Over the recent years, our understanding of the cell death machinery of mature erythrocytes has been greatly expanded. It resulted in the discovery of several regulated cell death (RCD) pathways in red blood cells. Apoptosis (eryptosis) and necroptosis of erythrocytes share certain features with their counterparts in nucleated cells, but they are also critically different in particular details. In this review article, we summarize the cell death subroutines in the erythroid precursors (apoptosis, necroptosis, and ferroptosis) in comparison to mature erythrocytes (eryptosis and erythronecroptosis) to highlight the consequences of organelle clearance and associated loss of multiple components of the cell death machinery upon erythrocyte maturation. Recent advances in understanding the role of erythrocyte RCDs in health and disease have expanded potential clinical applications of these lethal subroutines, emphasizing their contribution to the development of anemia, microthrombosis, and endothelial dysfunction, as well as their role as diagnostic biomarkers and markers of erythrocyte storage-induced lesions. Fas signaling and the functional caspase-8/caspase-3 system are not indispensable for eryptosis, but might be retained in mature erythrocytes to mediate the crosstalk between both erythrocyte-associated RCDs. The ability of erythrocytes to switch between eryptosis and necroptosis suggests that their cell death is not a simple unregulated mechanical disintegration, but a tightly controlled process. This allows investigation of eventual pharmacological interventions aimed at individual cell death subroutines of erythrocytes.
- MeSH
- Apoptosis MeSH
- Cell Death MeSH
- Eryptosis * MeSH
- Erythrocytes * metabolism cytology MeSH
- Ferroptosis MeSH
- Humans MeSH
- Necroptosis MeSH
- Regulated Cell Death MeSH
- Signal Transduction * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Eryptosis is a regulated cell death (RCD) of mature erythrocytes initially described as a counterpart of apoptosis for enucleated cells. However, over the recent years, a growing number of studies have emphasized certain differences between both cell death modalities. In this review paper, we underline the hallmarks of eryptosis and apoptosis and highlight resemblances and dissimilarities between both RCDs. We summarize and critically discuss differences in the impact of caspase-3, Ca2+ signaling, ROS signaling pathways, opposing roles of casein kinase 1α, protein kinase C, Janus kinase 3, cyclin-dependent kinase 4, and AMP-activated protein kinase to highlight a certain degree of divergence between apoptosis and eryptosis. This review emphasizes the crucial importance of further studies that focus on deepening our knowledge of cell death machinery and identifying novel differences between cell death of nucleated and enucleated cells. This might provide evidence that erythrocytes can be defined as viable entities capable of programmed cell destruction. Additionally, the revealed cell type-specific patterns in cell death can facilitate the development of cell death-modulating therapeutic agents.
AIMS: We investigated whether a short period of tightly controlled low-carbohydrate diet (LCD) leads to higher time in range without increasing the associated risks in children and young people with diabetes (CYPwD). METHODS: Thirty-five (CYPwD) were recruited into this randomized controlled cross-over study (20 female; 20 CSII; age 14.5 ± 2.9 years; HbA1c 48.9 ± 9.4 mmol/mol). The interventions were five and five weeks of ready-made food box deliveries of isocaloric diets in random order: either LCD (94.5 ± 4.7 g/day) or recommended carbohydrate diet (RCD) (191 ± 19.2 g/day). The outcomes were continuous glucose monitoring parameters, anthropometric, laboratory and quality of life (QoL) data. RESULTS: Time in range was significantly higher in the LCD than in the RCD period (77.1 % vs. 73.8 %, P=0.008). Times in hyperglycemia and average glycaemia were significantly lower in the LCD. There was no difference between the diets in time in hypoglycemia or glycemic variability. The subjects' body weight and BMI were significantly lower during the LCD. There was no significant difference in the LDL-cholesterol levels. No significant differences were observed in the self-assessed QoL. CONCLUSIONS: Short-term LCD led to an improvement of glycemic parameters without increasing time in hypoglycemia, disturbing the lipid profile or negatively affecting the quality of life of CYPwD.
- MeSH
- Diabetes Mellitus, Type 1 * diet therapy blood MeSH
- Diet, Carbohydrate-Restricted * methods MeSH
- Child MeSH
- Glycated Hemoglobin metabolism analysis MeSH
- Cross-Over Studies * MeSH
- Blood Glucose metabolism analysis MeSH
- Quality of Life MeSH
- Humans MeSH
- Adolescent MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
Studies of vitality/mortality of cortex cells, as well as of the concentrations of ethylene (ETH), gibberellins (GAs), indolic compounds/auxins (ICs/AUXs) and cytokinins (CKs), were undertaken to explain the hormonal background of kinetin (Kin)-regulated cell death (RCD), which is induced in the cortex of the apical parts of roots of faba bean (Vicia faba ssp. minor) seedlings. Quantification was carried out with fluorescence microscopy, ETH sensors, spectrophotometry and ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC‒MS/MS). The results indicated that Kin was metabolized to the transport form, i.e., kinetin-9-glucoside (Kin9G) and kinetin riboside (KinR). KinR was then converted to cis-zeatin (cZ) in apical parts of roots with meristems, to cis-zeatin riboside (cZR) in apical parts of roots without meristems and finally to cis-zeatin riboside 5'-monophosphate (cZR5'MP), which is indicated to be a ligand of cytokinin-dependent receptors inducing CD. The process may be enhanced by an increase in the amount of dihydrozeatin riboside (DHZR) as a byproduct of the pathway of zeatin metabolism. It seems that crosstalk of ETH, ICs/AUXs, GAs and CKs with the cZR5'MP, the cis-zeatin-dependent pathway, but not the trans-zeatin-dependent pathway, is responsible for Kin-RCD, indicating that the process is very specific and offers a useful model for studies of CD hallmarks in plants.
Nanomedicine is a fast-growing field of nanotechnology. One of the major obstacles for a wider use of nanomaterials for medical application is the lack of standardized toxicity screening protocols for assessing the safety of newly synthesized nanomaterials. In this review, we focus on less frequently studied nanomaterials-induced regulated cell death (RCD) modalities, including eryptosis, necroptosis, pyroptosis, and ferroptosis, as a tool for in vitro nanomaterials safety evaluation. We summarize the latest insights into the mechanisms that mediate these RCDs in response to nanomaterials exposure. Comprehensive data from reviewed studies suggest that ROS (reactive oxygen species) overproduction and ROS-mediated pathways play a central role in nanomaterials-induced RCDs activation. On the other hand, studies also suggest that individual properties of nanomaterials, including size, shape, or surface charge, could determine specific toxicity pathways with consequent RCD induction as well. We anticipate that the evaluation of RCDs can become one of the mechanism-based screening methods in nanotoxicology. In addition to the toxicity assessment, evaluation of necroptosis-, pyroptosis-, and ferroptosis-promoting capacity of nanomaterials could simultaneously provide useful information for specific medical applications as could be their anti-tumor potential. Moreover, a detailed understanding of molecular mechanisms driving nanomaterials-mediated induction of immunogenic RCDs will substantially aid novel anti-tumor nanodrugs development.
- MeSH
- Humans MeSH
- Neoplasms * MeSH
- Nanomedicine MeSH
- Nanostructures * toxicity MeSH
- Nanotechnology MeSH
- Necroptosis MeSH
- Reactive Oxygen Species metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Overall, reactive oxygen species (ROS) signalling significantly contributes to initiation and mo-dulation of multiple regulated cell death (RCD) pathways. Lately, more information has become available about RCD modalities of erythrocytes, including the role of ROS. ROS accumulation has therefore been increasingly recognized as a critical factor involved in eryptosis (apoptosis of erythrocytes) and erythro-necroptosis (necroptosis of erythrocytes). Eryptosis is a Ca2+-dependent apoptosis-like RCD of erythrocytes that occurs in response to oxidative stress, hyperosmolarity, ATP depletion, and a wide range of xenobiotics. Moreover, eryptosis seems to be involved in the pathogenesis of multiple human diseases and pathological processes. Several studies have reported that erythrocytes can also undergo necroptosis, a lytic RIPK1/RIPK3/MLKL-mediated RCD. As an example, erythronecroptosis can occur in response to CD59-specific pore-forming toxins. We have systematically summarized available studies regarding the involvement of ROS and oxidative stress in these two distinct RCDs of erythrocytes. We have focused specifically on cellular signalling pathways involved in ROS-mediated cell death decisions in erythrocytes. Furthermore, we have summarized dysregulation of related erythrocytic antioxidant defence systems. The general concept of the ROS role in eryptotic and necroptotic cell death pathways in erythrocytes seems to be established. However, further studies are required to uncover the complex role of ROS in the crosstalk and interplay between the survival and RCDs of erythrocytes.
- MeSH
- Eryptosis * physiology MeSH
- Erythrocytes metabolism MeSH
- Humans MeSH
- Oxidation-Reduction MeSH
- Reactive Oxygen Species metabolism MeSH
- Calcium metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
High doses of corticosteroids in combination with rituximab remain an alternative in the treatment in relapsed or refractory chronic lymphocytic leukaemia (CLL) in the current era of targeted therapies. This study retrospectively evaluates the efficacy of an RCD (rituximab, cyclophosphamide and dexamethasone) regimen in the treatment of 51 patients with relapsed CLL (median age, 72 years). Unfavourable prognostic features, such as Rai stage III/IV, unmutated IGHV, del11q, TP53 mutation/deletion, complex karyotype and bulky lymphadenopathy, were frequent. The overall response or complete remission was of 57% and 7%, respectively, and the median progression-free survival (PFS) was of 12.3 months, median time to next treatment 23.1 months and median overall survival 39.2 months. Significant independent predictors of shorter PFS were TP53 deletion/mutation, advanced Rai stage and ≥2 previous lines of treatment. The incidence of neutropenia grade ≥ 3 was of 13%. Serious (CTCAE grade 3-5) infections were found in 20% of patients. Steroid-induced diabetes or diabetes decompensation occurred in 20% patients. Treatment-related adverse events resulted in RCD dose reduction in 35% of patients. In comparison with a historical R-Dex patient group, the treatment response and/or toxicity in our group was largely similar. However, the substantial differences in the baseline clinical characteristics of the groups may affect this comparison. In conclusion, the RCD regimen is an active, time-limited therapeutic strategy for elderly patients with relapsed CLL. Further, the results of our analysis indicate that the addition of cyclophosphamide to the R-Dex regimen maintains a similar efficacy, even after 50% reduction in the dexamethasone dose.
- MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell drug therapy genetics pathology MeSH
- Cyclophosphamide administration & dosage MeSH
- Dexamethasone administration & dosage MeSH
- Diabetes Mellitus chemically induced epidemiology MeSH
- Progression-Free Survival MeSH
- Remission Induction MeSH
- Infections epidemiology MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local drug therapy genetics pathology MeSH
- Survival Rate MeSH
- Tumor Suppressor Protein p53 genetics MeSH
- Neutropenia chemically induced epidemiology MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Retrospective Studies MeSH
- Rituximab administration & dosage MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Neoplasm Staging MeSH
- Drug Tapering MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
- MeSH
- Immunogenic Cell Death genetics MeSH
- Consensus MeSH
- Humans MeSH
- Molecular Biology methods MeSH
- Guidelines as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Narušení mikrobiálního ekosystému střeva dnes představuje významný patogenetický faktor řady onemocnění. Známá je úloha alterace intestinální mikrobioty u rekurentní klostridiové kolitidy (rCDI – recurent Clostridioides difficile infection). Přenosem stolice od zdravého dárce do zažívacího traktu nemocného dokážeme navrátit přirozenou homeostázu střevní mikrobioty, a tím efektivně přerušit "bludný kruh“ chronicky relabující klostridiové infekce. Do budoucna očekáváme dominantně perorální způsob podání fekálního transplantátu v podobě enterosolventních kapslí či komerčně vyráběných fekálních derivátů. Tato cesta podání minimalizuje riziko nežádoucích komplikací, které vzácně pozorujeme při administraci suspenze stolice nazoenterální sondou, endoskopicky nebo rektálním klyzmatem. V posledních letech je transplantace střevní mikrobioty testována i u dalších chorobných stavů, jejichž patogeneze je pravděpodobně asociována s intestinální dysbiózou. V tomto smyslu jsou nejčastěji diskutovány idiopatické střevní záněty, syndrom dráždivého tračníku, jaterní encefalopatie a v posledních letech i "civilizační nemoci“, jako jsou diabetes mellitus 2. typu, roztroušená skleróza, Parkinsonova nemoc či metabolický syndrom. Efekt fekální bakterioterapie je pozorován i při eradikaci multirezistentních bakteriálních kmenů kolonizujících střevo pacientů. U rCDI je dnes v rámci medicíny založené na důkazech fekální bakterioterapie celosvětově akceptovaným a doporučovaným terapeutickým postupem. U ostatních onemocnění se jedná stále o metodu experimentální, na přesvědčivé výsledky randomizovaných kontrolovaných studií prozatím čekáme.
Distortions in intestinal microbial ecosystems are important pathogenetic factors of numerous diseases. The role of alterations in intestinal microbiota in the pathogenesis of recurrent clostridium colitis is well known. A fecal transfer from a healthy donor can restore natural homeostasis in intestinal microbiota and thus disrupt a "vicious circle“ of chronic relapsing clostridium infection. In the future, it should be possible to perform peroral fecal microbiota transplantations using enterosolvent tablets or commercially produced fecal derivatives. This administration route minimises the risk of adverse complications, which are rarely observed when fecal suspensions are administered via a nasoenteral probe, endoscopy, or by rectal clysma. In the past few years, intestinal microbiota transplantation has been used for the treatment of other diseases, the pathogenesis of which is probably associated with intestinal dysbiosis. In this respect, the most discussed issues are idiopathic intestinal inflammations, irritable bowel syndrome, liver encephalopathy and recently, "civilisation diseases“ such as diabetes mellitus type 2, multiple sclerosis, Parkinson‘s disease, and metabolic syndrome. The fecal bacteriotherapy effect is observed also during the eradication of multi-resistant bacterial strains that colonise patients‘ intestines. At present, fecal bacteriotherapy for recurrent clostridium colitis, as a proved medical method, is an accepted and world-wide recommended therapy. As for other diseases, this method is still in the experimental stage. Conclusive results of randomised control trials are expected.
BACKGROUND: Celiac disease (CD) is an organ-specific autoimmune disease, and both adaptive and innate immunity are involved in its development. OBJECTIVES: The aim of the study was to determine whether the markers of intestinal mucosal inflammation in CD can be detected in peripheral blood monocytes (PBMs), and whether the immune properties of PBMs change as the clinical signs and symptoms of CD improve after the introduction of a gluten-free diet (GFD). The focus was on changes in mRNA expression of selected toll-like receptors (TLR2, TLR4, TLR7), stress cytokine prolactin (PRL), and proand anti-inflammatory cytokines (TNF-α, IL-6, IL-12, IL-10) in PBMs. MATERIAL AND METHODS: The study involved 20 CD patients diagnosed according to the European Society for Pediatric Gastroenterology, Hepatology and Nutrition criteria and Marsh criteria: 10 recently-diagnosed cases (rCD) and 10 on a GFD for a minimum of one year. The control group comprised 10 ageand sex-matched healthy volunteers. PBMs from peripheral blood specimens were separated using immunomagnetic CD14+ beads. Total RNA was isolated using a standard commercial kit. Cytokine and TLR mRNA levels were quantified by relative qPCR with PGK1 as a reference gene. RESULTS: Significantly higher expression of TLR4 and TLR7 mRNA was observed in PBMs from rCD patients compared to the healthy controls (1.63 times higher; p < 0.05). TLR7 mRNA levels in rCDs were also significantly elevated in comparison to the CD-GFD patients (2.11 times higher; p < 0.01). TNF-α mRNA expression tended to be higher in both groups of patients; by contrast, in IL-6 mRNA, a trend to a fourfold decrease was detected in PBMs from the CD-GFD subjects. IL-10, IL-12 and PRL levels did not differ among the groups. CONCLUSIONS: The data suggest that the inflammatory process in rCD intestinal mucosa and submucosa reflecting enterocyte damage can be detected in PBMs in peripheral blood. Further, the cytokine and TLR expression profile in PBMs alters after one year of GFD treatment.
- MeSH
- Celiac Disease blood genetics MeSH
- Adult MeSH
- Interleukin-6 genetics metabolism MeSH
- Leukocytes, Mononuclear metabolism MeSH
- Humans MeSH
- RNA, Messenger MeSH
- Prolactin blood genetics metabolism MeSH
- Tumor Necrosis Factor-alpha genetics metabolism MeSH
- Toll-Like Receptor 4 blood genetics MeSH
- Toll-Like Receptor 7 blood genetics MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
