Kv1.5 in the Immune System: the Good, the Bad, or the Ugly?

For the last 20 years, knowledge of the physiological role of voltage-dependent potassium channels (Kv) in the immune system has grown exponentially. Leukocytes express a limited repertoire of Kv channels, which contribute to the membrane potential. These proteins are involved in the immune response and are therefore considered good pharmacological targets. Although there is a clear consensus about the physiological relevance of Kv1.3, the expression and the role of Kv1.5 are controversial. However, recent reports indicate that certain heteromeric Kv1.3/Kv1.5 associations may provide insight on Kv1.5. Here, we summarize what is known about this issue and highlight the role of Kv1.5 partnership interactions that could be responsible for this debate. The Kv1.3/Kv1.5 heterotetrameric composition of the channel and their possible differential associations with accessory regulatory proteins warrant further investigation

Persones grans estrangeres residents a les llars dels ancians. Estudi de cas

En la darrera dècada s’ha produït un canvi social, demogràfic i cultural de gran transcendència. Es tracta d’un fenomen migratori caracteritzat per una elevada entrada de població immigrant. Tot i que l’imaginari social relacionava principalment aquest fenomen demogràfic amb la població estrangera extracomunitària, reflectit per exemple en la premsa escrita (Vecina, 2008), en realitat l’entrada de població ha tingut orígens diversos, persones d’altres comunitats autònomes i estrangeres, tant de la UE com d’altres països. Si ens centram en la població estrangera gran, el pes principal recau en els provinents de la UE. Aquesta realitat respon a un procés d’entrada i assentament força diferenciat: migració laboral de població jove dels diferents orígens mencionats, fenomen destacat els darrers anys, d’una banda, i, de l’altra, migració de tipus residencial, fenomen que va sorgir paral·lelament al desenvolupament mateix de la comunitat com a destinació turística de primer ordre. Aquesta darrera particularitat està relacionada amb el tipus de població gran estrangera, el seu origen, les raons d’acabar residint a les Illes i en alguns casos, la situació actual de vulnerabilitat social. Aquest estudi mostra la realitat d’una sèrie de persones estrangeres residents a les llars dels ancians de l’Institut Mallorquí d’Afers Socials.En la última década se ha producido un cambio social, demográfico y cultural de gran trascendencia; se trata de un fenómeno migratorio caracterizado por una elevada entrada de población inmigrante. A pesar de que el imaginario social relacionaba principalmente este fenómeno demográfico con la población extranjera extracomunitaria, reflejado por ejemplo en la prensa escrita (Vecina, 2008), en realidad la entrada de población ha estado formada por diversos orígenes, tanto por personas procedentes de otras comunidades autónomas como de países extranjeros, de la UE y de otros países. Si nos centramos en las personas mayores extranjeras, el peso principal recae sobre los procedentes de la UE. Esta realidad responde a un proceso de entrada y asentamiento bastante diferenciado: migración laboral de población joven, de los diferentes orígenes mencionados, junto a migración de tipo residencial, fenómeno que surgió paralelamente al propio desarrollo de la comunidad como destino turístico de primer orden. Esta última particularidad está relacionada con el tipo de personas mayores extranjeras, su origen, las razones de acabar residiendo en las Islas y en algunos casos, la situación actual de vulnerabilidad social. Este estudio muestra la realidad de una serie de personas extranjeras que llegaron en la década de los sesenta, actualmente residentes en los hogares de ancianos de l’Institut Mallorquí d’Afers Socials

Individual epidermal growth factor receptor autophosphorylation sites do not stringently define association motifs for several SH2-containing proteins

To determine whether individual autophosphorylation sites in the epidermal growth factor (EGF) receptor define specific interaction sites for the in vivo association of signal transduction proteins that contain src homology 2 (SH2) domains, the capacity of wild-type and mutant EGF receptors to associate with several SH2 domain-containing proteins has been assayed. Mutants included receptors with single autophosphorylation site mutations at each of five autophosphorylation sites and receptors in which multiple autophosphorylation sites were removed by point mutation or deletion of carboxyl-terminal residues. Receptor association, as measured by coimmunoprecipitation, has been determined for phospholipase C-gamma 1, the ras GTPase-activating protein, the p85 subunit of phosphatidylinositol 3-kinase, and the src homology and collagen protein. In contrast to data obtained with single autophosphorylation site mutants of other receptor tyrosine kinases, none of the EGF receptor single site mutants was dramatically impaired in its capacity to associate with any of these SH2-containing proteins. However, association was completely abrogated when all five autophosphorylation sites were mutated or removed by deletion. These results indicate that individual autophosphorylation sites in the EGF receptor are not stringently required for the recognition and association of different SH2-containing substrates. Thus, EGF receptor autophosphorylation sites seem to be flexible and/or compensatory in their capacity to mediate association with these four SH2-containing substrates

Exonucleases: degrading DNA to deal with genome damage, cell death, inflammation and cancer

Although DNA degradation might seem an unwanted event, it is essential in many cellular processes that are key to maintaining genomic stability and cell and organism homeostasis. The capacity to cut out nucleotides one at a time from the end of a DNA chain is present in enzymes called exonucleases. Exonuclease activity might come from enzymes with multiple other functions or specialized enzymes only dedicated to this function. Exonucleases are involved in central pathways of cell biology such as DNA replication, repair, and death, as well as tuning the immune response. Of note, malfunctioning of these enzymes is associated with immune disorders and cancer. In this review, we will dissect the impact of DNA degradation on the DNA damage response and its links with inflammation and cancer

Sodium-glucose cotransporter inhibitors: beyond glycaemic control

SGLT2; Chronic kidney disease; Diabetic nephropathySGLT2; Malaltia renal crònica; Nefropatia diabèticaSGLT2; Enfermedad renal crónica; Nefropatía diabéticaDiabetes increases the risk of adverse cardiovascular and renal events. Recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to reduce cardiovascular complications and slow diabetic kidney disease progression in patients with type 2 diabetes. The glycaemic control exerted by these drugs is not greater than the one achieved with other classical glucose-lowering medications such as sulphonylureas. For that reason, plausible renoprotective mechanisms independent from glycaemic control have been proposed such as blood pressure control, body weight loss, intraglomerular pressure reduction and a decrease in urinary proximal tubular injury biomarkers. Interestingly, the hypothesis that SGLT2 inhibitors have a direct renoprotective effect has been addressed in diabetic and non-diabetic models. In this editorial, we update the different postulated mechanisms involved in the cardiorenal protection afforded by SGLT2 inhibition in chronic kidney disease.The authors are current recipients of research grants from the FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII, PI17/00257 and REDINREN, RD16/0009/0030

A Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy

The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analogue of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effect

Proyectos de intervención en Gambia de alimentación

II Congreso de Alimentación, Nutrición y Dietética. Avances en Nutrición y Dietética Clínica: Prevención, Tratamiento y Gestión - Rol del Dietista-Nutricionist

Antioxidant Roles of SGLT2 Inhibitors in the Kidney

Diabetic kidney disease; Mitochondrial dysfunction; Oxidative stressMalaltia renal diabètica; Disfunció mitocondrial; Estrès oxidatiuEnfermedad renal diabética; Disfunción mitocondrial; Estrés oxidativoThe reduction-oxidation (redox) system consists of the coupling and coordination of various electron gradients that are generated thanks to serial reduction-oxidation enzymatic reactions. These reactions happen in every cell and produce radical oxidants that can be mainly classified into reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS modulate cell-signaling pathways and cellular processes fundamental to normal cell function. However, overproduction of oxidative species can lead to oxidative stress (OS) that is pathological. Oxidative stress is a main contributor to diabetic kidney disease (DKD) onset. In the kidney, the proximal tubular cells require a high energy supply to reabsorb proteins, metabolites, ions, and water. In a diabetic milieu, glucose-induced toxicity promotes oxidative stress and mitochondrial dysfunction, impairing tubular function. Increased glucose level in urine and ROS enhance the activity of sodium/glucose co-transporter type 2 (SGLT2), which in turn exacerbates OS. SGLT2 inhibitors have demonstrated clear cardiovascular benefits in DKD which may be in part ascribed to the generation of a beneficial equilibrium between oxidant and antioxidant mechanisms.The authors are current recipients of grants from FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII (PI17/00257 and RICORS RD21/0005/0016), and Fundació la Marató de TV3 (421/C/2020, 759/U/2020 and 215/C/2021)

The transcription factor PU.1 is involved in macrophage proliferation

PU.1 is a tissue-specific transcription factor that is expressed in cells of the hematopoietic lineage including macrophages, granulocytes, and B lymphocytes. Bone marrow-derived macrophages transfected with an antisense PU.1 expression construct or treated with antisense oligonucleotides showed a decrease in proliferation compared with controls. In contrast, bone marrow macrophages transfected with a sense PU.1 expression construct displayed enhanced macrophage colony- stimulating factor (M-CSF)-dependent proliferation. Interestingly, there was no effect of sense or antisense constructs of PU.1 on the proliferation of the M-CSF-independent cell line, suggesting that the response was M-CSF dependent. This was further supported by the finding that macrophages transfected with a sense or an antisense PU.1 construct showed, respectively, an increased or a reduced level of surface expression of receptors for M-CSF. The enhancement of proliferation seems to be selective for PU.1, since transfections with several other members of the ets family, including ets-2 and fli-1, had no effect. Various mutants of PU.1 were also tested for their ability to affect macrophage proliferation. A reduction in macrophage proliferation was found when cells were transfected with a construct in which the DNA-binding domain of PU.1 was expressed. The PEST (proline-, glutamic acid-, serine-, and threonine-rich region) sequence of the PU.1 protein, which is an important domain for protein-protein interactions in B cells, was found to have no influence on PU.1- enhanced macrophage proliferation when an expression construct containing PU.1 minus the PEST domain was transfected into bone marrow- derived macrophages. In vivo, PU.1 is phosphorylated on several serine residues. The transfection of plasmids containing PU.1 with mutations at each of five serines showed that only positions 41 and 45 are critical for enhanced macrophage proliferation. We conclude that PU.1 is necessary for the M-CSF-dependent proliferation of macrophages. One of the proliferation-relevant targets of this transcription factor could be the M-CSF receptor

Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression

Dose of Trp53, the main keeper of genome stability, influences tumorigenesis; however, the causes underlying and driving tumorigenesis over time by the loss of a single p53 allele are still poorly characterized. Here, we found that single p53 allele loss specifically impacted the oxidative, DNA damage and inflammatory status of hematopoietic lineages. In particular, single Trp53 allele loss in mice triggered oxidative stress in peripheral blood granulocytes and spleenocytes, whereas lack of two Trp53 alleles produced enhanced oxidative stress in thymus cells, resulting in a higher incidence of lymphomas in the Trp53 knockout (KO) mice compared with hemizygous (HEM). In addition, single or complete loss of Trp53 alleles, as well as p53 downregulation, led to a differential increase in basal, LPS- and UVB-induced expression of a plethora of pro-inflammatory cytokine, such as interleukin-12 (Il-12a), TNFα (Tnfa) and interleukin (Il-23a) in bone marrow-derived macrophage cells (BMDMs) compared to WT cells. Interestingly, p53-dependent increased inflammatory gene expression correlated with deregulated expression of the NF-κB pathway inhibitor IκBα. Chromatin immunoprecipitation data revealed decreased p65 binding to Nfkbia in the absence of p53 and p53 binding to Nfkbia promoter, uncovering a novel crosstalk mechanism between p53 and NF-κB transcription factors. Overall, our data suggest that single Trp53 allele loss can drive a sustained inflammatory, DNA damage and oxidative stress response that, over time, facilitate and support carcinogenesis