Cancer, Carcinogens and Screening in the Kidney

This chapter examines a number of different aspects of renal cancer. Firstly, an introduction into the numerous forms of renal cancers is provided, focusing on renal cell carcinomas their causes and the different treatment options currently available. This chapter also takes a look at renal cancer from a toxicological point of view. Due to the crucial role of the kidneys in blood filtration, this allows them to become susceptible to the exposure and accumulation of potentially carcinogenic chemicals. For this reason, renal carcinogens are looked at in detail focusing on the varying mechanisms of genotoxic renal carcinogens such as aristolochic acid and potassium bromate, and their non-genotoxic renal carcinogens counterparts including ochratoxin A and chlorothalonil. This chapter also examines the different methods currently used to detect a compound’s carcinogenic potential, including the in vitro Ames test and animal based carcinogenicity screening methods

Identification of the multifaceted chemopreventive activity of curcumin against the carcinogenic potential of the food additive, KBrO3

Background: Potassium bromate (KBrO3), a food additive, has been used in many bakery products as an oxidizing agent. It has been shown to induce renal cancer in many in-vitro and in-vivo experimental models Objectives: This study evaluated the carcinogenic potential of potassium bromate (KBrO3) and the chemopreventive mechanisms of the anti-oxidant and anti-inflammatory phytochemical, curcumin against KBrO3-induced carcinogenicity Method: Lactate dehydrogenase (LDH) cytotoxicity assay and morphological characteristics were used to assess curcumin's cytoprotective potential against KBrO3 toxicity. To assess the chemopreventive potential of curcumin against KBrO3-induced oxidative insult, intracellular H2O2 and the nuclear concentration of the DNA adduct 8-OHdG were measured. PCR array, qRT-PCR, and western blot analysis were used to identify dysregulated genes by KBrO3 exposure. Furthermore, immunofluorescence was used to evaluate the ciliary loss and the disturbance of cellular tight junction induced by KBrO3. Results: Oxidative stress assays showed that KBrO3 increased the levels of intracellular H2O2 and the DNA adduct 8-OHdG. Combination of curcumin with KBrO3 efficiently reduced the level of H2O2 and 8-OHdG while up-regulating the expression of catalase. PCR array, qRT-PCR, and western blot analysis revealed that KBrO3 dysregulated multiple genes involved in inflammation, proliferation, and apoptosis, namely CTGF, IL-1, and TRAF3. Moreover, qRT-PCR and immunofluorescence studies showed that KBrO3 negatively affected the tight junctional protein (ZO-1) and induced a degeneration of primary ciliary proteins. The negative impact of KBrO3 on cilia was markedly repressed by curcumin. Conclusion: Curcumin could potentially be used as a protective agent against carcinogenicity of KBrO

Design, Synthesis And Biological Evaluation Of A Novel Bioactive Indane scaffold 2-(diphenylmethylene)c-2,3-dihydro-1H-inden-1-one with potential anticancer activity

Over the past decades, designing of privileged structures has emerged as a useful approach to the discovery and optimisation of novel biologically active molecules, and many have been successfully exploited across and within different target families. Examples include indole, quinolone, isoquinoline, benzofuran and chromone, etc. In the current study, we focus on synthesising a novel hybrid scaffold constituting naturally occurring benzophenone (14) and indanone (22) ring systems, leading to a general structure of 2-(diphenylmethylene)-2,3-dihydro-1H-inden-1-one (23). It was hypothesised this new hybrid system would provide enhanced anti-cancer activity owing to the presence of the common features associated with the tubulin binding small molecule indanocine (10) and the estrogen receptor (ER) antagonist tamoxifen (24). Key hybrid molecules were successfully synthesised and characterised, and the in vitro cytotoxicity assays were performed against cancer cell lines: MCF7 (breast) and SKBR3 (breast), DU145 (prostate) and A549 (lung). The methyl-, chloro- and methoxy-, para-substituted benzophenone hybrids displayed the greatest degree of cytotoxicity and the E-configuration derivatives 45, 47 and 49 being significantly most potent. We further verified that the second benzyl moiety of this novel hybrid scaffold is fundamental to enhance the cytotoxicity, especially in the SKBR3 (HER2+) by the E-methyl lead molecule 47, MCF7 (ER+) by 45 and 49, and A549 (NSCLC) cell lines by 49. These hybrid molecules also showed a significant accumulation of SKBR3 cells at S-phase of the cell cycle after 72 hrs, which demonstrates besides of being cytotoxic in vitro against SKBR3 cells, 47 disturbs the replication and development of this type of cancer causing a dose-dependent cell cycle arrest at S-phase. Our results suggest that DNA damage might be involved in the induction of SKBR3 cell death caused by the hybrid molecules, and therefore, this novel system may be an effective suppressor of HER2+/Neu-driven cancer growth and progression. The present study points to potential structural optimisation of the series and encourages further focussed investigation of analogues of this scaffold series toward their applications in cancer chemoprevention or chemotherapy

Mammalian cell culture for production of recombinant proteins: A review of the critical steps in their biomanufacturing

The manufacturing of recombinant protein is traditionally undertaken in mammalian cell culture. Today, speed, cost and safety are the primary considerations for process improvements in both upstream and downstream manufacturing. Leaders in the biopharmaceutical industry are striving for continuous improvements to increase throughput, lower costs and produce safer more efficacious drugs. This can be achieved through advances in cell line engineering, process development of cell culture, development of chemically defined media and increased emphasis on product characterization. In the first part, this review provides a historical perspective on approved biotherapeutics by regulatory bodies which pave the way for next-generation products (including gene therapy). In the second part, it focuses on the application of in vitro and in vivo cell line engineering approaches, modern process development improvements including continuous manufacturing, recent developments in media formulation, and improvements in critical quality attribute determinations for products produced predominantly in mammalian cells

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

The intercultural representation in french language learning by Iraqi student in academic situation in France

Cette étude examine les représentations interculturelles chez les boursiers irakiens en mobilité académique en France afin d’analyser l’influence de ces représentations sur le processus de l’apprentissage du français. Nous avons d’abord étudié le contexte culturel et d’études en Irak pour mettre à jour les repères sur lesquels sont construites ces représentations. Nous avons ensuite présenté les différentes théories de la représentation, des sciences du langage et de l’interculturalité qui ont servi de jalons dans le cheminement de l’analyse. Ces apports ont permis d’analyser les données collectées auprès des étudiants irakiens en mobilité en France par deux enquêtes différentes, l’une quantitative, l’autre qualitative. L’analyse linguistique des discours a permis la mise à jour des différentes représentations et l’évaluation des niveaux de français. Les résultats obtenus en croisant les données ont dressé un état des lieux des différents facteurs influençant l’apprentissage du français. Ces éléments ont éclairé la nature de la motivation des étudiants boursiers irakiens. Nous avons comparé ces résultats à nos hypothèses afin de voir si celles-ci sont validées. Nous avons enfin proposé des recommandations en vue d’améliorer cet apprentissage du français par les étudiants boursiers irakiens.This study examines the intercultural performances for Iraqi scholarship students in situation of mobility in France. To analyze the impact of these representations on the process of learning French language. We first studied the cultural context in Iraq to update landmarks on which are built these representations. We presented then the various theories of representation, sciences of language and intercultural which served as milestones or foundations in the process of analysis. These reports have analyzed data collected from Iraqi students in mobility in France by two surveys. One is quantitative and the other is qualitative.The linguistic analyses of discourse which we have made, update differentre presentations and evaluation of their French level. The results obtained by crossing data compiled an inventory of the various factors influencing learning French language. These have informed the nature of the motivation of Iraqi scholarship students. We compared these results with our assumptions to see if they are validated. We finally propose recommendations to improve learning of French language by Iraqi scholarship student

Curcumin Sensitises Cancerous Kidney Cells to TRAIL Induced Apoptosis via Let-7C Mediated Deregulation of Cell Cycle Proteins and Cellular Metabolism

Targeted therapies are the most attractive options in the treatment of different tumours, including kidney cancers. Such therapies have entered a golden era due to advancements in research, breakthroughs in scientific knowledge, and a better understanding of cancer therapy mechanisms, which significantly improve the survival rates and life expectancy of patients. The use of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) as an anticancer therapy has attracted the attention of the scientific community and created great excitement due to its selectivity in targeting cancerous cells with no toxic impacts on normal tissues. However, clinical studies disappointingly showed the emergence of resistance against TRAIL. This study aimed to employ curcumin to sensitise TRAIL-resistant kidney cancerous ACHN cells, as well as to gain insight into the molecular mechanisms of TRAIL sensitization. Curcumin deregulated the expression of apoptosis-regulating micro Ribonucleic Acid (miRNAs), most notably, let-7C. Transfecting ACHN cells with a let-7C antagomir significantly increased the expression of several cell cycle protein, namely beta (β)-catenin, cyclin dependent kinase (CDK)1/2/4/6 and cyclin B/D. Further, it overexpressed the expression of the two key glycolysis regulating proteins including hypoxia-inducible factor 1-alpha (HIF-1α) and pyruvate dehydrogenase kinase 1 (PDK1). Curcumin also suppressed the expression of the overexpressed proteins when added to the antagomir transfected cells. Overall, curcumin targeted ACHN cell cycle and cellular metabolism by promoting the differential expression of let-7C. To the best of our knowledge, this is the first study to mechanistically report the cancer chemosensitisation potential of curcumin in kidney cancer cells via induction of let-7C

A new lanosyl guanidine from <i>Vertebrata lanosa</i> with anti-inflammatory activity

N-Lanosyl guanidine (1), a new bromophenol containing a guanidine moiety was isolated from the red alga Vertebrata lanosa (L.) T.A. Christensen, which is frequently used for cosmetic purposes. Structure elucidation was performed by means of mass spectrometry as well as 1D and 2D NMR spectroscopy. Due to its structural features, 1 might share a common biosynthetic route with known bromophenolic ureido derivatives. Regarding potential bioactivities, 1 has shown clear anti-inflammatory properties, reducing cytokine release in lipopolysaccharide-stimulated phorbol 12-myristate 13-acetate-differentiated THP-1 macrophages. No signs of toxicity were observed, in either the cell line nor in the nematode Caenorhabditis elegans. However, 1 was inactive against the gram-negative bacterium Pseudomonas aeruginosa.</p

Curcumin Sensitizes Kidney Cancer Cells to TRAIL-Induced Apoptosis via ROS Mediated Activation of JNK-CHOP Pathway and Upregulation of DR4

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), is a selective anticancer cytokine capable of exerting a targeted therapy approach. Disappointingly, recent research has highlighted the development of TRAIL resistance in cancer cells, thus minimising its usefulness in clinical settings. However, several recent studies have demonstrated that cancer cells can be sensitised to TRAIL through the employment of a combinatorial approach, utilizing TRAIL in conjunction with other natural or synthetic anticancer agents. In the present study, the chemo-sensitising effect of curcumin on TRAIL-induced apoptosis in renal carcinoma cells (RCC) was investigated. The results indicate that exposure of kidney cancer ACHN cells to curcumin sensitised the cells to TRAIL, with the combination treatment of TRAIL and curcumin synergistically targeting the cancer cells without affecting the normal renal proximal tubular epithelial cells (RPTEC/TERT1) cells. Furthermore, this combination treatment was shown to induce caspase-dependent apoptosis, inhibition of the proteasome, induction of ROS, upregulation of death receptor 4 (DR4), alterations in mitogen-activated protein kinase (MAPK) signalling and induction of endoplasmic reticulum stress. An in vivo zebrafish embryo study demonstrated the effectiveness of the combinatorial regime to inhibit tumour formation without affecting zebrafish embryo viability or development. Overall, the results arising from this study demonstrate that curcumin has the ability to sensitise TRAIL-resistant ACHN cells to TRAIL-induced apoptosis