Molecular Docking, Drug Likeness, and ADMET Analyses of Passiflora Compounds as P-Glycoprotein (P-gp) Inhibitor for the Treatment of Cancer

Cancer disease leads to deaths worldwide. Anti-cancer drugs have a high prevalence of side effects and cause multidrug resistance (MDR) that remains a significant barrier to major cancer therapy. To date, chemical and herbal substances have been analyzed for their MDR modulatory activity. However, research on new and safe molecules has been continued to overcome MDR in cancer. The plant compounds can be an effective inhibitor for successful cancer therapy. Recently, computational models have gained importance to discover new inhibitors. In the present study, we aimed to explore the various compounds of Passiflora species as P-gp inhibitor. P-gp protein was docked with the active substrate and inhibitor, respectively, including tamoxifen and verapamil. Besides, 3D structure of P-gp was docked with 11 compounds (luteolin, beta amyrin, beta-sitosterol, chimaphilin, chrysin, edulan I and II, apigenin, oleanolic acid, stigmasterol, hydroxyflavone) of plant origin using AutoDock4.2 program. Furthermore, the compounds were analyzed for ADMET and drug likeness properties of compounds determined as Lipinski, Veber, and Ghose’s rules (http://www.swissadme.ch/). As obtained molecular docking analysis results, luteolin, chrysin, hydroxyflavone, and apigenin may be a candidate for being P-gp inhibitor. Hence, it may be of attention to consider these compounds for further in vitro and in vivo evaluation. © 2020, Springer Nature Switzerland AG

The Cytotoxic Effect of Annona muricata-Loaded PHB-Coated Magnetic Nanoparticles on Cancer Cell Lines and Molecular Docking Analyses

In this study, we designed PHB-coated iron oxide–based nanoparticle for the delivery of Annona muricata to breast cancer cells and analyzed its therapeutic efficacy in vitro. The structural properties, functional groups, size distribution, and magnetic properties of the synthesized PHB-coated magnetic nanoparticles (MNPs) were characterized in our previous study. The current study visualized protein–ligand interactions by the use of molecular docking. The plant extract was loaded onto PHB-MNPs in different concentrations and the release efficiencies at different pHs were studied under in vitro conditions. The most efficient loading concentration was found about 55% in pH 7.4. The extract-loaded MNPs were stable up to 3 months in neutral pH for mimicking physiological conditions. The release studies were performed with acetate buffer (pH 4.2) that mimics endosomal pH. The plant extract-loaded PHB-MNPs were about 2.5–3-fold more cytotoxic as compared with free plant extract on HeLa and MDA-MB-231 in vitro, respectively. The cytotoxicity results also confirm that anti-apoptotic proteins have the best docking score for isoquercetin–PHB-MNPs, roseoside–PHB-MNPs, and anonaine–PHB-MNPs with molecular docking analyses. Based on the results obtained, this system can be used effectively in cancer treatment. © 2020, Springer Nature Switzerland AG

Antiproliferative activity and interaction with proteins of N-cyclohexylacrylamide

N-cyclohexylacrylamıde (NCA), the synthesized compound, was evaluated for their cytotoxic activities against HeLa cancer cell line. Also, the current study has been analyzed by the use of molecular docking as protein-ligand interactions play a vital role in drug design. The docking study of NCA was performed with BCL-2, BCL-W, MCl-1, AKT, BRAF, CDK2, VEGFR, EGFR PARP1, CDK6 proteins. The 3D structures of proteins were obtained from the protein data bank and 3D structure of NCA compounds using GAUSSIAN. The in silico molecular docking results indicated that NCA compound can inhibit cancer-related proteins and can play a role as potential lead compounds for developing new drugs for cancer therapy with chemical modification. © 202

Exosomes as delivery tools in cancer therapy: Future perspectives

Exosomes, which are one of the extracellular vesicles, are considered necessary tools of intracellular communication that abundant in our body in physiological and pathological conditions with a diameter of 30-150 nm. The nanotubes, dendrimeric, metallic, nanoparticles have been used in the medical area. However, these nano-based systems are lack of standardized manufacturing methods and therefore, it has toxic effects on cells. The delivery methods of growth factors, exosomes, cells, and engineered tissues have notably advanced in the medical area. The fact that they contain bioactive molecules such as protein, lipid, RNA and DNA revealed that these structures may play an important role in the treatment of cancer. Here, we review work on the contribution exosomal mediated cancer treatment in two main topics as exogenous molecule carrier and self-use. We also emphasize the development of exosome-based systems by referring to the advantages and disadvantages of using exosomes and future perspectives in cancer therapy. © 2021 Mashhad University of Medical Sciences. All Rights Reserved

In silico detection of Cucurbitacin-E on antioxidant enzymes of model organism Galleria mellonella L. (Lepidoptera: Pyralidae) and variation of antioxidant enzyme activities and lipid peroxidation in treated larvae

Background: In silico studies further provided predictive binding properties of selected ligands for inhibition of target protein. In the study, molecular binding poses of Cucurbitacin-E and antioxidant enzymes (glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and acetylcholinesterase (AChE) of Galleria mellonella were determined in silico. Cucurbitacins are the most important components of Ecballium elaterium. The first cucurbitacin isolated from the plant was Cucurbitacin-E. In this study, the toxic effect of E. elaterium (L.) A. Rich. (Cucurbitaceae) fruit juice on G. mellonella (Lepidoptera: Pyralidae) larvae, which is known as a good model insect, was also detected, and its effect on antioxidant enzyme activities and lipid peroxidation was revealed. Results: The plant fruit juice was tested on the target larvae of G. mellonella with different doses for 24 h. After the application, mortality rate, LC50, LC90 and LC99 values, the malondialdehyde (MDA) level and the activity changes of antioxidant enzymes were determined. Mortality increased with the increasing concentration of fruit juice. Also, increasing doses of essential oil caused decreasing in SOD, CAT, GST GPx, GR and AChE activities and increasing in MDA levels. As a result of in silico studies, maximum binding energy was obtained from G. mellonella CAT enzyme with Cucurbitacin E as a ligand. Conclusions: This is the first study to demonstrate the in silico binding potential of Cucurbitacin E on G. mellonella enzymes. The results indicate that E. elaterium can be used against G. mellonella in a pest control program

Sequence variants of CYP345a1 and CYP6a14 gene regions in tribolium castaneum (Coleoptera: Tenebrionidae) adults treated with the novel characterized bolanthus turcicus (Caryophyllaceae) extract

In this study, various doses of plant extracts that obtained from Bolanthus turcicus was applied to an important storage pest Tribolium castaneum adults. Bolanthus turcicus is an endemic species and spreads on the Hasan Mountain above Karkin town (Turkey, Aksaray province). The plant species was collected from June to July with the field study to be carried out in this region. Obtained extract of plant was analyzed by gas chromatography mass spectrometry (GC-MS) method. The doses were defined during the study and the concentrations that kill 50% and 99% of the population were determined after applications. After 24 h, DNA was isolated from live and dead individuals that obtained from LC50 and LC99 concentration applications and analyzed for Cytochrome P450-mediated detoxification resistance genes, CYP345A1 and CYP6A14 gene regions, by polymerase chain reaction (PCR). CYP genes in insects are known to be rapidly regulated when exposed to insecticides. In the study, in order to screen for 206 bp and 353 bp fragments of CYP345A1 and CYP6A14 genes in T. castaneum adults were amplified using specific primers, respectively. DNA direct sequencing was performed on each template using the forward primer. When compared to the control, it is believed that mutation differences in live and dead individuals according to the sequencing results obtained from survival and dead adults, may allow these genes to play a protective role against the toxic effect of B. turcicus extract. © Shiraz University

EVALUATION ON THE SECONDARY SCHOOL PHYSICS PROGRAM ARRANGEMENTS IN 2005 WITH RESPECT TO THE VIEWS OF PROSPECTIVE PHYSICS TEACHERS AND PHYSICS TEACHERS

ilgili görüĞ¢leriyle karĞ¢ılaĞ¢tırarak fizik programı düzenlemelerini değerlendirmektir. ÇalıĞ¢manın örneklemini, Ğ zmir‟deki bir devlet üniversitesinin fizik öğretmenliği programı 4. ve 5. sınıflarında okumakta olan 80 öğretmen adayı oluĞ¢turmaktadır. Veri toplama aracı olarak daha önce fizik öğretmenlerine uygulanan 35 kapalı uçlu ve 11 açık uçlu sorudan oluĞ¢an bir anket kullanılmıĞ¢tır. Ankette yer alan sorulardan elde edilen verilerin frekans dağılımları belirlenmiĞ¢tir. Öğretmen adayları ve öğretmenler fizik uygulama derslerinin yeniden programda yer alması ve fizik ders saatlerinin artırılması, 9. sınıf programındaki konuların genel kültür düzeyinde kalması, 10. sınıf programında mekanik konularının ve 11. sınıfta ise elektrik konularının tümünün yer alması gerektiğini belirtmiĞ¢lerdir. Bu bulgular doğrultusunda ortaöğretim fizik ders konularının yıllara göre sıralanması, aĞ¢amalılık ve önkoĞ¢ul ilkeleri dikkate alınarak tablo halinde sunulmuĞ¢tur. \r\n\r\nABSTRACT: The purpose of this study is to evaluate the physics program arrangements by determining the ideas of prospective physics teachers on the the secondary school physics program arrangements in 2005 following the increase from three years to four years period, and by comparing them with the ideas of the physics teachers on the same subject. The sampling of the study consisted of 80 prospective teachers who attend 4th and 5th classes at a state university‟s physics education program. In order to collect the views of prospective teachers, a questionnaire, including 35 close-ended and 11 open-ended questions was used. The frequency distribution of data that was obtained from close-ended and open-ended questions was determined. Suggestions of prospective teachers and physics teachers regarding the physics program arrangements are; Physics Application courses should be included in the program and the hours of the physics courses should be increased, making 9th degree physics program should only be on general culture level, the content of 10th level should be only for mechanical topics and the content of 11th level should be only for electrical topics. According to the findings, suggestions were presented as a table for listing year-based secondary school physics courses by considering the principles of progressiveness in unit order and prerequisite for other lessons

Outcomes of high-risk breast lesions diagnosed using image-guided core needle biopsy: results from a multicenter retrospective study

PURPOSEThe clinical management of high-risk lesions using image-guided biopsy is challenging. This study aimed to evaluate the rates at which such lesions were upgraded to malignancy and identify possible predictive factors for upgrading high-risk lesions.METHODSThis retrospective multicenter analysis included 1.343 patients diagnosed with high-risk lesions using an image-guided core needle or vacuum-assisted biopsy (VAB). Only patients managed using an excisional biopsy or with at least one year of documented radiological follow-up were included. For each, the Breast Imaging Reporting and Data System (BI-RADS) category, number of samples, needle thickness, and lesion size were correlated with malignancy upgrade rates in different histologic subtypes. Pearson’s chi-squared test, the Fisher–Freeman–Halton test, and Fisher’s exact test were used for the statistical analyses.RESULTSThe overall upgrade rate was 20.6%, with the highest rates in the subtypes of intraductal papilloma (IP) with atypia (44.7%; 55/123), followed by atypical ductal hyperplasia (ADH) (38.4%; 144/375), lobular neoplasia (LN) (12.7%; 7/55), papilloma without atypia (9.4%; 58/611), flat epithelial atypia (FEA) (8.7%; 10/114), and radial scars (RSs) (4.6%; 3/65). There was a significant relationship between the upgrade rate and BI-RADS category, number of samples, and lesion size Lesion size was the most predictive factor for an upgrade in all subtypes.CONCLUSIONADH and atypical IP showed considerable upgrade rates to malignancy, requiring surgical excision. The LN, IP without atypia, pure FEA, and RS subtypes showed lower malignancy rates when the BI-RADS category was lower and in smaller lesions that had been adequately sampled using VAB. After being discussed in a multidisciplinary meeting, these cases could be managed with follow-up instead of excision

Diagnosis of comorbid migraine without aura in patients with idiopathic/genetic epilepsy based on the gray zone approach to the International Classification of Headache Disorders 3 criteria

BackgroundMigraine without aura (MwoA) is a very frequent and remarkable comorbidity in patients with idiopathic/genetic epilepsy (I/GE). Frequently in clinical practice, diagnosis of MwoA may be challenging despite the guidance of current diagnostic criteria of the International Classification of Headache Disorders 3 (ICHD-3). In this study, we aimed to disclose the diagnostic gaps in the diagnosis of comorbid MwoA, using a zone concept, in patients with I/GEs with headaches who were diagnosed by an experienced headache expert.MethodsIn this multicenter study including 809 consecutive patients with a diagnosis of I/GE with or without headache, 163 patients who were diagnosed by an experienced headache expert as having a comorbid MwoA were reevaluated. Eligible patients were divided into three subgroups, namely, full diagnosis, zone I, and zone II according to their status of fulfilling the ICHD-3 criteria. A Classification and Regression Tree (CART) analysis was performed to bring out the meaningful predictors when evaluating patients with I/GEs for MwoA comorbidity, using the variables that were significant in the univariate analysis.ResultsLonger headache duration (<4 h) followed by throbbing pain, higher visual analog scale (VAS) scores, increase of pain by physical activity, nausea/vomiting, and photophobia and/or phonophobia are the main distinguishing clinical characteristics of comorbid MwoA in patients with I/GE, for being classified in the full diagnosis group. Despite being not a part of the main ICHD-3 criteria, the presence of associated symptoms mainly osmophobia and also vertigo/dizziness had the distinguishing capability of being classified into zone subgroups. The most common epilepsy syndromes fulfilling full diagnosis criteria (n = 62) in the CART analysis were 48.39% Juvenile myoclonic epilepsy followed by 25.81% epilepsy with generalized tonic-clonic seizures alone.ConclusionLonger headache duration, throbbing pain, increase of pain by physical activity, photophobia and/or phonophobia, presence of vertigo/dizziness, osmophobia, and higher VAS scores are the main supportive associated factors when applying the ICHD-3 criteria for the comorbid MwoA diagnosis in patients with I/GEs. Evaluating these characteristics could be helpful to close the diagnostic gaps in everyday clinical practice and fasten the diagnostic process of comorbid MwoA in patients with I/GEs

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.The EU-ROS consortium (COST Action BM1203) was supported by the European Cooperation in Science and Technology (COST). The present overview represents the final Action dissemination summarizing the major achievements of COST Action BM1203 (EU-ROS) as well as research news and personal views of its members. Some authors were also supported by COST Actions BM1005 (ENOG) and BM1307 (PROTEOSTASIS), as well as funding from the European Commission FP7 and H2020 programmes, and several national funding agencies