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Targeting MDM2-p53 Axis through Drug Repurposing for Cancer Therapy: A Multidisciplinary Approach
No full textCancer remains a major cause of morbidity and mortality worldwide, and while current therapies, such as chemotherapy, immunotherapy, and cell therapy, have been effective in many patients, the development of novel therapeutic options remains an urgent priority. Mouse double minute 2 (MDM2) is a key regulator of the tumor suppressor protein p53, which plays a critical role in regulating cellular growth, apoptosis, and DNA repair. Consequently, MDM2 has been the subject of extensive research aimed at developing novel cancer therapies. In this study, we employed a machine learning-based approach to establish a quantitative structure-activity relationship model capable of predicting the potential in vitro efficacy of small molecules as MDM2 inhibitors. Our model was used to screen 5883 FDA-approved drugs, resulting in the identification of promising hits that were subsequently evaluated using molecular docking and molecular dynamics simulations. Two antihistamine drugs, cetirizine (CZ) and rupatadine (RP), exhibited particularly favorable results in the initial in silico analyses. To further assess their potential use as the activators of the p53 pathway, we investigated the antiproliferative capability of the abovementioned drugs on human glioblastoma and neuroblastoma cell lines. Both the compounds exhibited significant antiproliferative effects on the abovementioned cell lines in a dose-dependent manner. The half-maximal inhibitory concentration (IC50) of CZ was found to be 697.87 and 941.37 μM on U87 and SH-SY5Y cell lines, respectively, while the IC50 of RP was found to be 524.28 and 617.07 μM on the same cell lines, respectively. Further investigation by quantitative reverse transcriptase polymerase chain reaction analysis revealed that the CZ-treated cell lines upregulate the expression of the p53-regulated genes involved in cell cycle arrest, apoptosis, and DNA damage response compared to their respective vehicle controls. These findings suggest that CZ activates the p53 pathway by inhibiting MDM2. Our results provide compelling preclinical evidence supporting the potential use of CZ as a modulator of the MDM2-p53 axis and its plausible repurposing for cancer treatment
TNF-α, IL-1B and IL-6 affect the differentiation ability of dental pulp stem cells
No full textBackground: This in vitro study examined the effect of the inflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6) on osteogenic, chondrogenic, and adipogenic differentiation of dental pulp stem cells (DPSCs) which have significant relevance in future regenerative therapies.
Methods: DPSCs were isolated from the impacted third molar dental pulp and determined with flow cytometry analysis. DPSCs were divided into into 5 main groups with 3 subdivisions for each group making a total of 15 groups. Experimental groups were stimulated with TNF-α, IL-1β, IL-6, and a combination of all three to undergo osteogenic, chondrogenic, and adipogenic differentiation protocols. Next, the differentiation of each group was examined with different staining procedures under a light microscope. Histological analysis of osteogenic, chondrogenic, and adipogenic differentiated pellets was assessed using a modified Bern score. Statistical significance determined using one-way analysis of variance, and correlations were assessed using Pearson's test (two-tailed).
Results: Stimulation with inflammatory cytokines significantly inhibited the osteogenic, chondrogenic and adipogenic differentiation of DPSCs in terms of matrix and cell formation resulting in weak staining than the unstimulated groups with inflammatory cytokines. On contrary, the unstimulated groups of MSCs have shown to be highly proliferative ability in terms of osteogenic, chondrogenic, and adipogenic differentiation.
Conclusions: DPSCs have high osteogenic, chondrogenic, and adipogenic differentiation capabilities. Pretreatment with inflammatory cytokines decreases the differentiation ability in vitro, thus inhibiting tissue formation
Retrospective evaluation of candida infections in pediatric intensive care units
No full textObjective: Candida species are the most common infectious agents among the pathogens responsible for nosocomial fungal infections. Transmissions in intensive care units account for a significant proportion of the mortality and morbidity associated with candida infections. The present study evaluates the prevalence, type, treatment approach, underlying risk factors, and outcomes of candida infections in patients treated in a pediatric intensive care unit in Türkiye with a dense population of children who have fled the war in Syria. Methods: The study was conducted in the 14-bed tertiary pediatric intensive care unit of a city hospital between March 2018 and March 2019. Results: Candida species were reproduced in the studied samples of 28 (15.7%) of the 176 patients treated in the intensive care unit during the study period. Mortality occurred in six (21.4%) patients with invasive candidiasis of varying species, namely: C. lusitaniae (n=2); C. parapsilosis (n=2); C. krusei (n=1), and C. albicans (n=1), and candida was considered the cause of mortality in five of the six non-survivors. Resistance to liposomal amphotericin-B was observed in the Candida species isolated from the non-survivors. Conclusion: In the present study, a prolonged stay in the intensive care unit, a higher number of indwelling medical devices, the use of broad-spectrum antibiotics, the presence of an underlying condition, and renal failure were observed to increase incidence of candida infection
Magnetic properties of fcc and ? phases in equiatomic and off-equiatomic high-entropy Cantor alloys
No full textThe equiatomic face-centered-cubic (fcc) high-entropy alloy CrMnFeCoNi has a valence electron concentra-tion of 8 electrons per atom, equivalent to that of Fe. Its ground-state properties are similar to that of fcc-Fe and exhibits the anti-Invar effect at finite temperatures. It additionally exhibits various magnetic interactions at low temperatures which are not fully understood. To resolve this, we prepare and investigate the magnetic and structural properties of off-equiatomic Cr20+xMn20Fe20Co20Ni20-x high-entropy alloys with 0 x 20 at.% by making use of the composition-dependent transformation from the fcc to the a phase with increasing x. We employ x-ray diffraction, scanning electron microscopy, magnetization, and microhardness studies. The results suggest that these alloys order antiferromagnetically around 75-90 K before entering into a spin-frozen state below 40 K
Effect of mid-urethral sling surgery on sleep quality and quality of life in the treatment of stress urinary incontinence
No full textObjectives: This study aims to evaluate the effect of surgical outcomes on quality of life and sleep quality following stress urinary incontinence (SUI) surgery. Materials and Methods: Patients diagnosed with SUI and treated with a mid-urethral sling were evaluated retrospectively. Fifty-six patients aged 40-75 years who had a follow-up period of more than 12 months, could not be treated conservatively, and had not previously undergone anti-incontinence or urogynaecological surgery were included in the study. Demographic findings of the patients and the pelvic examination were performed. The patients were evaluated preoperatively and postoperatively using the incontinence quality of life scoring system (I-QOL), Pittsburgh sleep quality index (PSQI), and cough stress pad test. Results: A success rate of approximately 93% was achieved, with an objective cure in 46 patients (82.1%) and a subjective cure in six patients (10.8%). Statistically significant improvements were found in the patients postoperative I-QOL and PSQI scores. According to Spearman correlation analysis, there was a correlation between I-QOL and PSQI (r=-0.974). In women 65 years and older, the duration of incontinence symptoms was significantly longer (p<0.001); frequency of persistent incontinence (p=0.026) and incontinence episodes were evaluated as during sleep and/or spontaneous (p=0.011). Conclusion: There is a relationship between quality of life and sleep quality in women with SUI. It was determined that surgical treatment significantly improved the quality of life and sleep quality of women with SUI
Changes in lipid profile of obese patients undergoing sleeve gastrectomy with Transit Bipartition surgery
No full textThe aim of this study was to investigate the short- and long-term changes in lipid profile caused by Sleeve Gastrectomy with Transit Bipartition Surgery (SG+TBS), which is one of the current metabolic surgery techniques. The study included patients who underwent SG+TBS between June 2015 and May 2019. The analyzed data included patients' demographic datas, obesity classification (Overweight, Class 1, 2, 3), and cardiovascular risk groups. Total Cholesterol (TC), triglycerides, Low-Density-Lipoprotein-Cholesterol (LDL-C), High-Density-Lipoprotein-cholesterol (HDL-C) serum concentrations of patients were measured at the time of admission to the outpatient clinic and at 3 and 12 months postoperatively.
The study population consisted of a total of 499 patients, 263 males and 236 females, with a mean BMI of 34.86 +/- 4.90 kg/m(2) and a mean age of 53.84 +/- 8.93 years, who underwent SG+TBS. There was a significant decrease in the 3-month and 12-month TC levels, in the 12-month triglyceride levels of all classification groups, compared to the baseline value (p<0.001), There was also a significant decrease in the 3-month and 12-month LDL-C levels of overweight, class 1 and 2 obese patients compared to the baseline values. Although the change in the 3-month value of class 3 obese patients was insignificant, there was a significant decrease in the 12-month value, as in other obesity classification groups (p<0.05) and a significant increase in the 12-month HDL-C values for all classification groups compared to both baseline and 3-month values (p<0.05).
There were significant improvements in serum lipid profiles on SG+TBS patients, which are thought to be important in reducing the risks of cardiovascular diseas
Photodynamic Anti-Inflammatory Activity of Porphyrin Derivative on In-Vitro Activated Macrophages
No full textPorphyrin derivatives have been known for their photodynamic therapy (PDT) application potential. In the present work, we have studied an asymmetric tetraphenyl substituted porphyrin derivative synthesized previously. Although traditional PDT applications focus on antibacterial and anti-cancer activities of the drug candidates, these compounds may have functional properties at subtoxic concentrations due to the chemically active groups that they carry. In this study, we aimed to investigate the anti-inflammatory PDT potential of this porphyrin derivative. For this purpose, mammalian macrophage cells were used. Trypan blue staining was done to confirm that this compound was effective at non-toxic concentrations. Moreover, TNF and IL6 ELISAs were done to the supernatants of the stimulated cells. Xenon light exposure was done to activate the porphyrin derivative. Our results suggest that this derivative had differential effects on these cytokine production levels by activated macrophages. These effects are light activation-dependent which makes this derivative a viable option for anti-inflammatory PDT applications. Moreover, it did not exert any cytotoxic effect at concentration used both in the dark and under light conditions
Differences of University Students' Awareness of Sustainable Development by Demographic Characteristics
No full textBu çalışmanın amacı sürdürülebilir kalkınma farkındalığına yönelik üniversite öğrencilerinin demografik özelliklerine göre farklılıklarının var olup olmadığının tespit edilmesidir. Çalışma kapsamında nicel veri toplama yöntemlerinden biri olan anket tekniğinden yararlanılmıştır. Hazırlanan anket formları, Google Forms dijital platformuna yüklenmiş dijital ve sanal ortamlarda; WhatsApp ve online formlar aracılığı ve gönüllü katılım esası ile üniversite öğrencilerine ulaştırılmıştır. Sosyal medya ve internet uygulamaları aracılığıyla kolayda örnekleme yöntemi ile ulaşılan ve çalışmanın anketine katılmayı kabul eden üniversite öğrencileri çalışmanın örneklemini oluşturmuştur. Araştırmanın amacı doğrultusunda hazırlanan ankete gönüllü katılımlar ile toplanan verilerden hatalı, eksik anket formlarının ayıklanması sonrası kalan 599 öğrenciden elde edilen verilere Kruskal Wallis ve Whitney U testleri yapılmıştır. Yapılan testler sonucunda “öğrencilerin sürdürülebilir kalkınmaya yönelik farkındalıkları istatistiksel olarak demografik özelliklerine göre anlamlı farklılık gösterir” ana hipotezi sosyal, ekonomik ve çevresel faktörler çerçevesinde kabul edilmiştir
Assessment of eco-toxicological and health risks of core sediment from İzmit Gulf, Marmara Sea, Türkiye
No full textA comprehensive geochemical study was carried out to evaluate the environmental and human health effects of metal pollution in the Gulf of İzmit. For this purpose, the toxic and ecological risk distributions of a sediment core collected from 156 m water depth were determined. The mean concentrations of the studied metals as mg/kg dry weight in the İzmit Gulf core sediments were found to be in the following order: Cr (150.3) > Zn (122.7) > Pb (48.3) > Cu (35) > As (28) > Co (19.7) > Cd (3.6). A Contamination Factor (CF), Pollution Load Index (PLI), and Geo-Accumulation Index (Igeo) were used to assess sediment pollution. Increased industrial and agricultural activities around the İzmit Gulf has caused contamination in metals concentration, such as Cu (CF = 1.2), Zn (CF = 1.7), and Pb (CF = 1.5). This finding showed that Cu, Zn, and Pb contamination levels in the inspected core samples were moderate. Additionally, mean PLI values (1.2) point to human-induced contamination in the Izmit Gulf. The adverse effects of toxic metals on the organisms living in benthic environments were determined according to the Sediment Quality Guidelines (SQGs). According to SQG, living is exposed to toxic effects in terms of Cr, As, and Cd. The impacts of these toxic metals on human health were investigated by the Hazard Index (HI) and Cumulative Cancer Risk (LCR) parameters. Adults are not at risk from HI-As, however children have a value greater than 1 and require attention. LCR is another risk factor for Cd in adults and Cd and Cr in children
Theoretical and numerical analysis of a chaotic model with nonlocal and stochastic differential operators
No full textA set of nonlinear ordinary differential equations has been considered in this paper. The work tries to establish some theoretical and analytical insights when the usual time-deferential operator is replaced with the Caputo fractional derivative. Using the Caratheodory principle and other additional conditions, we established that the system has a unique system of solutions. A variety of well-known approaches were used to investigate the system. The stochastic version of this system was solved using a numerical approach based on Lagrange interpolation, and numerical simulation results were produced