The aryl hydrocarbon receptor (AHR) is a markedly established regulator of a plethora of cellular and molecular processes. Its initial role in the detoxification of xenobiotic compounds has been ...partially overshadowed by its involvement in homeostatic and organ physiology processes. In fact, the discovery of its ability to bind specific target regulatory sequences has allowed for the understanding of how AHR modulates such processes. Thereby, AHR presents functions in transcriptional regulation, chromatin architecture modifications and participation in different key signaling pathways. Interestingly, such fields of influence end up affecting organ and tissue homeostasis, including regenerative response both to endogenous and exogenous stimuli. Therefore, from classical spheres such as canonical transcriptional regulation in embryonic development, cell migration, differentiation or tumor progression to modern approaches in epigenetics, senescence, immune system or microbiome, this review covers all aspects derived from the balance between regulation/deregulation of AHR and its physio-pathological consequences.
The liver is among the few organs having the ability to self-regenerate in response to a severe damage compromising its functionality. The Aryl hydrocarbon receptor (Ahr) is a transcription factor ...relevant for the detoxification of xenobiotics but also largely important for liver development and homeostasis. Hence, liver cell differentiation is developmentally modulated by Ahr through the controlled expression of pluripotency and stemness-inducing genes. Here, 2/3 partial hepatectomy (PH) was used as a clinically relevant approach to induce liver regeneration in Ahr-expressing (Ahr
) and Ahr-null (Ahr
) mice. Ahr expression and activity were early induced after 2/3 PH to be gradually downmodulated latter during regeneration. Ahr
mice triggered liver regeneration much faster than AhR
animals, although both reached full regeneration at the latest times. At initial stages after PHx, earlier regenerating Ahr
livers had upregulation of cell proliferation markers and increased activation of signalling pathways related to stemness such as Hippo-YAP and Wnt/β-catenin, concomitantly with the induction of pro-inflammatory cytokines TNFa, IL6 and p65. These phenotypes, together with the improved metabolic adaptation of Ahr
mice after PHx and their induced sustained cell proliferation, could likely result from the expansion of undifferentiated stem cells residing in the liver expressing OCT4, SOX2, KLF4 and NANOG. We propose that Ahr needs to be induced early during regeneration to fine-tune liver regrowth to physiological values. Since Ahr deficiency did not result in liver overgrowth, its transient pharmacological inhibition could serve to improve liver regeneration in hepatectomized and transplanted patients and in those exposed to damaging liver toxins and carcinogens.
Aging impairs organismal homeostasis leading to multiple pathologies. Yet, the mechanisms and molecular intermediates involved are largely unknown. Here, we report that aged aryl hydrocarbon ...receptor-null mice (
) had exacerbated cellular senescence and more liver progenitor cells. Senescence-associated markers β-galactosidase (SA-β-Gal), p16
and p21
and genes encoding senescence-associated secretory phenotype (SASP) factors TNF and IL1 were overexpressed in aged
livers. Chromatin immunoprecipitation showed that AhR binding to those gene promoters repressed their expression, thus adjusting physiological levels in
livers. MCP-2, MMP12 and FGF secreted by senescent cells were overproduced in aged AhR-null livers. Supporting the relationship between senescence and stemness, liver progenitor cells were overrepresented in
mice, probably contributing to increased hepatocarcinoma burden. These AhR roles are not liver-specific since adult and embryonic AhR-null fibroblasts underwent senescence in culture, overexpressing SA-β-Gal, p16
and p21
. Notably, depletion of senescent cells with the senolytic agent navitoclax restored expression of senescent markers in
fibroblasts, whereas senescence induction by palbociclib induced an AhR-null-like phenotype in
fibroblasts. AhR levels were downregulated by senescence in mouse lungs but restored upon depletion of p16
-expressing senescent cells. Thus, AhR restricts age-induced senescence associated to a differentiated phenotype eventually inducing resistance to liver tumorigenesis.
(1)
: Because life events when there is a family member with a disability can affect the overall family wellbeing, contributing to enhance family quality of life (FQoL) in the field of early ...childhood intervention has become a priority. However, it is a distal outcome that needs other short-term outcomes to be addressed, some of them under the potential impact of support services. This study examines the relationships between caregiver burden, family confidence, and FQoL, as well as the influence of child and family variables. (2)
: A total of 58 families with children in early intervention from four Spanish communities participated. Hierarchical regression was conducted to assess the relevance of each predictor. Also, a mediation was performed to investigate the mediating role of family confidence. (3)
: The family income impacted FQoL scores, and when burden and confidence were added, it was no longer relevant. Mothers with higher levels of confidence predicted a higher FQoL. Finally, we found a complete mediation of family confidence in the relations between severity and caregiver burden on FQoL. (4)
: Caregiver burden and family confidence affect FQoL. Building families' confidence contributes to attenuating the impact of burden on FQoL.
Aim: To assess the acute effect of empagliflozin versus dapagliflozin administration on flow-mediated vasodilation in patients with type 2 diabetes mellitus. Design: A double-blind clinical trial, at ...the Experimental and Clinical Therapeutics Institute, University Health Sciences Center, at the Universidad de Guadalajara, in inpatients with T2D according to the 2023 ADA criteria. Methods: Thirty patients (15 males and 15 females), aged between 35 and 65 years, were included in this study, according to the 2023 ADA criteria. The eligible patients were randomly assigned to three groups: empagliflozin 25 mg once daily, dapagliflozin 10 mg once daily, or placebo once daily. Anthropometric parameters were taken using validated techniques. FMD was measured using a high-resolution semiautomatic ultrasound UNEX-EF 38G (UNEX Co., Ltd., Nagoya, Japan). Arterial tension was determined with the OMRON electronic digital sphygmomanometer (HEM 907 XL, Kyoto, Japan). Results: The group of patients who received empagliflozin had a significantly lower baseline flow-mediated dilation (FMD) compared to the group receiving dapagliflozin (p = 0.017); at the end of this study, the empagliflozin group achieved a comparable FMD to the dapagliflozin group (p = 0.88). Conclusion: After the treatment period, the empagliflozin and dapagliflozin groups achieved similar FMD, suggesting a class effect.
Patients on hemodialysis show dysregulated immunity, basal hyperinflammation and a marked vulnerability to COVID-19. We evaluated the immune profile in COVID-19 hemodialysis patients and the changes ...associated with clinical deterioration after the hemodialysis session. Recruited patients included eight hemodialysis subjects with active, PCR-confirmed SARS-CoV-2 infection, five uninfected hemodialysis patients and five healthy controls. In SARS-CoV-2-infected hemodialysis patients TNF-α, IL-6 and IL-8 were particularly increased. Lymphopenia was mostly due to reduction in CD4+ T, B and central memory CD8+ T cells. There was a predominance of classical and intermediate monocytes with reduced HLA-DR expression and enhanced production of pro-inflammatory molecules. Immune parameters were analysed pre- and post-hemodialysis in three patients with COVID-19 symptoms worsening after the hemodialysis session. There was a higher than 2.5-fold increase in GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-17A and IL-21 in serum, and augmentation of monocytes-derived TNF-α, IL-1β and IL-8 and CXCL10 (p < 0.05). In conclusion, COVID-19 in hemodialysis patients associates with alteration of lymphocyte subsets, increasing of pro-inflammatory cytokines and monocyte activation. The observed worsening during the hemodialysis session in some patients was accompanied by augmentation of particular inflammatory cytokines, which might suggest biomarkers and therapeutic targets to prevent or mitigate the hemodialysis-related deterioration during SARS-CoV-2 infection.
The field of telepractice is generating increasing interest in recent years. In recent years, early childhood services have used resources such as support for interventions in families with children ...with autism spectrum disorder. Due to this situation, the social validity of such resources has emerged in this sector, receiving individual attention from academics and practitioners. However, a further deepening of such analyses is needed. Therefore, the main objective of this work is to analyze papers published in the Web of Science on social validity and telepractice in autism spectrum disorders. Bibliometric analysis allows us to discover the current state of a research field, to identify the main authors, articles, and topics, and to propose future lines of research to develop it further. Articles published between 2000 and 2021 were analyzed quantitatively, and by co-occurrence of words and authors. Subsequently, through bibliographic linking, the articles were grouped into different clusters. Five central themes were found, with social skills and the effectiveness of intervention programs being the most developed areas of research. Furthermore, studies focusing on evidence-based practices are necessary for the development of this research field. Thus, the analysis of social validity in the field of telepractice in children with autism spectrum disorders is a developing field within the early childhood sector.
The SNF1 (sucrose non-fermenting 1)-related protein kinases 1 (SnRKs1) are the plant orthologs of the budding yeast SNF1 and mammalian AMPK (AMP-activated protein kinase). These evolutionarily ...conserved kinases are metabolic sensors that undergo activation in response to declining energy levels. Upon activation, SNF1/AMPK/SnRK1 kinases trigger a vast transcriptional and metabolic reprograming that restores energy homeostasis and promotes tolerance to adverse conditions, partly through an induction of catabolic processes and a general repression of anabolism. These kinases typically function as a heterotrimeric complex composed of two regulatory subunits, β and γ, and an α-catalytic subunit, which requires phosphorylation of a conserved activation loop residue for activity. Additionally, SNF1/AMPK/SnRK1 kinases are controlled by multiple mechanisms that have an impact on kinase activity, stability, and/or subcellular localization. Here we will review current knowledge on the regulation of SNF1/AMPK/SnRK1 by upstream components, post-translational modifications, various metabolites, hormones, and others, in an attempt to highlight both the commonalities of these essential eukaryotic kinases and the divergences that have evolved to cope with the particularities of each one of these systems.
Non-small cell lung adenocarcinoma (NSCLC) bearing K-RasG12D mutations is one of the most prevalent types of lung cancer worldwide. Aryl hydrocarbon receptor (AHR) expression varies in human lung ...tumors and has been associated with either increased or reduced lung metastasis. In the mouse, Ahr also adjusts lung regeneration upon injury by limiting the expansion of resident stem cells. Here, we show that the loss of Ahr enhances K-RasG12D-driven NSCLC in mice through the amplification of stem cell subpopulations. Consistent with this, we show that K-RasG12D;Ahr−/− lungs contain larger numbers of cells expressing markers for both progenitor Clara (SCGB1A1 and CC10) and alveolar type-II (SFTPC) cells when compared to K-RasG12D;Ahr+/+-driven tumors. They also have elevated numbers of cells positive for pluripotent stem cells markers such as SOX2, ALDH1, EPCAM, LGR5 and PORCN. Typical pluripotency genes Nanog, Sox2 and c-Myc were also upregulated in K-RasG12D;Ahr−/− lung tumors as found by RNAseq analysis. In line with this, purified K-RasG12D/+;Ahr−/− lung cells generate larger numbers of organoids in culture that can subsequently differentiate into bronchioalveolar structures enriched in both pluripotency and stemness genes. Collectively, these data indicate that Ahr antagonizes K-RasG12D-driven NSCLC by restricting the number of cancer-initiating stem cells. They also suggest that Ahr expression might represent a good prognostic marker to determine the progression of K-RasG12D-positive NSCLC patients.
Mammalian embryogenesis is a complex process controlled by transcription factors that regulate the balance between pluripotency and differentiation. Transcription factor aryl hydrocarbon receptor ...(AhR) regulates OCT4/POU5F1 and NANOG, both essential controllers of pluripotency, stemness and early embryo development. Molecular mechanisms controlling OCT4/POU5F1 and NANOG during embryogenesis remain unidentified. We show that AhR regulates pluripotency factors and maintains the metabolic activity required for proper embryo differentiation. AhR-lacking embryos (AhR−/−) showed a pluripotent phenotype characterized by a delayed expression of trophectoderm differentiation markers. Accordingly, central pluripotency factors OCT4/POU5F1 and NANOG were overexpressed in AhR−/− embryos at initial developmental stages. An altered intracellular localization of these factors was observed in the absence of AhR and, importantly, Oct4 had an opposite expression pattern with respect to AhR from the two-cell stage to blastocyst, suggesting a negative regulation of OCT4/POU5F by AhR. We propose that AhR is a regulator of pluripotency and differentiation in early mouse embryogenesis.
•AhR regulates pluripotency factors OCT4 and NANOG during early embryo differentiation•AhR lacking embryos (AhR−/−) show a pluripotent phenotype•Pluripotent phenotype of AhR−/− embryos show enhanced glycolytic metabolism
In this article, Fernández-Salguero and colleagues show that transcription factor AhR regulates pluripotency factors and maintains the metabolic activity required for proper embryo differentiation. AhR-lacking embryos (AhR−/−) showed a pluripotent phenotype characterized by a delayed expression of trophectoderm differentiation markers. Accordingly, central pluripotency factors were overexpressed in AhR−/− embryos at initial developmental stages.
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