Search results for: receptor activator of nuclear factor kappa-B ligand

Authors: Elham Zamiri

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In this research, we have focused on numeral simulation of a fuel rod in order to examine distribution of heat temperature in components of fuel rod by Fluent software by providing steady state, single phase fluid flow, frequency heat flux in a fuel rod in nuclear reactor to numeral simulation. Results of examining different layers of a fuel rod consist of fuel layer, gap, pod, and fluid cooling flow, also examining thermal properties and fluids such as heat transition rate and pressure drop. The obtained results through analytical method and results of other sources have been compared and have appropriate correspondence. Results show that using heavy water as cooling fluid along with few layers of gas and pod have the ability of reducing the temperature from above 300 ^◦C to 70 ^◦C. This investigation is developable for any geometry and material used in the nuclear reactor.

Keywords: nuclear fuel fission, numberal simulation, fuel rod, reactor, Fluent software

Procedia PDF Downloads 139

Authors: Azza Gaber Farag, Yasser Atta Shehata, Sara Elsayed Elghazouly, Mustafa Elsayed Elshaib, Nesreen Gamal Elden Elhelbawy

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Background: Androgen receptor (AR) polymorphism in cytosine adenineguanine (CAG) repeat has an effect on the functional capacity of AR in males. However, little researches in this field are available regarding female sexual function. Aim: To investigate the possible link between polymorphism in the CAG repeat of AR gene and female sexual function in a sample of the Egyptian population. Materials and methods: 500 Egyptian married females completed a questionnaire regarding sociodemographic, reproductive, and sexual data. AR CAG repeat length was analyzed for those having female sexual dysfunctions (FSD) using real-time PCR. Results: The most sensitive domain to AR CAG repeat length was the orgasm domain that showed significant positive correlations with short allele (p=0.001), long allele (p=.015), biallellic mean (p=.000), and X weighted biallelic mean (p=.000). The satisfaction domain had significant positive correlations with the biallelic mean (p=.035), and the X weighted biallelic mean (p=. 032). However, the pain domain was of significant negative correlations with AR polymorphism of short allele (p=.002), biallelic mean (p=.013), and X weighted biallelic mean (p = . 011). Conclusions: AR polymorphism could represent a non-negligible aspect in female sexual function. The lower AR CAG repeat polymorphism was of significant impact on FSD, affecting mainly female orgasm followed by pain disorders that finally reflected On her sexual satisfaction.

Keywords: female sexual dysfunction, androgen receptor, CAG repeat polymorphism, androgen

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Authors: Hamid Mustafa, Adeela Ajmal, Kim EuiSoo, Noor-ul-Ain

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World wild, buffalo production is considered as most important component of food industry. Efficient buffalo production is related with reproductive performance of this species. Lack of knowledge of reproductive efficiency and its related genes in buffalo species is a major constraint for sustainable buffalo production. In this study, we performed some bioinformatics analysis on Follicle Stimulating Hormone Receptor (FSHR) gene and explored the possible relationship of this gene among different buffalo breeds and with other farm animals. We also found the evolution pattern for this gene among these species. We investigate CDS lengths, Stop codon variation, homology search, signal peptide, isoelectic point, tertiary structure, motifs and phylogenetic tree. The results of this study indicate 4 different motif in this gene, which are Activin-recp, GS motif, STYKc Protein kinase and transmembrane. The results also indicate that this gene has very close relationship with cattle, bison, sheep and goat. Multiple alignment (MA) showed high conservation of motif which indicates constancy of this gene during evolution. The results of this study can be used and applied for better understanding of this gene for better characterization of Follicle Stimulating Hormone Receptor (FSHR) gene structure in different farm animals, which would be helpful for efficient breeding plans for animal’s production.

Keywords: buffalo, FSHR gene, bioinformatics, production

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Authors: Hye Jin Kim, Hwa Sung Shin

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Ischemic stroke means the caused brain damage due to neurological defects, occurring occlusion of cerebral vascular resulting in thrombus or embolism. t-PA (tissue Plasminogen Activator) is the only thrombolytic agent passed the FDA (Food and Drug Administration). However, t-PA directly dissolves the thrombus (direct activity) through fibrinolysis, showing side effects such as re-occlusion. In this study, we evaluated the thrombolytic activities of the serine protease extracted from lugworms inhabiting tidal flats. The new serine protease identified as 38 kDa by SDS-PAGE was not toxic to brain endothelial cells line (hCMEC/D3). Also, the plasmin synthesis inhibition activity (indirect activity) of the new serine protease was confirmed through fibrin zymography assay and fibrin plate assay. It was higher than direct activity as compared to u-PA (urokinase Plasminogen Activator). The activities were found to be maintained at a wide range of temperature (4-70 ℃) and pH 7-10 compared to previous thrombolytic agents from the azocasein assay. In addition, the new serine protease has shown anticoagulant activity from fibrinogenolytic activity assay. In conclusion, the serine protease in lug worms inhabiting the tidal flats could be considered a promising thrombolytic candidate for the treatment of ischemic stroke.

Keywords: alkaline serine protease, bifunctional thrombolytic activity, fibrinolytic activity, ischemic stroke, lug worms

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Authors: Adebisi Adunola Demehin, Wanlaya Thamnarak, Jaruwan Chatwichien, Chatchakorn Eurtivong, Kiattawee Choowongkomon, Somsak Ruchirawat, Nopporn Thasana

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The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein involved in cellular signalling processes and, its aberrant activity is crucial in the development of many cancers such as lung cancer. Selaginellaceae are fern allies that have long been used in Chinese traditional medicine to treat various cancer types, especially lung cancer. Biflavonoids, the major secondary metabolites in Selaginellaceae, have numerous pharmacological activities, including anti-cancer and anti-inflammatory. For instance, amentoflavone induces a cytotoxic effect in the human NSCLC cell line via the inhibition of PARP-1. However, to the best of our knowledge, there are no studies on biflavonoids as EGFR inhibitors. Thus, this study aims to investigate the EGFR inhibitory activities of biflavonoids isolated from Selaginella siamensis and Selaginella bryopteris. Amentoflavone, tetrahydroamentoflavone, sciadopitysin, robustaflavone, robustaflavone-4-methylether, delicaflavone, and chrysocauloflavone were isolated from the ethyl-acetate extract of the whole plants. The structures were determined using NMR spectroscopy and mass spectrometry. In vitro study was conducted to evaluate their cytotoxicity against A549, HEPG2, and T47D human cancer cell lines using the MTT assay. In addition, a target-based assay was performed to investigate their EGFR inhibitory activity using the kinase inhibition assay. Finally, a molecular docking study was conducted to predict the binding modes of the compounds. Robustaflavone-4-methylether and delicaflavone showed the best cytotoxic activity on all the cell lines with IC50 (µM) values of 18.9 ± 2.1 and 22.7 ± 3.3 on A549, respectively. Of these biflavonoids, delicaflavone showed the most potent EGFR inhibitory activity with an 84% relative inhibition at 0.02 nM using erlotinib as a positive control. Robustaflavone-4-methylether showed a 78% inhibition at 0.15 nM. The docking scores obtained from the molecular docking study correlated with the kinase inhibition assay. Robustaflavone-4-methylether and delicaflavone had a docking score of 72.0 and 86.5, respectively. The inhibitory activity of delicaflavone seemed to be linked with the C2”=C3” and 3-O-4”’ linkage pattern. Thus, this study suggests that the structural features of these compounds could serve as a basis for developing new EGFR-TK inhibitors.

Keywords: anticancer, biflavonoids, EGFR, molecular docking, Selaginellaceae

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Authors: Alexander A. Osmolovskiy, Anastasia V. Orekhova, Daria M. Bednenko, Yelyzaveta Boiko

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Micromycetes from Aspergillus genus can produce proteases capable of promoting proteolysis of hemostasis proteins or, along with hydrolytic activity, to show the ability to convert proenzymes of this system activating them into an active form. At the same time, practical medicine needs specific activators for quantitation of the level of some plasma enzymes, especially protein C and factor X, the lack of which leads to the development of thromboembolic diseases. Thus, some micromycetes of the genus Aspergillus were screened for the ability to synthesize extracellular proteases with promising activity for designing anti-thrombotic and diagnostic preparations. Such standard methods like salting out, electrophoresis, isoelectrofocusing were used for isolation, purification and study of physicochemical properties of proteases. Enzyme activity was measured spectrophotometrically fibrin as a substrate of the reaction and chromogenic peptide substrates of different proteases of the human hemostasis system. As a result of the screening, four active producers were selected: Aspergillus janus 301, A. flavus 1, A. terreus 2, and A. ochraceus L-1. The enzyme of A. janus 301 showed the greatest fibrinolytic activity (around 329.2 μmol Tyr/(ml × min)). The protease produced by A. terreus 2 had the highest plasmin-like activity (54.1 nmol pNA/(ml × min)), but fibrinolytic activity was lower than A. janus 301 demonstrated (25.2 μmol Tyr/(ml × min)). For extracellular protease of micromycete A. flavus a high plasmin-like activity was also shown (39.8 nmol pNA / (ml × min)). Moreover, according to our results proteases one of the fungi - A. terreus 2 were able to activate protein C of human plasma - the key factor of the human anticoagulant hemostasis system. This type of activity was 39.8 nmol pNA/(ml × min)). It was also shown that A. ochraceus L-1 could produce extracellular proteases with protein C and factor X activator activities (65.9 nmol pNA/(ml × min) and 34.6 nmol pNA/(ml × min) respectively). The maximum accumulation of the proteases falls on the 4th day of cultivation. Using isoelectrofocusing was demonstrated that the activation of both proenzymes might proceed via limited proteolysis induced by proteases of A. ochraceus L-1. The activatory activity of A. ochraceus L-1 proteases toward essential hemostatic proenzymes, protein C and X factor may be useful for practical needs. It is well known that similar enzymes, activators of protein C and X factor isolated from snake venom, South American copperhead Agkistrodon contortrix contortrix and Russell’s viper Daboia russelli russeli, respectively, are used for the in vitro diagnostics of the functional state of these proteins in blood plasma. Thus, the proteases of Aspergillus genus can be used as cheap components for enzyme thrombolytic preparations.

Keywords: anti-trombotic drugs, fibrinolysis, diagnostics, proteases, micromycetes

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Authors: Aneek Kuila, Yaron Paz

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MIP 177 LT and HT are two-phase transformable metal organic frameworks consisting of a Ti12O15 oxocluster and a tetracarboxylate ligand that exhibits robust chemical stability and improved photoactivity. LT to HT only shows the changes in dimensionality from 0D to 1D without any change in the overall chemical structure. In terms of chemical and photoactivity MIP 177 LT is found to perform better than the MIP 177HT. Step-scan Fourier transform absorption difference time-resolved spectroscopy has been used to collect mid-IR time-resolved infrared spectra of the transient electronic excited states of a nano-porous metal–organic framework MIP 177-LT and HT with 2.5 ns time resolution. Analyzing the time-resolved vibrational data after 355nm LASER excitation reveals the presence of the temporal changes of ν (O-Ti-O) of Ti-O metal cluster and ν (-COO) of the ligand concluding the fact that these moieties are the ultimate acceptors of the excited charges which are localized over those regions on the nanosecond timescale. A direct negative correlation between the differential absorbance (Δ Absorbance) reveals the charge transfer relation among these two moieties. A longer-lived transient signal up to 180ns for MIP 177 LT compared to the 100 ns of MIP 177 HT shows the extended lifetime of the reactive charges over the surface that exerts in their effectivity. An ultrafast change of bidentate to monodentate bridging in the -COO-Ti-O ligand-metal coordination environment was observed after the photoexcitation of MIP 177 LT which remains and lives with for seconds after photoexcitation is halted. This phenomenon is very unique to MIP 177 LT but not observed with HT. This in-situ change in the coordination denticity during the photoexcitation was not observed previously which can rationalize the reason behind the ability of MIP 177 LT to accumulate electrons during continuous photoexcitation leading to a superior photocatalytic activity.

Keywords: time resolved FTIR, metal organic framework, denticity, photoacatalysis

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Authors: Simone F. Medeiros, Isabela F. Santos, Rodolfo M. Moraes, Jaspreet K. Kular, Marcus A. Johns, Ram Sharma, Amilton M. Santos

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Tissue engineering aims to develop alternatives to treat damaged tissues by promoting their regeneration. Its basic principle is to place cells on a scaffold capable of promoting cell functions, and for this purpose, polymeric nanoparticles have been successfully used due to the ability of some macro chains to mimic the extracellular matrix and influence cell functions. In general, nanoparticles require surface chemical modification to achieve cell adhesion, and recent advances in their synthesis include methods for modifying the ligand density and distribution onto nanoparticles surface. However, this work reports the development of biodegradable polymeric nanoparticles capable of promoting cellular adhesion without any surface chemical modification by ligands. Biocompatible and biodegradable nanoparticles based on poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) were synthesized by solvent evaporation method. The produced nanoparticles were small in size (85 and 125 nm) and colloidally stable against time in aqueous solution. Morphology evaluation showed their spherical shape with small polydispersity. Human osteoblast-like cells (MG63) were cultured in the presence of PHBHV nanoparticles, and growth kinetics were compared to those grown on tissue culture polystyrene (TCPS). Cell attachment on non-tissue culture polystyrene (non-TCPS) pre-coated with nanoparticles was assessed and compared to attachment on TCPS. These findings reveal the potential of PHBHV nanoparticles for cell adhesion and growth, without requiring a matrix ligand to support cells, to be used as scaffolds, in tissue engineering applications.

Keywords: tissue engineering, PHBHV, stem cells, cellular attachment

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Authors: Mukunda Upreti, Jill Storry, Rafael Björk, Emilie Louvet, Johan Normark, Sven Bergström

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Borrelia duttonii and most other relapsing fever species are Gram-negative bacteria which cause a blood borne infection characterized by the binding of bacterium to erythrocytes. The bacteria associate with two or more erythrocytes to form clusters of cells into rosettes. Rosetting is a major virulence factor and the mechanism is believed to facilitate persistence of bacteria in the circulatory system and the avoidance of host immune cells through masking or steric hindrance effects. However, the molecular mechanisms of rosette formation are still poorly understood. This study aims at determining the molecules involved in the rosette formation phenomenon. Fractionated serum, using different affinity purification methods, was investigated as a rosetting agent and IgG and at least one other serum components were needed for rosettes to form. An IgG titration curve demonstrated that IgG alone is not enough to restore rosette formation level to the level whole serum gives. IgG hydrolysis by IdeS ( Immunoglobulin G-degrading enzyme of Streptococcus pyogenes) and deglycosylation using N-Glycanase proved that the whole IgG molecule regardless of saccharide moieties is critical for Borrelia induced rosetting. Complement components C3 and C4 were also important serum molecules necessary to maintain optimum rosetting rates. The deactivation of complement network and serum depletion with C3 and C4 significantly reduced the rosette formation rate. The dependency of IgG and complement components also implied involvement of the complement receptor (CR1). Rosette formation test with Knops null RBC and sCR1 confirmed that CR1 is also part of Borrelia induced rosette formation.

Keywords: complement components C3 and C4, complement receptor 1, Immunoglobulin G, Knops null, Rosetting

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Authors: Youjeong Hwang

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Purpose: Insulin-like growth factor-I (IGF-I) promotes B-cell development, immunoglobulin formation, and interleukin-6 (IL-6) production, then regulate the immune response and inflammation. As IGF-I and their receptor also exist in the periodontal tissue, they may affect the immune response caused by periodontal pathogens in aggressive periodontitis (AgP) patients. The function of IGF is regulated by IGF binding proteins (IGFBPs), and IGFBP-3 is known to most abundant in plasma. The aim of the present study was to assess the concentration of IGF-I and IGFBP-3 in plasma and gingival crevicular fluid (GCF) in AgP patients and to find out their association. Methods: Nine patients with AgP (test group) and nine healthy subjects (control group) were included in this study. None of the subjects had a history of systemic disease, smoking or steroids medication. GCF samples were collected by microcapillary pipettes and plasma samples were obtained by venipuncture. Probing pocket depth (PD), clinical attachment level (CAL) and bleeding on probing (BOP) were recorded. Samples were assayed for IGF-I and IGFBP-3 levels using ELISA. Results: Mean IGF-I level in GCF was higher in the test group than control. Mean IGF-I level in plasma and IGFBP-3 level in GCF and plasma in control group were higher than that of the test group. However, there was no statistical significance (p > 0.05). The mean level of IGF-I and IGFBP-3 in GCF was lower than those in plasma. Mean IGF-I level in plasma showed a negative correlation with PD and CAL (p < 0.05) in both groups. The levels of IGF-I and IGFBP-3 in GCF seemed to be negatively correlated with BOP in the test group (p < 0.05). Conclusions: The difference in the level of IGF-I and IGFBP-3 between AgP and healthy subjects was not significant. Further studies that explain the mechanism of the protective role of IGF-I with more samples are needed.

Keywords: aggressive periodontitis, pathogenesis, insulin-like growth factor, insulin-like growth factor binding protein

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Authors: Csilla Dudás, Éva Böszörményi, Bence Kutus, István Pálinkó, Pál Sipos

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In this study the behavior of alpha-D-isosaccharinate (2-hydroxymethyl-3-deoxy-D-erythro-pentonate, ISA−) in alkaline medium in the presence of calcium was studied. At first the Ca–ISA system was studied by Ca-ion selective electrode (Ca-ISE) in neutral medium at T = 25 °C and I = 1 M NaCl to determine the formation constant of the CaISA+ monocomplex, which was found to be logK = 1.01 ± 0.01 for the reaction of Ca2+ + ISA– = CaISA+. In alkaline medium pH potentiometric titrations were carried out to determine the composition and stability constant of the complex(es) formed. It was found that in these systems above pH = 12.5 the predominant species is the CaISAOH complex. Its formation constant was found to be logK = 3.04 ± 0.05 for the reaction of Ca2+ + ISA– + H2O = CaISAOH + H+ at T = 25 °C and I = 1 M NaCl. Solubility measurements resulted in data consistent with those of the potentiometric titrations. Temperature dependent NMR spectra showed that the slow exchange range between the complex and the free ligand is below 5 °C. It was also showed that ISA– acts as a multidentate ligand forming macrochelate Ca-complexes. The structure of the complexes was determined by using ab initio quantum chemical calculations.

Keywords: Ca-ISE potentiometry, calcium complexes, isosaccharinate ion, NMR spectroscopy, pH potentiometry

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Authors: Kai Chun Yang, Shao-Wen Chen, Jong-Rong Wang, Chunkuan Shih, Jung-Hua Yang, Hsiung-Chih Chen, Wen-Sheng Hsu

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In this study, we build RADionuclide Transport, Removal And Dose Estimation/Symbolic Nuclear Analysis Package (SNAP/RADTRAD) model of Kuosheng Nuclear Power Plant which is based on the Final Safety Evaluation Report (FSAR) and other data of Kuosheng Nuclear Power Plant. It is used to estimate the radiation dose of the Exclusion Area Boundary (EAB), the Low Population Zone (LPZ), and the control room following ‘release from the containment’ case in Loss Of Coolant Accident (LOCA). The RADTRAD analysis result shows that the evaluation dose at EAB, LPZ, and the control room are close to the FSAR data, and all of the doses are lower than the regulatory limits. At last, we do a sensitivity analysis and observe that the evaluation doses increase as the intake rate of the control room increases.

Keywords: RADTRAD, radionuclide transport, removal and dose estimation, snap, symbolic nuclear analysis package, boiling water reactor, NPP, kuosheng

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Authors: Hendrik Bernard Van Der Walt, Frik Van Niekerk

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Heterogeneous thorium-based fuels have been proposed as an alternative for conventional reactor fuels and many studies have shown promising results. Fuel cycle characteristics still have to be explored in detail. This study investigates the use of a novel thorium-based fuel design aimed at increasing fuel cycle length of a typical PWR with an explicit focus on thorium- uranium content, neutron spectrum, flux considerations and neutron economy.As nuclear reactions are highly dependent on reactor flux and material matrix, analytical and numerical calculations have been completed to predict the behaviour of the proposed nuclear fuel. The proposed design utilizes various ratios of thorium oxide and uranium oxide pellets within fuel pins, divided into heterogeneous sections of specified length. This design renders multiple regions with unique characteristics. The goal of this study is to determine and optimally utilize these characteristics. Proliferation considerations result in the need for denaturing of heterogeneous regions, which renders more unique characteristics, these aspects were examined in this study. Finally, the use of fertile thorium to emulate a burnable poison for managing excess BOL reactivity has been investigated, as well as an option for flux shaping in a typical PWR.

Keywords: nuclear fuel, nuclear characteristics, nuclear fuel cycle, thorium-based fuel, heterogeneous design

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Authors: Md. Samsuddin Ansari, Ashish Arora

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Every year 10 million people fall ill with one of the oldest diseases known as tuberculosis, caused by Mycobacterium tuberculosis. The success of M. tuberculosis as a pathogen is because of its ability to persist in host tissues. Multidrug resistance (MDR) mycobacteria cases increase every day, which is associated with efflux pumps controlled at the level of transcription. The transcription regulators of MDR transporters in bacteria belong to one of the following four regulatory protein families: AraC, MarR, MerR, and TetR. Phenolic acid decarboxylase repressor (PadR), like a family of transcription regulators, is closely related to the MarR family. Phenolic acid decarboxylase repressor (PadR) was first identified as a transcription factor involved in the regulation of phenolic acid stress response in various microorganisms (including Mycobacterium tuberculosis H37Rv). Recently research has shown that the PadR family transcription factors are global, multifunction transcription regulators. Rv0047c is a PadR subfamily-1 protein. We are exploring the biophysical and structural characterization of Rv0047c. The Rv0047 gene was amplified by PCR using the primers containing EcoRI and HindIII restriction enzyme sites cloned in pET-NH6 vector and overexpressed in DH5α and BL21 (λDE3) cells of E. coli following purification with Ni2+-NTA column and size exclusion chromatography. We did DSC to know the thermal stability; the Tm (transition temperature) of protein is 55.29ºC, and ΔH (enthalpy change) of 6.92 kcal/mol. Circular dichroism to know the secondary structure and conformation and fluorescence spectroscopy for tertiary structure study of protein. To understand the effect of pH on the structure, function, and stability of Rv0047c we employed spectroscopy techniques such as circular dichroism, fluorescence, and absorbance measurements in a wide range of pH (from pH-2.0 to pH-12). At low and high pH, it shows drastic changes in the secondary and tertiary structure of the protein. EMSA studies showed the specific binding of Rv0047c with its own 30-bp promoter region. To determine the effect of complex formation on the secondary structure of Rv0047c, we examined the CD spectra of the complex of Rv0047c with promoter DNA of rv0047. The functional role of Rv0047c was characterized by over-expressing the Rv0047c gene under the control of hsp60 promoter in Mycobacterium tuberculosis H37Rv. We have predicted the three-dimensional structure of Rv0047c using the Swiss Model and Modeller, with validity checked by the Ramachandra plot. We did molecular docking of Rv0047c with dnaA, through PatchDock following refinement through FireDock. Through this, it is possible to easily identify the binding hot-stop of the receptor molecule with that of the ligand, the nature of the interface itself, and the conformational change undergone by the protein pattern. We are using X-crystallography to unravel the structure of Rv0047c. Overall the studies show that Rv0047c may have transcription regulation along with providing an insight into the activity of Rv0047c in the pH range of subcellular environment and helps to understand the protein-protein interaction, a novel target to kill dormant bacteria and potential strategy for tuberculosis control.

Keywords: mycobacterium tuberculosis, phenolic acid decarboxylase repressor, Rv0047c, Circular dichroism, fluorescence spectroscopy, docking, protein-protein interaction

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Authors: Jumanah S. Alawfi

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Polycystic ovary syndrome (PCOS) is a common endocrinopathy among females in their reproductive years. The incidence cases are nearly 1.55 million among females across the globe, with 0.43 million associated disability-adjusted life-years (DALYs). This syndrome is associated with intricate mechanisms typically characterized by insulin resistance (IR), infertility, overweight and/or obesity. Lifestyle interventions are often prescribed as an adjective treatment. Nonetheless, obesity is a complex disease that encompasses multiple dimensions, such as excessive energy intake and genetics. The melanocortin 4 receptor mutation (MC4R) is an important mediator in appetite. There is emerging evidence that suggests its role in the Body Mass Index (BMI) among PCOS subjects, which poses the question of obesity and/or overweight among the PCOS patients who carry the MC4R variants may be caused by overconsumption. Thereby, using other satiety techniques may be beneficial as a part of personalized nutrition. Therefore, the aim of the current mini-review is to discuss the effect of the vegan low glycemic diet on reducing appetite among PCOS patients. The review shows that there is a gap in the knowledge of the effect of the vegan diet on PCOS patients who carry MC4R variants which need further research.

Keywords: polycystic ovarian syndrome (PCOS), Appetite, Melanocortin 4 Receptor Mutation (MC4R)., Obesity

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Authors: Juan Antonio Mondragon Sanchez, Ruben Santamaria

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The DNA G-quadruplex is a four-stranded DNA structure formed by stacked planes of four base paired guanines (G-quartet). Guanine rich DNA sequences appear in many sites of genomic DNA and can potential form G-quadruplexes, such as those occurring at 3'-terminus of the human telomeric DNA. The formation and stabilization of a G-quadruplex by small ligands at the telomeric region can inhibit the telomerase activity. In turn, the ligands can be used to down regulate oncogene expression making G-quadruplex an attractive target for anticancer therapy. Many G-quadruplex ligands have been proposed with a planar core to facilitate the pi–pi stacking and electrostatic interactions with the G-quartets. However, many drug candidates are impossibilitated to discriminate a G-quadruplex from a double helix DNA structure. In this context, it is important to investigate the site topology for the interaction of a G-quadruplex with a ligand. In this work, we determine the free energy surface of a G-quadruplex-ligand to study the binding modes of the G-quadruplex (TG4T) with the daunomycin (DM) drug. The complex TG4T-DM is studied using classical molecular dynamics in combination with metadynamics simulations. The metadynamics simulations permit an enhanced sampling of the conformational space with a modest computational cost and obtain free energy surfaces in terms of the collective variables (CV). The free energy surfaces of TG4T-DM exhibit other local minima, indicating the presence of additional binding modes of daunomycin that are not observed in short MD simulations without the metadynamics approach. The results are compared with similar calculations on a different structure (the mutated mu-G4T-DM where the 5' thymines on TG4T-DM have been deleted). The results should be of help to design new G-quadruplex drugs, and understand the differences in the recognition topology sites of the duplex and quadruplex DNA structures in their interaction with ligands.

Keywords: g-quadruplex, cancer, molecular dynamics, metadynamics

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Authors: Noura Kichou, Manel Tafergguenit, Nabila Ghechtouli, Zakia Hank

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The aim of this work is to synthesize, characterize and evaluate the biological activity of two Ligands : glyoxime and dimethylglyoxime, and their metal Ni(II) chelates. The newly chelates were characterized by elemental analysis, IR, EPR, nuclear magnetic resonances (1H and 13C), and biological activity. The antibacterial and antifungal activities of the ligands and its metal complexes were screened against bacterial species (Staphylococcus aureus, Bacillus subtilis, and Escherichia coli) and fungi (Candida albicans). Ampicillin and amphotericin were used as references for antibacterial and antifungal studies. The activity data show that the metal complexes have a promising biological activity comparable with parent free ligand against bacterial and fungal species. A structural, energetic, and electronic theoretical study was carried out using the DFT method, with the functional B3LYP and the gaussian program 09. A complete optimization of geometries was made, followed by a calculation of the frequencies of the normal modes of vibration. The UV spectrum was also interpreted. The theoretical results were compared with the experimental data.

Keywords: glyoxime, dimetylglyoxime, nickel, antibacterial activity

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Authors: Noura Kichou, Manel Tafergguenit, Nabila Ghechtouli, Zakia Hank

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The aim of this work is to synthesize, characterize and evaluate the biological activity of two Ligands: glyoxime and dimethylglyoxime, and their metal Ni(II) chelates. The newly chelates were characterized by elemental analysis, IR, EPR, nuclear magnetic resonances (1H and 13C), and biological activity. The antibacterial and antifungal activities of the ligands and its metal complexes were screened against bacterial species (Staphylococcus aureus, Bacillus subtilis, and Escherichia coli) and fungi (Candida albicans). Ampicillin and amphotericin were used as references for antibacterial and antifungal studies. The activity data show that the metal complexes have a promising biological activity comparable with parent free ligand against bacterial and fungal species. A structural, energetic, and electronic theoretical study was carried out using the DFT method, with the functional B3LYP and the gaussian program 09. A complete optimization of geometries was made, followed by a calculation of the frequencies of the normal modes of vibration. The UV spectrum was also interpreted. The theoretical results were compared with the experimental data.

Keywords: glyoxime, dimetylglyoxime, nickel, antibacterial activity

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Authors: Surapong Vongvatcharanon, Fardeela Binalee, Wandee Udomuksorn, Ekkasit Kumarnsit, Uraporn Vongvatcharanon

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Hypogonadism is characterized by a decline in sex hormone levels, especially testosterone. It has been shown to be an important contributor to the decrease in muscle mass, muscle strength and performance, a condition known as sarcopenia. Preparations from Butea superba Roxb. (red Kwao Krua) have been reported to have androgenic properties. The active compounds are proposed to be flavonoids and flavonoid glycosides. Treatment with B. superba has been shown to improve erectile dysfunction in males. Parvalbumin (PV) is a relaxing factor and identified in fast twitch fibers. Alterations of the PV levels affects skeletal muscle functions. This study aimed to investigate the effects of orhchidectomy, testosterone replacement and different doses of Butea superba Roxb. on the structure, performance, levels of parvalbumin, parvalbumin and androgen receptor immunoreactivities in the extensor digitorum longus (EDL) and gastrocnemius muscles of orchidectomized rats. Twelve-week old male Wistar rats were randomly divided into 6 groups; sham-operated (SHAM), orchidectomized (BS-0), orchidectomized group that was treated with testosterone replacement of 6 µg/kg (TP) or an orchidectomized group that was treated with various doses of an extract from Butea superba Roxb.; 5 mg/kg (BS-5), 50 mg/kg (BS-50) and 500 mg/kg (BS-500) all for 90 days. The testosterone level, epididymis, seminal vesicle, prostate gland, vas deference weight, muscle fiber size, strength and endurance in both the EDL and gastrocnemius muscle were decreased in the BS-0 group but increased in the testosterone replacement group. Treatment with the B. superba Roxb. extract replacement group improved muscle fiber size, strength and endurance, but not total testosterone levels, or the epididymis, seminal vesicle, prostate gland, vas deference weight. Furthermore, the parvalbumin level, parvalbumin and androgen receptor immunoreactivities were reduced in the BS-0 group but increased in the testosterone replacement group and the B. superba Roxb. extract groups for both the EDL and gastrocnemius muscle. This study indicated that the reduction of testosterone level led to a decrease of the androgen receptor density resulting in a decline in the muscle mass and parvalbumin levels. The decrease of parvalbumin levels affected muscle performance. Testosterone replacement increased the androgen receptor density and led to an increase of muscle mass and parvalbumin levels. The increase in the parvalbumin levels may result in an improvement of muscle performance. This may explain one mechanism of testosterone on muscle mass and strength in the testosterone dependent sarcopenia. The B. superba Roxb. extract groups also had improved muscle mass, strength and endurance, parvalbumin level, parvalbumin and androgen immunoreactivities compared to the BS-O group . Butea superba Roxb. Extracts contains a flavonoid (3, 7, 3'-Trihydroxy-4'-methoxyflavone), flavonoiglycoside (3, 3'-dihydroxy-4'-methoxyflavone-7-O-β-D-glucopyranoside) and isoflavanolignans (butesuperins A and butesuperins B) all known to inhibit the cAMP phosphodiesterase enzyme. Therefore, cAMP signaling may have adaptive effects on skeletal muscle by increasing muscle mass, strength and endurance.

Keywords: Butea superba, parvalbumin, skeletal muscle, orchidectomy

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Authors: Ananya Govindarajan

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Tetrahymena thermophila is a single-cell, eukaryotic organism that belongs to the Protozoa Kingdom. Tetrahymena thermophila is often used in signal transduction pathway studies because of its ability to model sensory input and the effects of environmental conditions such as chemicals and temperature. The recently discovered G37 chemorepellent receptor showed increased responsiveness to all chemorepellents. Investigating the mutant G37 Tetrahymena gene in various test solutions, including ferric chloride, ferrous sulfate, hydrogen peroxide, tetrazolium blue, potassium chloride, and dithiothreitol were performed to determine the role of oxidants and reducing agents with the mutant and wild-type cells (CU427) to assess the role of the receptor. Behavioral assays and recordings processed by ImageJ indicated that ferric chloride, hydrogen peroxide, and tetrazolium blue yielded little to no chemorepellent responses from G37 cells (<20% ARs). CU427 cells were over-responsive based on the mean percent of cells (>50% ARs). Reducing agents elicited chemorepellent responses from both G37 and CU427, in addition to potassium chloride. Cell responses were classified as over-responsive (>50% ARs). Dithiothreitol yielded unexpected results as G37 (37.0% ARs) and CU427 (38.1% ARs) had relatively similar responses and were only responsive and not over-responsive to the reducing agent test chemical solution. Ultimately, this indicates that the G37 receptor is more interactive with molecules that are reducing agents or non-oxidant compounds; G37 may be unable to sense and respond to oxidants effectively, further elucidating the pathways of the G37 strain and nature of this receptor. Results also indicate that the CSF most likely contained an oxidant, like ferric chloride. This research can be further applied to neuronal influences and how specific compounds may affect human neurons individually and their excitability as the responses model action potentials and membrane potential.

Keywords: tetrahymena thermophila, signal transduction, chemosensory, oxidant, reducing agent

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Authors: Mengistu G. Woldu, Hani Y. Zaki, Areeg Faggad, Badreldin E. Abdalla

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Background: Type 2 diabetes mellitus (T2DM) is a complex, degenerative, and multi-factorial disease, which is culpable for huge mortality and morbidity worldwide. Even though relatively significant numbers of studies are conducted on the genetics domain of this disease in the developed world, there is huge information gap in the sub-Saharan Africa region in general and in Eritrea in particular. Objective: The principal aim of this study was to investigate the association of common variants of the Insulin Receptor Substrate 1 (IRS1) and Transcription Factor 7-Like 2 (TCF7L2) genes with T2DM in the Eritrean population. Method: In this cross-sectional case control study 200 T2DM patients and 112 non-diabetes subjects were participated and genotyping of the IRS1 (rs13431179, rs16822615, 16822644rs, rs1801123) and TCF7L2 (rs7092484) tag SNPs were carries out using PCR-RFLP method of analysis. Haplotype analyses were carried out using Plink version 1.07, and Haploview 4.2 software. Linkage disequilibrium (LD), and Hardy-Weinberg equilibrium (HWE) analyses were performed using the Plink software. All descriptive statistical data analyses were carried out using SPSS (Version-20) software. Throughout the analysis p-value ≤0.05 was considered statistically significant. Result: Significant association was found between rs13431179 SNP of the IRS1 gene and T2DM under the recessive model of inheritance (OR=9.00, 95%CI=1.17-69.07, p=0.035), and marginally significant association found in the genotypic model (OR=7.50, 95%CI=0.94-60.06, p=0.058). The rs7092484 SNP of the TCF7L2 gene also showed markedly significant association with T2DM in the recessive (OR=3.61, 95%CI=1.70-7.67, p=0.001); and allelic (OR=1.80, 95%CI=1.23-2.62, p=0.002) models. Moreover, eight haplotypes of the IRS1 gene found to have significant association withT2DM (p=0.013 to 0.049). Assessments made on the interactions of genotypes of the rs13431179 and rs7092484 SNPs with various parameters demonstrated that high density lipoprotein (HDL), low density lipoprotein (LDL), waist circumference (WC), and systolic blood pressure (SBP) are the best T2DM onset predicting models. Furthermore, genotypes of the rs7092484 SNP showed significant association with various atherogenic indexes (Atherogenic index of plasma, LDL/HDL, and CHLO/HDL); and Eritreans carrying the GG or GA genotypes were predicted to be more susceptible to cardiovascular diseases onset. Conclusions: Results of this study suggest that IRS1 (rs13431179) and TCF7L2 (rs7092484) gene polymorphisms are associated with increased risk of T2DM in Eritreans.

Keywords: IRS1, SNP, TCF7L2, type 2 diabetes

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Authors: Islam Nowisser, Noha Farag, Mohamed El Azizi

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Helicobacter pylori is a highly important human pathogen which inhabits about 50% of the population worldwide. Infection with this bacteria is very hard to treat, with high probability of recurrence. H. pylori causes severe gastric diseases, including peptic ulcer, gastritis, and gastric cancer, which has been linked to chronic inflammation. The infection has been reported to be associated with high levels of pro-inflammatory cytokines, especially IL-1β and TNF-α. The aim of the current study is to investigate the molecular mechanisms by which H. pylori activates NLRP3 inflammasome and its contribution to Il-1 β production in an innate cellular model. H. pylori PMSS1 and G27 standard strains, as well as the PMSS1 isogenic mutant strain PMSS1ΔVacA and G27ΔVacA, G27ΔCagA in addition to clinical isolates obtained from biopsy samples from the antrum and corpus mucosa of chronic gastritis patients, were used to establish infection in RAW-264.7 macrophages. The production levels of TNF-α and IL-1β was assessed using ELISA. Since expression of these cytokines is often regulated by the transcription factor complex, nuclear factor-kB (NF-kB), the activation of NF-κB in H. pylori infected cells was also evaluated by luciferase assay. Genomic DNA was extracted from bacterial cultures of H. pylori clinical isolates as well as the standard strains and their corresponding mutants, where they were evaluated for the cagA pathogenicity island and vacA expression. The correlation between these findings and expression of the cagA Pathogenicity Island and vacA in the bacteria was also investigated. The results showed IL-1β, and TNF-α production significantly increased in raw macrophages following H. pylori infection. The cagA+ and vacA+ H. pylori strains induced significant production of IL-1β compared to cagA- and vacA- strains. The activation pattern of NF-κB was correlated in the isolates to their cagA and vacA expression profiles. A similar finding could not be confirmed for TNF-α production. Our study shows the ability of H. pylori to activate NF-kB and induce significant IL-1β production as a possible mechanism for the augmented inflammatory response seen in subjects infected with cagA+ and vacA+ H. pylori strains that would lead to the progression to more severe form of the disease.

Keywords: Helicobacter pylori, IL-1β, inflammatory cytokines, nuclear factor KB, TNF-α

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Authors: Zhaoguo Liu, Cunsi Shen, Yin Lu

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Growing evidence has shown that menthol has potent anticancer activity in various human cancers. However, its effect on skin cancer remains largely unknown. In the present study, we investigated the chemopreventive potential of menthol against 7, 12-dimethylbenz[a] anthracene(DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin tumorigenesis in ICR mice. Our results showed that menthol significantly inhibited TPA-induced inflammatory responses and pro-inflammatory cytokine release. We also found that menthol treatment significantly inhibited TPA-induced lipid peroxidation (LPO), mouse UDP-glucumno-syltransferase (UGT), mouse NADH Dehydrogenase, Quinone 1 (NQO1) release. Furthermore, we found menthol treatment significantly inhibited the tumor incidence and number of tumors (P < 0.001). Interestingly, we observed that menthol treatment significantly inhibited TPA-induced altered activity of NF-κB in skin tumor. Consistently, menthol-treated tumors also showed significantly suppressed the Ras-Raf-ERK signaling pathway. Thus, our results suggest that menthol inhibits DMBA/TPA-induced skin tumorigenesis by attenuating the Ras and inhibiting NF-κB activity via inhibition of inflammation responses and pro-inflammatory cytokine release.

Keywords: DMBA/TPA, NF-κB, Ras-Raf-ERK, skin tumorigenesis

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Authors: Milica Karadzic, Lidija Jevric, Sanja Podunavac-Kuzmanovic, Strahinja Kovacevic, Sinisa Markov, Aleksandar Okljesa, Andrea Nikolic, Marija Sakac, Katarina Penov Gasi

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This study considered the microbiological activity determination and molecular docking study for selected steroid derivatives of biomedical importance. Minimal inhibitory concentration (MIC) was determined for steroid derivatives against Staphylococcus aureus using macrodilution method. Some of the investigated steroid derivatives express bacteriostatic effect against Staphylococcus aureus. Molecular docking approaches are the most widely used techniques for predicting the binding mode of a ligand. Molecular docking study was done for steroid derivatives for androgen receptor negative prostate cancer cell line (PC-3) toward Human Cytochrome P450 CYP17A1. The molecules that had the smallest experimental IC50 values confirmed their ability to dock into active place using suitable molecular docking procedure. The binding disposition of those molecules was thoroughly investigated. Microbiological analysis and molecular docking study were conducted with aim to additionally characterize selected steroid derivatives for future investigation regarding their biological activity and to estimate the binding-affinities of investigated derivatives. This article is based upon work from COST Action (TD1305), supported by COST (European Cooperation and Science and Technology).

Keywords: binding affinity, minimal inhibitory concentration, molecular docking, pc-3 cell line, staphylococcus aureus, steroids

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Authors: Ramdas Sonawane, Mahaveer Gadiya

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The control problem associated with nuclear dynamics is represented by nonlinear integro-differential equation with additive controls. To control chain reaction, certain amount of neutrons is added into (or withdrawn out of) chamber as and when required. It is not realistic. So, we can think of controlling the reactor dynamics by bilinear control, which enters the system as coefficient of state. In this paper, we study the approximate and exact controllability of parabolic integro-differential equation controlled by bilinear control with non-homogeneous boundary conditions in bounded domain. We prove the existence of control and propose an explicit control strategy.

Keywords: approximate control, exact control, bilinear control, nuclear dynamics, integro-differential equations

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Authors: Ahmed Atwa, Ashraf Hafez, Mohamed Abdelhameed, Adel Nabeeh, Mohamed Dawaba, Tamer Helmy

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Introduction and Objective: Tumour staging and grading do not usually reflect the future behavior of Wilms' tumor (WT) regarding mortality. Therefore, in this study, P53, Ki67 and cyclin A immunohistochemistry were used in a trial to predict WT cancer-specific survival (CSS). Methods: In this nonconcurrent cohort study, patients' archived data, including age at presentation, gender, history, clinical examination and radiological investigations, were retrieved then the patients were reviewed at the outpatient clinic of a tertiary care center by history-taking, clinical examination and radiological investigations to detect the oncological outcome. Cases that received preoperative chemotherapy or died due to causes other than WT were excluded. Formalin-fixed, paraffin-embedded specimens obtained from the previously preserved blocks at the pathology laboratory were taken on positively charged slides for IHC with p53, Ki67 and cyclin A. All specimens were examined by an experienced histopathologist devoted to the urological practice and blinded to the patient's clinical findings. P53 and cyclin A staining were scored as 0 (no nuclear staining),1 (<10% nuclear staining), 2 (10-50% nuclear staining) and 3 (>50% nuclear staining). Ki67 proliferation index (PI) was graded as low, borderline and high. Results: Of the 75 cases, 40 (53.3%) were males and 35 (46.7%) were females, and the median age was 36 months (2-216). With a mean follow-up of 78.6±31 months, cancer-specific mortality (CSM) occurred in 15 (20%) and 11 (14.7%) patients, respectively. Kaplan-Meier curve was used for survival analysis, and groups were compared using the Log-rank test. Multivariate logistic regression and Cox regression were not used because only one variable (cyclin A) had shown statistical significance (P=.02), whereas the other significant factor (residual tumor) had few cases. Conclusions: Cyclin A IHC should be considered as a marker for the prediction of WT CSS. Prospective studies with a larger sample size are needed.

Keywords: wilms’ tumour, nephroblastoma, urology, survival

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Authors: Soujanya Pasumarthi

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Inverse docking is a relatively new technique that has been used to identify potential receptor targets of small molecules. Our docking software package MDock is well suited for such an application as it is both computationally efficient, yet simultaneously shows adequate results in binding affinity predictions and enrichment tests. As a validation study, we present the first stage results of an inverse-docking study which seeks to identify potential direct targets of PRIMA-1. PRIMA-1 is well known for its ability to restore mutant p53's tumor suppressor function, leading to apoptosis in several types of cancer cells. For this reason, we believe that potential direct targets of PRIMA-1 identified in silico should be experimentally screened for their ability to inhibitcancer cell growth. The highest-ranked human protein of our PRIMA-1 docking results is oxidosqualene cyclase (OSC), which is part of the cholesterol synthetic pathway. The results of two followup experiments which treat OSC as a possible anti-cancer target are promising. We show that both PRIMA-1 and Ro 48-8071, a known potent OSC inhibitor, significantly reduce theviability of BT-474 breast cancer cells relative to normal mammary cells. In addition, like PRIMA-1, we find that Ro 48-8071 results in increased binding of mutant p53 to DNA in BT- 474cells (which highly express p53). For the first time, Ro 48-8071 is shown as a potent agent in killing human breast cancer cells. The potential of OSC as a new target for developing anticancer therapies is worth further investigation.

Keywords: inverse docking, in silico screening, protein-ligand interactions, molecular docking

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Authors: Denise Levy

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Nuclear technology is part of our everyday life and its beneficial applications help to improve the quality of our lives. Nevertheless, in Brazil, most often the media and social networks tend to associate radiation to nuclear weapons and major accidents, and there is still great misunderstanding about the peaceful applications of nuclear science. The Educational Portal Radioatividades (Radioactivities) is a corporate social responsibility initiative that takes advantage of the growing impact of Internet to offer high quality scientific information for teachers and students throughout Brazil. This web-based initiative focusses on the positive applications of nuclear technology, presenting the several contributions of ionizing radiation in different contexts, such as nuclear medicine, agriculture techniques, food safety and electric power generation, proving nuclear technology as part of modern life and a must to improve the quality of our lifestyle. This educational project aims to contribute for democratization of scientific education and social inclusion, approaching society to scientific knowledge, promoting critical thinking and inspiring further reflections. The website offers a wide variety of ludic activities such as curiosities, interactive exercises and short courses. Moreover, teachers are offered free web-based material with full instructions to be developed in class. Since year 2013, the project has been developed and improved according to a comprehensive study about the realistic scenario of ICTs infrastructure in Brazilian schools and in full compliance with the best e-learning national and international recommendations.

Keywords: information and communication technologies, nuclear technology, science communication, society and education

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Authors: Nicole C. Valdez, Vincent L. Borromeo, Conrad C. Chong, Ahmad F. Mazahery

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Breast cancer is the most prevalent cancer worldwide, where the majority of cases are estrogen-receptor positive and involve 2 receptor proteins. The binding of estrogen to estrogen receptor alpha (ERα) promotes breast cancer growth, while it's binding to estrogen-receptor beta (ERβ) inhibits tumor growth. While natural products have been a promising source of chemotherapeutic agents, the challenge remains in finding a bioactive compound that specifically targets cancer cells, minimizing side effects on normal cells. Flavonoids are natural products that act as phytoestrogens and induce the same response as estrogen. They are able to compete with estrogen for binding to ERα; however, it has a higher binding affinity for ERβ. Their abundance in nature and low toxicity make them a potential candidate for breast cancer treatment. This study aimed to determine which particular flavonoids can specifically recognize ERβ and potentially be used for breast cancer treatment through molecular docking. A total of 206 flavonoids comprised of 97 isoflavones and 109 flavanones were collected from ZINC15, while the 3D structures of ERβ and ERα were obtained from Protein Data Bank. These flavonoid subclasses were chosen as they bind more strongly to ERs due to their chemical structure. The structures of the flavonoid ligands were converted using Open Babel, while the estrogen receptor protein structures were prepared using Autodock MGL Tools. The optimal binding site was found using BIOVIA Discovery Studio Visualizer before docking all flavonoids on both ERβ and ERα through Autodock Vina. Genistein is a flavonoid that exhibits anticancer effects by binding to ERβ, so its binding affinity was used as a baseline. Eriodictyol and 4”,6”-Di-O-Galloylprunin both exceeded genistein’s binding affinity for ERβ and was lower than its binding affinity for ERα. Of the two, eriodictyol was pursued due to its antitumor properties on a lung cancer cell line and on glioma cells. It is able to arrest the cell cycle at the G2/M phase by inhibiting the mTOR/PI3k/Akt cascade and is able to induce apoptosis via the PI3K/Akt/NF-kB pathway. Protein pathway and gene analysis were also conducted using ChEMBL and PANTHER and it was shown that eriodictyol might induce anticancer effects through the ROS1, CA7, KMO, and KDM1A genes which are involved in cell proliferation in breast cancer, non-small cell lung cancer, and other diseases. The high binding affinity of eriodictyol to ERβ, as well as its potential affected genes and antitumor effects, therefore, make it a candidate for the development of new breast cancer treatment. Verification through in vitro experiments such as checking the upregulation and downregulation of genes through qPCR and checking cell cycle arrest using a flow cytometry assay is recommended.

Keywords: breast cancer, estrogen receptor, flavonoid, molecular docking

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Authors: Chargui Abderrahman, Nehdi Afef , BelaïD Amine , Djerbi Nadir, Tauc Michel, Hofman Paul, Mograbi Baharia, El May MichèLe

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K63-linked ubiquitination — i.e. conjugation of a chain of ubiquitins (Ub) linked through lys63 — has emerged as a key mechanism regulating signalling transduction pathways. Although critical, very little information is currently available about how subversion of K63 ubiquitination might contribute to cancers and inflammatory diseases. The present study provides the first evidence that Cadmium (Cd), a widespread environmental carcinogen and toxicant, is a powerful activator of K63 ubiquitination. Indeed, Cd induces accumulation of K63 polyUb proteins. Importantly, Cd-induced ubiquitination does not stem on oxidative damage or proteasome impairment. Rather, we demonstrate that Cd not only activates K63 ubiquitination but also amplifies their accumulation by overloading the capacity of autophagy pathway. At molecular level, Cd-induced ubiquitination is correlated with stabilization of HIF-1 and the activation of NF-B, two transcription factors. Strikingly, prolonged cell exposure to high Cd concentrations induces an exaggerated K63 ubiquitination that fosters aggresome formation, thus precluding these proteins from interacting with their downstream nuclear targets. We therefore propose that the aberrant activation of K63 ubiquitination by the carcinogen Cadmium could promote cell proliferation and inflammation at low levels while high levels committed cell to death.

Keywords: cadmium, environmental exposure, Lysine-63-ubiquitination, kidney, apoptosis, proliferation, autophagy

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