power of the genes were 0.727, 0.538, 0.815, 0.734, and 0.936, respectively. Some serum parameters were significant (age, PCR, urea, LDH, WBC, ferritin, and pO2). Conclusions: The upregulation of some genes in the hypoxia pathway in COVID-19 pneumonia shows that these genes and protein products are candidates for treatment targets. At the same time, the high discriminative power of two genes (NF-kappa B and EGFR) in patients compared to controls indicates their diagnostic potential in serum samples.Öğe Evaluation of the Antioxidative and Protective Effects of Thymoquinone in a Pentylenetetrazole-induced Epilepsy Model(2025) Pala, Mukaddes; Meral, Ismail; acikgoz, nilgun; Hanikoglu, Ferhat; Kucukcetin, Ikbal Ozen; OZDEM, SEBAHAT; Yılmaz, Şenay GörücüObjective: Epilepsy is a common neurological disorder that leads to neuronal excitability and provokes various forms of cellular reorganization in the brain. We investigated the antioxidative and protective effects of thymoquinone (TQ) from the perspective of biomarkers in serum samples of rats using a pentylenetetrazol (PTZ)-induced epilepsy model. Methods: Twenty-one adult, male Wistar albino rats were randomly assigned to three groups. (1) Control (n=6); 0.5 mL saline (i.p.). (2) PTZ (n=7); 35 mg/kg PTZ (i.p.). (3) TQ+PTZ (n=8); 20 mg/kg TQ orally (p.o.)+ 35 mg/kg PTZ (i.p.). To induce kindling, PTZ was injected at a subconvulsive dose (35 mg/kg, i.p.) every other day for 24 days. Then, on the 26th day of the study, a single loading dose of PTZ (75 mg/kg) was injected into the animals. Seizure severity was evaluated with the Racine scale. Blood samples were taken from rats under anesthesia by the cardiac puncture method. The serum levels of myeloperoxidase (MPO), ischemia-modified albumin, total oxidant status (TOS), total antioxidant status (TAS), advanced oxidation protein products (AOPP), total sulfhydryl (T. sulfhydryl), and paraoxonase-1 (PON-1) were evaluated colorimetrically by the ELISA method, using a spectrophotometer. Results: A significant relationship was found between PTZ and TQ+PTZ groups for TAS (p=0.020), TOS (p=0.006), AOPP (p=0.015), and T. sulfhydryl (p=0.009). MPO and PON-1 were not significant (p>0.05). Conclusion: TQ may be used as an adjuvant agent in the regulation of epileptic seizures with its antioxidative and protective functions in the PTZ-induced epilepsy model. At the same time, serum parameters can potentially be diagnostic tools for the effective managing of treatment.Öğe Exercise and microrna(Georgian Association of Business Press, 2023) Pala, MukaddesPhysical activity stimulates numerous structural, metabolic, and morphological adaptations. These adaptations are vital for maintaining human health throughout life. Developments in molecular biology, biochemistry, and bioinformatics, along with exercise physiology have identified many signaling pathways, and transcriptional and translational processes responsible for exercise-related adaptations. The molecular mechanisms underlying the beneficial effects of exercise are not fully understood. Recently, the focus has been on microRNAs (miRNAs). They are small noncoding RNA molecules that negatively modulate gene expression and are involved in fundamental biological processes. This review describes miRNAs whose activities change in the heart, skeletal muscle, and circulation due to exercise. In addition, miRNAs with altered activity may be parameters adaptation to exercise, preventing injuries, and monitoring health status. © 2023 Georgian Association of Business Press. All rights reserved.Öğe How does social media impact the number of citations? An altmetric analysis of the 50 most-cited MicroRNA articles(Gaziantep Üniversitesi, 2021) Pala, Mukaddes; Demirbilek, Mahmut; Pala Açıkgöz, Nilgün; Dokur, MehmetObjective: Altmetric analysis is web-based a metric analysis. Social media platforms affect medical literature over the last few years. The altmetric Attention Score (AAS) is an automatically calculated metric for monitoring social media. This study aimed to determine the correlation between AAS and the number of citations received from important articles published in the last 11 years with microRNAs. Methods: MicroRNA as a search term was entered into the Web of Science database to identify all articles. The most 50 cited articles were analyzed by Topic, Journal Name, First Author, Publication Year, Citation, Average Citation Per Year (ACPY), Impact Factor (IF), Quartile (Q) Category, H Index, and AAS. Results: Altmetric explorer identified 45.911 articles as being referred to online. Correlation analysis revealed that there was a weak correlation between AAS and the number of citations (p<0.15), while a very strong correlation was found between the number of citations and ACPY (p<0.01). Conclusion: These results give some clues about the articles studied did not lose their currency. They are cited regularly each year so they are very popular in academia. This study provides a detailed list of 50 most cited microRNA articles and social media interest using the Altmetric.com database. miRNAs can be used in the diagnosis, prognosis, or treatment of various diseases.Öğe mTOR signaling pathway genes effect in COVID-19 infection(Inonu University, 2024) Pala, Mukaddes; Yılmaz, Şenay Görücü; Tanriverdi, Elif Seren; Gunduz, Ayten; Delen, Leman Acun; Ozturk, Dilara Altay; Öterkuş, MesutCoronavirus disease 2019 (Covid-19) is an infectious disease that causes severe acute respiratory illness caused by coronavirus 2 (SARS-CoV-2). SARS-CoV-2 uses host-specific metabolic pathways, including mTOR. The mTOR pathway is hyperactive in viral respiratory tract infections and contributes positively to viral replication. 100 samples were evaluated, 50 patients (Female=23, Male=27), and 50 controls (Female=29, Male=21). The patients were individuals who were COVID-19 positive. We detected expression changes of 5 genes in mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (MLST8, mTOR, RPTOR, MAPKAP1 and RICTOR). Serum samples were obtained from all patients. The expression changes of mTORC1 and mTORC2 Complex genes were evaluated with Real-time PCR method. Receiver operating curve (ROC) analysis was performed to define the diagnostic power of these genes. Expression changes of five genes in the mTORC1 and mTORC2 complex were statistically significant (p =0.001) and upregulated in serum. The area under the ROC Curve values indicating the diagnostic power of genes were 0.948, 0.771, 0.851, 0.798, and 0.805, respectively. These genes may be candidate for treatment targets. The high discriminative power of these genes in patients from controls indicates their diagnostic potential in serum samples.Öğe Pentylenetetrazole-induced kindling rat model: miR-182 and miR-27b-3p mediated neuroprotective effect of thymoquinone in the hippocampus(TAYLOR & FRANCIS, 2022) Pala, Mukaddes; Meral, İsmail; Açıkgöz Pala, Nilgün; Taşlıdere, Elif; Karaca Okur, Sema; Acar, Şeyma; Akbaş, SabriObjectives: Epilepsy is a neurological disease that pathologically affects brain functions. The epileptic hippocampus has modified microRNA(miRNA) levels. Therefore, we aimed to evaluate the neuroprotective effect of thymoquinone (TQ) in PTZ-induced epilepsy and to demonstrate the overlap between miRNA and mRNA expression profiles. Methods: Male adult Wistar albino rats (200–230 g, n = 20) were divided into three groups as control (n = 6), PTZ (n = 7), and TQ + PTZ (n = 7). The PTZ kindling model was created by injecting PTZ in sub convulsive doses to rats on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, and 24 of the study into animals. Clonic and tonic seizures were induced by injecting a convulsive dose of PTZ on day 26 of the study. Rats in the TQ+PTZ group were treated by oral gavage with a 20 mg/kg TQ 2 h before each PTZ injection. The rats in the control group were treated with 0.5 ml saline. Seizure severity was evaluated with the Racine scale. The genes and signaling pathways targeted by miRNAs were determined by bioinformatics analysis. Results: In the rat hippocampus, mature 728 miRNAs were analyzed by microarray and the nine miRNA were verified by quantitative Real-Time PCR. rno-miR-182 and rno-miR-27b-3p were up-regulated in the PTZ group and down-regulated in the TQ + PTZ group. Discussion: In the PTZ kindling epilepsy model, the expression of these two miRNAs was regulated by TQ and exerted a neuroprotective effect by controlling the activities of target genes.Öğe PTZ KINDLING MODEL: EVALUATION OF EEG FACTOR AND BIOCHEMISTRY PARAMETERS UNDER THE INFLUENCE OF RAMELTEON(2024) Pala, Mukaddes; kozan, ramazan; Kose, Hayrullah; Yılmaz, Şenay GörücüMany selective synthetic melatonin receptor agonists have anticonvulsant/anti-epileptogenic properties. These agonists bind to melatonin receptor 1 (MT1) and receptor 2 (MT2), causing their activation. Therefore, we evaluated the anticonvulsant effect of Ramelteon (RMLT) as a melatonin agonist in the PTZ (Pentylenetetrazol)-kindling model. In the study, 36 male Wistar Albino rats were assessed in 6 groups (Sham, PTZ, dimethylsulphoxide (DMSO), Valproic acid (VPA) (150 mg/kg) + PTZ, RMLT (30 mg/kg)+PTZ, VPA+RMLT+PTZ). Cortical electroencephalography (EEG) data were recorded for all groups. Seizures were scored according to the Racine scale. Seizure scores and onset times of the first myoclonic movements were compared in EEG traces. Total antioxidant status (TAS), total oxidant status (TOS), catalase, myeloperoxidase (MPO), and Thiol levels were measured in serum samples. Also, Calcineurin (CaN), Neuropeptide-Y (NPY), Neuron Specific Enolase (NSE), and S100B levels were measured in brain tissue samples. There was a significant difference between the PTZ and PTZ+Valproic acid+RMLT groups for the onset of the first myoclonic movements and the rate of spikes in the EEG traces in Racine's convulsion stages (P 0.05). RMLT has anticonvulsant properties. Additionally, the receptor preference of RMLT can be investigated.Öğe The effect of regularly performed moderate-intensity exercise program on thiol/disulfide homeostasis, and ischemia-modified albumin(2022) Pala, Mukaddes; Altan, Mehmet; Hanikoglu, Ferhat; neselioglu, salim; EREL, Ozcan; Metin, GökhanAim: Thiol/disulfide homeostasis is an indicator of oxidative stress and antioxidant capacity. Ischemia-modified albumin (IMA) is an important marker for both oxidative stress and ischemia. We aimed to evaluate the possible effects of regularly performed moderate-intensity exercise on thiol/disulfide homeostasis, and IMA levels.Methods: Sprague Dawley rats were used. The study was composed of an Exercise group (EG, n=9) and Control group (CG, n=6). A 10-weeks swimming exercise was performed. Thiol/disulfide homeostasis measurement method was used in this study. IMA levels were measured by a cobalt-albumin binding method.Results: In the EG, total thiol levels were significantly higher compared to the CG (p<0.01). The disulfide/total thiol ratio was lower in the EG compared to the CG (p<0.01). We observed that there was a slight increase in IMA levels in EG (p=0.18). This increase was not statistically significant.Conclusion: Regularly performed moderate-intensity exercise has increased native and total thiol levels. Increase of thiol levels can prevent oxidative stress. Regularly performed moderate-intensity exercise programs appear to provide favourable effects on oxidative stress.Öğe The Effects of MicroRNAs on Cardiomyopathy in a Rat Model of Streptozotocin-induced Diabetes Mellitus(2025) Doğan, Aslıhan Şeyda; Pala, Mukaddes; Yılmaz, Şenay Görücü; BECEREN, AYFER; Karabulut, Aydın; Polat, Yalçın; ELÇIOGLU, HATICE KÜBRAObjective: Diabetic cardiomyopathy (DCM) is characterized by complex pathophysiological events. miRNAs play a role in the DCM. In our study, the potential of miRNAs as a biomarker in the diagnosis and treatment of DCM was evaluated in the diabetes model induced by streptozotocin in rats. Methods: Therefore, miRNAs obtained from rat heart tissue were analyzed by microarray, and twelve miRNAs (rno-miR-200c-3p, rno-miR-129-5p, rno-miR-150-3p, rno-miR-3584-5p, rno-miR-34c-3p, rno-miR-342-3p, rno-miR-466b-3p, rno-miR-466c-3p, rno-miR-31a-3p, rno-miR-15b-5p, rno-miR-196b-3p, and rno-miR-208a-5p) with changed expression levels were validated by real-time polymerase chain reaction analysis. Results: As a result of the validation, it was determined that three miRNAs (rno-miR-15b-5p, rno-miR-196b-3p, and rno-miR-208a-5p) were downregulated, one miRNA (rno-miR-200c-3p) was upregulated (p<0.05). MiR-15b-5p, miR-196b-3p, miR-200c-3p, and miR-15b-5p are involved in the regulation of DCM, and the GRAP2 gene is one of the possible targets of these miRNAs. Conclusion: miR-200c-3p has diagnostic value and may be a biomarker candidate.Öğe Thymoquinone ameliorates symptoms of Parkinson's disease in a 6-OHDA rat model by downregulation of miR-204-3p(Lippincott Williams & Wilkins, 2024) Pala, Mukaddes; Meral, Ismail; Acikgoz, Nilguen Pala; Mengi, Murat; Gokce, Meryem Betul Erdim; Unsal, Rumeysa; Yilmaz, Senay GorucumicroRNAs (miRNAs) play a significant role in the pathophysiology of Parkinson's disease. In this study, we evaluated the neuroprotective effect of thymoquinone on the expression profiles of miRNA and cognitive functions in the 6-hydroxydopamine (6-OHDA)-induced Parkinson's model. Male adult Wistar albino rats (200-230 g, n = 36) were randomly assigned to six groups: Sham, thymoquinone (10 mg/kg, p.o.), 6-OHDA, 6-OHDA + thymoquinone (10 mg/kg), 6-OHDA + thymoquinone (20 mg/kg), and 6-OHDA + thymoquinone (50 mg/kg). Behavioral changes were detected using the open field and the elevated plus maze tests. The mature 728 miRNA expressions were evaluated by miRNA microarray (GeneChip miRNA 4.0). Ten miRNAs were selected (rno-miR-212-5p, rno-miR-146b-5p, rno-miR-150-5p, rno-miR-29b-2-5p, rno-miR-126a-3p, rno-miR-187-3p, rno-miR-34a-5p, rno-miR-181d-5p, rno-miR-204-3p, and rno-miR-30c-2-3p) and confirmed by real-time PCR. Striatum samples were stained with hematoxylin-eosin to determine the effect of dopaminergic lesions. One-way ANOVA test and independent sample t-test were used for statistical analyses. rno-miR-204-3p was upregulated at 6-OHDA and downregulated at the 50 mg/kg dose of thymoquinone. In conclusion, thymoquinone at a dose of 50 mg/kg ameliorates symptoms of Parkinson's disease in a 6-OHDA rat model by downregulation of miR-204-3p. Also, the results showed that thymoquinone can improve locomotor activity and willing exploration and decreased anxiety. Therefore, thymoquinone can be used as a therapeutic agent.
