Search results for: tyrosine kinase inhibitors

Authors: Sanjay M. Tailor, Urmila H. Patel

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Phthalyl Sulfacetamide belongs to well-known member of antimicrobial sulfonamide family. It is a potent antitumor drug. Structural characteristics of 4-amino-N-(2quinoxalinyl) benzene-sulfonamides (Phthalyl Sulfacetamide), C14H12N4O2S has been studied by method of X-ray crystallography. The compound crystallizes in monoclinic space group P21/n with unit cell parameters a= 7.9841 Ǻ, b= 12.8208 Ǻ, c= 16.6607 Ǻ, α= 90˚, β= 93.23˚, γ= 90˚and Z=4. The X-ray based three-dimensional structure analysis has been carried out by direct methods and refined to an R-value of 0.0419. The crystal structure is stabilized by intermolecular N-H…N, N-H…O and π-π interactions. The Hirshfeld surfaces and consequently the fingerprint analysis have been performed to study the nature of interactions and their quantitative contributions towards the crystal packing. An analysis of Hirshfeld surfaces and fingerprint plots facilitates a comparison of intermolecular interactions, which are the key elements in building different supramolecular architectures. Docking is used for virtual screening for the prediction of the strongest binders based on various scoring functions. Docking studies are carried out on Phthalyl Sulfacetamide for better activity, which is important for the development of a new class of inhibitors.

Keywords: phthalyl sulfacetamide, crystal structure, hirshfeld surface analysis, docking

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Authors: Paras Gupta, Rohit Goyal, Yamini Chauhan, Pyare Lal Sharma

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Background: Bombax ceiba Linn., commonly called as Semal, is used in various gastro-intestinal disturbances. It contains lupeol which inhibits PTP-1B, adipogenesis, TG synthesis and accumulation of lipids in adipocytes and adipokines whereas the flavonoids isolated from B. ceiba has FAS inhibitory activity. The present study was aimed to investigate ameliorative potential of Bombax ceiba to experimental obesity in Wistar rats, and its possible mechanism of action. Methods: Male Wistar albino rats weighing 180–220 g were employed in present study. Experimental obesity was induced by feeding high fat diet for 10 weeks. Methanolic extract of B. ceiba extract 100, 200 and 400 mg/kg and Gemfibrozil 50 mg/kg as standard drug were given orally from 7th to 10th week. Results: Induction with HFD for 10 weeks caused significant (p < 0.05) increase in % body wt, BMI, LEE indices; serum glucose, triglyceride, LDL, VLDL, cholesterol, free fatty acid, ALT, AST; tissue TBARS, nitrate/nitrite levels; different fat pads and relative liver weight; and significant decrease in food intake (g and kcal), serum HDL and tissue glutathione levels in HFD control rats. Treatment with B. ceiba extract and Gemfibrozil significantly attenuated these HFD induced changes, as compared to HFD control. The effect of B. ceiba 200 and 400 mg/kg was more pronounced in comparison to Gemfibrozil. Conclusion: On the basis of results obtained, it may be concluded that the methanolic extract of stem bark of Bombax ceiba has significant ameliorative potential against HFD induced obesity in rats, possibly through modulation of FAS and PTP-1B signaling due to the presence of flavonoids and lupeol.

Keywords: obesity, Bombax ceiba, free fatty acid, protein tyrosine phosphatase-1B, fatty acid synthase

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Authors: Ram Sharma, Esha Chatterjee, Santosh Kumar Guru, Kunal Nepali

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A tractable anti-lung cancer agent was identified via the installation of a Ring C expanded synthetic analogue of the alkaloid vasicinone [7,8,9,10-tetrahydroazepino[2,1-b] quinazolin-12(6H)-one (TAZQ)] as a surface recognition part in the HDAC inhibitory three-component model. Noteworthy to mention that the candidature of TAZQ was deemed suitable for accommodation in HDAC inhibitory pharmacophore as per the results of the fragment recruitment process conducted by our laboratory. TAZQ was pinpointed through the fragment screening program as a synthetically flexible fragment endowed with some moderate cell growth inhibitory activity against the lung cancer cell lines, and it was anticipated that the use of the aforementioned fragment to generate hydroxamic acid functionality (zinc-binding motif) bearing HDAC inhibitors would boost the antitumor efficacy of TAZQ. Consistent with our aim of applying epigenetic targets to the treatment of lung cancer, a strikingly potent anti-lung cancer scaffold (compound 6) was pinpointed through a series of in-vitro experiments. Notably, the compounds manifested a magnificent activity profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80 - 0.96 µM), and the effects were found to be mediated through preferential HDAC6 inhibition (IC50 = 12.9 nM). In addition to HDAC6 inhibition, the compounds also elicited HDAC1 and HDAC3 inhibitory activity with an IC50 value of 49.9 nM and 68.5 nM, respectively. The HDAC inhibitory ability of compound 6 was also confirmed from the results of the western blot experiment that revealed its potential to decrease the expression levels of HDAC isoforms (HDAC1, HDAC3, and HDAC6). Noteworthy to mention that complete downregulation of the HDAC6 isoform was exerted by compound 6 at 0.5 and 1 µM. Moreover, in another western blot experiment, treatment with hydroxamic acid 6 led to upregulation of H3 acK9 and α-Tubulin acK40 levels, ascertaining its inhibitory activity toward both the class I HDACs and Class II B HDACs. The results of other assays were also encouraging as treatment with compound 6 led to the suppression of the colony formation ability of A549 cells, induction of apoptosis, and increase in autophagic flux. In silico studies led us to rationalize the results of the experimental assay, and some key interactions of compound 6 with the amino acid residues of HDAC isoforms were identified. In light of the impressive activity spectrum of compound 6, a pH-responsive nanocarrier (hyaluronic acid-compound 6 nanoparticles) was prepared. The dialysis bag approach was used for the assessment of the nanoparticles under both normal and acidic circumstances, and the pH-sensitive nature of hyaluronic acid-compound 6 nanoparticles was confirmed. Delightfully, the nanoformulation was devoid of cytotoxicity against the L929 mouse fibroblast cells (normal settings) and exhibited selective cytotoxicity towards the A549 lung cancer cell lines. In a nutshell, compound 6 appears to be a promising adduct, and a detailed investigation of this compound might yield a therapeutic for the treatment of lung cancer.

Keywords: HDAC inhibitors, lung cancer, scaffold, hyaluronic acid, nanoparticles

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Authors: Devasis Ghosh

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The main hindrance to total cure of cancer is a) the failure to control continued production of cancer cells, b) its sustenance and c) its metastasis. This review study has tried to address this issue of total cancer cure in a more innovative way. A 10-pronged “CRAB METHOD”, a novel holistic scientific approach of Cancer treatment has been hypothesized in this paper. Apart from available Chemotherapy, Radiotherapy and Oncosurgery, (which shall not be discussed here), seven other points of interference and treatment has been suggested, i.e. 1. Efficient stress management. 2. Dampening of ATF3 expression. 3. Selective inhibition of Platelet Activity. 4. Modulation of serotonin production, metabolism and 5HT receptor antagonism. 5. Auxin, its anti-proliferative potential and its modulation. 6. Melatonin supplementation because of its oncostatic properties. 7. HDAC Inhibitors especially valproic acid use due to its apoptotic role in many cancers. If all the above stated seven steps are thoroughly taken care of at the time of initial diagnosis of cancer along with the available treatment modalities of Chemotherapy, Radiotherapy and Oncosurgery, then perhaps, the morbidity and mortality rate of cancer may be greatly reduced.

Keywords: ATF3 dampening, auxin modulation, cancer, platelet activation, serotonin, stress, valproic acid

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Authors: Disaphon Boobpachat, Nuttaset Manimmanakorn, Apiwan Manimmanakorn, Worrawut Thuwakum, Michael J. Hamlin

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Objectives: To evaluate effect of kinesio tape compared to placebo tape and static stretching on recovery of anaerobic power and maximal oxygen uptake (Vo₂max) after intensive exercise. Methods: Thirty nine untrained healthy volunteers were randomized to 3 groups for each intervention: elastic tape, placebo tape and stretching. The participants performed intensive exercise on the dominant quadriceps by using isokinetic dynamometry machine. The recovery process was evaluated by creatine kinase (CK), pressure pain threshold (PPT), muscle soreness scale (MSS), maximum voluntary contraction (MVC), jump height, anaerobic power and Vo₂max at baseline, immediately post-exercise and post-exercise day 1, 2, 3 and 7. Results: The kinesio tape, placebo tape and stretching groups had significant changes of PPT, MVC, jump height at immediately post-exercise compared to baseline (p < 0.05), and changes of MSS, CK, anaerobic power and Vo₂max at day 1 post-exercise compared to baseline (p < 0.05). There was no significant difference of those outcomes among three groups. Additionally, all experimental groups had little effects on anaerobic power and Vo₂max compared to baseline and compared among three groups (p > 0.05). Conclusion: Kinesio tape and stretching did not improve recovery of anaerobic power and Vo₂max after eccentric exercise compared to placebo tape.

Keywords: stretching, eccentric exercise, Wingate test, muscle soreness

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Authors: Murat Emre, Zeynep Tufekcioglu

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Objective: We describe a patient with late onset phenylketonuria which presented with rapidly progressive dementia and parkinsonism that were reversible after management. Background: Phenylketonuria is an autosomal recessive disorder due to mutations in the phenylalanine hydroxlase gene. It normally presents in childhood, in rare cases, however, it may have its onset in adulthood and may mimic other neurological disorders. Case description: A previously normal functioning, 59 year old man was admitted for blurred vision, cognitive impairment and gait difficulty which emerged over the past eight months. In neurological examination he had brisk reflexes, slow gait and left-dominant parkinsonism. Mini-mental state examination score was 25/30, neuropsychological testing revealed a dysexecutive syndrome with constructional apraxia and simultanagnosia. In cranial MRI there were bilateral diffuse hyper-intense lesions in parietal and occipital white matter with no significant atrophy. Electroencephalography showed diffuse slowing with predominance of teta waves. In cerebrospinal fluid examination protein level was slightly elevated (61mg/dL), oligoclonal bands were negative. Electromyography was normal. Routine laboratory examinations for rapidly progressive dementia and parkinsonism were also normal. Serum amino acid levels were determined to explore metabolic leukodystrophies and phenylalanine level was found to be highly elevated (1075 µmol/L) with normal tyrosine (61,20 µmol/L). His cognitive impairment and parkinsonian symptoms improved following three months of phenylalanine restricted diet. Conclusions: Late onset phenylketonuria is a rare, potentially reversible cause of rapidly progressive parkinsonism with dementia. It should be considered in the differential diagnosis of patients with suspicious features.

Keywords: dementia, neurology, Phenylketonuria, rapidly progressive parkinsonism

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Authors: P. J. Sweeney, T. Ahtoniemi, J. Puoliväli, T. Laitinen, K.Lehtimäki, A. Nurmi, D. Wells

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Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscle wasting disease for which there are currently no treatment that effectively prevents the muscle necrosis and progressive muscle loss. DMD is among the most common of inherited diseases affecting around 1/3500 live male births. MDX (X-linked muscular dystrophy) mice only partially encapsulate the disease in humans and display weakness in muscles, muscle damage and edema during a period deemed the “critical period” when these mice go through cycles of muscular degeneration and regeneration. Although the MDX mutant mouse model has been extensively studied as a model for DMD, to-date an extensive temporal, non-invasive imaging profile that utilizes magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (1H-MRS) has not been performed.. In addition, longitudinal imaging characterization has not coincided with attempts to exacerbate the progressive muscle damage by exercise. In this study we employed an 11.7 T small animal MRI in order to characterize the MRI and MRS profile of MDX mice longitudinally during a 12 month period during which MDX mice were subjected to exercise. Male mutant MDX mice (n=15) and male wild-type mice (n=15) were subjected to a chronic exercise regime of treadmill walking (30 min/ session) bi-weekly over the whole 12 month follow-up period. Mouse gastrocnemius and tibialis anterior muscles were profiled with baseline T2-MRI and 1H-MRS at 6 weeks of age. Imaging and spectroscopy was repeated again at 3 months, 6 months, 9 months and 12 months of age. Plasma creatine kinase (CK) level measurements were coincided with time-points for T2-MRI and 1H-MRS, but also after the “critical period” at 10 weeks of age. The results obtained from this study indicate that chronic exercise extends dystrophic phenotype of MDX mice as evidenced by T2-MRI and1H-MRS. T2-MRI revealed extent and location of the muscle damage in gastrocnemius and tibialis anterior muscles as hyperintensities (lesions and edema) in exercised MDX mice over follow-up period.. The magnitude of the muscle damage remained stable over time in exercised mice. No evident fat infiltration or cumulation to the muscle tissues was seen at any time-point in exercised MDX mice. Creatine, choline and taurine levels evaluated by 1H-MRS from the same muscles were found significantly decreased in each time-point, Extramyocellular (EMCL) and intramyocellular lipids (IMCL) did not change in exercised mice supporting the findings from anatomical T2-MRI scans for fat content. Creatine kinase levels were found to be significantly higher in exercised MDX mice during the follow-up period and importantly CK levels remained stable over the whole follow-up period. Taken together, we have described here longitudinal prophile for muscle damage and muscle metabolic changes in MDX mice subjected to chronic exercised. The extent of the muscle damage by T2-MRI was found to be stable through the follow-up period in muscles examined. In addition, metabolic profile, especially creatine, choline and taurine levels in muscles, was found to be sustained between time-points. The anatomical muscle damage evaluated by T2-MRI was supported by plasma CK levels which remained stable over the follow-up period. These findings show that non-invasive imaging and spectroscopy can be used effectively to evaluate chronic muscle pathology. These techniques can be also used to evaluate the effect of various manipulations, like here exercise, on the phenotype of the mice. Many of the findings we present here are translatable to clinical disease, such as decreased creatine, choline and taurine levels in muscles. Imaging by T2-MRI and 1H-MRS also revealed that fat content or extramyocellar and intramyocellular lipids, respectively, are not changed in MDX mice, which is in contrast to clinical manifestation of the Duchenne’s muscle dystrophy. Findings show that non-invasive imaging can be used to characterize the phenotype of a MDX model and its translatability to clinical disease, and to study events that have traditionally been not examined, like here rigorous exercise related sustained muscle damage after the “critical period”. The ability for this model to display sustained damage beyond the spontaneous “critical period“ and in turn to study drug effects on this extended phenotype will increase the value of the MDX mouse model as a tool to study therapies and treatments aimed at DMD and associated diseases.

Keywords: 1H-MRS, MRI, muscular dystrophy, mouse model

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Authors: Aida Kalantari, Boyang Ji, Tao Chen, Ivan Mijakovic

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3-hydroxypropanoic acid (3-HP) is one of the most important biomass-derivable platform chemicals that can be converted into a number of industrially important compounds. There have been several attempts at production of 3-HP from renewable sources in cell factories, focusing mainly on Escherichia coli, Klebsiella pneumoniae, and Saccharomyces cerevisiae. Despite the significant progress made in this field, commercially exploitable large-scale production of 3-HP in microbial strains has still not been achieved. In this study, we investigated the potential of Bacillus subtilis to be used as a microbial platform for bioconversion of glycerol into 3-HP. Our recombinant B. subtilis strains overexpress the two-step heterologous pathway containing glycerol dehydratase and aldehyde dehydrogenase from various backgrounds. The recombinant strains harboring the codon-optimized synthetic pathway from K. pneumoniae produced low levels of 3-HP. Since the enzymes in the heterologous pathway are sensitive to oxygen, we had to perform our experiments in micro-aerobic conditions. Under these conditions, the cell produces lactate in order to regenerate NAD+, and we found the lactate production to be in competition with the production of 3-HP. Therefore, based on the in silico predictions, we knocked out the glycerol kinase (glpk), which in combination with growth on glucose, resulted in improving the 3-HP titer to 1 g/L and the removal of lactate. Cultivation of the same strain in an enriched medium improved the 3-HP titer up to 7.6 g/L. Our findings provide the first report of successful introduction of the biosynthetic pathway for conversion of glycerol into 3-HP in B. subtilis.

Keywords: bacillus subtilis, glycerol, 3-hydroxypropanoic acid, metabolic engineering

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Authors: Christy Rosaline, Rathankar Roa, Waheeta Hopper

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Persistence of tuberculosis, emergence of multidrug-resistance and extensively drug-resistant forms of the disease, has increased the interest in developing new antitubercular drugs. Developing inhibitors for 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase from Mycobacterium tuberculosis (MtbDAH7Ps), an enzyme involved in shikimate pathway, gives a selective target for antitubercular agents. MtbDAH7Ps was screened against ZINC database, and shortlisted compounds were subjected to induce fit docking. Prime/Molecular Mechanics Generalized Born Surface Area calculation was used to validate the binding energy of ligand-protein complex. Molecular Dynamics analysis for of the lead compounds–MtbDAH7Ps complexes showed that the backbone of MtbDAH7Ps in their complexes were stable. These results suggest that the shortlisted lead compounds ZINC04097114, ZINC15163225, ZINC16857013, ZINC06275603, and ZINC05331260 could be developed into novel drug leads to inhibit DAH7Ps in Mycobacterium tuberculosis.

Keywords: MtbDAH7Ps, Mycobacterium tuberculosis, HTVS, molecular dynamics

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Authors: Jiang Xu, Daoping Wang, Qun Li, Yinghong Pan

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2,4-Epibrassinolide (EBR), which is a kind of plant hormone Brassinosteroids (BRs), is widely studied and applied in the global scale but the proteomic characteristics of EBR alleviating low temperature stress in rice seedling leaves are still not clear. In this study, seeding rice of Nipponbare were treated with EBR and distilled water, then stressed at 4℃ or 26 ℃, and analyzed by mass spectrometry analysis, verified by parallel reaction monitoring technique (PRM). The results showed that 5778 proteins were identified in total and 4834 proteins were identified with quantitative information. Among them, 401 up-regulated and 220 down-regulated proteins may be related to EBR alleviating low temperature stress in rice seedling leaves. The molecular functions of most of up-regulated proteins are RNA binding and hydrolase activity and are mainly enriched in the pathways of carbon metabolism, folic acid synthesis, and amino acid biosynthesis. The down-regulated proteins are mainly related to catalytic activity and oxidoreductase activity and are mainly enriched in the pathways of limonene and pinene degradation, riboflavin metabolism, porphyrin and chlorophyll metabolism, and other metabolic pathways. PRM validation and literature analysis showed that NADP-malic acidase, peroxidase, 3-phosphoglycerate dehydrogenase, enolase, glyceraldehyde-3- phosphate dehydrogenase and pyruvate kinase are closely related to the effect of EBR on low temperature stress. These results also suggested that BRs could relieve the effect of low temperature stress on rice seed germination in many ways.

Keywords: 2, 4-Epibrassinolid, low temperature stress, proteomic analysis, rice

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Authors: Salah A. Al-Garyani, Yousef Swesi

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Gas hydrates can be hazardous to upstream operations. On the other hand, the high gas storage capacity of hydrate may be utilized for natural gas storage and transport. Research on the promotion of hydrate formation, as related to natural gas storage and transport, has received relatively little attention. The primary objective of this study is to gain a better understanding of the effects of ionic surfactants, particularly their molecular structures and concentration, on the formation of tetrahydrofuran (THF) hydrate, which is often used as a model hydrate former for screening hydrate promoters or inhibitors. The surfactants studied were sodium n-dodecyl sulfate (SDS), sodium n-hexadecyl sulfate (SHS). Our results show that, at concentrations below the solubility limit, the induction time decreases with increasing surfactant concentration. At concentrations near or above the solubility, however, the surfactant concentration no longer has any effect on the induction time. These observations suggest that the effect of surfactant on THF hydrate formation is associated with surfactant monomers, not the formation of micelle as previously reported. The lowest induction time (141.25 ± 21 s, n = 4) was observed in a solution containing 7.5 mM SDS. The induction time decreases by a factor of three at concentrations near or above the solubility, compared to that without surfactant.

Keywords: tetrahydrofuran, hydrate, surfactant, induction time, monomers, micelle

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Authors: Suman Bala, Sunil Kamboj, Vipin Saini

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Quantitative Structure Activity Relationship (QSAR) analysis has been developed to relate antifungal activity of novel substituted 1,3,4-oxadiazole against Candida albicans and Aspergillus niger using computer assisted multiple regression analysis. The study has shown the better relationship between antifungal activities with respect to various descriptors established by multiple regression analysis. The analysis has shown statistically significant correlation with R² values 0.932 and 0.782 against Candida albicans and Aspergillus niger respectively. These derivatives were further subjected to molecular docking studies to investigate the interactions between the target compounds and amino acid residues present in the active site of glucosamine-6-phosphate synthase. All the synthesized compounds have better docking score as compared to standard fluconazole. Our results could be used for the further design as well as development of optimal and potential antifungal agents.

Keywords: 1, 3, 4-oxadiazole, QSAR, multiple linear regression, docking, glucosamine-6-phosphate synthase

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Authors: Kwanchai Ratanamanee, Pattra Ahmadi Pirshahid, Yaowaluk Khamphan, Sirinan Thubthimthad

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Obesity is a main global health problem. The obesity rated has continued to be higher and higher. It causes to serious systems, diabetes, coronary artery disease, stroke, and some types of cancer. Oristat is one of the best drugs worldwide used as a pancreatic lipase inhibitor. To develop the new therapeutic drugs from medicinal plant always explored. In this study, 24 medicinal plants were investigated for their pancreatic lipase and cholesterol esterase inhibitory effects with Fluorometer assay and oristat as a positive control. It showed that the ethanolic extract of pods of Acacia concinna (Willd.) D.C., possess pancreatic lipase and cholesterol esterase inhibitory activities of IC50 at 2.73 and 3.77 mg/ml respectively as well as oral acute toxicity of the extract (LD50) was 6,300 mg/kg body weight. The extract of A.concinna should be further investigated in animal testing. The results of pancreatic lipase and cholesterol esterase inhibitor of the extracts will lead us to utilize A.concinna for developing as obesity dietary supplement from a medicinal plant.

Keywords: Acacia concinna (Willd.) D. C., cholesterol esterase, obesity, pancreatic lipase

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Authors: Jade Edey, Andrew Bennett, Gareth Hathway

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Nuclear receptor-related 1 protein (also known as Nurr1 or NR4A2) is an orphan nuclear receptor which plays a vital role in the development, survival and maintenance of dopaminergic (DA) neurons particularly in the substantia nigra (SN). Increasing research has investigated Nurr1’s additional role within microglia and astrocytes where it has been suggested to act as a negative regulator of inflammation; potentially offering neuroprotection. Considering both DA neurodegeneration and neuroinflammation are commonly accepted constituents of Parkinson’s Disease (PD), understanding the mechanisms by which Nurr1 regulates inflammatory processes could provide an attractive therapeutic target. Nurr1 regulates inflammation via a transrepressive mechanism possibly dependent upon SUMOylation. In addition, Nurr1 can transactivate numerous genes involved in DA synthesis, such as Tyrosine Hydroxylase (TH). A C-terminal splice variant of Nurr1, Nurr-1a, has been reported in both neuronal and glial cells. However, research into its transcriptional activity is minimal. We employed in vitro methods such as SUMO-Pulldown experiments alongside Luciferase reporter assays to investigate the SUMOylation status and transactivation capabilities of Nurr1 and Nurr-1a respectively. The SUMO-Pulldown assay demonstrated Nurr-1a undergoes significantly more SUMO modification than its full-length variant. Consequently, despite having less transcriptional activation than Nurr1, Nurr1a may play a more prominent role in repression of microglial inflammation. Contrary to published literature we also identified that SUMOylation enhances transcriptional activation by Nurr1 and Nurr1a. SUMOylation-dependent increases in Nurr1 and Nurr1a transcriptional activation were only evident in neuronal SHSY5Y cells but not in HEK293 cells. This research provides novel insight into the regulation of Nurr-1a and indicates differential effects of SUMOylation dependent regulation in neuronal and inflammatory cells.

Keywords: nuclear receptors, Parkinson’s disease, inflammation, transcriptional regulation

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Authors: Aref Zribi, Sonia Ben Nasr, Sana Fendri, Mahdi Balti, Abderazzek Haddaoui

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Background: Despite their benefit, Endocrine therapies (ET) are known to have substantial adverse events (AEs) such as hot flashes, mood disorders and osteoarticular pain. ET induced alopecia(EIA) is less frequently noted by patients and is less reported in the literature. The aim of our study was to report ET alopecia characteristics and their influence on patient and treatment observance. Method: We conducted a retrospective study including luminal BC patients treated in the oncology department of the military hospital of Tunis between January 2015 and December 2020. Patients treated with previous chemotherapy-inducing alopecia were excluded. Results: 145 female patients were included. The median age was 59 years. EIA was reported in 44% of cases. Alopecia was attributed to aromatase inhibitors in 53% and tamoxifen in 21%. Severity was grade 1 in 80% and grade 2 in the remaining cases. ET discontinuation because of alopecia was noted in 6.5 % of patients. Moderate improvement of alopecia was observed with topical minoxidil and Thallium metallicum 9CH homeopathy during ET in 60% of patients. Conclusions: EIA is frequent in BC patients and should be considered to improve treatment observance and patients’ quality of life.

Keywords: endocrine therapy, alopecia, breast cancer, Tunisia

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Authors: Bert H. Jacobson, Taylor Monaghan, John Sellers

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Intense resistance-type activity generally elicits delayed onset muscle soreness (DOMS) in individuals unaccustomed to such action. DOMS is a combination of contractile tissue microtrauma, osmotic pressure changes, alteration calcium regulation, and inflammation. Elevated muscle-specific enzyme creatine kinase (CK) is a marker of striated muscle damage. Avian immunoglobulin (IgY) mediates inflammation and may thereby reduce post-exercise DOMS. Purpose: The aim of this study was to compare the effect of oral IgY and placebo (Pl) on CK, serum relevels, and perceived pain following induced DOMS. Methods: Healthy college-aged females (N=16) were randomly divided into an experimental group (IgY) and a control group (PL). CK serum levels were recorded followed by 14 days of supplementation of either IgY or Pl at the following doses: days 1-2 =4.5 g, days 3-5 =9.0 g, and days 6-14 =13.5 g. Following the 14 d, lower limb DOMS was induced using two methods of resistance training. After 48 hours, subjects reported for a second blood draw. Results: One-way ANOVA resulted in the IgY group posting significantly less (p < 0.05) serum CK than the PL group. Furthermore, the IgY group experienced significantly less post-test perceived soreness than the Pl group. Conclusion: IgY supplementation lessens muscle CK levels and perceived muscle soreness following exercise, possibly due to an anti-inflammatory effect. It was suggested that IgY may serve as a buffer for DOMS thereby allowing the participant to continue vigorous exercise without discomfort.

Keywords: muscle, soreness, damage, serum

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Authors: Gadiri Sabiha

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Introduction: Current allergy diagnostic tools using Multiplex technology have made it possible to increase the efficiency of the search for specific IgE. This opportunity is provided by the newly developed “Alex Biochip”, consisting of a panel of 282 allergens in native and molecular form, a CCD inhibitor, and the potential for detecting cross-reactive allergens. We evaluated the performance of this technology in detecting cross-reactivity in previously explored patients. Material/Method: The sera of 39 patients presenting sensitization and polysensitization profiles were explored. The search for specific IgE is carried out by the Alex ® IgE Biochip, and the results are analyzed by nature and by molecular family of allergens using specific software. Results/Discussion: The analysis gave a particular profile of cross-reactivity allergens: 33% for the Ole e1 family, 31% for NPC2, 26% for storage proteins, 20% for Tropomyosin, 10% for LTPs, 10% for Arginine Kinase and 10% for Uteroglobin CCDs were absent in all patients. The “Ole e1” allergen is responsible for a pollen-pollen cross allergy. The storage proteins found and LTP are not species-specific, causing cross-pollen-food allergy. The nDer p2 of the NPC2 family is responsible for cross-reactivity between mite species. Conclusion: The cross-reactivities responsible for mixed syndromes at diagnosis in our patients were dominated by pollen-pollen and pollen-food syndromes. They allow the identification of severity factors linked to the prognosis and the best-adapted immunotherapy.

Keywords: specific IgE, allergy, cross reactivity, molecular allergens

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Authors: T. Abohalkuma, J. Telegdi

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Preparation, characterization, and application of self-assembled monolayers (SAM) formed by fluorophosphonic and undecenyl phosphonic acids on carbon steel surfaces as anticorrosive nanocoatings were demonstrated. The anticorrosive efficacy of these SAM layers was followed by atomic force microscopy, as the change in the surface morphology caused by layer deposition and corrosion processes was monitored. The corrosion process was determined by electrochemical potentiodynamic polarization, whereas the surface wettability of the carbon steel samples was tested with the use of static and dynamic contact angle measurements. Results showed that both chemicals produced good protection against corrosion as they performed as anodic inhibitors, especially with increasing the time of layer formation, which results in a more compact molecular film. According to the atomic force microscope (AFM) images, the fluoro-phosphonic acid self-assembled molecular layer can control the general as well as the pitting corrosion, but the SAM layers of the undecenyl-phosphonic acid cannot inhibit the pitting corrosion. The AFM and the contact angle measurements confirmed the results achieved by electrochemical measurements.

Keywords: nanolayers, corrosion, phosphonic acids, coatings

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Authors: Ruth Leitch, Joanne Hughes

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This paper presents the findings of a three-year government-funded study (ILiAD) that aimed to understand the reasons for differential educational achievement within and between socially and economically deprived areas in Northern Ireland. Previous international studies have concluded that there is a positive correlation between deprivation and underachievement. Our preliminary secondary data analysis suggested that the factors involved in educational achievement within multiple deprived areas may be more complex than this, with some areas of high multiple deprivation having high levels of student attainment, whereas other less deprived areas demonstrated much lower levels of student attainment, as measured by outcomes on high stakes national tests. The study proposed that no single explanation or disparate set of explanations could easily account for the linkage between levels of deprivation and patterns of educational achievement. Using a social capital perspective that centralizes the connections within and between individuals and social networks in a community as a valuable resource for educational achievement, the ILiAD study involved a multi-level case study analysis of seven community sites in Northern Ireland, selected on the basis of religious composition (housing areas are largely segregated by religious affiliation), measures of multiple deprivation and differentials in educational achievement. The case study approach involved three (interconnecting) levels of qualitative data collection and analysis - what we have termed Micro (or community/grassroots level) understandings, Meso (or school level) explanations and Macro (or policy/structural) factors. The analysis combines a statistical mapping of factors with qualitative, in-depth data interpretation which, together, allow for deeper understandings of the dynamics and contributory factors within and between the case study sites. Thematic analysis of the qualitative data reveals both cross-cutting factors (e.g. demographic shifts and loss of community, place of the school in the community, parental capacity) and analytic case studies of explanatory factors associated with each of the community sites also permit a comparative element. Issues arising from the qualitative analysis are classified either as drivers or inhibitors of educational achievement within and between communities. Key issues that are emerging as inhibitors/drivers to attainment include: the legacy of the community conflict in Northern Ireland, not least in terms of inter-generational stress, related with substance abuse and mental health issues; differing discourses on notions of ‘community’ and ‘achievement’ within/between community sites; inter-agency and intra-agency levels of collaboration and joined-up working; relationship between the home/school/community triad and; school leadership and school ethos. At this stage, the balance of these factors can be conceptualized in terms of bonding social capital (or lack of it) within families, within schools, within each community, within agencies and also bridging social capital between the home/school/community, between different communities and between key statutory and voluntary organisations. The presentation will outline the study rationale, its methodology, present some cross-cutting findings and use an illustrative case study of the findings from a community site to underscore the importance of attending to community differences when trying to engage in research to understand and improve educational attainment for all.

Keywords: educational achievement, multiple deprivation, community case studies, social capital

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Authors: Hu-Jiang Shi, Li-Juan Zhu

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The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) in affective behaviors is a topic of debate, and the underlying mechanisms remain largely unclear. Here, we elucidate that the interaction between hippocampal neuronal nitric oxide synthase (nNOS) and carboxy-terminal PDZ ligand of nNOS (CAPON) contributes to the disruption of hippocampal excitation-inhibition (E/I) balance, which is responsible for the anxiety- and depressive-like behaviors caused by chronic stress-related 5-HT2CR signaling deficiency. In detail, activation or inhibition of 5-HT2CR by CP809101 or SB242084 modulates nNOS-CAPON interaction by influencing intracellular Ca²⁺ release. Notably, the dissociation of nNOS-CAPON abolishes SB242084-induced anxiety- and depressive-like behaviors, as well as the reduction in extracellular signal-regulated kinase (ERK)/cAMP-response element binding protein (CREB)/synapsin signaling and SNARE complex assembly. Furthermore, nNOS-CAPON blockers restore the impairments caused by SB242084, including the reduction in SNARE assembly-mediated γ-aminobutyric acid (GABA) vesicle release and a consequent shift of the E/I balance toward excitation in CA3 pyramidal neurons. Conclusively, our findings disclose the regulatory role of 5-HT2CR in anxiety- and depressive-like behaviors and highlight the hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioral consequences of 5-HT2CR inhibition.

Keywords: 5-HT2CR, anxiety, depression, nNOS-CAPON coupling, excitation-inhibition balance, neurotransmitter release

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Authors: S. Ghalem, M. Mesmoudi, I. Daoudand, H. Allali

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The nitrogen-containing bisphosphonates (N-BPs) are well established as the treatments of choice for disorders of excessive bone resorption, myeloma and bone metastases, and osteoporosis. They inhibit farnesyl pyrophosphate synthase (FFPS), a key enzyme in the mevalonate pathway, resulting in inhibition of the prenylation of small GTP-binding proteins in osteoclasts and disruption of their cytoskeleton, adhesion/spreading, and invasion of cancer cells. A very few examples for synthesis of α-amino bisphosphonates based on several amino acids are known from the literature. In the present work, esters of aminoacid react with ketophsophonate (or their analog acid or acyl) to afford the desired products, α-iminophosphonates. The reaction of imine with dimethyl phosphate in the presence of catalytic amount of I2 give ester of α-aminobisphosphonate as sole product in good yield. Finally, we used computational docking methods to predict how several α-aminobisphosphonates bind to FPPS and how R and X influence. Pamidronate, β-aminobisphosphonate already marketed, was used as reference. These results are of interest since they represent a new and simple way to sythesize α-aminobisphosphonates with a free COOH group increased by R2 functionalisable and opening up the possibility of using the molecular docking to facilitate the design of other, novel FFPS inhibitors.

Keywords: drug research, cancer, α-amino bisphosphonates, molecular docking

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Authors: Olaitan Akanji, Cleophas Loto, Patricia Popoola, Andrei Kolesnikov

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Studies involving performance of corrosion inhibitors had been identified as one of the critical research needs for improving the durability of mild steel used in various industrial applications. This paper investigates the inhibiting effect of calcium gluconate against the corrosion of mild steel in 2.5M magnesium chloride using weight loss method and linear polarization technique, calculated corrosion rates from the obtained weight loss data, potentiodynamic polarization measurements are in good agreement. Results revealed calcium gluconate has strong inhibitory effects with inhibitor efficiency increasing with increase in inhibitor concentration at ambient temperature, the efficiency of the inhibitor increased in the following order of concentrations 2%g/vol,1.5%g/vol,1%g/vol,0.5%g/vol. Further results obtained from potentiodynamics experiments had good correlation with those of the gravimetric methods, the adsorption of the inhibitor on the mild steel surface from the chloride has been found to obey Langmuir, Frumkin and Freudlich adsorption isotherm. Scanning electron microscopy (SEM) observation confirmed the existence of an absorbed protective film on the metal surface.

Keywords: calcium gluconate, corrosion, magnesium chloride, mild steel

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Authors: Sehrish Iftikhar, Ahmad Ali Shahid, Kiran Nawaz, Waheed Anwar

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Discovery and development of new compounds require intense studies in chemistry, biochemistry. Numerous experiments under laboratory-, greenhouse- and field conditions can be performed to select suitable candidates and to understand their full potential. Novel fungicides are fundamental to combat plant diseases. Fusarium solani is important plant pathogen. New broad spectrum foliar fungicides against complex II were designed in this study. Complex II, namely succinate dehydrogenase (SDH), or succinate quinone oxidoreductase (SQR) is a multi-subunit enzyme at the crossroads of TCA and ETC at the inner mitochondrial membrane. The need for new and innovative fungicides is driven by resistance management, regulatory hurdles and increasing customer expectations amongst others. Fungicidal activity was assessed for the effect on mycelial growth and spore germination of the fungi using fungicide amended media assay. In mycelial growth assay compounds C10 and C6 were highly active against all the isolates. The compounds C1 and C10 were found most potent in spore germination test. It fully proved that the SDHIs designed in this paper displayed as good inhibitory effects against Fusarium solani.

Keywords: Wilt, Fusarium, SDH, antifungal

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Authors: A. Asselah, A. Khalfi, M. A.Toumi, A.Tazerouti

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The study of the corrosion inhibition of a standard carbon steel "API 5L grade X70" by two biodegradable anionic surfactants derived from fatty acids by photo sulfochlorination, called sodium lauryl methyl ester sulfonates and sodium palmityl methyl ester sulfonates was carried. A solution at 2.5 g/l NaCl saturated with carbon dioxide is used as a corrosive medium. The gravimetric and electrochemical technics (stationary and transient) were used in order to quantify the rate of corrosion and to evaluate the electrochemical inhibition efficiency, thus the nature of the mode of action of the inhibitor, in addition to a surface characterization by scanning electron microscopy (MEB) coupled to energy dispersive X-ray spectroscopy (EDX). The variation of the concentration and the temperature were examined, and the mode of adsorption of these inhibitors on the surface of the metal was established by assigning it the appropriate isotherm and determining the corresponding thermodynamic parameters. The MEB-EDX allowed the visualization of good adhesion of the protective film formed by the surfactants to the surface of the steel. The corrosion inhibition was evaluated at around 93% for sodium lauryl methyl ester sulfonate surfactant at 20 ppm and 87.2% at 50 ppm for sodium palmityl methyl ester sulfonate surfactant.

Keywords: carbon steel, oilfield, corrosion, anionic surfactants

Procedia PDF Downloads 69

Authors: Nisrine Benzbiria, Abderrahmane Thoume, Mustapha Zertoubi

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The goal of this research is to investigate the corrosion inhibition potential of functionalized graphene oxide (GO) with oxime derivative on AA2024-T3 surface in synthetic seawater. The utilization of functionalized graphene oxide is creating a category of corrosion inhibitors known as organically modified nanomaterials. In our work, the functionalization of GO by chalcone oxime enables graphene oxide to have enhanced water solubility and a good corrosion mitigation capacity. Fourier-transform infrared (FT-IR) spectroscopy was utilized to evaluate the main functional groups of the inhibitor. Electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization curves (PDP) showed that the inhibitor acts as a mixed-type inhibitor. The inhibitory efficiency (IE) improved as the concentration increased to a value of 96% after one hour of exposure to a medium containing 60 mg/L ppm of the inhibitor. According to thermodynamic calculations, the adsorption of the inhibitor on the AA2024-T3 surface in 3% NaCl followed the Langmuir isotherm. The formation of a barrier layer was further confirmed by surface analysis. The protective film prevented the alloy dissolution and limited the accessibility of attacking ions, as evinced by solution analysis techniques.

Keywords: AA2024-T3, NaCl, electrochemical methods, FT-IR, SEM/AFM, DFT, MC simulation

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Authors: Sally Shepherd, Richard De Boer, Craig Murphy

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Background: Invasive lobular carcinoma (ILC) can metastasize to atypical sites within the peritoneal cavity, gastrointestinal, or genitourinary tract. Management varies depending on the symptom presentation, extent of disease burden, particularly if the primary disease is occult, and patient wishes. Case Series: 6 patients presented with general surgical presentations of ILC, including incomplete large bowel obstruction, cholecystitis, persistent lower abdominal pain, and faecal incontinence. 3 were diagnosed with their primary and metastatic disease in the same presentation, whilst 3 patients developed metastasis from 5 to 8 years post primary diagnosis of ILC. Management included resection of the metastasis (laparoscopic cholecystectomy), excision of the primary (mastectomy and axillary clearance), followed by a combination of aromatase inhibitors, biologic therapy, and chemotherapy. Survival post diagnosis of metastasis ranged from 3 weeks to 7 years. Conclusion: Metastatic ILC must be considered with any gastrointestinal or genitourinary symptoms in patients with a current or past history of ILC. Management may not be straightforward to chemotherapy if the acute pathology is resulting in a surgically resectable disease.

Keywords: breast cancer, gastrointestinal metastasis, invasive lobular carcinoma, metastasis

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Authors: Ali Driouiche, Abdallah Hadfi

Abstract:

During this work on scaling phenomenon observed in the irrigation water pipes in the agricultural region of Greater Agadir, a follow-up was carried out during a year of the physico-chemical quality of these waters. Sampling was conducted from 120 sampling points, well distributed in the study area and involved 120 water samples. The parameters measured for each sample are temperature, pH, conductivity, total hardness and the concentrations of the ions HCO₃₋, Ca²⁺, Mg²⁺, Na⁺, K⁺, SO₄₋, NO₃₋, Cl₋ and OH₋. Indeed, the monitoring of the physico-chemical quality shows that the total hardness varies between 20 and 65 °F and the complete alkalimetric title varies from 14 °F to 42 °F. For the kinetic study of the scaling power, an object of this work, 6 samples which have high hardness were selected from the 120 samples analyzed. This study was carried out using the controlled degassing method Laboratoire de Chimie et de Génie de l’Environnement (LCGE) where it was developed) and showed that the studied waters are calcifying. The germination time Tg varies between 16 and 34 minutes. The highlighting of new scale inhibitors to prevent the formation of scale in the pipelines of the agricultural sector of Greater Agadir will also be discussed.

Keywords: agadir, clogging pipes, localized irrigation, scaling power

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Authors: Houria Hamitouche, Abdellah Khelifa

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Quaternary ammonium salts (QACs) are the most common cationic surfactants of natural or synthetic origin usually. They possess one or more hydrophobic hydrocarbon chains and hydrophilic cationic group. In fact, the hydrophobic groups are derived from three main sources: petrochemicals, vegetable oils, and animal fats. These QACs have attracted the attention of chemists for a long time, due to their general simple synthesis and their broad application in several fields. They are important as ingredients of cosmetic products and are also used as corrosion inhibitors, in emulsion polymerization and textile processing. Within biological applications, QACs show a good antimicrobial activity and can be used as medicines, gene delivery agents or in DNA extraction methods. The 2004 worldwide annual consumption of QACs was reported as 500,000 tons. The petroleum product is considered a true reservoir of a variety of chemical species, which can be used in the synthesis of quaternary ammonium salts. The purpose of the present contribution is to synthesize the quaternary ammonium salts by Menschutkin reaction, via chloromethylation/quaternization sequences, from Algerian petroleum products namely: reformate, light naphtha and kerosene and characterize.

Keywords: quaternary ammonium salts, reformate, light naphtha, kerosene

Procedia PDF Downloads 310

Authors: L. M. Al-Harbi, A. M. Shokry, J. S. M. Sabir, A. Chaudhary, J. Manikandan, K. S. Saini

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Breast cancer is the second most common cause of cancer death worldwide and is the most common malignancy among Saudi females. During breast carcinogenesis, a wide-array of cytogenetic changes involving deletions, or amplification, or translocations, of part or whole of chromosome regions have been observed. Because of the limitations of various earlier technologies, newer tools are developed to scan for changes at the genomic level. Recently, Array Comparative Genomic Hybridization (aCGH) technique has been applied for detecting segmental genomic alterations at molecular level. In this study, aCGH was performed on twenty breast cancer tumors and their matching non-tumor (normal) counterparts using the Agilent 2x400K. Several regions were identified to be either amplified or deleted in a tumor-specific manner. Most frequent alterations were amplification of chromosome 1q, chromosome 8q, 20q, and deletions at 16q were also detected. The amplification of genetic events at 1q and 8q were further validated using FISH analysis using probes targeting 1q25 and 8q (MYC gene). The copy number changes at these loci can potentially cause a significant change in the tumor behavior, as deletions in the E-Cadherin (CDH1)-tumor suppressor gene as well as amplification of the oncogenes-Aurora Kinase A. (AURKA) and MYC could make these tumors highly metastatic. This study validates the use of aCGH in Saudi breast cancer patients and sets the foundations necessary for performing larger cohort studies searching for ethnicity-specific biomarkers and gene copy number variations.

Keywords: breast cancer, molecular biology, ecology, environment

Procedia PDF Downloads 350

Authors: Ga-Young Lee, Hyun-Man Kim

Abstract:

The modulation of the cell-cell junction is critical in epithelial-mesenchymal transition during tumorigenesis. As RhoA activity is known to be up-regulated to dissociate cell-cell junction by contracting acto-myosin complex in various cancer cells, the present study investigated if RhoA activity was also associated with the disruption of the cell-cell junction of oral cancer cells. We studied SCC-25 cells which are established from oral squamous cell carcinoma if their E-cadherin junction (ECJ) was under control of RhoA. Interestingly, development of ECJ of SCC-25 cells depended on the amount of fibronectin (FN) coated on the culture dishes. Seeded cells promptly aggregated to develop ECJ on the substrates coated with a low amount of FN, whereas they were retarded in the development of ECJ on the substrates coated with a high amount of FN. However, it was an unexpected finding that total RhoA activity was lower in the dissociated cells on the substrates of high FN than in the aggregated cells on the substrates of low FN. Treating the dissociated cells on the substrates of high FN with LPA, a RhoA activator, promoted the development to ECJ. In contrast, treating the aggregated cells on the substrates of low FN with Clostridium botulinum C3, a toxin decreasing RhoA activity, dissociated cells concomitant with the disruption of ECJ. Genetical knockdown of RhoA expression by transfecting RhoA siRNA also down-regulated the development of ECJ in SCC-25 cells. Furthermore, PMA, an activator of protein kinase C (PKC), down-regulated the development of ECJ junction of SCC-25 cells on the substrates coated with low FN. In contrast, GO6976, a PKC inhibitor, up-regulated the development of ECJ of SCC-25 cells with the activation of RhoA on the substrates coated with high FN. In conclusion, in the present study, we demonstrated unexpected results that the activation of RhoA promotes the development of ECJ, whereas the inhibition of RhoA retards the development of ECJ in SCC-25 cells.

Keywords: E-cadherin junction, oral squamous cell carcinoma, PKC, RhoA, SCC-25

Procedia PDF Downloads 308