Transferrin Receptor-Mediated Cellular Uptake of Fluorinated Chlorido[,'-bis(salicylidene)-1,2-phenylenediamine]iron(III) Complexes.

Fluorinated chlorido[salophene]iron(III) complexes (salophene = ,'-bis(salicylidene)-1,2-phenylenediamine) are promising anticancer agents. Apoptosis and necrosis induction have already been described as part of their mode of action. However, the involvement of ferroptosis in cell death induction, as confirmed for other chlorido[salophene]iron(III) complexes, has not yet been investigated.

Design, synthesis, and biological evaluation of novel halogenated chlorido[N,N'-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes as anticancer agents.

Iron(III) complexes based on N,N´-bis(salicylidene)ethylenediamine (salene) scaffolds have demonstrated promising anticancer features like induction of ferroptosis, an iron dependent cell death. Since poor cellular uptake limits their therapeutical potential, this study aimed to enhance the lipophilic character of chlorido[N,N'-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes by introducing lipophilicity improving ligands such as fluorine (X1), chlorine (X2) and bromine (X3) in 5-position in the salicylidene moieties. After detailed characterization the binding to nucleophiles, logP values and cellular uptake were determined.

Dopamine‑iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease.

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene.

Design, Synthesis, Electrochemical, and Biological Evaluation of Fluorescent Chlorido[,'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) Complexes as Anticancer Agents.

The impact of methoxy and hydroxyl groups at the salicylidene moiety of chlorido[,'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) complexes was evaluated on human MDA-MB 231 breast cancer and HL-60 leukemia cells. Methoxylated complexes (-) inhibited proliferation, migration, and metabolic activity in a concentration-dependent manner following the rank order: > > . In particular, was highly cytotoxic with an IC of 4.

Enzymatic Cleavage of Stx2a in the Gut and Identification of Pancreatic Elastase and Trypsin as Possible Main Cleavers.

Shiga toxins (Stxs), especially the Stx2a subtype, are the major virulence factors involved in enterohemorrhagic (EHEC)-associated hemolytic uremic syndrome (eHUS), a life-threatening disease causing acute kidney injury, especially in children. After oral transmission and colonization in the gut, EHEC release Stx. Intracellular cleavage of the Stx A subunit, when followed by reduction, boosts the enzymatic activity that causes damage to targeted cells.

Availability of Ferritin-Bound Iron to Enterobacteriaceae.

The sequestration of iron in case of infection, termed nutritional immunity, is an established strategy of host defense. However, the interaction between pathogens and the mammalian iron storage protein ferritin is hitherto not completely understood. To better characterize the function of ferritin in Gram-negative infections, we incubated iron-starved cultures of Typhimurium and knockout mutant strains defective for major iron uptake pathways or with horse spleen ferritin or ionic iron as the sole iron source.

Breathing, (S)Training and the Pelvic Floor-A Basic Concept.

Background: The current scientific literature is inconsistent regarding the potential beneficial or deleterious effects of high-intensity physical activities on the pelvic floor (PF) in women. So far, it has not been established with certainty whether disparate breathing mechanisms may exert short- or long-term influence on the PF function in this context, although based on the established physiological interrelationship of breathing with PF activation, this seems plausible.

Objective: To propose a basic concept of the influence of different breathing patterns on the PF during strenuous physical efforts.

Ambient Availability of Amino Acids, Proteins, and Iron Impacts Copper Resistance of .

The transition metals iron and copper are required by virtually all organisms but are toxic in excess. Acquisition of both metals and resistance to copper excess have previously been shown to be important for virulence of the most common airborne human mold pathogen, . Here we demonstrate that the ambient availability of amino acids and proteins increases the copper resistance of wild type and particularly of the Δ mutant that lacks export-mediated copper detoxification.

Intracerebral Iron Accumulation may be Associated with Secondary Brain Injury in Patients with Poor Grade Subarachnoid Hemorrhage.

Background: The amount of intracranial blood is a strong predictor of poor outcome after subarachnoid hemorrhage (SAH). Here, we aimed to measure iron concentrations in the cerebral white matter, using the cerebral microdialysis (CMD) technique, and to associate iron levels with the local metabolic profile, complications, and functional outcome.

Methods: For the observational cohort study, 36 patients with consecutive poor grade SAH (Hunt & Hess grade of 4 or 5, Glasgow Coma Scale Score ≤ 8) undergoing multimodal neuromonitoring were analyzed for brain metabolic changes, including CMD iron levels quantified by graphite furnace atomic absorption spectrometry.

Shiga Toxin 2a Binds to Complement Components C3b and C5 and Upregulates Their Gene Expression in Human Cell Lines.

Enterohemorrhagic (EHEC) infections can cause EHEC-associated hemolytic uremic syndrome (eHUS) via its main virulent factor, Shiga toxins (Stxs). Complement has been reported to be involved in the progression of eHUS. The aim of this study was to investigate the interactions of the most effective subtype of the toxin, Stx2a, with pivotal complement proteins C3b and C5.

Cell-specific expression of determines the outcome of serovar Typhimurium infection in mice.

Mutations in HFE cause hereditary hemochromatosis type I hallmarked by increased iron absorption, iron accumulation in hepatocytes and iron deficiency in myeloid cells. HFE encodes an MHC-I like molecule, but its function in immune responses to infection remains incompletely understood. Here, we investigated putative roles of Hfe in myeloid cells and hepatocytes, separately, upon infection with Salmonella Typhimurium, an intracellular bacterium with iron-dependent virulence.

The structure of the Shiga toxin 2a A-subunit dictates the interactions of the toxin with blood components.

Hemolytic uremic syndrome (eHUS) is a severe complication of human infections with Shiga toxins (Stxs)-producing Escherichia coli. A key step in the pathogenesis of eHUS is the interaction of Stxs with blood components before the targeting of renal endothelial cells. Here, we show that a single proteolytic cleavage in the Stx2a A-subunit, resulting into two fragments (A1 and A2) linked by a disulfide bridge (cleaved Stx2a), dictates different binding abilities.

Shiga toxin 2a binds antithrombin and heparin, but does not directly activate platelets.

Escherichia coli-induced hemolytic uremic syndrome (eHUS) is a life-threatening complication of infection with Shiga toxin (Stx), in particular Stx2a-producing Escherichia coli. Enhanced coagulation activation with formation of microthrombi seems to be a key event in development of eHUS. Platelet activation has been postulated as a possible, but controversially debated mechanism.

Comparing the effect of strontium-functionalized and fluoride-modified surfaces on early osseointegration.

Background: Studies have shown that medical devices comprising strontium contribute to bone healing and osseointegration. The aim of this study was to evaluate the in vivo performance of surface-functionalized implants (Ti-Sr-O) showing predictable release characteristics of strontium and compare it to performance a commercially available fluoride-modified surface.

Methods: Ti-Sr-O functionalized, fluoride-modified,  Grade 4 titanium implants were inserted in the femoral condyle of adult male New Zealand white rabbits.

Effect of strontium surface-functionalized implants on early and late osseointegration: A histological, spectrometric and tomographic evaluation.

Unlabelled: Numerous in vivo, in vitro and clinical studies report on beneficial effects of strontium with respect to increased bone growth. Based on this knowledge the aim of this study was to evaluate early and late osseointegration stages of functionalized titanium implants showing sustained release of strontium (Sr) and further investigate its potential systemic effect. Strontium functionalized (Ti-Sr-O) and Grade 4 (Control) titanium implants were inserted in the femoral condyle of New Zealand White rabbits.

Salmonella Utilizes Zinc To Subvert Antimicrobial Host Defense of Macrophages via Modulation of NF-κB Signaling.

Zinc sequestration by macrophages is considered a crucial host defense strategy against infection by the intracellular bacterium serovar Typhimurium. However, the underlying mechanisms remain elusive. In this study, we found that zinc favors pathogen survival within macrophages.

Use of Underarm Cosmetic Products in Relation to Risk of Breast Cancer: A Case-Control Study.

Background: Previous studies on breast cancer (BC), underarm cosmetic products (UCP) and aluminum salts have shown conflicting results. We conducted a 1:1 age-matched case-control study to investigate the risk for BC in relation to self-reported UCP application.

Methods: Self-reported history of UCP use was compared between 209 female BC patients (cases) and 209 healthy controls.

Oxidative phosphorylation and mitochondrial function differ between human prostate tissue and cultured cells.

Altered mitochondrial metabolism plays a pivotal role in the development and progression of various diseases, including cancer. Cell lines are frequently used as models to study mitochondrial (dys)function, but little is known about their mitochondrial respiration and metabolic properties in comparison to the primary tissue of origin. We have developed a method for assessment of oxidative phosphorylation in prostate tissue samples of only 2 mg wet weight using high-resolution respirometry.

Heme oxygenase 1 controls early innate immune response of macrophages to Salmonella Typhimurium infection.

Macrophages are central for the immune control of intracellular microbes. Heme oxygenase 1 (HO-1, hmox) is the first and rate limiting enzyme in the breakdown of heme originating from degraded senescent erythrocytes and heme-proteins, yielding equal amounts of iron, carbon monoxide and biliverdin. HO-1 is strongly up-regulated in macrophages in response to inflammatory signals, including bacterial endotoxin.

Lipocalin-2 ensures host defense against Salmonella Typhimurium by controlling macrophage iron homeostasis and immune response.

Lipocalin-2 (Lcn2) is an innate immune peptide with pleiotropic effects. Lcn2 binds iron-laden bacterial siderophores, chemo-attracts neutrophils and has immunomodulatory and apoptosis-regulating effects. In this study, we show that upon infection with Salmonella enterica serovar Typhimurium, Lcn2 promotes iron export from Salmonella-infected macrophages, which reduces cellular iron content and enhances the generation of pro-inflammatory cytokines.

Characterization of the Link between Ornithine, Arginine, Polyamine and Siderophore Metabolism in Aspergillus fumigatus.

The opportunistic fungal pathogen Aspergillus fumigatus produces siderophores for uptake and storage of iron, which is essential for its virulence. The main precursor of siderophore biosynthesis (SB), ornithine, can be produced from glutamate in the mitochondria or by cytosolic hydrolysis of ornithine-derived arginine. Here, we studied the impact of mitochondrial versus cytosolic ornithine biosynthesis on SB by comparison of the arginine auxotrophic mutants ΔargEF and ΔargB, which lack and possess mitochondrial ornithine production, respectively.

Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection.

Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2(-/-) macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium.

Neutrophil gelatinase-associated lipocalin and interleukin-10 regulate intramacrophage Chlamydia pneumoniae replication by modulating intracellular iron homeostasis.

Neutrophil gelatinase-associated lipocalin (NGAL/Lipocalin-2/Lcn-2) is a 25kDa protein which is involved in host defence against certain Gram negative bacteria upon binding of iron loaded bacterial siderophores thereby limiting the availability of this essential nutrient to bacteria resulting in inhibition of their growth and pathogenicity. As iron is important for the growth of the intracellular bacterium Chlamydia pneumoniae we questioned whether Lcn-2 affects the course of this infection. We employed primary peritoneal macrophages obtained from wildtype and Lcn-2 -/- mice and RAW 264.

Nifedipine affects the course of Salmonella enterica serovar Typhimurium infection by modulating macrophage iron homeostasis.

Background: Iron overload can adversely influence the course of infection by increasing microbial replication and suppressing antimicrobial immune effector pathways. Recently, we have shown that the calcium channel blocker nifedipine can mobilize tissue iron in mouse models of iron overload. We therefore investigated whether nifedipine treatment affects the course of infection with intracellular bacteria via modulation of iron homeostasis.