Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca2+ entry in tumor cells.

Most cancer cells show the Warburg effect, the rewiring of aerobic metabolism to glycolysis due to defective mitochondrial ATP synthesis. As a consequence, tumor cells display enhanced mitochondrial potential (∆Ψ), the driving force for mitochondrial Ca2+ uptake. Mitochondria control the Ca2+-dependent inactivation of store-operated channels (SOCs), leading to enhanced and sustained store-operated Ca2+ entry (SOCE) involved in cancer hallmarks. We asked here whether the transfer of mitochondria (mitoception) from normal cells to tumor cells may reverse SOCE remodeling in cancer cells. For this end, we labeled mitochondria in normal NCM460 human colonic cells, isolated them and transferred them to tumor HT29 cells. We tested the viability and efficiency of mitoception using flow cytometry and confocal microscopy, as well as calcium imaging to investigate the effects of mitoception on SOCE. Our results show that mitoception of tumor HT29 cells with normal mitochondria restores a low ∆Ψ and SOCE. Conversely, self-mitoception of tumor HT29 cells with tumor cell mitochondria increases further ∆Ψ and SOCE, thus excluding the possibility that effects of mitoception are due to increased mitochondrial mass. Strikingly, mitoception of normal NCM460 cells with tumor cell mitochondria has no effects on either ∆Ψ or SOCE. These results are consistent with the previous proposal that transformed mitochondria may modulate SOC channels involved in SOCE. Further research is warranted to test whether mitoception of cancer cells with normal mitochondria may reverse Ca2+ remodeling associated to cancer.

SARS-CoV-2 Viroporin E Induces Ca2+ Release and Neuron Cell Death in Primary Cultures of Rat Hippocampal Cells Aged In Vitro.

The COVID-19 pandemic was caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which may lead to serious respiratory, vascular and neurological dysfunctions. The SARS-CoV-2 envelope protein (E protein) is a structural viroporin able to form ion channels in cell membranes, which is critical for viral replication. However, its effects in primary neurons have not been addressed. Here we used fluorescence microscopy and calcium imaging to study SARS-CoV-2 viroporin E localization and the effects on neuron damage and intracellular Ca2+ homeostasis in a model of rat hippocampal neurons aged in vitro. We found that the E protein quickly enters hippocampal neurons and colocalizes with the endoplasmic reticulum (ER) in both short-term (6-8 days in vitro, DIV) and long-term (20-22 DIV) cultures resembling young and aged neurons, respectively. Strikingly, E protein treatment induces apoptosis in aged neurons but not in young neurons. The E protein induces variable increases in cytosolic Ca2+ concentration in hippocampal neurons. Ca2+ responses to the E protein are due to Ca2+ release from intracellular stores at the ER. Moreover, E protein-induced Ca2+ release is very small in young neurons and increases dramatically in aged neurons, consistent with the enhanced Ca2+ store content in aged neurons. We conclude that the SARS-CoV-2 E protein quickly translocates to ER endomembranes of rat hippocampal neurons where it releases Ca2+, probably acting like a viroporin, thus producing Ca2+ store depletion and neuron apoptosis in aged neurons and likely contributing to neurological damage in COVID-19 patients.

lncRNA CDKN2B-AS1 is downregulated in patients with ventricular fibrillation in acute myocardial infarction.

Ventricular fibrillation (VF) in acute myocardial infarction (AMI) is the main cause of deaths occurring in the acute phase of an ischemic event. Although it is known that genetics may play an important role in this pathology, the possible role of long non-coding RNAs (lncRNA) has never been studied. Therefore, the aim of this work is to study the expression of 10 lncRNAs in patients with and without VF in AMI. For this purpose, the expression of CDKN2B-AS1, KCNQ1OT1, LIPCAR, MALAT1, MIAT, NEAT1, SLC16A1-AS1, lnc-TK2-4:2, TNFRSF14-AS1, and UCA1 were analyzed. After the analysis and Bonferroni correction, the lncRNA CDKN2B-AS showed a statistical significance lower expression (P values of 2.514 x 10-5). In silico analysis revealed that six proteins could be related to the possible effect of lncRNA CDKN2B-AS1: AGO3, PLD4, POU4F1, ZNF26, ZNF326 and ZNF431. These in silico proteins predicted to have a low cardiac expression, although there is no literature indicating a potential relationship with VF in AMI. Thus, the lncRNA CDKN2B-AS1 shows a significant lower expression in patients with VF in AMI vs patients without VF in AMI. Literature data suggest that the role of CDKN2B1-AS is related to the miR-181a/SIRT1 pathway.

Analysis of the Association between Copy Number Variation and Ventricular Fibrillation in ST-Elevation Acute Myocardial Infarction.

Sudden cardiac death due to ventricular fibrillation (VF) during ST-elevation acute myocardial infarction (STEAMI) significantly contributes to cardiovascular-related deaths. Although VF has been linked to genetic factors, variations in copy number variation (CNV), a significant source of genetic variation, have remained largely unexplored in this context. To address this knowledge gap, this study performed whole exome sequencing analysis on a cohort of 39 patients with STEAMI who experienced VF, aiming to elucidate the role of CNVs in this pathology. The analysis revealed CNVs in the form of duplications in the PARP2 and TTC5 genes as well as CNVs in the form of deletions in the MUC15 and PPP6R1 genes, which could potentially serve as risk indicators for VF during STEAMI. The analysis also underscores notable CNVs with an average gene copy number equal to or greater than four in DEFB134, FCGR2C, GREM1, PARM1, SCG5, and UNC79 genes. These findings provide further insight into the role of CNVs in VF in the context of STEAMI.

[Social, demographic and morbimortality characteristics of the cases treated for COVID-19 at the Ignacio Chávez National Institute of Cardiology. A descriptive cross-sectional study]. / Características sociales, demográficas y de morbimortalidad de los casos atendidos por COVID-19 en el Instituto Nacional de Cardiología Ignacio Chávez. Un estudio transversal descriptivo.

Introduction: The COVID-19 pandemic brought with it a large number of adverse consequences for public health with serious socioeconomic repercussions. In this study we characterize the social, demographic, morbidity and mortality conditions of individuals treated for COVID-19 in one of the SARS-CoV-2 reference hospitals in Mexico City. Method: A descriptive cross-sectional study was carried out in 259 patients discharged from the Instituto Nacional de Cardiología Ignacio Chávez, between April 11, 2020 and March 14, 2021. A multivariate logistic regression model was used to identify the association between sociodemographic and clinical variables. An optimization was performed using maximum likelihood calculations to choose the best model compatible with the data. The maximum likelihood model was evaluated using ROC curves, goodnessof-fit estimators, and multicollinearity analysis. Statistically significant patterns of comorbidities were inferred by evaluating a hypergeometric test over the frequencies of co-occurrence of pairs of conditions. A network analysis was implemented to determine connectivity patterns based on degree centrality, between comorbidities and outcome variables. Results: The main social disadvantages of the studied population are related to the lack of social security (96.5%) and the lag in housing conditions (81%). Variables associated with the probability of survival were being younger (p < 0.0001), having more durable material goods (p = 0.0034) and avoiding: pneumonia (p = 0.0072), septic shock (p < 0.0001) and acute respiratory failure (p < 0.0001); (AUROC: 91.5%). The comorbidity network for survival cases has a high degree of connectivity between conditions such as cardiac arrhythmias and essential arterial hypertension (Degree Centrality = 90 and 78, respectively). Conclusions: Given that among the factors associated with survival to COVID-19 there are clinical, sociodemographic and social determinants of health variables, in addition to age; It is imperative to consider the various factors that may affect or modify the health status of a population, especially when addressing emerging epidemic phenomena such as the current COVID-19 pandemic.

Introducción: La pandemia de enfermedad por coronavirus 2019 (COVID-19) trajo aparejadas una gran cantidad de consecuencias adversas para la salud pública con serias repercusiones socioeconómicas. En este estudio caracterizamos las condiciones sociales, demográficas y de morbimortalidad de los casos atendidos por COVID-19 en uno de los hospitales de referencia de coronavirus 2 del síndrome respiratorio agudo grave (SARS-CoV-2) en la Ciudad de México. Método: Se llevó a cabo un estudio transversal descriptivo en 259 pacientes egresados del Instituto Nacional de Cardiología Ignacio Chávez, entre el 11 de abril de 2020 y el 14 de marzo de 2021. Se utilizó un modelo de regresión logística multivariante para identificar la asociación entre variables sociodemográficas y clínicas. Se realizó una optimización mediante cálculos de máxima verosimilitud para elegir el mejor modelo compatible con los datos. El modelo de máxima verosimilitud fue evaluado mediante curvas ROC, estimadores de bondad de ajuste y análisis de multicolinealidad. Se infirieron patrones de comorbilidades estadísticamente significativos mediante la evaluación de una prueba hipergeométrica en las frecuencias de coocurrencia de pares de condiciones. Se implementó un análisis de redes para determinar los patrones de conectividad basado en la centralidad de grado, entre algunas comorbilidades y las variables de desenlace. Resultados: Las principales desventajas sociales de la población estudiada se relacionan con la falta de seguridad social (96.5%) y el rezago en las condiciones de vivienda (81%). Las variables asociadas a la probabilidad de sobrevivir fueron tener una menor edad (p < 0.0001), contar con más bienes materiales durables (p = 0.0034) y evitar: la neumonía (p = 0.0072), el choque séptico (p < 0.0001) y la insuficiencia respiratoria aguda (p < 0.0001); (AUROC: 91.5%). Las red de comorbilidades para los casos de supervivencia tienen un alto grado de conectividad entre padecimientos como las arritmias cardiacas e hipertensión arterial esencial (centralidad de grado: 90 y 78 respectivamente). Conclusiones: En vista de que entre los factores asociados a supervivencia existen variables clínicas, sociodemográficas y determinantes sociales de la salud, además de la edad, resulta imperativo considerar los diversos factores que puedan incidir o modificar el estado de salud de una población, sobre todo al abordar los fenómenos epidémicos emergentes como es el caso de la actual pandemia de COVID-19.

Transfusion-associated adverse events incidence and severity after the implementation of an active hemovigilance program with 24 h follow-up. A prospective cohort study.

BACKGROUND: Hemovigilance (HV) is usually based on voluntary reports (passive HV). Our aim is to ascertain credible incidence, severity, and mortality of transfusion-associated adverse events (TAAEs) using an active HV program. STUDY DESIGN AND METHODS: Prospective cohort study to estimate transfusion risk after 46,488 transfusions in 5830 patients, using an active HV program with follow-up within the first 24 h after transfusion. We compared these results to those with the previously established passive HV program during the same 30 months of the study. We explored factors associated with the occurrence of TAAEs using generalized estimating equations models. RESULTS: With the active HV program TAAEs incidence was 57.3 (95% CI, 50.5-64.2) and mortality 1.1 (95% CI, 0.13-2.01) per 10,000 transfusions. Incidence with the new surveillance model was 14.0 times higher than with the passive. Most events occurred when transfusions had already finished (60.2%); especially pulmonary events (80.4%). Three out of five deaths and 50.3% of severe TAAEs were pulmonary. In the multivariate analysis surgical patients had half TAAEs risk when compared to medical patients (OR, 0.53; 95% CI, 0.34-0.78) and women had nearly twice the risk of a pulmonary event compared to men (OR, 1.84; 95% CI, 1.03-3.32). Patient's age, blood component type, or blood component shelf-life were unrelated to TAAEs risk. DISCUSSION: Active hemovigilance programs provide additional data which may lead to better recognition and understanding of TAAEs and their frequency and severity.

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer's Disease and Parkinson's Disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases in the elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca2+ dyshomeostasis, plays a vital role in the pathophysiology of these neurological disorders. Due to an improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. However, there is no effective protective treatment or therapy available but rather only very limited palliative treatment. Therefore, there is an urgent need for the development of preventive strategies and disease-modifying therapies to treat AD/PD. Because dysregulated Ca2+ metabolism drives oxidative damage and neuropathology in these diseases, the identification or development of compounds capable of restoring Ca2+ homeostasis and signaling may provide a neuroprotective avenue for the treatment of neurodegenerative diseases. In addition, a set of strategies to control mitochondrial Ca2+ homeostasis and signaling has been reported, including decreased Ca2+ uptake through voltage-operated Ca2+ channels (VOCCs). In this article, we review the modulatory effects of several heterocyclic compounds on Ca2+ homeostasis and trafficking, as well as their ability to regulate compromised mitochondrial function and associated free-radical production during the onset and progression of AD or PD. This comprehensive review also describes the chemical synthesis of the heterocycles and summarizes the clinical trial outcomes.

Transcriptional Basis of Ca2+ Remodeling Reversal Induced by Polyamine Synthesis Inhibition in Colorectal Cancer Cells.

Colorectal cancer (CRC) is associated with mutations in APC/Wnt leading to c-myc activation and the overexpression of ODC1, the limiting step in polyamine synthesis. CRC cells also display a remodeling of intracellular Ca2+ homeostasis that contributes to cancer hallmarks. As polyamines may modulate Ca2+ homeostasis during epithelial tissue repair, we investigated whether polyamine synthesis inhibition may reverse Ca2+ remodeling in CRC cells and, if so, the molecular basis for this reversal. To this end, we used calcium imaging and transcriptomic analysis in normal and CRC cells treated with DFMO, an ODC1 suicide inhibitor. We found that polyamine synthesis inhibition partially reversed changes in Ca2+ homeostasis associated with CRC, including a decrease in resting Ca2+ and SOCE along with an increased Ca2+ store content. We also found that polyamine synthesis inhibition reversed transcriptomic changes in CRC cells without affecting normal cells. Specifically, DFMO treatment enhanced the transcription of SOCE modulators CRACR2A; ORMDL3; and SEPTINS 6, 7, 8, 9, and 11, whereas it decreased SPCA2, involved in store-independent Orai1 activation. Therefore, DFMO treatment probably decreased store-independent Ca2+ entry and enhanced SOCE control. Conversely, DFMO treatment decreased the transcription of the TRP channels TRPC1 and 5, TRPV6, and TRPP1 while increasing TRPP2, thus probably decreasing Ca2+ entry through TRP channels. Finally, DFMO treatment enhanced the transcription of the PMCA4 Ca2+ pump and mitochondrial channels MCU and VDAC3 for enhanced Ca2+ extrusion through the plasma membrane and mitochondria. Collectively, these findings suggested the critical role of polyamines in Ca2+ remodeling in colorectal cancer.

Rare Variants in Genes of the Cholesterol Pathway Are Present in 60% of Patients with Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is a pandemic in which conventional risk factors are inadequate to detect who is at risk early in the asymptomatic stage. Although gene variants in genes related to cholesterol, which may increase the risk of AMI, have been identified, no studies have systematically screened the genes involved in this pathway. In this study, we included 105 patients diagnosed with AMI with an elevation of the ST segment (STEMI) and treated with primary percutaneous coronary intervention (PPCI). Using next-generation sequencing, we examined the presence of rare variants in 40 genes proposed to be involved in lipid metabolism and we found that 60% of AMI patients had a rare variant in the genes involved in the cholesterol pathway. Our data show the importance of considering the wide scope of the cholesterol pathway in order to assess the genetic risk related to AMI.

Sentiment Analysis in Understanding the Potential of Online News in the Public Health Crisis Response.

This study analyzes online news disseminated throughout the pre-, during-, and post-intervention periods of the "Syphilis No!" Project, which was developed in Brazil between November 2018 and March 2019. We investigated the influence of sentiment aspects of news to explore their possible relationships with syphilis testing data in response to the syphilis epidemic in Brazil. A dictionary-based technique (VADER) was chosen to perform sentiment analysis considering the Brazilian Portuguese language. Finally, the data collected were used in statistical tests to obtain other indicators, such as correlation and distribution analysis. Of the 627 news items, 198 (31.58%) were classified as a sentiment of security (TP2; stands for the news type 2), whereas 429 (68.42%) were classified as sentiments that instilled vulnerability (TP3; stands for the news type 3). The correlation between the number of syphilis tests and the number of news types TP2 and TP3 was verified from (i) 2015 to 2017 and (ii) 2018 to 2019. For the TP2 type news, in all periods, the p-values were greater than 0.05, thus generating inconclusive results. From 2015 to 2017, there was an ρ = 0.33 correlation between TP3 news and testing data (p-value = 0.04); the years 2018 and 2019 presented a ρ = 0.67 correlation between TP3 news and the number of syphilis tests performed per month, with p-value = 0.0003. In addition, Granger's test was performed between TP3 news and syphilis testing, which resulted in a p-value = 0.002, thus indicating the existence of Granger causality between these time series. By applying natural language processing to sentiment and informational content analysis of public health campaigns, it was found that the most substantial increase in testing was strongly related to attitude-inducing content (TP3).

Amyloid Beta Oligomers-Induced Ca2+ Entry Pathways: Role of Neuronal Networks, NMDA Receptors and Amyloid Channel Formation.

The molecular basis of amyloid toxicity in Alzheimer's disease (AD) remains controversial. Amyloid ß (Aß) oligomers promote Ca2+ influx, mitochondrial Ca2+ overload and apoptosis in hippocampal neurons in vivo and in vitro, but the primary Ca2+ entry pathways are unclear. We studied Ca2+ entry pathways induced by Aß oligomers in rat hippocampal and cerebellar neurons. Aß oligomers induce Ca2+ entry in neurons. Ca2+ responses to Aß oligomers are large after synaptic networking and prevented by blockers of synaptic transmission. In contrast, in neurons devoid of synaptic connections, Ca2+ responses to Aß oligomers are small and prevented only by blockers of amyloid channels (NA7) and NMDA receptors (MK801). A combination of NA7 and MK801 nearly abolished Ca2+ responses. Non-neuronal cells bearing NMDA receptors showed Ca2+ responses to oligomers, whereas cells without NMDA receptors did not exhibit Ca2+ responses. The expression of subunits of the NMDA receptor NR1/ NR2A and NR1/NR2B in HEK293 cells lacking endogenous NMDA receptors restored Ca2+ responses to NMDA but not to Aß oligomers. We conclude that Aß oligomers promote Ca2+ entry via amyloid channels and NMDA receptors. This may recruit distant neurons intertwisted by synaptic connections, spreading excitation and recruiting further NMDA receptors and voltage-gated Ca2+ channels, leading to excitotoxicity and neuron degeneration in AD.

Psychotherapeutic change in children and adolescents who have been sexually abused: a model from participants' perspectives.

INTRODUCTION: Change in psychotherapy research in cases of child sexual abuse (CSA) has mainly emerged from a symptomatologic view, which needs to be complemented by a subjective perspective of change. Thus, this article aim is to describe different outcomes and stages of change during psychotherapy in children and adolescents who have been sexually abused, from the subjective perspectives of those involved in the process. METHODS: A longitudinal qualitative study was developed. Qualitative interviews were conducted at different moments of the psychotherapeutic process (at around 6 months of therapy, 12 months and at the end of therapy) with 28 children and adolescents aged 6 to 17, with their caregivers and therapists. All children and adolescents attended and then completed psychotherapy due to sexual abuse in natural settings, in public specialized centres in Santiago, Chile. Sexual abuse occurred mainly in an intrafamilial context or by acquaintances. Data analysis was conducted using narrative analysis. RESULTS: Three stages of therapy were identified: (1) settling into therapy, (2) approaching CSA and (3) healing from abuse. Three different outcomes of psychotherapeutic change were also identified: (1) protective and psychosocial changes, (2) changes related to diminishing the effects of abuse and (3) changes related to healing from abuse. Psychosocial characteristics of the cases and features of the therapeutic process are described in each group. DISCUSSION: The outcomes of change and the stages of therapy are interrelated in a dynamic and gradual process where change is linked with the case's psychosocial characteristics and the features of the therapeutic process. Results allowed the authors to situate the voices of the participants within a proposed model of psychotherapeutic change for CSA, with clinical practical implications.

The therapeutic relationship and change processes in child psychotherapy: a qualitative, longitudinal study of the views of children, parents and therapists.

Through the perspectives of children, parents and therapists, this study explored the therapeutic relationship as a change facilitator in different moments of psychotherapy. The children, parents, and therapists (N=15) who formed part of five therapeutic treatments were studied using a qualitative, longitudinal design. Thirty semi-structured interviews were done; half at the beginning and half after four months of psychotherapy. Children's drawings were incorporated, and data were analysed through grounded theory methods and qualitative analysis guidelines for drawings. Participants identified several aspects of the therapeutic relationship as change facilitators. From the first encounters, the therapists' close and adaptable attitude promoted an improved motivation for psychotherapy and enhanced engagement among children and parents. Later in the process, a positive, child-centred and affective therapeutic relationship fostered the child's trust with the therapist as well as a positive relational experience, promoting associated changes in children and the development of socio-affective tools. Parents and therapists saw their own relationship as a change facilitator, as well as a broader understanding in parents of their children and an improved relationship with them. Parent's and child's changes helped each other. Specific and common aspects between participants' perspectives provided a richer understanding of the studied phenomena. This study supports the view that a positive therapeutic relationship facilitates early changes in the motivation of children and parents, and provides them with a healing, relational experience as it develops. A positive parent-therapist relationship is also key for changes to further progress.

Benefits of D-005, a lipid extract from Acrocomia crispa fruits, in the prevention of acute kidney njury induced by nephrotoxicity in rats / Benefícios do D-005, um extrato lipídico de frutos da Acrocomia crispa, na prevenção de lesão renal aguda induzida por nefrotoxicidade em ratos

Abstract Introduction: Aminoglycoside-induced acute kidney injury (AKI) is a pathology closely linked to oxidative and inflammatory reactions. Taking into account the previous reported antioxidant and anti-inflammatory effects of D-005, a lipid extract obtained from Cuban palm Acrocomia crispa (Arecaceae) fruits, this work aimed to evaluate the effects of D-005 on kanamycin-induced AKI. Methods: Male Wistar rats were divided into 7 groups: negative control (vehicle, Tween 65/H2O) and six groups treated with kanamycin to induce AKI: positive control (vehicle), D-005 (25, 100, 200, and 400 mg/kg) and grape seed extract (GSE, 200 mg/kg). D-005, vehicle, and GSE oral treatments were administered once daily for seven days, 1 h before kanamycin (500 mg/kg, i.p.). Serum uric acid and urea concentrations, renal histopathology, and oxidative markers (malondialdehyde (MDA), sulfhydryl (SH) groups, and catalase (CAT) activity) were assessed. Results: D-005 significantly reduced uric acid and urea levels, starting from D-005 100 mg/kg. Histopathologically, D-005, at all the tested doses, protected renal parenchyma structures (glomeruli, proximal tubules, and interstitium). These findings were accompanied by a significant reduction of MDA and SH group concentrations as well as restoration of CAT activity. The highest percentages of inhibition were obtained with the dose of 400 mg/kg. GSE, the reference substance, also prevented kanamycin-induced biochemical and histopathological changes, as well as reduced MDA and SH groups and restored CAT activity. Conclusion: The administration of repeated oral doses of D-005 significantly protected against kanamycin-induced AKI, which could be associated with the antioxidant and anti-inflammatory effects of this extract.

Resumo Introdução: Lesão renal aguda induzida por aminoglicosídeos é uma patologia intimamente ligada a reações oxidativas e inflamatórias. Considerando efeitos antioxidantes e anti-inflamatórios relatados anteriormente do D-005, um extrato lipídico de frutos da palmeira cubana Acrocomia crispa (Arecaceae), este trabalho avaliou efeitos do D-005 na LRA induzida por canamicina. Métodos: Dividiu-se ratos Wistar machos em 7 grupos: controle negativo (veículo, Tween 65/H2O) e seis grupos tratados com canamicina para induzir LRA: controle positivo (veículo), D-005 (25, 100, 200, 400 mg/kg) e extrato de semente de uva (ESU, 200 mg/kg). D-005, veículo, e tratamentos orais com ESU foram administrados uma vez por dia durante sete dias, 1 h antes da canamicina (500 mg/kg, i.p.). Avaliou-se concentrações séricas de ácido úrico e ureia, histopatologia renal e marcadores oxidativos (malondialdeído (MDA), grupos sulfidrila (SH), atividade de catalase (CAT)). Resultados: D-005 reduziu significativamente níveis de ácido úrico e ureia, partindo de D-005 100 mg/kg. Histopatologicamente, D-005, em todas as doses testadas, protegeu estruturas do parênquima renal (glomérulos, túbulos proximais e interstício). Estes achados foram acompanhados por uma redução significativa das concentrações de MDA e grupo SH, e pela restauração da atividade CAT. As maiores porcentagens de inibição foram obtidas com a dose de 400 mg/kg. ESU, a substância de referência, também evitou alterações bioquímicas e histopatológicas induzidas por canamicina, reduziu MDA e grupos SH e restaurou atividade CAT. Conclusão: A administração de doses orais repetidas de D-005 protegeu significativamente contra LRA induzida por canamicina, que pode estar associada aos efeitos antioxidantes e anti-inflamatórios deste extrato.

Role of parenting practices, mother's personality and depressive symptoms in early child development.

In this study we explore the possibility that maternal depressive symptomatology and personality would influence parenting practices which would in turn influence their offspring's socio-emotional and cognitive-motor development. We used a large representative sample of Uruguayan children and their mothers. The Big Five Inventory (BFI), subscales of the Home Observation for Measurement of Environment (HOME), Ages & Stages Questionnaires - third edition (n = 3596), Child Behavior Checklist (n = 3750), and a sociodemographic (SES) questionnaire were administered. We found that favorable scores in child development measures were correlated with maternal openness, extraversion, conscientiousness, agreeableness, low neuroticism, depressive symptomatology, positive parenting practices and high income households. We then elaborated pathway models that allowed us to account for covariance between relevant variables. We found that openness was indirectly associated with aspects of both socioemotional and cognitive motor development via parenting practices and maternal depressive symptomatology. The association between SES and both child development outcomes was fully explained by intermediary variables. Collectively, our results provide support for Belsky's model of child development and can be used by professionals to better target interventions geared at infants and young children and their mothers.

Benefits of D-005, a lipid extract from Acrocomia crispa fruits, in the prevention of acute kidney njury induced by nephrotoxicity in rats.

INTRODUCTION: Aminoglycoside-induced acute kidney injury (AKI) is a pathology closely linked to oxidative and inflammatory reactions. Taking into account the previous reported antioxidant and anti-inflammatory effects of D-005, a lipid extract obtained from Cuban palm Acrocomia crispa (Arecaceae) fruits, this work aimed to evaluate the effects of D-005 on kanamycin-induced AKI. METHODS: Male Wistar rats were divided into 7 groups: negative control (vehicle, Tween 65/H2O) and six groups treated with kanamycin to induce AKI: positive control (vehicle), D-005 (25, 100, 200, and 400 mg/kg) and grape seed extract (GSE, 200 mg/kg). D-005, vehicle, and GSE oral treatments were administered once daily for seven days, 1 h before kanamycin (500 mg/kg, i.p.). Serum uric acid and urea concentrations, renal histopathology, and oxidative markers (malondialdehyde (MDA), sulfhydryl (SH) groups, and catalase (CAT) activity) were assessed. RESULTS: D-005 significantly reduced uric acid and urea levels, starting from D-005 100 mg/kg. Histopathologically, D-005, at all the tested doses, protected renal parenchyma structures (glomeruli, proximal tubules, and interstitium). These findings were accompanied by a significant reduction of MDA and SH group concentrations as well as restoration of CAT activity. The highest percentages of inhibition were obtained with the dose of 400 mg/kg. GSE, the reference substance, also prevented kanamycin-induced biochemical and histopathological changes, as well as reduced MDA and SH groups and restored CAT activity. CONCLUSION: The administration of repeated oral doses of D-005 significantly protected against kanamycin-induced AKI, which could be associated with the antioxidant and anti-inflammatory effects of this extract.

Cell Therapy for Colorectal Cancer: The Promise of Chimeric Antigen Receptor (CAR)-T Cells.

Colorectal cancer (CRC) is a global public health problem as it is the third most prevalent and the second most lethal cancer worldwide. Major efforts are underway to understand its molecular pathways as well as to define the tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs) or neoantigens, in order to develop an effective treatment. Cell therapies are currently gaining importance, and more specifically chimeric antigen receptor (CAR)-T cell therapy, in which genetically modified T cells are redirected against the tumour antigen of interest. This immunotherapy has emerged as one of the most promising advances in cancer treatment, having successfully demonstrated its efficacy in haematological malignancies. However, in solid tumours, such as colon cancer, it is proving difficult to achieve the same results due to the shortage of TSAs, on-target off-tumour effects, low CAR-T cell infiltration and the immunosuppressive microenvironment. To address these challenges in CRC, new approaches are proposed, including combined therapies, the regional administration of CAR-T cells and more complex CAR structures, among others. This review comprehensively summarises the current landscape of CAR-T cell therapy in CRC from the potential tumour targets to the preclinical studies and clinical trials, as well as the limitations and future perspectives of this novel antitumour strategy.

Paradoxical implication of BAX/BAK in the persistence of tetraploid cells.

Pro-apoptotic multi-domain proteins of the BCL2 family such as BAX and BAK are well known for their important role in the induction of mitochondrial outer membrane permeabilization (MOMP), which is the rate-limiting step of the intrinsic pathway of apoptosis. Human or mouse cells lacking both BAX and BAK (due to a double knockout, DKO) are notoriously resistant to MOMP and cell death induction. Here we report the surprising finding that BAX/BAK DKO cells proliferate less than control cells expressing both BAX and BAK (or either BAX or BAK) when they are driven into tetraploidy by transient exposure to the microtubule inhibitor nocodazole. Mechanistically, in contrast to their BAX/BAK-sufficient controls, tetraploid DKO cells activate a senescent program, as indicated by the overexpression of several cyclin-dependent kinase inhibitors and the activation of ß-galactosidase. Moreover, DKO cells manifest alterations in ionomycin-mobilizable endoplasmic reticulum (ER) Ca2+ stores and store-operated Ca2+ entry that are affected by tetraploidization. DKO cells manifested reduced expression of endogenous sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (Serca2a) and transfection-enforced reintroduction of Serca2a, or reintroduction of an ER-targeted variant of BAK into DKO cells reestablished the same pattern of Ca2+ fluxes as observed in BAX/BAK-sufficient control cells. Serca2a reexpression and ER-targeted BAK also abolished the tetraploidy-induced senescence of DKO cells, placing ER Ca2+ fluxes downstream of the regulation of senescence by BAX/BAK. In conclusion, it appears that BAX/BAK prevent the induction of a tetraploidization-associated senescence program. Speculatively, this may contribute to the low incidence of cancers in BAX/BAK DKO mice and explain why human cancers rarely lose the expression of both BAX and BAK.

Severe infections in patients with lymphoproliferative diseases treated with new targeted drugs: A multicentric real-world study.

BACKGROUND: Lymphoid neoplasms treatment has recently been renewed to increase antitumor efficacy and conventional chemotherapies toxicities. Limited data have been published about the infection risk associated with these new drugs, therefore this study analyzes the infectious complications in patients with lymphoproliferative diseases (LPD) treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab, or pembrolizumab), BTK inhibitors (ibrutinib and acalabrutinib), PI3K inhibitors (idelalisib) and BCL2 inhibitors (venetoclax). METHODS: Multicenter retrospective study of 458 LPD patients treated with targeted therapies in real-life setting, in 18 Spanish institutions, from the time of their commercial availability to August 2020. RESULTS: Severe infections incidence was 23% during 17-month median follow-up; cumulative incidence was higher in the first 3-6 months of targeted drug treatment and then decreased. The most frequent etiology was bacterial (54%). Nine (6%) Invasive fungal infections (IFI) were observed, in its majority in chronic lymphocytic leukemia (CLL) patients treated predominantly with ibrutinib. Significant risk factors for severe infection were: severe lymphopenia (p = 0.009, OR 4.7, range 1.3-1.7), combined targeted treatment vs single agent treatment (p = 0.014 OR 2.2 range 1.1-4.2) and previous rituximab (p = 0.03 OR 1.8, range 1.05-3.3). Infection-related mortality was 6%. In 22% of patients with severe infections, definitive discontinuation of the targeted drug was observed. CONCLUSION: A high proportion of patients presented severe infections during follow-up, with non-negligible attributable mortality, but infection incidence is not superior to the one observed during the chemotherapy era. In selected cases with specific risk factors for infection, antimicrobial prophylaxis should be considered.

Toll-like receptors in neuroinflammation, neurodegeneration, and alcohol-induced brain damage.

Toll-like receptors (TLRs) or pattern recognition receptors respond to pathogen-associated molecular patterns (PAMPs) or internal damage-associated molecular patterns (DAMPs). TLRs are integral membrane proteins with both extracellular leucine-rich and cytoplasmic domains that initiate downstream signaling through kinases by activating transcription factors like AP-1 and NF-κB, which lead to the release of various inflammatory cytokines and immune modulators. In the central nervous system, different TLRs are expressed mainly in microglia and astroglial cells, although some TLRs are also expressed in oligodendroglia and neurons. Activation of TLRs triggers signaling cascades by the host as a defense mechanism against invaders to repair damaged tissue. However, overactivation of TLRs disrupts the sustained immune homeostasis-induced production of pro-inflammatory molecules, such as cytokines, miRNAs, and inflammatory components of extracellular vesicles. These inflammatory mediators can, in turn, induce neuroinflammation, and neural tissue damage associated with many neurodegenerative diseases. This review discusses the critical role of TLRs response in Alzheimer's disease, Parkinson's disease, ischemic stroke, amyotrophic lateral sclerosis, and alcohol-induced brain damage and neurodegeneration.