Iron-induced parafibrin formation in tumors fosters immune evasion

Although efficacious in vitro, it is well known that adoptive immunotherapeutic modalities lose their potency when applied in vivo. Furthermore, malignant cell exposure to blood platelets attenuates the anticancer activity of natural killer (NK) cells. We argue that upon contact with redox iron, fibrinogen is converted to a hydrophobic fibrin-like polymer that coats tumor cells and provides protection from immune-mediated destruction

Iron-Induced Fibrin in Cardiovascular Disease

Accumulating evidence within the last two decades indicates the association between cardiovascular disease (CVD) and chronic inflammatory state. Under normal conditions fibrin clots are gradually degraded by the fibrinolytic enzyme system, so no permanent insoluble deposits remain in the circulation. However, fibrinolytic therapy in coronary and cerebral thrombosis is ineffective unless it is installed within 3-5 hours of the onset. We have shown that trivalent iron (FeIII) initiates a hydroxyl radical-catalyzed conversion of fibrinogen into a fibrin-like polymer (parafibrin) that is remarkably resistant to the proteolytic dissolution and thus promotes its intravascular deposition. Here we suggest that the persistent presence of proteolysis-resistant fibrin clots causes chronic inflammation. We study the effects of certain amphiphilic substances on the iron- and thrombin-induced fibrinogen polymerization visualized using scanning electron microscopy. We argue that the culprit is an excessive accumulation of free iron in blood, known to be associated with CVD. The only way to prevent iron overload is by supplementation with iron chelating agents. However, administration of free radical scavengers as effective protection against persistent presence of fibrin-like deposits should also be investigated to contribute to the prevention of cardiovascular and other degenerative diseases

The Role of Iron-Induced Fibrin in the Pathogenesis of Alzheimer’s Disease and the Protective Role of Magnesium

Amyloid hypothesis of Alzheimer’s disease (AD) has recently been challenged by the increasing evidence for the role of vascular and hemostatic components that impair oxygen delivery to the brain. One such component is fibrin clots, which, when they become resistant to thrombolysis, can cause chronic inflammation. It is not known, however, why some cerebral thrombi are resistant to the fibrinolytic degradation, whereas fibrin clots formed at the site of vessel wall injuries are completely, although gradually, removed to ensure proper wound healing. This phenomenon can now be explained in terms of the iron-induced free radicals that generate fibrin-like polymers remarkably resistant to the proteolytic degradation. It should be noted that similar insoluble deposits are present in AD brains in the form of aggregates with Abeta peptides that are resistant to fibrinolytic degradation. In addition, iron-induced fibrin fibers can irreversibly trap red blood cells (RBCs) and in this way obstruct oxygen delivery to the brain and induce chronic hypoxia that may contribute to AD. The RBC-fibrin aggregates can be disaggregated by magnesium ions and can also be prevented by certain polyphenols that are known to have beneficial effects in AD. In conclusion, we argue that AD can be prevented by: (1) limiting the dietary supply of trivalent iron contained in red and processed meat; (2) increasing the intake of chlorophyll-derived magnesium; and (3) consumption of foods rich in polyphenolic substances and certain aliphatic and aromatic unsaturated compounds. These dietary components are present in the Mediterranean diet known to be associated with the lower incidence of AD and other degenerative diseases

High ferritin levels have major effects on the morphology of erythrocytes in Alzheimer's disease

Introduction: Unliganded iron both contributes to the pathology of Alzheimer's disease (AD) and also changes the morphology of erythrocytes (RBCs). We tested the hypothesis that these two facts might be linked, i.e., that the RBCs of AD individuals have a variant morphology, that might have diagnostic or prognostic value. Methods: We included a literature survey of AD and its relationships to the vascular system, followed by a laboratory study. Four different microscopy techniques were used and results statistically compared to analyze trends between high and normal serum ferritin (SF) AD individuals. Results: Light and scanning electron microscopies showed little difference between the morphologies of RBCs taken from healthy individuals and from normal SF AD individuals. By contrast, there were substantial changes in the morphology of RBCs taken from high SF AD individuals. These differences were also observed using confocal microscopy and as a significantly greater membrane stiffness (measured using force-distance curves). Conclusion: We argue that high ferritin levels may contribute to an accelerated pathology in AD. Our findings reinforce the importance of (unliganded) iron in AD, and suggest the possibility both of an early diagnosis and some means of treating or slowing down the progress of this disease

Profound Morphological Changes in the Erythrocytes and Fibrin Networks of Patients with Hemochromatosis or with Hyperferritinemia, and Their Normalization by Iron Chelators and Other Agents

It is well-known that individuals with increased iron levels are more prone to thrombotic diseases, mainly due to the presence of unliganded iron, and thereby the increased production of hydroxyl radicals. It is also known that erythrocytes (RBCs) may play an important role during thrombotic events. Therefore the purpose of the current study was to assess whether RBCs had an altered morphology in individuals with hereditary hemochromatosis (HH), as well as some who displayed hyperferritinemia (HF). Using scanning electron microscopy, we also assessed means by which the RBC and fibrin morphology might be normalized. An important objective was to test the hypothesis that the altered RBC morphology was due to the presence of excess unliganded iron by removing it through chelation. Very striking differences were observed, in that the erythrocytes from HH and HF individuals were distorted and had a much greater axial ratio compared to that accompanying the discoid appearance seen in the normal samples. The response to thrombin, and the appearance of a platelet-rich plasma smear, were also markedly different. These differences could largely be reversed by the iron chelator desferal and to some degree by the iron chelator clioquinol, or by the free radical trapping agents salicylate or selenite (that may themselves also be iron chelators). These findings are consistent with the view that the aberrant morphology of the HH and HF erythrocytes is caused, at least in part, by unliganded (‘free’) iron, whether derived directly via raised ferritin levels or otherwise, and that lowering it or affecting the consequences of its action may be of therapeutic benefit. The findings also bear on the question of the extent to which accepting blood donations from HH individuals may be desirable or otherwise

Changes in red blood cell membrane structure in type 2 diabetes : a scanning electron and atomic force microscopy study

Red blood cells (RBCs) are highly deformable and possess a robust membrane that can withstand shear force. Previous research showed that in diabetic patients, there is a changed RBC ultrastructure, where these cells are elongated and twist around spontaneously formed fibrin fibers. These changes may impact erythrocyte function. Ultrastructural analysis of RBCs in inflammatory and degenerative diseases can no longer be ignored and should form a fundamental research tool in clinical studies. Consequently, we investigated the membrane roughness and ultrastructural changes in type 2 diabetes. Atomic force microscopy (AFM) was used to study membrane roughness and we correlate this with scanning electron microscopy (SEM) to compare results of both the techniques with the RBCs of healthy individuals. We show that the combined AFM and SEM analyses of RBCs give valuable information about the disease status of patients with diabetes. Effectiveness of treatment regimes on the integrity, cell shape and roughness of RBCs may be tracked, as this cell’s health status is crucial to the overall wellness of the diabetic patient.http://cardiab.biomedcentral.comam2016Physiolog

Nowy mechanizm krzepnięcia krwi wywołanego żelazem – znaczenie w cukrzycy i jej powikłaniach

Fibrinogen (FBG) is a high‑molecular‑weight protein and precursor to the enzymatically formed fibrin. It has been recently discovered that FBG can be converted into an insoluble, fibrin‑like polymer by a nonenzymatic action of hydroxyl radicals (HRs). These free radicals are generated due to the reaction between hydroxyl groups of water and trivalent ferric ions without the participation of any redox agent. The interaction between HRs and FBG occurs in a purified system, as well as in human plasma and in whole blood. Scanning electron microscopy (SEM) of thrombin‑induced fibers and those generated with ferric chloride has shown substantial differences in their morphology and susceptibility to enzymatic degradation. Fibrin strands caused by thrombin are thick and easily digested with chymotrypsin. By contrast, the dense matted deposits formed from FBG in the presence of ferric ions are remarkably resistant to proteolytic and chemical degradations due to the presence of intermolecular hydrophobic bonds. Thus, we postulate that this iron‑catalyzed reaction represents a novel blood coagulation pathway operating in degenerative diseases. By means of SEM, we showed the presence of dense fibrin‑like deposits in the blood of diabetic patients. Therefore, the prothrombotic state and cardiovascular complications observed in diabetes can be explained in terms of the persistent in vivo action of free iron. This phenomenon may explain hemorheologic disturbances in patients with metabolic syndrome and other diseases caused by iron overload. Of note, HRs can be effectively scavenged by phenolic substances; therefore, certain natural polyphenolic substances, which also scavenge HRs, may be considered to have a potential antidiabetic effect. Moreover, natural or synthetic iron-binding substances may also be considered as a new class of antidiabetic drugs.Fibrynogen (FBG) jest wielkocząsteczkowym białkiem osocza i prekursorem enzymatycznie wytwarzanej fibryny. Jak ostatnio wykazano, FBG może być również przekształcony w nierozpuszczalny fibrynopodobny polimer pod wpływem nieenzymatycznego działania rodników hydroksylowych (hydroxyl radicals – HR). Te wolne rodniki są wytwarzane w wyniku reakcji między wodorotlenowymi grupami wody a trójwartościowymi jonami żelaza, bez udziału jakiegokolwiek czynnika redoks. Interakcja między HR a FBG zachodzi w układzie oczyszczonym oraz w osoczu i w pełnej krwi. Analiza za pomocą elektronowego mikroskopu skaningowego (scanning electron microscopy – SEM) skrzepów fibrynowych wytworzonych przez trombinę oraz w obecności chlorku żelaza wykazała ich zasadnicze różnice morfologiczne i różną podatność na enzymatyczną degradację. Włókna fibrynowe powstałe pod wpływem trombiny są grube i łatwo rozkładane przez chymotrypsynę, natomiast gęsto upakowane depozyty fibryny powstające pod wpływem jonów żelaza są, z powodu obecnych w nich międzycząsteczkowych wiązań hydrofobowych, w znacznym stopniu oporne na degradację enzymatyczną i chemiczną. Postulujemy zatem, że ta katalizowana przez żelazo reakcja przedstawia nowy mechanizm krzepnięcia krwi w chorobach degeneracyjnych. Za pomocą analizy SEM wykazaliśmy obecność takich gęsto upakowanych złogów fibryny we krwi chorych na cukrzycę. Stan nadkrzepliwości krwi i powikłania sercowo‑naczyniowe spotykane w cukrzycy można zatem tłumaczyć stałym działaniem wolnego żelaza in vivo. Co więcej, wykazaliśmy, że jony żelazowe wytwarzają rozpuszczalne protofibryle, które wiążą się do hydrofobowych rejonów na błonach komórkowych czerwonych krwinek. Zjawisko to może tłumaczyć zaburzenia reologiczne krwi obserwowane u chorych z zespołem metabolicznym oraz innymi chorobami wywołanymi nadmiarem żelaza. Należy zaznaczyć, że HR mogą być skutecznie zmiatane przez substancje fenolowe, dlatego pewne naturalne substancje polifenolowe, które również zmiatają HR, można uznać za substancje o potencjalnym działaniu przeciwcukrzycowym. Ponadto naturalne lub syntetyczne substancje wiążące żelazo można również rozpatrywać jako nową klasę leków przeciwcukrzycowych.http://www.pamw.pl/am201