Involvement of histone methylation in the regulation of neuronal death

Neuronal death occurs in various physiological and pathological processes, and apoptosis, necrosis, and ferroptosis are three major forms of neuronal death. Neuronal apoptosis, necrosis, and ferroptosis are widely identified to involve the progress of stroke, Parkinson’s disease, and Alzheimer’s disease. A growing body of evidence has pointed out that neuronal death is tightly associated with expression of related genes and alteration of signaling molecules. In addition, recently, epigenetics has been increasingly focused on as a vital regulatory mechanism for neuronal apoptosis, necrosis, and ferroptosis, providing a new direction for treating nervous system diseases. Moreover, growing researches suggest that histone methylation or demethylation is involved in the processes of neuronal apoptosis, necrosis, and ferroptosis. These researches may imply that studying the potential roles of histone methylation is essential for treating the nervous system diseases. Here, we review potential roles of histone methylation and demethylation in neuronal death, which may give us a new direction in treating the nervous system diseases. (AU)

A novel nomogram integrated with PDL1 and CEA to predict the prognosis of patients with gastric cancer

Introduction This study aimed to develop a prognostic nomogram for patients with gastric cancer (GC) based on the levels of programmed death 1 ligand 1 (PDL1) and carcinoembryonic antigen (CEA). Methods The nomogram was developed using data from a primary cohort of 247 patients who had been clinicopathologically diagnosed with GC, as well as a validation cohort of 63 patients. Furthermore, the nomogram divided the patients into three different risk groups for overall survival (OS)—the low-risk, middle-risk, and high-risk groups. Univariate and multivariate Cox hazard analyses were used to determine all of the factors included in the model. Decision curve analysis and receiver operating characteristic (ROC) curves were used to assess the accuracy of the nomogram. Results The Kaplan–Meier survival analysis revealed that metastasis stage, clinical stage, and CEA and PDL1 levels were predictors for progress-free survival (PFS) and OS of patients with GC. Metastasis stage, clinical stage, and CEA and PDL1 levels were found to be independent risk factors for the PFS and OS of patients with GC in a multivariate analysis, and the nomogram was based on these factors. The concordance index of the nomogram was 0.763 [95% confidence interval (CI) 0.740–0.787]. The area under the concentration–time curve of the nomogram model was 0.81 (95% CI 0.780–0.900). According to the decision curve analysis and ROC curves, the nomogram model had a higher overall net efficiency in forecasting OS than clinical stage, CEA and PDL1 levels. Conclusion In conclusion, we proposed a novel nomogram that integrated PDL1 and CEA, and the proposed nomogram provided more accurate and useful prognostic predictions for patients with GC (AU)

Overexpression of ferroptosis-related genes FSP1 and CISD1 is related to prognosis and tumor immune infiltration in gastric cancer

Purpose Gastric cancer (GC) is one of the highest incidence rate cancers worldwide and the search for new biomarkers remains urgent due to its relatively poor prognosis and limited treatment methods. Ferroptosis suppressor protein 1 (FSP1) and iron sulfur domain 1 (CISD1) promoted malignant tumor progression as ferroptosis suppressors in a variety of tumors, but their study in GC remains to be explored. Methods In our study, FSP1 and CISD1 expression were predicted through different databases and confirmed by qRT-PCR, immunohistochemistry and western blotting. Enrichment analyses were exploited to explore the potential functions of FSP1 and CISD1. Finally, their relationship with immune infiltration was determined by Tumor Immune Estimation Resource and ssGSEA algorithm. Results The expression of FSP1 and CISD1 was higher in GC tissues. Their strongly positive immunostaining was associated with increased tumor size, degree of differentiation, depth of invasion and lymph node metastasis in GC patients. Up-regulated FSP1 and CISD1 predicted poorer overall survival of patients with GC. Furthermore, FSP1 and CISD1 as ferroptosis inhibitors were predicted to be involved in GC immune cell infiltration. Conclusions Our study suggested that FSP1 and CISD1 acted as biomarkers of poor prognosis and promising immunotherapeutic targets for GC (AU)

A comprehensive analysis of immunogenic cell death and its key gene HSP90AA1 in bladder cancer

Background Bladder cancer (BLCA) is defined as a type of urinary cancer with high incidence and lack of specific biomarkers and drug targets. Immunogenic cell death (ICD) has been classified as a regulated type of cell death. Growing evidence suggested that ICD can reshape the tumor immune microenvironment, which may contribute to the development of immunotherapy strategies. The aim of this study was to reveal the specific mechanism of ICD in bladder cancer and to further predict the prognostic immunotherapy outcomes. Methods By consensus clustering analysis, bladder cancer patients in TCGA database were divided into different ICD subtypes. Additionally, we developed an ICD-scoring system and constructed the ICD score-based risk signature and nomogram to better characterize patients. Furthermore, we carried out a series of experiments to verify the relevant findings. Results Based on the transcriptome expression levels of ICD-related genes, a total of 403 BLCA patients in the TCGA database were divided into two subgroups with different ICD molecular patterns by consensus cluster analysis. These subgroups showed different clinicopathological features, survival outcomes, tumor microenvironment (TME) characteristics, immune-related scores, and treatment response. Moreover, the established prediction model and ICD score can effectively distinguish high risk/score patients from low risk/score patients, which has excellent predictive value. Finally, we found that the key gene HSP90AA1 was highly expressed in the high-ICD score group and in bladder cancer tissues, and was confirmed to be associated with the proliferation of bladder cancer cells (AU)

Research advances in the understanding of how exosomes regulate ferroptosis in cancer

Exosomes are extracellular vesicles that can release different bioactive substances to affect tumor cells and cell death pathways. As an important mediator of cell communication, exosomes participate in the occurrence and development of a variety of diseases. Ferroptosis, one of the newly defined forms of regulated cell death, is characterized by massive accumulation of iron ions and lipid peroxidation. An increasing number of studies have shown that ferroptosis plays an important role in malignant tumors. Moreover, exosomes have been recognized for their potential in cancer therapy based on ferroptosis. To further describe how could exosomes regulate ferroptosis in cancer and provide better understanding of the mechanisms involved, this paper reviews the definition as well as the underlying molecular mechanisms of ferroptosis, including iron metabolism, amino acid metabolism, lipid metabolism and so on. Then, we illustrated how could exosomes regulate the ferroptosis pathway and suggested their promising potential as a novel tumor therapy for cancer patients. Finally, we described the perspectives of ferroptosis by exosomes in tumor treatment. Therefore, exosomes have the potential to regulate ferroptosis in clinical cancer treatmen (AU)

ALKBH5 decreases SLC7A11 expression by erasing m6A modification and promotes the ferroptosis of colorectal cancer cells

Background Colorectal cancer (CRC) is the major subtype of gastrointestinal malignancy and involves cancer-related genes and signaling pathways to regulate ferroptosis. The present study was conducted to analyze the role of alkB homolog 5 (ALKBH5) in the ferroptosis of CRC cells and provide novel targets for CRC treatment. Methods The transcriptional and protein levels of ALKBH5 and solute carrier family 7 members 11 (SLC7A11) in tissues and cells were determined by qRT-PCR and Western blot assay. HCT116 and SW620 cells were transfected with ALKBH5 overexpression vectors to determine cell viability and levels of reactive oxygen species (ROS), Fe+, glutathione, and glutathione peroxidase 4 using cell counting kit-8, colony formation, fluorescence probe, assay kits, and Western blot assay. The N6-methyladenosine (m6A) level and the enrichment of m6A on SLC7A11 mRNA were measured by m6A quantitative analysis and m6A methylated RNA immunoprecipitation-qPCR, and the mRNA stability was determined after actinomycin D treatment. CRC cells were treated with the combination of SLC7A11 and ALKBH5 overexpression vectors to confirm the mechanism. Nude mice were subcutaneously injected with CRC cells overexpressing ALKBH5. Results ALKBH5 was downregulated in CRC and ALKBH5 overexpression promoted ROS release and ferroptosis. ALKBH5 erased the m6A modification on SLC7A11 mRNA to reduce the mRNA stability of SLC7A11, further reducing SLC7A11 expression. SLC7A11 overexpression reversed the promotive role of ALKBH5 overexpression in ferroptosis. ALKBH5 upregulation mitigated tumor growth in vivo. Conclusions ALKBH5 reduced SLC7A11 transcription by erasing m6A modification, thus promoting the ferroptosis of CRC cells (AU)

Klotho improves cardiac fibrosis, inflammatory cytokines, ferroptosis, and oxidative stress in mice with myocardial infarction

The anti-aging protein Klotho has been associated with cardiovascular health protection. Nevertheless, the protective mechanism remains unknown. The present study is aimed at exploring the effect of Klotho on cardiac remodeling and its potential mechanism in mice with myocardial infarction (MI). We used left anterior coronary artery descending ligation to develop an MI model for in vivo analyses. In contrast, H9C2 cells and cardiac fibroblasts were used to establish the oxygen–glucose deprivation (OGD) model in in vitro analyses. In vivo and in vitro models were treated with Klotho. Compound C, an AMPK signaling inhibitor, was used to determine whether Klotho’s effects are mediated through the AMPK/mTOR signaling pathway. Echocardiography, Masson trichrome staining, immunofluorescence, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot were used to detect the related indicators. The findings of the in vivo model indicate that Klotho treatment improved the mice’s cardiac function, reduced cardiac fibrosis, and attenuated myocardial inflammatory factors, ferroptosis, and oxidative stress. The results of the in vitro model were in line with the findings of in vivo modeling. An AMPK inhibitor, Compound C, reversed all these effects. In conclusion, Klotho potentially improves cardiac remodeling in MI mice by regulating AMPK/mTOR signaling, demonstrating Klotho as an effective MI therapeutic agent. (AU)

Integrated analysis of ferroptosis-related gene signature for overall survival prediction in Asian patients with hepatocellular carcinoma

Purpose Hepatocellular carcinoma (HCC) is one of the most prevalent types of cancers in Asia. Accumulating evidence suggests that ferroptosis is a non-apoptotic form of cell death, and has played an important role in cancer biology. Methods Based on the manually curated ferroptosis-related gene set and TCGA-LIHC dataset of Asian patients, we used DESeq2, Kaplan–Meier analysis, and univariate Cox regression to identify differentially expressed ferroptosis-related genes with significantly prognostic capacity. A risk signature was constructed based on the selected genes for predicting the survival of HCC patients in Asia. The survival prediction accuracy was confirmed by the time-dependent receiver operating characteristic (ROC) curve analysis. Gene set variation analysis (GSVA) was used to explore the functional associations of the signature. Ferroptosis potential index (FPI) and xCell algorithm was applied to quantify ferroptosis and immune cell infiltration, respectively. Two independent datasets from the GEO and the ICGC database were used for external validation. Results The ferroptosis-related signature could accurately predict the survival outcomes of HCC patients in Asian (p value < 0.0001). We showed that the signature was an independent factor and was beneficial in elevating risk stratification of current clinicopathologic features, such as the amount of alpha-fetoprotein (AFP) and residual tumor classification. Functional characterization showed that critical processes in tumorigenesis belonged to the high-risk groups, for example inflammatory response, which may be the main driver of HCC. The high-risk group had higher FPIs and infiltrations of macrophages and T-helper cells than the low-risk group. Furthermore, two independent cohorts confirmed the prognostic value of our signature (AU)

Immunogenic cell death (ICD)-inducers in non-small-cell lung carcinoma (NSCLC): current knowledge and future perspective

The prevalence of non-small-cell lung cancer (NSCLC) is rising every year all around the world. The interaction between cancer cells and the tumor microenvironment (TME) is a crucial factor in determining the development of human neoplasms. Organellar and cellular stress are induced during immunogenic cell death (ICD), a particularly functional response pattern. ICD is a separate but poorly characterized entity caused by various cancer treatments. The induction of ICD has the potential to change TME and the recruitment of tumor-infiltrating lymphocytes (TILs), and the coupling of ICD-inducers and other therapeutic approaches can have a synergistic role in boosting anticancer impacts. The purpose of this study is to review the studies in the field of NSCLC using ICD-inducers as a treatment strategy or as a combination therapy. This review provide for researches a better view of what has been done so far and the challenges they face in the future (AU)

Ferroptosis: an iron-dependent cell death form linking metabolism, diseases, immune cell and targeted therapy / Ferroptosis: una forma de muerte celular dependiente de hierro que vincula el metabolismo, las enfermedades, las células inmunitarias y la terapia dirigida

Compared with the traditional forms of cell death—apoptosis, necrosis and autophagy, ferroptosis is a novel form of iron-dependent programmed cell death forms which is different from the above traditional forms of cell death. Brent R Stockwell, a Professor of Columbia University, firstly proposed that this from of cell death was named ferroptosis in 2012. The main characteristics of ferroptosis is increasing iron loading and driving a lot of lipid peroxide generated and ultimately lead to cell death. In this paper, the mechanism of ferroptosis, relationship between ferroptosis and common diseases and immune state of body are reviewed, and the inhibitors and inducers related to ferroptosis that have been found are summarized to provide medicine exploration targeted of ferroptosis and reference for the research in the future.

Toxicidad inmuno-relacionada asociada al uso de pembrolizumab en la práctica asistencial / Inmune-related toxicity with pembrolizumab in health care practice

Introducción: Los inhibidores del checkpoint inmunológico (ICIs) han conseguido buenos resultados en salud, pero pueden presentar eventos adversos inmunorelacionados (EAir), en ocasiones, graves y poco predecibles.Objetivo principal: Identificar los EAir asociados al uso de pembrolizumab y conocer su incidencia, características y tratamiento, en nuestro centro.Material y métodos: Estudio observacional y retrospectivo que incluye pacientes con cáncer oncohematológico tratados con pembrolizumab, excluyendo los que participaron en ensayos clínicos. Se recogen variables sociodemográficas, clínicas, y las relacionadas con el tratamiento, incluyendo EAir. El tratamiento estadístico se realizó mediante el paquete estadístico STATA/IC 12.1.Resultados: Se incluyeron 31 pacientes, 81% varones, con una mediana de edad de 67 años (rango 26-88), siendo los diagnósticos mayoritarios: cáncer de pulmón (55%) y melanoma (16%). 81% de los pacientes presentaban estadio IV y el 71%, PDL-1 positivo. La mediana de duración fue de 3,4 meses (rango 0,7-26). El 77% de los pacientes experimentaron EAir y las más frecuentes fueron: astenia, linfopenia e hipotiroidismo. Respecto a la gravedad, el 91% fueron leves o moderadas y en el 9% grado 3. Las reacciones adversas más graves fueron encefalitis, nefritis, anemia grado 3, liquen plano y polineuropatía motora desmielinizante. 11 de los pacientes suspendieron pembrolizumab, de los cuales el 36% fue de forma definitiva. Conclusión: La mayoría de los EAir que aparecen son leves, aunque los casos graves observados y el tiempo de aparición variable hacen que sea importante realizar una monitorización continua de la toxicidad de estos fármacos durante tratamiento, incluso después de suspenderlo. (AU)

Background: Immune checkpoint inhibitors (ICIs) have achieved good health outcomes but it presents immunorelated adverse events (AEsir), sometimes serious and not very predictable.Main objective: To identify the immune-mediated adverse effects (irAE) associated with the use of pembrolizumab and to know its incidence, characteristics and treatment in our center.Material and methods: Observational and retrospective study including oncohematological cancer patients treated with pembrolizumab, excluding those who participated in clinical trials. Sociodemographic, clinical, and treatment-related variables were collected, including EAir. Statistical treatment was performed using the STATA/IC 12.1 statistical package.Results: 31 patients, 81% male, with a median age of 67 years (range 26-88), the main diagnoses being lung cancer (55%) and melanoma (16%). Eighty-one percent of the patients had stage IV and PDL-1 positive in 71%. The median duration was 3.4 months (range 0.7-26). Seventy-seven percent of patients experienced AEir and the most frequent were: asthenia, lymphopenia and hypothyroidism. Regarding severity, 91% were mild or moderate and 9% were grade 3. The most serious adverse reactions were encephalitis, nephritis, grade 3 anemia, lichen planus and demyelinating motor polyneuropathy. Eleven of the patients discontinued pembrolizumab, 36% of whom discontinued permanently. Conclusions: Most of the AEs that appeared were mild, although the severe cases observed and the variable time of onset make it important to continuously monitor the toxicity of these drugs during treatment, even after discontinuation. (AU)

10 ns PEFs induce a histological response linked to cell death and cytotoxic T-lymphocytes in an immunocompetent mouse model of peritoneal metastasis

Purpose The application of nanosecond pulsed electric fields (nsPEFs) could be an effective therapeutic strategy for peritoneal metastasis (PM) from colorectal cancer (CRC). The aim of this study was to evaluate in vitro the sensitivity of CT-26 CRC cells to nsPEFs in combination with chemotherapeutic agents, and to observe the subsequent in vivo histologic response. Methods In vitro cellular assays were performed to assess the effects of exposure to 1, 10, 100, 500 and 1000 10 ns pulses in a cuvette or bi-electrode system at 10 and 200 Hz. nsPEF treatment was applied alone or in combination with oxaliplatin and mitomycin. Cell death was detected by flow cytometry, and permeabilization and intracellular calcium levels by fluorescent confocal microscopy after treatment. A mouse model of PM was used to investigate the effects of in vivo exposure to pulses delivered using a bi-electrode system; morphological changes in mitochondria were assessed by electron microscopy. Fibrosis was measured by multiphoton microscopy, while the histological response (HR; hematoxylin–eosin–safran stain), proliferation (KI67, DAPI), and expression of immunological factors (CD3, CD4, CD8) were evaluated by classic histology. Results 10 ns PEFs exerted a dose-dependent effect on CT-26 cells in vitro and in vivo, by inducing cell death and altering mitochondrial morphology after plasma membrane permeabilization. In vivo results indicated a specific CD8+ T cell immune response, together with a strong HR according to the Peritoneal Regression Grading Score (PRGS). Conclusions The effects of nsPEFs on CT-26 were confirmed in a mouse model of CRC with PM (AU)

Ferroptosis and kidney disease / Ferroptosis y nefropatía

Cell death is a finely regulated process occurring through different pathways. Regulated cell death, either through apoptosis or regulated necrosis offers the possibility of therapeutic intervention. Necroptosis and ferroptosis are among the best studied forms of regulated necrosis in the context of kidney disease. We now review the current evidence supporting a role for ferroptosis in kidney disease and the implications of this knowledge for the design of novel therapeutic strategies. Ferroptosis is defined functionally, as a cell modality characterized by peroxidation of certain lipids, constitutively suppressed by GPX4 and inhibited by iron chelators and lipophilic antioxidants. There is functional evidence of the involvement of ferroptosis in diverse forms of kidneys disease. In a well characterized nephrotoxic acute kidney injury model, ferroptosis caused an initial wave of death, triggering an inflammatory response that in turn promoted necroptotic cell death that perpetuated kidney dysfunction. This suggests that ferroptosis inhibitors may be explored as prophylactic agents in clinical nephrotoxicity or ischemia-reperfusion injury such as during kidney transplantation. Transplantation offers the unique opportunity of using anti-ferroptosis agent ex vivo, thus avoiding bioavailability and in vivo pharmacokinetics and pharmacodynamics issues

La muerte celular es un proceso minuciosamente regulado que se desarrolla a través de diferentes vías. La muerte celular regulada, ya sea mediante apoptosis o necrosis regulada, ofrece la posibilidad de introducir una intervención terapéutica. La necroptosis y la ferroptosis se encuentran entre las formas mejor estudiadas de necrosis regulada en el contexto de la nefropatía. Revisamos los datos actuales que avalan que la ferroptosis desempeña una función en la nefropatía y las repercusiones que tiene este conocimiento en el diseño de nuevas estrategias terapéuticas. La ferroptosis se define de forma funcional como una modalidad celular caracterizada por la peroxidación de ciertos lípidos, constitutivamente suprimida por GPX4 e inhibida por quelantes férricos y antioxidantes lipofílicos. Existen datos probatorios funcionales de la implicación de la ferroptosis en diversas formas de nefropatía. En un modelo de lesión renal aguda nefrotóxica bien caracterizado, la ferroptosis provocó una ola inicial de muerte, la cual desencadenó una respuesta inflamatoria que a su vez promovió la muerte celular necroptótica que perpetuó la disfunción renal. Esto sugiere que los inhibidores de la ferroptosis pueden explorarse como agentes profilácticos en la nefrotoxicidad clínica o en la lesión por isquemia-reperfusión, como durante un trasplante de riñón. Los trasplantes ofrecen una oportunidad única para el uso de agentes inhibidores de la ferroptosis ex vivo, con lo que se evitarían los problemas de biodisponibilidad y los problemas de farmacocinética y farmacodinámica in vivo

Intestinal IgA positive lymphocytes in acute liver necrosis decrease due to lymphocyte homing disturbance and apoptosis

Aim: the number of intestinal IgA+ lymphocytes are decreased in acute liver necrosis and the mechanism remains poorly understood. The purpose of this study was to observe the role of lymphocyte homing and apoptosis associated with decreased intestinal IgA positive lymphocytes in acute liver necrosis. Methods: the acute liver necrosis mouse model and LTßR pre-treatment were used to assess intestinal mucosal addressin cell adhesion molecule-1 (MAdCAM - 1) expression, cell apoptosis, IgA+ cells and secretory immunoglobulin A (SIgA). Results: MAdCAM - 1 mRNA and protein expression decreased significantly in the acute necrosis group; 0.57 ± 0.032 fold vs. baseline (p < 0.05) and 0.45 ± 0.072 fold vs. baseline (p < 0.05), respectively. LTßR pre-treatment could significantly improve the decline of MAdCAM - 1 mRNA and protein expression in the intestinal mucosa (1.83 ± 0.064 fold vs. baseline, p < 0.05 and 1.75 ± 0.046 fold vs. baseline, p < 0.05, respectively) and partially restore the decline in IgA+ lymphocytes and SIgA levels. There were increased rates of enterocyte apoptosis in both the acute liver necrosis and LTßR pre-treatment group; 0.79% vs. control (p < 0.05) and 0.77% vs. control (p < 0.05), respectively). Conclusion: our results suggest that the dysfunction of lymphocyte homing and apoptosis are both involved with decreased intestinal IgA+ lymphocytes in acute liver necrosis. LTßR pre-treatment can partially restore IgA+ cells and SIgA by increasing MAdCAM - 1 expression, rather than inhibiting lymphocyte apoptosis

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Targeting of regulated necrosis in kidney disease / Análisis dirigido de la necrosis regulada en la enfermedad renal

The term acute tubular necrosis was thought to represent a misnomer derived from morphological studies of human necropsies and necrosis was thought to represent an unregulated passive form of cell death which was not amenable to therapeutic manipulation. Recent advances have improved our understanding of cell death in acute kidney injury. First, apoptosis results in cell loss, but does not trigger an inflammatory response. However, clumsy attempts at interfering with apoptosis (e.g. certain caspase inhibitors) may trigger necrosis and, thus, inflammation-mediated kidney injury. Second, and most revolutionary, the concept of regulated necrosis emerged. Several modalities of regulated necrosis were described, such as necroptosis, ferroptosis, pyroptosis and mitochondria permeability transition regulated necrosis. Similar to apoptosis, regulated necrosis is modulated by specific molecules that behave as therapeutic targets. Contrary to apoptosis, regulated necrosis may be extremely pro-inflammatory and, importantly for kidney transplantation, immunogenic. Furthermore, regulated necrosis may trigger synchronized necrosis, in which all cells within a given tubule die in a synchronized manner. We now review the different modalities of regulated necrosis, the evidence for a role in diverse forms of kidney injury and the new opportunities for therapeutic intervention (AU)

La idea de que el término necrosis tubular aguda supone una denominación inapropiada se deriva de estudios morfológicos de necropsias humanas. La opinión generalizada ha sido que la necrosis representa una forma pasiva de muerte celular no regulada que no es susceptible de manipulación terapéutica. Los recientes avances han mejorado nuestra comprensión de la muerte celular en la lesión renal aguda. En primer lugar, la apoptosis origina una pérdida celular, pero no desencadena una respuesta inflamatoria. Sin embargo, los intentos rudimentarios de interferir en la apoptosis (p. ej., con determinados inhibidores de la caspasa) pueden desencadenar una necrosis y, por lo tanto, una lesión renal mediada por inflamación. En segundo lugar, y lo que es más revolucionario, ha surgido el concepto de necrosis regulada. Se han descrito varias modalidades de necrosis regulada como necroptosis, ferroptosis, piroptosis y necrosis regulada por transición de permeabilidad mitocondrial. De forma análoga a la apoptosis, la necrosis regulada se modula a través de moléculas específicas que actúan como dianas terapéuticas. Al contrario que la apoptosis, la necrosis regulada puede ser extremadamente proinflamatoria y, lo que es importante para el trasplante renal, inmunogénica. Además, la necrosis regulada puede desencadenar una necrosis sincronizada, en la que todas las células del interior de un túbulo concreto mueren de manera sincronizada. Revisaremos las diferentes modalidades de necrosis regulada, la evidencia de una función en las diversas formas de lesión renal y las nuevas oportunidades de intervención terapéutica (AU)

Efectos adversos de la acumulación renal de hemoproteínas. Nuevas herramientas terapéuticas / Adverse effects of the renal accumulation of haem proteins. Novel therapeutic approaches

La hemoglobina y la mioglobina son hemoproteínas que juegan un papel fundamental en el organismo ya que participan en el transporte de oxígeno. Sin embargo, debido a su estructura química, estas moléculas pueden ejercer efectos deletéreos cuando se liberan al torrente sanguíneo de forma masiva, como sucede en determinadas condiciones patológicas asociadas a rabdomiólisis o hemólisis intravascular. Una vez en el plasma, estas hemoproteínas se pueden filtrar y acumular en el riñón, donde resultan citotóxicas, principalmente para el epitelio tubular, e inducen fracaso renal agudo y enfermedad renal crónica. En la presente revisión analizaremos los distintos contextos patológicos que provocan la acumulación renal de estas hemoproteínas, su relación con la pérdida de función renal a corto y largo plazo, los mecanismos fisiopatólogicos responsables de sus efectos adversos y los sistemas de defensa que contrarrestan tales acciones. Por último, describiremos los distintos tratamientos utilizados actualmente y mostraremos nuevas opciones terapéuticas basadas en la identificación de nuevas dianas celulares y moleculares, prestando especial atención a los diversos ensayos clínicos que se encuentran en marcha en la actualidad (AU)

Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body. However, because of their chemical structure, these molecules can exert harmful effects when they are released massively into the bloodstream, as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis. Once in the plasma, these haem proteins can be filtered and can accumulate in the kidney, where they become cytotoxic, particularly for the tubular epithelium, inducing acute kidney failure and chronic kidney disease. In this review, we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins, their relation to both acute and chronic loss of renal function, the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions. Finally, we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets, with particular emphasis on the numerous clinical trials that are currently ongoing (AU)

La interleucina-1Beta aumenta la muerte neuronal en el giro dentado del hipocampo asociada al estado epiléptico en la rata en desarrollo / Interleukin-1Beta increases neuronal death in the hippocampal dentate gyrus associated with status epilepticus in the developing rat

Introducción: La interleucina 1β (IL-1Beta) aumenta la muerte neuronal necrótica debido al estado epiléptico (EE) en el área CA1 del hipocampo de ratas en desarrollo; sin embargo, se desconoce si ejerce un efecto similar en el giro dentado (GD) hipocampal. El objetivo de esta investigación fue analizar el efecto de IL-1Beta en la muerte neuronal inducida por el EE en el GD de ratas Wistar de 14 días de edad. Métodos: El EE se indujo con el modelo de litio-pilocarpina. Seis horas después del inicio del EE, la IL-1Beta se inyectó intracerebroventricularmente (0, 0,3, 3, 30 o 300 ng/μl); grupos adicionales se inyectaron con el antagonista natural del receptor tipoi (IL-1RI) de IL-1Beta (IL-1Ra, 30 ng/μl) en ausencia o presencia de IL-1Beta (3 ng/μl). La muerte neuronal se evaluó en la capa granular del GD 24 h después del EE mediante la tinción de hematoxilina-eosina. Las células muertas se caracterizaron por presentar citosol eosinofílico y núcleos condensados y fragmentados. Resultados: Se observó un incremento en el número de células eosinofílicas en el GD ipsilateral a la inyección de 3 y 300 ng/μl de IL-1Beta en comparación con el grupo vehículo; en el GD contralateral se observó un efecto similar únicamente con 3 ng/μl de IL-1Beta. La coadministración de IL-1Beta con el IL-1Ra no evitó el aumento en el número de células eosinofílicas. Conclusión: La IL-1Beta aumenta la muerte neuronal con morfología apoptótica provocada por el EE en el GD del hipocampo, mecanismo independiente de la activación del receptor IL-1RI (AU)

Background: Interleukin-1Beta (IL-1Beta) increases necrotic neuronal cell death in the CA1 area after induced status epilepticus (SE) in developing rats. However, it remains uncertain whether IL-1Beta has a similar effect on the hippocampal dentate gyrus (DG). In this study, we analysed the effects of IL-1Beta on 14-day-old Wistar rats experiencing DG neuronal death induced by SE. Methods: SE was induced with lithium-pilocarpine. Six hours after SE onset, a group of pups was injected with IL-1β (at 0, 0.3, 3, 30, or 300 ng/μL) in the right ventricle; another group was injected with IL-1Beta receptor (IL-1R1) antagonist (IL-1Ra, at 30 ng/μL) of IL-1RI antagonist (IL-1Ra) alone, and additional group with 30 ng/μL of IL-1Ra plus 3 ng/μL of IL-1Beta. Twenty-four hours after SE onset, neuronal cell death in the dentate gyrus of the dorsal hippocampus was assessed using haematoxylin-eosin staining. Dead cells showed eosinophilic cytoplasm and condensed and fragmented nuclei. Results: We observed an increased number of eosinophilic cells in the hippocampal DG ipsilateral to the site of injection of 3ng/μL and 300 ng/μL of IL-1Beta in comparison with the vehicle group. A similar effect was observed in the hippocampal DG contralateral to the site of injection of 3 ng/μL of IL-1Beta. Administration of both of IL-1Beta and IL-1Ra failed to prevent an increase in the number of eosinophilic cells. Conclusion: Our data suggest that IL-1Betaincreases apoptotic neuronal cell death caused by SE in the hippocampal GD, which is a mechanism independent of IL-1RI activation (AU)

Posibilidades de organoprotección en la insuficiencia cardiaca aguda / Organ protection possibilities in acute heart failure

A diferencia de la insuficiencia cardiaca (IC) crónica, el tratamiento de la IC aguda no ha cambiado en la última década. Los fármacos empleados han demostrado controlar los síntomas, pero no han conseguido una protección orgánica ni una reducción de la morbimortalidad a medio y largo plazo. Los avances en el conocimiento de la fisiopatología de la IC aguda sugieren que el tratamiento debe dirigirse no solo a corregir las alteraciones hemodinámicas y a conseguir un alivio sintomático, sino sobre todo a prevenir el daño orgánico, contrarrestando el remodelado miocárdico y las alteraciones cardiacas y extracardiacas. Las moléculas que en la fase aguda de la IC puedan ejercer acciones vasodilatadoras y antiinflamatorias —y que sean capaces de detener la muerte celular, favoreciendo los mecanismos de reparación— podrían tener un papel esencial en la protección orgánica (AU)

Unlike chronic heart failure (HF), the treatment for acute HF has not changed over the last decade. The drugs employed have shown their ability to control symptoms but have not achieved organ protection or managed to reduce medium to long-term morbidity and mortality. Advances in our understanding of the pathophysiology of acute HF suggest that treatment should be directed not only towards correcting the haemodynamic disorders and achieving symptomatic relief but also towards preventing organ damage, thereby counteracting myocardial remodelling and cardiac and extracardiac disorders. Compounds that exert vasodilatory and anti-inflammatory action in the acute phase of HF and can stop cell death, thereby boosting repair mechanisms, could have an essential role in organ protection (AU)

Immunotherapy with liposome-bound TRAIL overcomes partial protection to soluble TRAIL-induced apoptosis offered by down-regulation of Bim in leukemic cells

Purpose. Human Apo2-Ligand/TRAIL secreted by natural killer cells and cytotoxic T lymphocytes plays an important role immunosurveillance controlling tumor growth and metastasis. Moreover, the fact that Apo2L/TRAIL is capable of inducing cell death in tumor cells but not in normal cells makes this death ligand a promising anti-tumor agent. Previous data from our group demonstrated that Apo2L/TRAIL was physiologically released as transmembrane protein inserted in lipid vesicles, called exosomes. Recently, we demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) resembling the natural exosomes, greatly improved Apo2L/TRAIL activity and were able to induce apoptosis in hematological malignancies. In this study, we have deepened in the underlying mechanism of action of LUV-TRAIL in hematologic cells. Methods/patients. Cytotoxic ability of LUV-TRAIL was assessed on Jurkat cells either over-expressing the anti-apoptotic protein Mcl1 or down-regulating the pro-apoptotic protein Bim previously generated in our laboratory. We also tested LUV-TRAIL cytotoxic ability against primary human leukemic cells from T-cell ALL patient. Results. Silencing Bim but not Mcl-1 over-expression partially protects Jurkat cells from apoptosis induced by sTRAIL. LUV-TRAIL induced caspase-8 and caspase-3 activation and killed Jurkat-Mcl1 and Jurkat-shBim more efficiently than sTRAIL independently of the mitochondrial pathway. On the other hand, LUV-TRAIL were clearly more cytotoxic against primary leukemic cells from a T-cell ALL patient than sTRAIL. Conclusion. Tethering Apo2L/TRAIL to the surface of lipid nanoparticles greatly increases its bioactivity and could be of potential use in anti-tumor therapeutics (AU)

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Lung metastases in oligometastatic patients: outcome with stereotactic body radiation therapy (SBRT)

Purpose. To assess the clinical results in terms of local control, toxicity, failure pattern and toxicity of SBRT in oligometastatic patients with inoperable lung metastases. Methods. Forty-four patients were treated (53 metastases). Dose regimen: 5 × 12 Gy (66 %), 8 × 7.5 Gy (20.8 %) and 10 × 5 Gy (13.2 %). Response was assessed using PET/CT at 6 months after SBRT. Results. Local control at 1 and 2 years was 86.7 %. Seventy-five percent of local failures had received a BED <105 Gy. After a median follow-up of 13.3 months, 25 % experienced distant progression. Overall survival at 1 and 2 years was 86.7 and 60.4 %, and cancer-specific survival was 95.3 and 75.2 %, respectively. Grade 2 toxicity was 6.8 %. There was no grade 3–4 toxicity. Conclusion. SBRT is effective and safe. The main failure pattern is distant progression. The selection of patients with a high probability of remaining oligometastatic is crucial for the efficiency of SBRT, both clinically and in terms of resources (AU)

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