Necroptosis is considered a programmed necrosis that requires receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and pore-forming mixed lineage kinase domain-like protein (MLKL) to trigger a regulated cell membrane lysis. Membrane rupture in necroptosis has been shown to fuel innate immune response due to release of damage-associated molecular patterns (DAMPs). Recently published studies indicate that mature erythrocytes can undergo necroptosis as well. In this review, we provide an outline of multiple cell death modes occurring in erythrocytes, discuss possible immunological aspects of diverse erythrocyte cell deaths, summarize available evidence related to the ability of erythrocytes to undergo necroptosis, outline key involved molecular mechanisms, and discuss the potential implication of erythrocyte necroptosis in the physiology and pathophysiology. Furthermore, we aim to highlight the interplay between necroptosis and eryptosis signaling in erythrocytes, emphasizing specific characteristics of these pathways distinct from their counterparts in nucleated cells. Thus, our review provides a comprehensive summary of the current knowledge of necroptosis in erythrocytes. To reflect critical differences between necroptosis of nucleated cells and necroptosis of erythrocytes, we suggest a term erythronecroptosis for necroptosis of enucleated cells.

• MeSH
• eryptóza MeSH
• erytrocyty * metabolismus   patologie   MeSH
• lidé MeSH
• nekroptóza * MeSH
• nekróza MeSH
• proteinkinasy metabolismus   MeSH
• serin-threoninkinasy interagující s receptory metabolismus   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The aim of the present study was to explore whether hydrogen sulfide (H2S) protects against ischemic heart failure (HF) by inhibiting the necroptosis pathway. Mice were randomized into Sham, myocardial infarction (MI), MI + propargylglycine (PAG) and MI + sodium hydrosulfide (NaHS) group, respectively. The MI model was induced by ligating the left anterior descending coronary artery. PAG was intraperitoneally administered at a dose of 50 mg/kg/day for 4 weeks, and NaHS at a dose of 4 mg/kg/day for the same period. At 4 weeks after MI, the following were observed: A significant decrease in the cardiac function, as evidenced by a decline in ejection fraction (EF) and fractional shortening (FS); an increase in plasma myocardial injury markers, such as creatine kinase-MB (CK-MB) and cardiac troponin I (cTNI); an increase in myocardial collagen content in the heart tissues; and a decrease of H2S level in plasma and heart tissues. Furthermore, the expression levels of necroptosis-related markers such as receptor interacting protein kinase 1 (RIP1), RIP3 and mixed lineage kinase domain-like protein (MLKL) were upregulated after MI. NaHS treatment increased H2S levels in plasma and heart tissues, preserving the cardiac function by increasing EF and FS, decreasing plasma CK-MB and cTNI and reducing collagen content. Additionally, NaHS treatment significantly downregulated the RIP1/RIP3/MLKL pathway. While, PAG treatment aggravated cardiac function by activated the RIP1/RIP3/MLKL pathway. Overall, the present study concluded that H2S protected against ischemic HF by inhibiting RIP1/RIP3/MLKL-mediated necroptosis which could be a potential target treatment for ischemic HF.

• MeSH
• infarkt myokardu * prevence a kontrola   MeSH
• myši MeSH
• nekroptóza MeSH
• proteinkinasy metabolismus   MeSH
• srdeční selhání * farmakoterapie   prevence a kontrola   MeSH
• sulfan * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Necroptosis has been recognized in heart failure (HF). In this study, we investigated detailed necroptotic signalling in infarcted and non-infarcted areas separately and its mechanistic link with main features of HF. Post-infarction HF in rats was induced by left coronary occlusion (60 minutes) followed by 42-day reperfusion. Heart function was assessed echocardiographically. Molecular signalling and proposed mechanisms (oxidative stress, collagen deposition and inflammation) were investigated in whole hearts and in subcellular fractions when appropriate. In post-infarction failing hearts, TNF and pSer229-RIP3 levels were comparably increased in both infarcted and non-infarcted areas. Its cytotoxic downstream molecule p-MLKL, indicating necroptosis execution, was detected in infarcted area. In non-infarcted area, despite increased pSer229-RIP3, p-MLKL was present in neither whole cells nor the cell membrane known to be associated with necroptosis execution. Likewise, increased membrane lipoperoxidation and NOX2 levels unlikely promoted pro-necroptotic environment in non-infarcted area. Collagen deposition and the inflammatory csp-1-IL-1β axis were active in both areas of failing hearts, while being more pronounced in infarcted tissue. Although apoptotic proteins were differently expressed in infarcted and non-infarcted tissue, apoptosis was found to play an insignificant role. p-MLKL-driven necroptosis and inflammation while inflammation only (without necroptotic cell death) seem to underlie fibrotic healing and progressive injury in infarcted and non-infarcted areas of failing hearts, respectively. Upregulation of pSer229-RIP3 in both HF areas suggests that this kinase, associated with both necroptosis and inflammation, is likely to play a dual role in HF progression.

• MeSH
• apoptóza fyziologie   MeSH
• buněčná smrt fyziologie   MeSH
• infarkt myokardu metabolismus   MeSH
• kardiomyocyty metabolismus   MeSH
• krysa rodu rattus MeSH
• nekroptóza fyziologie   MeSH
• nekróza metabolismus   MeSH
• oxidační stres fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• serin-threoninkinasy interagující s receptory metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• srdeční selhání metabolismus   MeSH
• upregulace fyziologie   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Long-lasting ischemia can result in cell loss; however, repeated episodes of brief ischemia increase the resistance of the heart against deleterious effects of subsequent prolonged ischemic insult and promote cell survival. Traditionally, it is believed that the supply of blood to the ischemic heart is associated with release of cytokines, activation of inflammatory response, and induction of necrotic cell death. In the past few years, this paradigm of passive necrosis as an uncontrolled cell death has been re-examined and the existence of a strictly regulated form of necrotic cell death, necroptosis, has been documented. This controlled cell death modality, resembling all morphological features of necrosis, has been investigated in different types of ischemia-associated heart injuries. The process of necroptosis has been found to be dependent on the activation of RIP1-RIP3-MLKL axis, which induces changes leading to the rupture of cell membrane. This pathway is activated by TNF-α, which has also been implicated in the cardioprotective signaling pathway of ischemic preconditioning. Thus, this review is intended to describe the TNF-α-mediated signaling leading to either cell survival or necroptotic cell death. In addition, some experimental data suggesting a link between heart dysfunction and the cellular loss due to necroptosis are discussed in various conditions of myocardial ischemia.

• MeSH
• apoptóza * účinky léků   MeSH
• ischemická choroba srdeční metabolismus   patologie   MeSH
• komplex proteinů jaderného póru metabolismus   MeSH
• lidé MeSH
• myokard metabolismus   patologie   MeSH
• nekróza MeSH
• proteinkinasy metabolismus   MeSH
• proteiny vázající RNA metabolismus   MeSH
• serin-threoninkinasy interagující s receptory metabolismus   MeSH
• signální transdukce MeSH
• TNF-alfa metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

We show that the plant quaternary benzo[c]phenanthridine alkaloid sanguilutine (SL) is a strong inducer of caspase-independent non-apoptotic death in human melanoma cells. Necrostatin-1, a specific inhibitor of necroptosis, completely reversed the cytotoxic effect of SL, suggesting that necroptosis was a predominant type of cell death induced by SL in these cells. In addition, we showed that SL can trigger an autophagic response, as confirmed by GFP-LC3 puncta formation and LC3-II accumulation. Interestingly, we observed a significant decrease in the viability of melanoma cells treated with combination of autophagy inhibitors (3-methyladenine, bafilomycin-A1 and LY294002) and SL. Our results further indicated that autophagy may serve as a pro-survival mechanism, delaying the induction of necroptosis in melanoma cells. The ability of SL to induce caspase-independent non-apoptotic cell death (necroptosis) suggests its possible therapeutic potential in the treatment of apoptosis-resistant melanoma tumours. Furthermore, SL might serve as a useful tool for studying the mechanisms of necroptosis and autophagy induction and the interplay between these two processes.

• MeSH
• adenin analogy a deriváty   farmakologie   MeSH
• autofagie účinky léků   MeSH
• benzofenantridiny antagonisté a inhibitory   farmakologie   MeSH
• imidazoly farmakologie   MeSH
• indoly farmakologie   MeSH
• kaspasy metabolismus   MeSH
• lidé MeSH
• melanom patologie   MeSH
• nádorové buněčné linie MeSH
• nekróza chemicky indukované   MeSH
• proteiny asociované s mikrotubuly metabolismus   MeSH
• protinádorové látky antagonisté a inhibitory   farmakologie   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Over activation of the endothelin-1 (ET-1) system in disease states contributes to endothelial dysfunction. On the other hand, ET-1 promotes proliferation and survival of endothelial cells. Regulation of programmed cell death (PCD) pathways is critical for cell survival. Recently discovered necroptosis (regulated necrosis) is a pathological PCD mechanism mediated by the activation of toll like receptor 4 (TLR4), which also happens to stimulate ET-1 production in dendritic cells. To establish the effect of ET-1 on PCD and survival of human brain microvascular endothelial cells (BMVECs) under control and inflammatory conditions, BMVECs were treated with ET-1 (10 nM, 100 nM and 1 microM) or lipopolysaccharide (LPS, 100 ng/ml). ET receptors were blocked with bosentan (10 microM). Under normal growth conditions, exogenous ET-1 reduced BMVEC viability and migration at a relatively high concentration (1 microM). This was accompanied with activation of necroptosis and apoptosis marker genes. LPS decreased endogenous ET-1 secretion, increased ET(B) receptor expression and activated necroptosis. Even though ET-1 levels were low (less than 10 nM levels used under normal growth conditions), blocking of ET receptors with bosentan inhibited the necroptosis pathway and improved the cell migration ability of BMVECs, suggesting that under inflammatory conditions, ET-1 activates PCD pathways in BMVECs even at physiological levels.

• MeSH
• antagonisté endotelinového receptoru farmakologie   MeSH
• apoptóza účinky léků   fyziologie   MeSH
• endoteliální buňky účinky léků   metabolismus   MeSH
• lidé MeSH
• lipopolysacharidy toxicita   MeSH
• mikrocévy účinky léků   metabolismus   MeSH
• mozek účinky léků   metabolismus   MeSH
• nekróza chemicky indukované   metabolismus   MeSH
• receptory endotelinů metabolismus   MeSH
• transformované buněčné linie MeSH
• viabilita buněk účinky léků   fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

An increasing number of studies have demonstrated the beneficial effects of human mesenchymal stem cells (hMSC) in the treatment of amyotrophic lateral sclerosis (ALS). We compared the effect of repeated intrathecal applications of hMSC or their conditioned medium (CondM) using lumbar puncture or injection into the muscle (quadriceps femoris), or a combination of both applications in symptomatic SOD1G93A rats. We further assessed the effect of the treatment on three major cell death pathways (necroptosis, apoptosis, and autophagy) in the spinal cord tissue. All the animals were behaviorally tested (grip strength test, Basso Beattie Bresnahan (BBB) test, and rotarod), and the tissue was analyzed immunohistochemically, by qPCR and Western blot. All symptomatic SOD1 rats treated with hMSC had a significantly increased lifespan, improved motor activity and reduced number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells. Moreover, a combined hMSC delivery increased motor neuron survival, maintained neuromuscular junctions in quadriceps femoris and substantially reduced the levels of proteins involved in necroptosis (Rip1, mixed lineage kinase-like protein, cl-casp8), apoptosis (cl-casp 9) and autophagy (beclin 1). Furthermore, astrogliosis and elevated levels of Connexin 43 were decreased after combined hMSC treatment. The repeated application of CondM, or intramuscular injections alone, improved motor activity; however, this improvement was not supported by changes at the molecular level. Our results provide new evidence that a combination of repeated intrathecal and intramuscular hMSC applications protects motor neurons and neuromuscular junctions, not only through a reduction of apoptosis and autophagy but also through the necroptosis pathway, which is significantly involved in cell death in rodent SOD1G93A model of ALS. Stem Cells Translational Medicine 2019;8:535-547.

• MeSH
• amyotrofická laterální skleróza terapie   MeSH
• beclin 1 metabolismus   MeSH
• čtyřhlavý sval stehenní cytologie   metabolismus   MeSH
• dlouhověkost MeSH
• injekce intramuskulární MeSH
• kaspasa 9 metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• mezenchymální kmenové buňky cytologie   metabolismus   MeSH
• mícha cytologie   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• motorické neurony metabolismus   MeSH
• nekroptóza * MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• spinální injekce MeSH
• superoxiddismutasa 1 genetika   metabolismus   MeSH
• transplantace mezenchymálních kmenových buněk * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Conventional chemotherapy is mostly effective in the treatment of rapidly-dividing differentiated tumor cells but has limited application toward eliminating cancer stem cell (CSC) population. The presence of a very small number of CSCs may contribute to the development of therapeutic resistance, metastases, and relapse. Thus, treatment failure by developing novel anticancer drugs capable of effective targeting of CSCs is at present a major challenge for research focused on chemotherapy of cancer. Here, we show that Os(II) complex 2 [Os(η6-pcym)(bphen)(dca)]PF6 (pcym = p-cymene, bphen = bathophenanthroline, and dca = dichloroacetate), is capable of efficient and selective killing CSCs in heterogeneous populations of human breast cancer cells MCF-7 and SKBR-3. Notably, its remarkable submicromolar potency to kill CSCs is considerably higher than that of its Ru analog, [Ru(η6-pcym)(bphen)(dca)]PF6 (complex 1) and salinomycin, one of the most selective CSC-targeting compounds hitherto identified. Furthermore, Os(II) complex 2 reduces the formation, size, and viability of three-dimensional mammospheres which more closely reflect the tumor microenvironment than cells in traditional two-dimensional cultures. The antiproliferation studies and propidium iodide staining using flow cytometry suggest that Os(II) complex 2 induces human breast cancer stem cell death predominantly by necroptosis, a programmed form of necrosis. The results of this study demonstrate the promise of Os(II) complex 2 in treating human breast tumors. They also represent the foundation for further preclinical and clinical studies and applications of Os(II) complex 2 to comply with the emergent need for human breast CSCs-specific chemotherapeutics capable to treat chemotherapy-resistant and relapsed human breast tumors.

• MeSH
• apoptóza účinky léků   MeSH
• chloracetáty farmakologie   MeSH
• cymeny farmakologie   MeSH
• fenantroliny farmakologie   MeSH
• komplexní sloučeniny farmakologie   MeSH
• lidé MeSH
• lokální recidiva nádoru patologie   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• nekroptóza účinky léků   MeSH
• nekróza metabolismus   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• osmium farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that can trigger apoptosis in many types of human cancer cells via engagement of its two pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). TRAIL can also activate several other signaling pathways such as activation of stress kinases, canonical NF-κB signaling and necroptosis. Though both receptors are ubiquitously expressed, their relative participation in TRAIL-induced signaling is still largely unknown. To analyze TRAIL receptor-specific signaling, we prepared Strep-tagged, trimerized variants of recombinant human TRAIL with high affinity for either DR4 or DR5 receptor. Using these receptor-specific ligands, we examined the contribution of individual pro-apoptotic receptors to TRAIL-induced signaling pathways. We found that in TRAIL-resistant colorectal HT-29 cells but not in pancreatic PANC-1 cancer cells, DISC formation and initial caspase-8 processing proceeds comparably via both DR4- and DR5-activated signaling. TRAIL-induced apoptosis, enhanced by the inhibitor of the Bcl-2 family ABT-737, or by the translation inhibitor homoharringtonine, proceeded in both cell lines predominantly via the DR5 receptor. ShRNA-mediated downregulation of DR4 or DR5 receptors in HT-29 cells also pointed to a stronger contribution of DR5 in TRAIL-induced apoptosis. In contrast to apoptosis, necroptotic signaling was activated similarly by both DR4- or DR5-specific ligands. Activation of auxiliary signaling pathways involving NF-κB or stress kinases proceeded under apoptotic conditions mainly in a DR5-dependent manner, while these signaling pathways were during necroptosis similarly activated by either of these ligands. Our study provides the first systematic insight into DR4-/DR5-specific signaling in colorectal and pancreatic cancer cells.

• MeSH
• apoptóza genetika   MeSH
• buňky HT-29 MeSH
• kaspasa 8 genetika   MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé MeSH
• malá interferující RNA MeSH
• nádory slinivky břišní genetika   patologie   MeSH
• nekróza genetika   patologie   MeSH
• NF-kappa B genetika   MeSH
• pankreas metabolismus   patologie   MeSH
• proliferace buněk genetika   MeSH
• protein TRAIL genetika   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce genetika   MeSH
• TRAIL receptory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Inhibition of receptor-interacting serine/threonine-protein kinase 1 (RIP1) by necrostatin-1 (Nec-1) alleviates cardiac injury due to prevention of necroptotic cell death. Its inactive analogue necrostatin-1i (Nec-1i), lacking RIP1 activity, serves as a suitable control. It is unknown if these agents influence the heart function in the absence of damaging stimuli. For this purpose, we measured intraarterial blood pressure (systolic - sBP and diastolic - dBP) and ECG parameters after a bolus administration of Nec-1 and Nec-1i in rats during 30 min. Nec-1, unlike Nec-1i, increased sBP and dBP, as well as heart rate reaching the peak at 20 min. The P wave duration tended to be decreased and the duration of the PR interval was shortened by Nec-1 indicating faster conduction of the impulses through atria to the ventricles. The drugs did not influence the QTc interval duration and no episode of ventricular arrhythmia was observed. In summary, Nec-1 temporarily modulates blood pressure and electrical function of the healthy heart. These effects of Nec-1 are likely due to its off-target action or RIP1 has an important role in the regulation of cardiovascular function independently of its action on the necroptotic pathway.

• MeSH
• elektrokardiografie MeSH
• imidazoly farmakologie   MeSH
• indoly farmakologie   MeSH
• krevní tlak účinky léků   MeSH
• náhodné rozdělení MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH