Goal: 03 - Sağlık ve Kaliteli Yaşam
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AMAÇ 3: SAĞLIKLI BİREYLER
Çocuk ölüm oranlarının azaltılması, anne sağlığının iyileştirilmesi, HIV/AIDS, sıtma ve diğer hastalıklar ile mücadelede büyük aşama kaydetmiş durumdayız. 1990 yılından bu yana, önlenebilir çocuk ölümlerinde dünya genelinde %50’yi aşan azalma olmuştur. Anne ölümleri de dünya genelinde %45 azalmıştır. 2000 ile 2013 arasında HIV/AIDS bulaşma oranı %30 azalmış, 6,2 milyonu aşkın insan sıtmadan kurtarılmıştır.
Bu ölümler; önleme ve tedavi, eğitim, aşı kampanyaları, cinsel ve üreme sağlığı hizmetleri vasıtasıyla önlenebilir. Sürdürülebilir Kalkınma Amaçları; AIDS, verem, sıtma ve diğer bulaşıcı hastalık salgınlarını 2030 yılına kadar ortadan kaldırmaya yönelik cesur bir taahhüttür. Amaç, herkesin genel sağlık hizmeti, güvenli ve erişilebilir ilaç ve aşıya kavuşmasını sağlamaktır. Aşı araştırma ve geliştirmelerinin desteklenmesi, bu sürecin vazgeçilmez bir parçasıdır.
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Publication Open Access Ivermectin Induces Oxidative Stress and DNA Damage in Breast Cancer Cells(2023-01-01) Güler E. M.; Günaydın Akyıldız A.; GÜNAYDIN AKYILDIZ, AYŞENURObjective: Breast cancer (BC) remains to be one of the most diagnosed cancer types among women around the world. Drug repurposing is suggested to be a convenient alternative for drug development in cancer treatment. Ivermectin, the antiparasitic agent produced by the bacterium Streptomyces avermitilis, is currently being examined thoroughly in oncology and has begun to be seen as a potential drug candidate for BC therapy. However, studies are limited, and the exact anti-tumorigenic mechanism is not yet clarified in breast cancer. Methods: For elucidating the molecular mechanisms of Ivermectin’s potential anticancer effects, we have examined its in vitro effects on BC cells in terms of cell viability, intracellular ROS levels, glutathione levels, mitochondrial membrane potential, apoptosis, and DNA damage. Results: Ivermectin induces apoptosis via oxidative stress and DNA damage in BC cells. Conclusion: The in vitro mechanistic studies of promising anticancer agents for repurposing are essential guides for drug developers. For this purpose, ivermectin should be further studied as a drug candidate for its potential in the treatment of breast cancer.Publication Open Access Large-Scale Production of Anti-RNase A VHH Expressed in pyrG Auxotrophic Aspergillus oryzae(2023-05-01) Karaman, Elif; Eyupoglu, Alp Ertunga; Mahmoudi Azar, Lena; Uysal, Serdar; KARAMAN, ELİF; UYSAL, SERDARNanobodies, also referred to as VHH antibodies, are the smallest fragments of naturally produced camelid antibodies and are ideal affinity reagents due to their remarkable properties. They are considered an alternative to monoclonal antibodies (mAbs) with potential utility in imaging, diagnostic, and other biotechnological applications given the difficulties associated with mAb expression.Aspergillus oryzae (A. oryzae)is a potential system for the large-scale expression and production of functional VHH antibodies that can be used to meet the demand for affinity reagents. In this study, anti-RNase A VHH was expressed under the control of the glucoamylase promoter inpyrGauxotrophicA. oryzaegrown in a fermenter. The feature ofpyrGauxotrophy, selected for the construction of a stable and efficient platform, was established using homologous recombination. Pull-down assay, size exclusion chromatography, and surface plasmon resonance were used to confirm the binding specificity of anti-RNase A VHH to RNase A. The affinity of anti-RNase A VHH was nearly 18.3-fold higher (1.9 nM) when expressed inpyrGauxotrophicA. oryzaerather than inEscherichia coli. This demonstrates thatpyrGauxotrophicA. oryzaeis a practical, industrially scalable, and promising biotechnological platform for the large-scale production of functional VHH antibodies with high binding activity.Publication Open Access Impact of Smoking Status on Mortality in STEMI Patients Undergoing Mechanical Reperfusion for STEMI: Insights from the ISACS-STEMI COVID-19 Registry(2022-11-01) De Luca G.; Algowhary M.; Uguz B.; Oliveira D. C.; Ganyukov V.; Zimbakov Z.; Cercek M.; Jensen L. O.; Loh P. H.; Calmac L.; et al.; YAMAÇ, AYLİN HATİCEThe so-called \"smoking paradox\", conditioning lower mortality in smokers among STEMI patients, has seldom been addressed in the settings of modern primary PCI protocols. The ISACS-STEMI COVID-19 is a large-scale retrospective multicenter registry addressing in-hospital mortality, reperfusion, and 30-day mortality among primary PCI patients in the era of the COVID-19 pandemic. Among the 16,083 STEMI patients, 6819 (42.3%) patients were active smokers, 2099 (13.1%) previous smokers, and 7165 (44.6%) non-smokers. Despite the impaired preprocedural recanalization (p < 0.001), active smokers had a significantly better postprocedural TIMI flow compared with non-smokers (p < 0.001); this was confirmed after adjustment for all baseline and procedural confounders, and the propensity score. Active smokers had a significantly lower in-hospital (p < 0.001) and 30-day (p < 0.001) mortality compared with non-smokers and previous smokers; this was confirmed after adjustment for all baseline and procedural confounders, and the propensity score. In conclusion, in our population, active smoking was significantly associated with improved epicardial recanalization and lower in-hospital and 30-day mortality compared with previous and non-smoking history.Publication Open Access Association of CHA2DS2-VASc score with successful recanalization in acute ischemic stroke patients undergoing endovascular thrombectomy(2022-01-01) Nasifov M.; Ozmen E.; Deniz C.; NADİR A.; Ozden O.; Bingol G.; Jafarov P.; Asil T.; Goktekin O.; Sari I.; NADİR, AYDINIntroduction: The CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes mellitus, stroke, vascular disease and sex) score is a simple risk stratification algorithm to estimate stroke/thromboembolic risk in patients with non-valvular atrial fibrillation (AF). Higher pre-stroke CHA2DS2-VASc score is known to be associated with greater stroke severity and poorer outcomes. AF patients generally have higher CHA2DS2-VASc scores than non-AF patients. The Modified Thrombolysis in Cerebral Infarction (mTICI) score is the most widely used grading system to assess the result of recanalizing therapies in acute ischemic stroke (AIS). mTICI 2c and mTICI 3 are conventionally accepted as successful recanalization. Aim: We investigated whether pre-stroke CHA2DS2-VASc score is associated with mTICI recanalization score in AIS patients with and without AF undergoing percutaneous thrombectomy. Material and methods: One hundred fifty-nine patients with the diagnosis of AIS who were admitted within 6 h from symptom onset were included in the study (mean age: 65.7 ±12.9). All subjects underwent endovascular treatment. CHA2DS2-VASc scores of the participants were calculated. Subjects were grouped according to mTICI scores achieved after endovascular treatment. mTICI 2c and mTICI 3 were accepted as successful recanalization. Results: Successful reperfusion was observed in 130 (81.8%) of all patients who underwent endovascular treatment (mTICI flow ≥ 2c) and first-pass reperfusion was observed in 107 (67.3%) patients. When the patients with successful (mTICI flow ≥ 2c) and unsuccessful (mTICI flow ≤ 2b) reperfusion were divided into groups, no significant difference was observed between the patients in terms of comorbidities such as AF, hypertension, hyperlipidemia, coronary artery disease and cerebrovascular accident history. Patients with unsuccessful reperfusion were older than patients with successful reperfusion (71.4 ±11.2 vs. 64.5 ±13.01, p = 0.006), with a higher CHA2DS2-VASc score (4.1 ±1.5 vs. 3.04 ±1.6, p = 0.002). In addition, the duration of the procedure was longer in the unsuccessful reperfusion group (92.4 ±27.2 min vs. 65.0 ±25.1 min, p < 0.001). CHA2DS2-VASc score significantly correlated with successful recanalization (correlation coefficient; 0.243, p = 0.002). Multivariate logistic regression analysis revealed that only CHA2DS2-VASc score (OR = 1.43, 95% CI: 1.09-1.87, p = 0.006) and procedure time (OR = 1.03, 95% CI: 1.01-1.05, p < 0.001) were independent predictors of successful reperfusion. The receiver-operating characteristic (ROC) curve was used to determine the cut-off value for the CHA2DS2-VASc score that best predicts successful reperfusion. The optimal threshold was 3.5, with a sensitivity of 58.6% and specificity of 59.2% (area under the curve (AUC): 0.669, p = 0.005). Conclusions: For the first time in the literature, we investigated and demonstrated that pre-stroke CHA2DS2-VASc score was associated with success of recanalization as assessed with mTICI 2c and mTICI 3 in a cohort of AIS patients regardless of AF presence who underwent endovascular treatment. Our findings deserve to be tested with large scale long term studies.Publication Open Access Synthesis and Evaluation of Quinazolin-4(3H)-one Derivatives as Multitarget Metabolic Enzyme Inhibitors: A Biochemistry-Oriented Drug Design(2023-07-01) Tokalı F. S.; Taslimi P.; Sadeghi M.; Şenol H.; ŞENOL, HALILIn this study, imines bearing quinazolin-4(3H)-one were synthesized and their inhibitory properties were investigated against some metabolic enzymes including Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), & alpha;-Glycosidase (& alpha;-Gly), and human Carbonic Anhydrase I-II (hCA I-II). All compounds had inhibitory strength with K-i values in the range of 38.55 & PLUSMN;4.08-159.05 & PLUSMN;10.68 nM and 41.04 & PLUSMN;6.73-177.12 & PLUSMN;8.06 nM against hCA I and hCA-II, respectively in comparison to the standard acetazolamide (AZA) K-i=125.15 & PLUSMN;0.78 nM (for hCA-I) and K-i=148.75 & PLUSMN;0.92 nM (for hCA-II). The compounds showed potent inhibitory activity against & alpha;-Gly enzyme with IC50 value 0.34-2.28 nM (standard inhibitor acarbose (ACR): 3.18 nM). Also, these analogs had potent inhibitory strength with K-i values in the range of 4.20 & PLUSMN;0.15-26.10 & PLUSMN;2.36 nM against AChE and 1.22 & PLUSMN;0.05-16.09 & PLUSMN;0.88 nM against BChE in comparison to the standard tacrine (TAC) K-i=37.62 & PLUSMN;6.86 nM (for AChE) and K-i=26.75 & PLUSMN;5.79 nM (for BChE). Additionally, the molecular docking and molecular dynamics simulation study was carried out for the determination of ligand-enzyme interactions. The docking scores of the most active compound were calculated as -7.31, -7.59, -6.66, -6.93 and -7.11 kcal/mol for AChE, BChE, hCA I, hCA II, and & alpha;-Gly, respectively.Publication Open Access Synthesis and anticancer activity of novel derivatives of α,β‐unsaturated ketones based on oleanolic acid: in vitro and in silico studies against prostate cancer cells(2023-08-01) Şenol H.; Ghaffari-Moghaddam M.; Bulut Ş.; Akbaş F.; Köse A.; Topçu G.; ŞENOL, HALIL; AKBAŞ, FAHRİ; TOPÇU, GÜLAÇTIHerein, new derivatives of α,β-unsaturated ketones based on oleanolic acid (4 a-i) were designed, synthesized, characterized, and tested against human prostate cancer (PC3). According to the in vitro cytotoxic study, title compounds (4 a-i) showed significantly lower toxicity toward healthy cells (HUVEC) in comparison with the reference drug doxorubicin. The compounds with the lowest IC50 values on PC3 cell lines were 4 b (7.785 μM), 4 c (8.869 μM), and 4 e (8.765 μM). The results of the ADME calculations showed that the drug-likeness parameters were within the defined ranges according to Lipinski's and Jorgensen's rules. For the most potent compounds 4 b, 4 c, and 4 e, a molecular docking analysis using the induced fit docking (IFD) protocol was performed against three protein targets (PARP, PI3K, and mTOR). Based on the IFD scores, compound 4 b had the highest calculated affinity for PARP1, while compound 4 c had higher affinities for mTOR and PI3K. The MM-GBSA calculations showed that the most potent compounds had high binding affinities and formed stable complexes with the protein targets. Finally, a 50 ns molecular dynamics simulation was performed to study the behavior of protein target complexes under in silico physiological conditions.