Background: The cancer cell fusion theory could be one of the best explanations for the metastasis from primary tumours. Methods: Herein, we co-cultured colorectal cancer (CRC) stem cells with human ...monocytes and analysed the properties of the generated tumour hybrid cells (THCs). The presence of THCs in the bloodstream together with samples from primary and metastatic lesions and their clinical correlations were evaluated in CRC patients and were detected by both FACS and immunofluorescence methods. Additionally, the role of SIGLEC5 as an immune evasion molecule in colorectal cancer was evaluated. Results: Our data demonstrated the generation of THCs after the in vitro co-culture of CRC stem cells and monocytes. These cells, defined as CD45+CD14+EpCAM+, showed enhanced migratory and proliferative abilities. The THC-specific cell surface signature allows identification in matched primary tumour tissues and metastases as well as in the bloodstream from patients with CRC, thus functioning as a biomarker. Moreover, SIG-LEC5 expression on in vitro generated THCs has shown to be involved in the mechanism for immune evasion. Additionally, sSIGLEC5 levels correlated with THC numbers in the prospective cohort of patients. Conclusions: Our results indicate the generation of a hybrid entity after the in vitro co-culture between CRC stem cells and human monocytes. Moreover, THC numbers present in patients are related to both prognosis and the later spread of metastases in CRC patients.
Obstructive sleep apnea (OSA) is a syndrome characterized by repeated pauses in breathing induced by a partial or complete collapse of the upper airways during sleep. Intermittent hypoxia (IH), a ...hallmark characteristic of OSA, has been proposed to be a major determinant of cancer development, and patients with OSA are at a higher risk of tumors. Both OSA and healthy monocytes have been found to show enhanced HIF1α expression under IH. Moreover, these cells under IH polarize toward a tumor-promoting phenotype in a HIF1α-dependent manner and influence tumor growth via vascular endothelial growth factor (VEGF). Monocytes from patients with OSA increased the tumor-induced microenvironment and exhibited an impaired cytotoxicity in a 3D tumor in vitro model as a result of the increased HIF1α secretion. Adequate oxygen restoration both in vivo (under continuous positive airway pressure treatment, CPAP) and in vitro leads the monocytes to revert the tumor-promoting phenotype, demonstrating the plasticity of the innate immune system and the oxygen recovery relevance in this context.
Circulating extracellular vesicles (EVs) are proposed to participate in enhancing pathways of recovery after stroke through paracrine signaling. To verify this hypothesis in a proof-of-concept study, ...blood-derived allogenic EVs from rats and xenogenic EVs from humans who experienced spontaneous good recovery after an intracerebral hemorrhage (ICH) were administered intravenously to rats at 24 h after a subcortical ICH. At 28 days, both treatments improved the motor function assessment scales score, showed greater fiber preservation in the perilesional zone (diffusion tensor-fractional anisotropy MRI), increased immunofluorescence markers of myelin (MOG), and decreased astrocyte markers (GFAP) compared with controls. Comparison of the protein cargo of circulating EVs at 28 days from animals with good vs. poor recovery showed down-expression of immune system activation pathways (CO4, KLKB1, PROC, FA9, and C1QA) and of restorative processes such as axon guidance (RAC1), myelination (MBP), and synaptic vesicle trafficking (SYN1), which is in line with better tissue preservation. Up-expression of PCSK9 (neuron differentiation) in xenogenic EVs-treated animals suggests enhancement of repair pathways. In conclusion, the administration of blood-derived EVs improved recovery after ICH. These findings open a new and promising opportunity for further development of restorative therapies to improve the outcomes after an ICH.
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Treatment with blood-derived extracellular vesicles (EVs) enhance brain protection and repair post-ICH and improve functional recovery. The administration of allogeneic or xenogenic blood-derived EVs, regardless of origin, is safe. Proteins in EVs are involved in biological pathways of neural protection and repair.
spp. is a well-recognized pathogen in neonates; however, limited data are available in adults. We studied microbiological and clinical characteristics of
spp. causing bloodstream infections (BSI) in ...our institution (January 2005-July 2020). Overall, 141 BSI episodes affecting 139 patients were identified and medical records reviewed. Antimicrobial susceptibility was recovered from our informatics system and 118 isolates from 116 patients were available for further microbiological studies. Whole genome sequencing (WGS) was completed in 107 isolates. Incidence of
BSI was 0.3/1000 overall admissions (range 0.12-0.60), with maximum prevalence (27 episodes, 19.1%) during 2017-2018. Relevant patients' clinical characteristics were 71.9% ≥60 years (
= 100), with high comorbidity rates (49%, ≥2), 23 (74.2%) of them died within 1 month of the BSI episode. WGS identified all isolates as
s when Kraken bioinformatics taxonomic tool was used despite some which were identified as
(32/118) or
(5/118) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Nevertheless, when using MASH distance,
(63/107),
(38/107), and
(6/107) were assigned. Carbapenemase (
) and extended-spectrum β-lactases (ESBL) (
) genes were found in seven and three isolates, respectively, one of them expressing both genes. The worldwide-disseminated IncL/M scaffold plasmid was identified in six VIM producers. Four genotypes were established based on their virulence factors and resistome.
spp. emerged as a relevant nosocomial pathogen causing BSI in elderly patients in our hospital, particularly in recent years with a remarkable increase in antibiotic resistance. ESBL and carbapenemases production related to plasmid dissemination are particularly noteworthy.IMPORTANCE
spp. is the third most frequent pathogen involved in outbreaks at neonatal facilities and is primarily associated with bacteremia episodes. In this study, we characterized all causing bloodstream infection (BSI) in patients admitted to our hospital during a 16-year period (2005-2020). Despite having no neonatal intensive care unit in our hospital, this study revealed that
spp. is a relevant pathogen causing BSI in elderly patients with high comorbidity rates. A significant increase of antimicrobial resistance was detected over time, particularly in 2020 and coinciding with the coronavirus disease (COVID-19) pandemic and nosocomial spread of multidrug-resistant
spp. isolates. extended-spectrum β-lactases and carbapenemases genes associated with plasmid dissemination, typically detected in other Enterobacterales species, were also identified, reinforcing the role of
spp. in the antimicrobial resistance landscape. Additionally, this work highlights the need to reclassify the species of
, since discrepancies were observed in the identification when using different tools.
Sepsis is a pathology in which patients suffer from a proinflammatory response and a dysregulated immune response, including T cell exhaustion. A number of therapeutic strategies to treat human ...sepsis, which are different from antimicrobial and fluid resuscitation treatments, have failed in clinical trials, and solid biomarkers for sepsis are still lacking. Herein, we classified 85 patients with sepsis into two groups according to their blood oxygen saturation (SaO
): group I (SaO
≤ 92%,
= 42) and group II (SaO
> 92%,
= 43). Blood samples were taken before any treatment, and the immune response after
LPS challenge was analyzed, as well as basal expression of PD-L1 on monocytes and levels of sPD-L1 in sera. The patients were followed up for 1 month. Taking into account reinfection and
frequency, a significantly poorer evolution was observed in patients from group I. The analysis of HLA-DR expression on monocytes, T cell proliferation and cytokine profile after
LPS stimulation confirmed an impaired immune response in group I. In addition, these patients showed both, high levels of PD-L1 on monocytes and sPD-L1 in serum, resulting in a down-regulation of the adaptive response. A blocking assay using an anti-PD-1 antibody reverted the impaired response. Our data indicated that SaO
levels on admission have emerged as a potential signature for immune status, including PD-L1 expression. An anti-PD-1 therapy could restore the T cell response in hypoxemic sepsis patients with SaO
≤ 92% and high PD-L1 levels.
Background: Tumor-associated macrophages (TAMs) play a crucial role in suppressing the immunosurveillance function of the immune system that prevents tumor growth. Indeed, macrophages can also be ...targeted by different chemotherapeutic agents improving the action over immune checkpoints to fight cancer. Here we describe the effect of trabectedin and lurbinectedin on human macrophage cell viability and function. Methods: Blood monocytes from healthy donors were differentiated into macrophages and exposed to different stimuli promoting functional polarization and differentiation into tumor-associated macrophages. Cells were challenged with the chemotherapeutic drugs and the effects on cell viability and function were analyzed. Results: Human macrophages exhibit at least two different profiles in response to these drugs. One-fourth of the blood donors assayed (164 individuals) were extremely sensitive to trabectedin and lurbinectedin, which promoted apoptotic cell death. Macrophages from other individuals retained viability but responded to the drugs increasing reactive oxygen production and showing a rapid intracellular calcium rise and a loss of mitochondrial oxygen consumption. Cell-membrane exposure of programmed-death ligand 1 (PD-L1) significantly decreased after treatment with therapeutic doses of these drugs, including changes in the gene expression profile of hypoxia-inducible factor 1 alpha (HIF-1α)-dependent genes, among other. Conclusions: The results provide evidence of additional onco-therapeutic actions for these drugs.
Agmatine, an endogenous neuromodulator, is a potential candidate to constitute an adjuvant/monotherapy for the management of depression. A recent study by our group demonstrated that agmatine induces ...Nrf2 and protects against corticosterone effects in a hippocampal neuronal cell line. The present study is an extension of this previous study by assessing the antidepressant-like effect of agmatine in an animal model of depression induced by corticosterone in mice. Swiss mice were treated simultaneously with agmatine or imipramine at a dose of 0.1 mg/kg/day (p.o.) and corticosterone for 21 days and the daily administrations of experimental drugs were given immediately prior to corticosterone (20 mg/kg/day, p.o.) administrations. Wild-type C57BL/6 mice (Nrf2 (+/+)) and Nrf2 KO (Nrf2 (−/−)) were treated during 21 days with agmatine (0.1 mg/kg/day, p.o.) or vehicle. Twenty-four hours after the last treatments, the behavioral tests and biochemical assays were performed. Agmatine treatment for 21 days was able to abolish the corticosterone-induced depressive-like behavior and the alterations in the immunocontent of mature BDNF and synaptotagmin I, and in the serotonin and glutamate levels. Agmatine also abolished the corticosterone-induced changes in the morphology of astrocytes and microglia in CA1 region of hippocampus. In addition, agmatine treatment in control mice increased noradrenaline, serotonin, and dopamine levels, CREB phosphorylation, mature BDNF and synaptotagmin I immunocontents, and reduced pro-BDNF immunocontent in the hippocampus. Agmatine’s ability to produce an antidepressant-like effect was abolished in Nrf2 (−/−) mice. The present results reinforce the participation of Nrf2 in the antidepressant-like effect produced by agmatine and expand literature data concerning its mechanisms of action.
Acute myocardial infarction (AMI) is associated with systemic inflammatory processes and metabolic alterations. Microbial-derived metabolites, such as short-chain fatty acids and trimethylamine ...N-oxide (TMAO), have emerged in recent years as key players in the modulation of inflammation, with potential implications for cardiovascular diseases. We performed a prospective observational study that monitored the serological concentration of bacterial metabolites in 45 young patients (<55 years) without cardiovascular risk factors but with AMI, at hospital admission and at 3 months of follow-up, and compared them with a control group. TMAO and acetate levels were significantly higher in AMI, whereas butyrate and propionate were significantly lower. The acetate/propionate ratio showed the most discrimination between AMI and controls by receiver operating characteristic analysis (area under the curve 0.769, P < 0.0001). A multivariate logistic regression model revealed that this ratio was independently associated with AMI. Short-chain fatty acid concentrations, but not TMAO, exhibited significant correlations with inflammatory and coagulation parameters. Three months after the acute AMI event, all metabolite levels returned to those observed in healthy controls except butyrate. In conclusion, our study reveals disturbances of the serological concentration of microbiota-derived metabolites in AMI that are also related to inflammatory and coagulation parameters. These findings highlight an interesting field of study in the potential role of microbial metabolites from gut in cardiovascular disease.
The bioavailability and regulation of iron is essential for central biological functions in mammals. The role of this element in ferroptosis and the dysregulation of its metabolism contribute to ...diseases, ranging from anemia to infections, alterations in the immune system, inflammation and atherosclerosis. In this sense, monocytes and macrophages modulate iron metabolism and splenic function, while at the same time they can worsen the atherosclerotic process in pathological conditions. Since the nucleotide-binding oligomerization domain 1 (NOD1) has been linked to numerous disorders, including inflammatory and cardiovascular diseases, we investigated its role in iron homeostasis. The iron content was measured in various tissues of Apoe-/- and Apoe-/-Nod1-/- mice fed a high-fat diet (HFD) for 4 weeks, under normal or reduced splenic function after ligation of the splenic artery. In the absence of NOD1 the iron levels decreased in spleen, heart and liver regardless the splenic function. This iron decrease was accompanied by an increase in the recruitment of F4/80+-macrophages in the spleen through a CXCR2-dependent signaling, as deduced by the reduced recruitment after administration of a CXCR2 inhibitor. CXCR2 mediates monocyte/macrophage chemotaxis to areas of inflammation and accumulation of leukocytes in the atherosclerotic plaque. Moreover, in the absence of NOD1, inhibition of CXCR2 enhanced atheroma progression. NOD1 activation increased the levels of GPX4 and other iron and ferroptosis regulatory proteins in macrophages. Our findings highlight the preeminent role of NOD1 in iron homeostasis and ferroptosis. These results suggest promising avenues of investigation for the diagnosis and treatment of iron-related diseases directed by NOD1.
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•Absence of NOD1 reduces splenic iron content under pro-atherogenic conditions.•Splenic NOD1 regulates iron homeostasis and macrophage metabolism.•Mobilization of CD68+-cells depends on NOD1 and CXCR2 interplay.•NOD1 activation protects against ferroptosis in macrophages.
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