Hepatic effects of tartrazine (E 102) after systemic exposure are independent of oestrogen receptor interactions in the mouse

Tartrazine is a food colour that activates the transcriptional function of the human oestrogen receptor alpha in an in vitro cell model. Since oestrogens are cholestatic, we hypothesised tartrazine will cause periportal injury to the liver in vivo. To test this hypothesis, tartrazine was initially administered systemically to mice resulting in a periportal recruitment of inflammatory cells, increased serum alkaline phosphatase activity and mild periportal fibrosis. To determine whether an oestrogenic effect may be a key event in this response, tartrazine, sulphonated metabolites and a food additive contaminant were screened for their ability to interact with murine oestrogen receptors. In all cases, there were no interactions as agonists or antagonists and further, no oestrogenicity was observed with tartrazine in an in vivo uterine growth assay. To examine the relevance of the hepatic effects of tartrazine to its use as a food additive, tartrazine was orally administered to transgenic NF-κB-Luc mice. Pre- and concurrent oral treatment with alcohol was incorporated given its potential to promote gut permeability and hepatic inflammation. Tartrazine alone induced NF- κB activities in the colon and liver but there was no periportal recruitment of inflammatory cells or fibrosis. Tartrazine, its sulphonated metabolites and the contaminant inhibited sulphotransferase activities in murine hepatic S9 extracts. Given the role of sulfotransferases in bile acid excretion, the initiating event giving rise to periportal inflammation and subsequent hepatic pathology through systemic tartrazine exposure is therefore potentially associated an inhibition of bile acid sulphation and excretion and not on oestrogen receptor-mediated transcriptional function. However, these effects were restricted to systemic exposures to tartrazine and did not occur to any significant effect after oral exposure

A 3D Heterotypic Breast Cancer Model Demonstrates a Role for Mesenchymal Stem Cells in Driving a Proliferative and Invasive Phenotype

Previous indirect 2D co-culture studies have demonstrated that mesenchymal stem cells (MSCs) promote breast cancer (BC) progression through secretion of paracrine factors including growth factors, cytokines and chemokines. In order to investigate this aspect of the tumour microenvironment in a more relevant 3D co-culture model, spheroids incorporating breast cancer cells (BCCs), both cell lines and primary BCCs expanded as patient-derived xenografts, and MSCs were established. MSCs in co-cultures were shown to enhance proliferation of estrogen receptor (ER)/progesterone receptor (PR)-positive BCCs. In addition, co-culture resulted in downregulation of E-cadherin in parallel with upregulation of the epithelial-mesenchymal transition (EMT)-relation transcription factor, SNAIL. Cytoplasmic relocalization of ski-related novel protein N (SnON), a negative regulator of transforming growth factor-beta (TGF-β) signalling, and of β-catenin, involved in a number of pathways including Wnt signalling, was also observed in BCCs in co-cultures in contrast to monocultures. In addition, the β-catenin inhibitor, 3-[[(4-methylphenyl)sulfonyl]amino]-benzoic acid methyl ester (MSAB), mediated reduced growth and invasion in the co-cultures. This study highlights the potential role for SnON as a biomarker for BC invasiveness, and the importance of interactions between TGF-β and Wnt signalling, involving SnON. Such pathways may contribute towards identifying possible targets for therapeutic intervention in BC patients

The toxicity of the methylimidazolium ionic liquids, with a focus on M8OI and hepatic effects

Ionic liquids are a diverse range of charged chemicals with low volatility and often liquids at ambient temperatures. This characteristic has in part lead to them being considered environmentally-friendly replacements for existing volatile solvents. However, methylimidazolium ionic liquids are slow to break down in the environment and a recent study at Newcastle detected 1 octyl 3 methylimidazolium (M8OI) – an 8 carbon variant methylimidazolium ionic liquid - in soils in close proximity to a landfill site. The current M8OI toxicity database in cultured mammalian cells, in experimental animal studies and in model indicators of environmental impact are reviewed. Selected analytical data from the Newcastle study suggest the soils in close proximity to the landfill site, an urban soil lacking overt contamination, had variable levels of M8OI. The potential for M8OI - or a structurally related ionic liquid – to trigger primary biliary cholangitis (PBC), an autoimmune liver disease thought to be triggered by an unknown agent(s) in the environment, is reviewed

British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials

Efficacy and Safety of Elective Switching from Intravenous to Subcutaneous Infliximab [CT-P13]: A Multicentre Cohort Study

BackgroundIntravenous [IV] infliximab is a well-established therapy for inflammatory bowel diseases [IBD] patients. A subcutaneous [SC] formulation of infliximab [CT-P13] has recently been shown to be as effective as IV infliximab after two doses of IV induction in a randomised trial, but there are no data to support elective switching of patients on maintenance IV infliximab therapy. We aimed to assess the effectiveness of an elective switching programme to SC CT-P13 in patients treated with IV infliximab.MethodsPatients on established maintenance IV infliximab, who switched to SC CT-P13, were included in this retrospective multicentre cohort study. Disease activity was monitored serially with the Harvey-Bradshaw Index [HBI] for Crohn's disease [CD] and the Simple Clinical Colitis Activity Index [SCCAI] for ulcerative colitis (UC) for up to 12 months at months 3, 6, and 12. Faecal calprotectin [FC] and C-reactive protein [CRP] were recorded at baseline and follow-up, if available. Infliximab trough levels were measured prior to switch and at months 3, 6, and 12 following switch. The primary outcome measure was treatment persistence at latest follow-up. Secondary outcome measures included infliximab pharmacokinetics [PK], safety, need for corticosteroid rescue therapy, and need for surgery.ResultsWe included 181 patients, of whom 115 [63.5%] had CD. The majority [72.4%] were on 8-weekly dosing of intravenous infliximab prior to switching, and more than half [59.1%] were on concomitant immunomodulatory therapy. The majority of patients (CD: 106, 92.2%; UC: 46, 76.7%; and IBD unclassified [IBD-U]: 5, 83.3%) were in clinical remission. Treatment persistence rate was high [n = 167, 92.3%] and only 14 patients [7.7%] stopped treatment during the follow-up period. There was no significant difference between baseline and repeat measurements at 3, 6, or 12 months for HBI, SCCAI, CRP, or FC. Of the total cohort, 25 patients (13.8%) had perianal CD. Of these, only two patients [8%] had worsening of perianal CD and required antibiotic therapy and further examination under anaesthesia [EUA]. Both these patients also switched back to intravenous infliximab. Median infliximab level increased from a baseline of 8.9 µg/dl [range 0.4-16] to 16.0 µg/dl [range 2.3-16, p ConclusionsAmong patients on IV infliximab maintenance therapy switched to SC CT-P13, we observed high treatment persistence rates and low rates of immunogenicity, with no change in clinical disease activity indices or biomarkers. Infliximab levels increased after switch to SC CT-P13, and only ATI was associated with serum infliximab levels. Patient acceptance and satisfaction rates were high with SC CT-P13

Recreational and occupational field exposure to freshwater cyanobacteria – a review of anecdotal and case reports, epidemiological studies and the challenges for epidemiologic assessment

Cyanobacteria are common inhabitants of freshwater lakes and reservoirs throughout the world. Under favourable conditions, certain cyanobacteria can dominate the phytoplankton within a waterbody and form nuisance blooms. Case reports and anecdotal references dating from 1949 describe a range of illnesses associated with recreational exposure to cyanobacteria: hay fever-like symptoms, pruritic skin rashes and gastro-intestinal symptoms are most frequently reported. Some papers give convincing descriptions of allergic reactions while others describe more serious acute illnesses, with symptoms such as severe headache, pneumonia, fever, myalgia, vertigo and blistering in the mouth. A coroner in the United States found that a teenage boy died as a result of accidentally ingesting a neurotoxic cyanotoxin from a golf course pond. This death is the first recorded human fatality attributed to recreational exposure to cyanobacteria, although uncertainties surround the forensic identification of the suspected cyanotoxin in this case. We systematically reviewed the literature on recreational exposure to freshwater cyanobacteria. Epidemiological data are limited, with six studies conducted since 1990. Statistically significant increases in symptoms were reported in individuals exposed to cyanobacteria compared to unexposed counterparts in two Australian cohort studies, though minor morbidity appeared to be the main finding. The four other small studies (three from the UK, one Australian) did not report any significant association. However, the potential for serious injury or death remains, as freshwater cyanobacteria under bloom conditions are capable of producing potent toxins that cause specific and severe dysfunction to hepatic or central nervous systems. The exposure route for these toxins is oral, from ingestion of recreational water, and possibly by inhalation. A range of freshwater microbial agents may cause acute conditions that present with features that resemble illnesses attributed to contact with cyanobacteria and, conversely, acute illness resulting from exposure to cyanobacteria or cyanotoxins in recreational waters could be misdiagnosed. Accurately assessing exposure to cyanobacteria in recreational waters is difficult and unreliable at present, as specific biomarkers are unavailable. However, diagnosis of cyanobacteria-related illness should be considered for individuals presenting with acute illness following freshwater contact if a description is given of a waterbody visibly affected by planktonic mass development

Progenitor-derived hepatocyte-like (B-13/H) cells metabolise 1'-hydroxyestragole to a genotoxic species via a SULT2B1-dependent mechanism

Rat B-13 progenitor cells are readily converted into functional hepatocyte-like B-13/H cells capable of phase I cytochrome P450-dependent activation of pro-carcinogens and induction of DNA damage. The aim of the present study was to investigate whether the cells are also capable of Phase II sulphotransferase (SULT)-dependent activation of a pro-carcinogen to an ultimate carcinogen. To this end we therefore examined the bioactivation of the model hepatic (hepato- and cholangio-) carcinogen estragole and its proximate SULT1A1-activated genotoxic metabolite 1'-hydroxyestragole. Exposing B-13 or B-13/H cells to estragole (at concentrations up to 1mM) resulted in the production of low levels of 1'-hydroxyestragole, but did not result in detectable DNA damage. Exposing B-13/H cells - but not B-13 cells - to 1'-hydroxyestragole resulted in a dose-dependent increase in DNA damage in comet assays, confirmed by detection of N2-(trans-isoestragol-3'-yl)-2'-deoxyguanosine adducts. Genotoxicity was inhibited by general SULT inhibitors, supporting a role for SULTS in the activation of 1-hydroxyestragole in B-13/H cells. However, B-13 and B-13/H cells did not express biologically significant levels of SULT1A1 as determined by qRT-PCR, Western blotting and its associated 7-hydroxycoumarin sulphation activity. B-13 and B-13/H cells expressed - relative to intact rat liver - high levels of SULT2B1 (primarily the b isoform) and SULT4A1 mRNAs and proteins. B-13 and B-13/H cells also expressed the 3'-phosphoadenosine 5'-phosphosulphate synthase 1 required for the generation of activated sulphate cofactor 3'-phosphoadenosine 5'-phosphosulphate. However, only B-13/H cells expressed functional SULT activities towards SULT2B1 substrates DHEA, pregnenolone and 4 methylumbelliferone. Since liver progenitor cells are bi-potential and also form cholangiocytes, we therefore hypothesised that B-13 cells express a cholangiocyte-like SULT profile. To test this hypothesis, the expression of SULTs was examined in liver by RT-PCR and immunohistochemistry. SULT2B1 - but not SULT1A1 - was determined to be expressed in both rat and human cholangiocytes. Since 1'-hydroxyestragole exposure readily produced DNA injury in B-13/H cells, these data suggest that cholangiocarcinomas generated in rats fed estragole may be dependent, in part, on SULT2B1 activation of the 1'-hydroxyestragole metabolite