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IntroductionSARS-CoV-2 viral load has been related to COVID-19 severity. The main aim of this study was to evaluate the relationship between SARS-CoV-2 viremia and SNPs in genes previously studied by our group as predictors of COVID-19 severity.Materials and methodsRetrospective observational study including 340 patients hospitalized for COVID-19 in the University Hospital La Princesa between March 2020 and December 2021, with at least one viremia determination. Positive viremia was considered when viral load was above the quantifiable threshold (20 copies/ml). A total of 38 SNPs were genotyped. To study their association with viremia a multivariate logistic regression was performed.ResultsThe mean age of the studied population was 64.5 years (SD 16.6), 60.9% patients were male and 79.4% white non-Hispanic. Only 126 patients (37.1%) had at least one positive viremia. After adjustment by confounders, the presence of the minor alleles of rs2071746 (HMOX1; T/T genotype OR 9.9 p

In recent decades, compelling evidence has emerged showing that organelles are not static structures but rather form a highly dynamic cellular network and exchange information through membrane contact sites. Although high-throughput techniques facilitate identification of novel contact sites (e.g., organelle-organelle and organelle-vesicle interactions), little is known about their impact on cellular physiology. Moreover, even less is known about how the dysregulation of these structures impacts on cellular function and therefore, disease. Particularly, cancer cells display altered signaling pathways involving several cell organelles; however, the relevance of interorganelle communication in oncogenesis and/or cancer progression remains largely unknown. This review will focus on organelle contacts relevant to cancer pathogenesis. We will highlight specific proteins and protein families residing in these organelle-interfaces that are known to be involved in cancer-related processes. First, we will review the relevance of endoplasmic reticulum (ER)-mitochondria interactions. This section will focus on mitochondria-associated membranes (MAMs) and particularly the tethering proteins at the ER-mitochondria interphase, as well as their role in cancer disease progression. Subsequently, the role of Ca2+ at the ER-mitochondria interphase in cancer disease progression will be discussed. Members of the Bcl-2 protein family, key regulators of cell death, also modulate Ca2+ transport pathways at the ER-mitochondria interphase. Furthermore, we will review the role of ER-mitochondria communication in the regulation of proteostasis, focusing on the ER stress sensor PERK (PRKR-like ER kinase), which exerts dual roles in cancer. Second, we will review the relevance of ER and mitochondria interactions with other organelles. This section will focus on peroxisome and lysosome organelle interactions and their impact on cancer disease progression. In this context, the peroxisome biogenesis factor (PEX) gene family has been linked to cancer. Moreover, the autophagy-lysosome system is emerging as a driving force in the progression of numerous human cancers. Thus, we will summarize our current understanding of the role of each of these organelles and their communication, highlighting how alterations in organelle interfaces participate in cancer development and progression. A better understanding of specific organelle communication sites and their relevant proteins may help to identify potential pharmacological targets for novel therapies in cancer control.

17β-estradiol is a neuronal survival factor against oxidative stress that triggers its protective effect even in the absence of classical estrogen receptors. The polymodal transient receptor potential vanilloid subtype 1 (TRPV1) channel has been proposed as a steroid receptor implied in tissue protection against oxidative damage. We show here that TRPV1 is sufficient condition for 17β-estradiol to enhance metabolic performance in injured cells. Specifically, in TRPV1 expressing cells, the application of 17β-estradiol within the first 3 h avoided H2O2-dependent mitochondrial depolarization and the activation of caspase 3/7 protecting against the irreversible damage triggered by H2O2. Furthermore, 17β-estradiol potentiates TRPV1 single channel activity associated with an increased open probability. This effect was not observed after the application of 17α-estradiol. We explored the TRPV1-Estrogen relationship also in primary culture of hippocampal-derived neurons and observed that 17β-estradiol cell protection against H2O2-induced damage was independent of estrogen receptors pathway activation, membrane started and stereospecific. These results support the role of TRPV1 as a 17β-estradiol-activated ionotropic membrane receptor coupling with mitochondrial function and cell survival.

Macrophage activation and polarization are closely linked with metabolic rewiring, which is required to sustain their biological functions. These metabolic alterations allow the macrophages to adapt to the microenvironment changes associated with inflammation or tissue damage (hypoxia, nutrient imbalance, oxidative stress, etc.) and to fulfill their highly energy-demanding proinflammatory and anti-microbial functions. This response is integrated via metabolic sensors that coordinate these metabolic fluxes with their functional requirements. Here we review how the metabolic and phenotypic plasticity of macrophages are intrinsically connected with the hypoxia stress sensors and the unfolded protein response in the endoplasmic reticulum, and how these molecular pathways participate in the maladaptive polarization of macrophages in human pathology and chronic inflammation.

Helicobacter pylori (H. pylori) infection is the major risk factor associated with the development of gastric cancer. The transition from normal mucosa to non-atrophic gastritis, triggered primarily by H. pylori infection, initiates precancerous lesions which may then progress to atrophic gastritis and intestinal metaplasia. Further progression to dysplasia and gastric cancer is generally believed to be attributable to processes that no longer require the presence of H. pylori. The responses that develop upon H. pylori infection are directly mediated through the action of bacterial virulence factors, which drive the initial events associated with transformation of infected gastric cells. Besides genetic and to date poorly defined environmental factors, alterations in gastric cell stress-adaptive mechanisms due to H. pylori appear to be crucial during chronic infection and gastric disease progression. Firstly, H. pylori infection promotes gastric cell death and reduced epithelial cell turnover in the majority of infected cells, resulting in primary tissue lesions associated with an initial inflammatory response. However, in the remaining gastric cell population, adaptive responses are induced that increase cell survival and proliferation, resulting in the acquisition of potentially malignant characteristics that may lead to precancerous gastric lesions. Thus, deregulation of these intrinsic survival-related responses to H. pylori infection emerge as potential culprits in promoting disease progression. This review will highlight the most relevant cellular adaptive mechanisms triggered upon H. pylori infection, including endoplasmic reticulum stress and the unfolded protein response, autophagy, oxidative stress, and inflammation, together with a subsequent discussion on how these factors may participate in the progression of a precancerous lesion. Finally, this review will shed light on how these mechanisms may be exploited as pharmacological targets, in the perspective of opening up new therapeutic alternatives for non-invasive risk control in gastric cancer.

Bactericidal activity of quinolones has been related to a combination of DNA fragmentation, reactive oxygen species (ROS) production and programmed cell death (PCD) systems. The underlying molecular systems responsible for reducing bactericidal effect during antimicrobial therapy in low-level quinolone resistance (LLQR) phenotypes need to be clarified. To do this and also define possible new antimicrobial targets, the transcriptome profile of isogenic Escherichia coli harboring quinolone resistance mechanisms in the presence of a clinical relevant concentration of ciprofloxacin was evaluated. A marked differential response to ciprofloxacin of either up- or downregulation was observed in LLQR strains. Multiple genes implicated in ROS modulation (related to the TCA cycle, aerobic respiration and detoxification systems) were upregulated (sdhC up to 63.5-fold) in mutants with LLQR. SOS system components were downregulated (recA up to 30.7-fold). yihE, a protective kinase coding for PCD, was also upregulated (up to 5.2-fold). SdhC inhibition sensitized LLQR phenotypes (up to ΔLog = 2.3 after 24 h). At clinically relevant concentrations of ciprofloxacin, gene expression patterns in critical systems to bacterial survival and mutant development were significantly modified in LLQR phenotypes. Chemical inhibition of SdhC (succinate dehydrogenase) validated modulation of ROS as an interesting target for bacterial sensitization.

The positive long-term effects of conversion to everolimus (EVL) after heart transplantation (HT) have been evaluated in several studies. However, the timing of EVL initiation, the best way to combine it with other immunosuppressive treatments, and the impact of these combinations on the immune response are poorly understood aspects. Here, we analyzed the immune phenotype and function of HT patients (n = 56) at short and long terms (prospective and retrospective cohorts), taking into account the time of EVL initiation: early (3 months post-transplant, EVL-E group) or late (>1 year post-transplant, EVL-L group) compared with mycophenolate mofetil treatment (MMF group). We show that early EVL conversion from MMF allows the increase of cytotoxic (CD56dim CD16+) NK and effector-memory (EM, CD45RA− CCR7−) CD8+ T cell subsets, which show a significantly higher level of expression of cytotoxic molecules, IFN-γ production and degranulation ability under activation. NK cell expansion is accompanied by an altered balance of receptor expression, increasing the activation state, and lytic activity of those cells. Those changes are detected after as little as 1 month after EVL conversion in association with the expansion of regulatory T cells and the decrease in B cell frequency. However, no changes in the immune cells subsets were observed after late EVL initiation (EVL-L) compared with the MMF group. Our results imply that only early EVL conversion induces key changes in the post-transplant immune response, preserving an efficient anti-viral response, but simultaneously showing a limited ability to counteract the cytotoxic response to the allograft.