Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients

Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients. To delineate the pathogenesis of the reduction in hemoglobin occurring in renal transplant patients treated with angiotensin converting enzyme inhibitors (ACEI) and azathioprine (AZA) a controlled, prospective trial of ACEI withdrawal was conducted. The ACEI was replaced by nifedipine or clonidine in 15 kidney transplant patients immunosuppressed with AZA and prednisone (enalapril in 14 and captopril in 1). Before and during 10 to 12 weeks after withdrawal of the ACEI, AZA metabolites, renal function parameters and hematological parameters including erythropoietin and reticulocytes were evaluated. Enalaprilat levels were measured and compared with 15 similar patients matched for transplant function and enalapril dosage immunosuppressed with cyclosporine and prednisone. AZA metabolites did not differ significantly in the presence or absence of the ACEI. Enalaprilat levels also showed no significant difference between the two patient groups treated with AZA or cyclosporine. Hematocrit and hemoglobin increased significantly from 37.5 ± 6.4 to 39.7 ± 3.6% (mean ± SD, P = 0.02) and 12.8 ± 2.2 to 13.5 ± 1.2 g/dl, P = 0.04, respectively, 10 to 12 weeks after ACEI treatment had been discontinued. Simultaneously numbers of reticulocytes and erythropoietin concentrations rose significantly after 2, 4 and 10 weeks, with a peak at two weeks (from 14.1 ± 3.8 to 20.6 ± 8.0%, P < 0.05 and from 14.3 ± 12.4 to 29.3 ± 54.5 mU/ml, P < 0.05, respectively). In conclusion, ACEI-related anemia in renal transplant recipients seems to be due to the erythropoietin-lowering effect of this group of drugs. A pharmacokinetic interaction between AZA and enalapril is not likely since plasma enalaprilat levels were independent of the immunosuppressive regimen and AZA metabolite levels were unchanged in the presence and absence of the ACEI. Several mechanisms by which angiotensin converting enzyme blockade may cause a decrease in circulating erythropoietin are discussed

Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data

Objective To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus.Design Systematic review and meta-analysis of individual patient data.Data sources Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013.Eligibility Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival.Results the search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. the most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.Conclusions Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. the benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.PfizerOttawa Hosp, Res Inst, Ottawa, ON K1H 7W9, CanadaUniv Ottawa, Ottawa, ON, CanadaCairo Univ, Cairo Kidney Ctr, Cairo, EgyptLimites Med Res, Vacallo, SwitzerlandUniv Manitoba, Dept Pediat & Childs Hlth, Winnipeg, MB, CanadaLund Univ, Dept Nephrol & Transplantat, Malmo, SwedenUniversidade Federal de São Paulo, Hosp Rim & Hipertensao, São Paulo, BrazilAddenbrookes Hosp, Dept Renal Med, Cambridge, EnglandNorthwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USAMaastricht Univ, Med Ctr, Maastricht, NetherlandsSt Louis Hosp, Dept Nephrol, Paris, FranceHosp JW Goethe, Div Nephrol, Frankfurt, GermanyUniv Munich, Dept Surg, Munich, GermanyGoethe Univ Frankfurt, JW Goethe Clin, Clin Dermatol Venerol & Allergol, Frankfurt, GermanyInst Klin Expt Med, Dept Nephrol, Prague, Czech RepublicUniv Cambridge, Addenbrookes Hosp, Dept Surg, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 2QQ, EnglandUniversidade Federal de São Paulo, Hosp Rim & Hipertensao, São Paulo, BrazilWeb of Scienc

Free Radicals, Salicylic Acid and Mycotoxins in Asparagus After Inoculation with Fusarium proliferatum and F. oxysporum

Electron paramagnetic resonance was used to monitor free radicals and paramagnetic species like Fe, Mn, Cu generation, stability and status in Asparagus officinalis infected by common pathogens Fusarium proliferatum and F. oxysporum. Occurrence of F. proliferatum and F. oxysporum, level of free radicals and other paramagnetic species, as well as salicylic acid and mycotoxins content in roots and stems of seedlings were estimated on the second and fourth week after inoculation. In the first term free and total salicylic acid contents were related to free radicals level in stem (P = 0.010 and P = 0.033, respectively). Concentration of Fe3+ ions in porphyrin complexes (g = 2.3, g = 2.9) was related to the species of pathogen. There was no significant difference between Mn2+ concentrations in stem samples; however, the level of free radicals in samples inoculated with F. proliferatum was significantly higher when compared to F. oxysporum

Acidic extracellular pH shifts colorectal cancer cell death from apoptosis to necrosis upon exposure to propionate and acetate, major end-products of the human probiotic propionibacteria.

International audienceThe human probiotic Propionibacterium freudenreichii kills colorectal adenocarcinoma cells through apoptosis in vitro via its metabolites, the short chain fatty acids (SCFA), acetate and propionate. However, the precise mechanisms, the kinetics of cellular events and the impact of environmental factors such as pH remained to be specified. For the first time, this study demonstrates a major impact of a shift in extracellular pH on the mode of propionibacterial SCFA-induced cell death of HT-29 cells, in the pH range 5.5 to 7.5 prevailing within the colon. Propionibacterial SCFA triggered apoptosis in the pH range 6.0 to 7.5, a lethal process lasting more than 96 h. Indeed at pH 7.5, SCFA induced cell cycle arrest in the G2/M phase, followed by a sequence of cellular events characteristic of apoptosis. By contrast, at pH 5.5, the same SCFA triggered a more rapid and drastic lethal process in less than 24 h. This was characterised by sudden mitochondrial depolarisation, inner membrane permeabilisation, drastic depletion in ATP levels and ROS accumulation, suggesting death by necrosis. Thus, in digestive cancer prophylaxis, the observed pH-mediated switch between apoptosis and necrosis has to be taken into account in strategies involving SCFA production by propionibacteria to kill colon cancer cells

ConCysFind: a pipeline tool to predict conserved amino acids of protein sequences across the plant kingdom

Moore M, Wesemann C, Gossmann N, et al. ConCysFind: a pipeline tool to predict conserved amino acids of protein sequences across the plant kingdom. BMC Bioinformatics. 2020;21(1): 490.Background Post-translational modifications (PTM) of amino acid (AA) side chains in peptides control protein structure and functionality. PTMs depend on the specific AA characteristics. The reactivity of cysteine thiol-based PTMs are unique among all proteinaceous AA. This pipeline aims to ease the identification of conserved AA of polypeptides or protein families based on the phylogenetic occurrence in the plant kingdom. The tool is customizable to include any species. The degree of AA conservation is taken as indicator for structural and functional significance, especially for PTM-based regulation. Further, this pipeline tool gives insight into the evolution of these potentially regulatory important peptides. Results The web-based or stand-alone pipeline tool Conserved Cysteine Finder (ConCysFind) was developed to identify conserved AA such as cysteine, tryptophan, serine, threonine, tyrosin and methionine. ConCysFind evaluates multiple alignments considering the proteome of 21 plant species. This exemplar study focused on Cys as evolutionarily conserved target for multiple redox PTM. Phylogenetic trees and tables with the compressed results of the scoring algorithm are generated for each Cys in the query polypeptide. Analysis of 33 translation elongation and release factors alongside of known redox proteins from Arabidopsis thaliana for conserved Cys residues confirmed the suitability of the tool for identifying conserved and functional PTM sites. Exemplarily, the redox sensitivity of cysteines in the eukaryotic release factor 1-1 (eRF1-1) was experimentally validated. Conclusion ConCysFind is a valuable tool for prediction of new potential protein PTM targets in a broad spectrum of species, based on conserved AA throughout the plant kingdom. The identified targets were successfully verified through protein biochemical assays. The pipeline is universally applicable to other phylogenetic branches by customization of the database

Ximelagatran increases membrane fluidity and changes membrane lipid composition in primary human hepatocytes.

International audienceXimelagatran, the first oral agent in the new class of direct thrombin inhibitors, was withdrawn from the market due to a potential risk of severe liver injury. Increased rates of liver enzyme elevations had been observed during clinical trials of chronic use. Despite intensive preclinical investigations the cellular mechanisms behind the observed hepatic effects remain unknown. The aim of this study was to investigate whether ximelagatran has an effect on the plasma membrane fluidity and the membrane lipid composition which may be important for the cell integrity. After 1h exposure of primary human hepatocytes with 10 or 100 microM ximelagatran, a significant elevation of membrane fluidity was observed. This elevation was maintained at 24h, but diminished at 48 h exposure. As changed membrane lipid composition could influence membrane fluidities, changes in membrane lipid profiles were also studied. After 1h exposure, the phosphatidylcholine/phosphatidylethanolamine molar ratio decreased, whereas the total cholesterol/phospholipid molar ratio decreased after a 48 h exposure. The change in membrane fluidity and lipid composition in human hepatocytes exposed to ximelagatran might indicate changes in plasma membrane properties that in susceptible subjects, could result in loss of membrane integrity and leakage of cellular proteins

Fermented dairy products in the context of digestive cancer : the case of [i]Propionibacterium freudenreichii[/i], a cheese starter bacterium with pro-apoptotic properties

Background and objectives.[br/] Dairy propionibacteria are isolated from various ecological niches, including soil, grass, silage, rumen, raw milk and dairy plants, showing great adaptability and robustness. Used as ripening starters in Swiss type cheeses, these food grade bacteria are described as nutraceutical producers and they release into the external medium short chain fatty acids (SCFA), folic acid, cobalamin and the bifidogenic 1,4- dihydroxy-2-naphthoic acid (DHNA). These compounds are known to play a pivotal role in the modulation of intestinal physiology through diet. Considering the pro-apoptotic potential of some of these metabolites, we investigated the potential of dairy products fermented by the main species, Propionibacterium freudenreichii, to prevent colon carcinogenesis. Methods.[br/] We developed a new fermented milk. Taking advantage of milk fractions, high and stable populations of P. freudenreichii were obtained in this product. It was tested in vitro on gastric HGT-1 and colic HT-29 cells with respect to the typical hallmarks of apoptosis. In vivo, the fermented milk was evaluated in piglets with respect to general health parameters and in human microbiota-associated rats, treated or not with dimethylhydrazine (DMH), with respect to intestinal proliferation and apoptosis. Results. Fermented milk induced cell death in both gastric and colon cancer cells. Cellular and molecular characterization of cells dying in response to SCFA treatment revealed cell cycle arrest, drop in intracellular ATP, depolarization of mitochondria, translocation of key apoptosis proteins, processing of caspases and fragmentation of the nucleus. Interestingly, the new fermented milk was shown to potentiate the cytotoxic effect of molecules used in cancer chemotherapy. In accordance, it modulated expression of key apoptotic proteins. In vivo, the fermented milk was evaluated in piglets. Daily oral gavage led to high colic P. freudenreichii populations, to modulation of the intestinal microbiota and modulation of intestinal cytokines. Promotion of piglets’ growth also revealed general probiotic effects of fermented milk. Considering that propionibacteria were metabolically active in the intestine, we further investigated their impact on colon carcinogenesis (induced by dimethylhydrazine, DMH) in human microbiota-associated rats. Consumption of selected strains of propionibacteria resulted in enhanced apoptotic depletion of DMH damaged epithelial cells, yet had no effect on neither proliferation nor apoptosis in healthy rats. Conclusions and perspectives.[br/] These results open new perspectives in the field of colon cancer cells prevention and/or treatment. The synergy with pro-apoptotic chemotherapy molecules suggests that such a fermented product may be proposed as a food supplement to enhance the effects of anticancer treatments

Lung cancer associated with combustion particles and fine particulate matter (PM2.5) - The roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR)

Air pollution is the leading cause of lung cancer after tobacco smoking, contributing to 20% of all lung cancer deaths. Increased risk associated with living near trafficked roads, occupational exposure to diesel exhaust, indoor coal combustion and cigarette smoking, suggest that combustion components in ambient fine particulate matter (PM2.5), such as polycyclic aromatic hydrocarbons (PAHs), may be central drivers of lung cancer. Activation of the aryl hydrocarbon receptor (AhR) induces expression of xenobiotic-metabolizing enzymes (XMEs) and increase PAH metabolism, formation of reactive metabolites, oxidative stress, DNA damage and mutagenesis. Lung cancer tissues from smokers and workers exposed to high combustion PM levels contain mutagenic signatures derived from PAHs. However, recent findings suggest that ambient air PM2.5 exposure primarily induces lung cancer development through tumor promotion of cells harboring naturally acquired oncogenic mutations, thus lacking typical PAH-induced mutations. On this background, we discuss the role of AhR and PAHs in lung cancer development caused by air pollution focusing on the tumor promoting properties including metabolism, immune system, cell proliferation and survival, tumor microenvironment, cell-to-cell communication, tumor growth and metastasis. We suggest that the dichotomy in lung cancer patterns observed between smoking and outdoor air PM2.5 represent the two ends of a dose-response continuum of combustion PM exposure, where tumor promotion in the peripheral lung appears to be the driving factor at the relatively low-dose exposures from ambient air PM2.5, whereas genotoxicity in the central airways becomes increasingly more important at the higher combustion PM levels encountered through smoking and occupational exposure

Lung cancer associated with combustion particles and fine particulate matter (PM2.5) - The roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR)

International audienceAir pollution is the leading cause of lung cancer after tobacco smoking, contributing to 20% of all lung cancer deaths. Increased risk associated with living near trafficked roads, occupational exposure to diesel exhaust, indoor coal combustion and cigarette smoking, suggest that combustion components in ambient fine particulate matter (PM2.5), such as polycyclic aromatic hydrocarbons (PAHs), may be central drivers of lung cancer. Activation of the aryl hydrocarbon receptor (AhR) induces expression of xenobiotic-metabolizing enzymes (XMEs) and increase PAH metabolism, formation of reactive metabolites, oxidative stress, DNA damage and mutagenesis. Lung cancer tissues from smokers and workers exposed to high combustion PM levels contain mutagenic signatures derived from PAHs. However, recent findings suggest that ambient air PM2.5 exposure primarily induces lung cancer development through tumor promotion of cells harboring naturally acquired oncogenic mutations, thus lacking typical PAH-induced mutations. On this background, we discuss the role of AhR and PAHs in lung cancer development caused by air pollution focusing on the tumor promoting properties including metabolism, immune system, cell proliferation and survival, tumor microenvironment, cell-to-cell communication, tumor growth and metastasis. We suggest that the dichotomy in lung cancer patterns observed between smoking and outdoor air PM2.5 represent the two ends of a dose–response continuum of combustion PM exposure, where tumor promotion in the peripheral lung appears to be the driving factor at the relatively low-dose exposures from ambient air PM2.5, whereas genotoxicity in the central airways becomes increasingly more important at the higher combustion PM levels encountered through smoking and occupational exposure. © 2023 The Author