Nuclear receptors: Lipid and hormone sensors with essential roles in the control of cancer development.

Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that act as biological sensors and use a combination of mechanisms to modulate positively and negatively gene expression in a spatial and temporal manner. The highly orchestrated biological actions of several NRs influence the proliferation, differentiation, and apoptosis of many different cell types. Synthetic ligands for several NRs have been the focus of extensive drug discovery efforts for cancer intervention. This review summarizes the roles in tumour growth and metastasis of several relevant NR family members, namely androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), thyroid hormone receptor (TR), retinoic acid receptors (RARs), retinoid X receptors (RXRs), peroxisome proliferator-activated receptors (PPARs), and liver X receptors (LXRs). These studies are key to develop improved therapeutic agents based on novel modes of action with reduced side effects and overcoming resistance.

Pain reduction of topical sevoflurane vs intravenous opioids in pressure ulcers.

Recently, it has been reported that topical irrigations of liquid sevoflurane on the bed of painful wounds produce a rapid, intense, and lasting analgesic effect. In this paper, A cohort of 112 patients with painful pressure ulcers who were refractory to opioids (or who exhibited undesirable adverse events to them) was treated with topical sevoflurane as per local institutional policy. These patients were recruited from an intensive care unit for a period of 3 years. The main aim was to determine the effectiveness of topical sevoflurane in reducing the pain of PUs and reducing the ulcer area. Study findings are reported and discussed herein and suggest that sevoflurane is a viable and promising treatment option for PUs.

Thyroid hormones inhibit TGF-ß signaling and attenuate fibrotic responses.

TGF-ß, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-ß/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMAD-binding elements in response to TGF-ß, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis.

Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor ß1 (TRß) appears to be associated with cancer onset and progression. We found that expression of TRß increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRß. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.

Map3k8 Modulates Monocyte State and Atherogenesis in ApoE-/- Mice.

OBJECTIVE: Map3k8 (Cot/Tpl2) activates the MKK1/2-ERK1/2, MAPK pathway downstream from interleukin-1R, tumor necrosis factor-αR, NOD-2R (nucleotide-binding oligomerization domain-like 2R), adiponectinR, and Toll-like receptors. Map3k8 plays a key role in innate and adaptive immunity and influences inflammatory processes by modulating the functions of different cell types. However, its role in atherogenesis remains unknown. In this study, we analyzed the role of this kinase in this pathology. APPROACH AND RESULTS: We show here that Map3k8 deficiency results in smaller numbers of Ly6ChighCD11clow and Ly6ClowCD11chigh monocytes in ApoE-/- mice fed a high-fat diet (HFD). Map3k8-/-ApoE-/- monocytes displayed high rates of apoptosis and reduced amounts of Nr4a1, a transcription factor known to modulate apoptosis in Ly6ClowCD11chigh monocytes. Map3k8-/-ApoE-/- splenocytes and macrophages showed irregular patterns of cytokine and chemokine expression. Map3k8 deficiency altered cell adhesion and migration in vivo and decreased CCR2 expression, a determinant chemokine receptor for monocyte mobilization, on circulating Ly6ChighCD11clow monocytes. Map3k8-/-ApoE-/- mice fed an HFD showed decreased cellular infiltration in the atherosclerotic plaque, with low lipid content. Lesions had similar size after Map3k8+/+ApoE-/- bone marrow transplant into Map3k8-/-ApoE-/- and Map3k8+/+ApoE-/- mice fed an HFD, whereas smaller plaques were observed after the transplantation of bone marrow lacking both ApoE and Map3k8. CONCLUSIONS: Map3k8 decreases apoptosis of monocytes and enhances CCR2 expression on Ly6ChighCD11clow monocytes of ApoE-/- mice fed an HFD. These findings explain the smaller aortic lesions in ApoE-/- mice with Map3k8-/-ApoE-/- bone marrow cells fed an HFD, supporting further studies of Map3k8 as an antiatherosclerotic target.

Spatio-Temporal Analysis of Urban Acoustic Environments with Binaural Psycho-Acoustical Considerations for IoT-Based Applications.

Sound pleasantness or annoyance perceived in urban soundscapes is a major concern in environmental acoustics. Binaural psychoacoustic parameters are helpful to describe generic acoustic environments, as it is stated within the ISO 12913 framework. In this paper, the application of a Wireless Acoustic Sensor Network (WASN) to evaluate the spatial distribution and the evolution of urban acoustic environments is described. Two experiments are presented using an indoor and an outdoor deployment of a WASN with several nodes using an Internet of Things (IoT) environment to collect audio data and calculate meaningful parameters such as the sound pressure level, binaural loudness and binaural sharpness. A chunk of audio is recorded in each node periodically with a microphone array and the binaural rendering is conducted by exploiting the estimated directional characteristics of the incoming sound by means of DOA estimation. Each node computes the parameters in a different location and sends the values to a cloud-based broker structure that allows spatial statistical analysis through Kriging techniques. A cross-validation analysis is also performed to confirm the usefulness of the proposed system.

Pro-apoptotic signaling induced by Retinoic acid and dsRNA is under the control of Interferon Regulatory Factor-3 in breast cancer cells.

Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.

Tumor suppressive actions of the nuclear receptor corepressor 1.

Nuclear Receptor Corepressor 1 (NCoR) is an important transcriptional regulator that interacts with nuclear receptors and other transcription factors. Recent results have shown the presence of inactivating mutations or deletions of the NCoR gene in human tumors. NCoR has a strong tumor suppressor activity, inhibiting invasion, metastasis formation and tumor growth in xenograft mouse models. These changes are associated to transcriptional inhibition of genes linked to bad prognosis and increased metastasis in cancer patients. NCoR loss causes a long-term repression of NCoR gene transcription, suggesting that NCoR deficiency in the cancer cell could be propagated playing a role in tumor progression in the absence of NCoR gene mutations. The thyroid hormone receptor TRß increases NCoR expression and this induction is essential in mediating the anti-metastatic and tumor suppressive actions of the receptor. Since metastasis is the main cause of cancer-related deaths, these results define NCoR as a potential target for cancer therapy.

Thyroid hormone receptors, cell growth and differentiation.

BACKGROUND: Tissue homeostasis depends on the balance between cell proliferation and differentiation. Thyroid hormones (THs), through binding to their nuclear receptors, can regulate the expression of many genes involved in cell cycle control and cellular differentiation. This can occur by direct transcriptional regulation or by modulation of the activity of different signaling pathways. SCOPE OF REVIEW: In this review we will summarize the role of the different receptor isoforms in growth and maturation of selected tissues and organs. We will focus on mammalian tissues, and therefore we will not address the fundamental role of the THs during amphibian metamorphosis. MAJOR CONCLUSIONS: The actions of THs are highly pleiotropic, affecting many tissues at different developmental stages. As a consequence, their effects on proliferation and differentiation are highly heterogeneous depending on the cell type, the cellular context, and the developmental or transformation status. Both during development and in the adult, stem cells are essential for proper organ formation, maintenance and regeneration. Recent evidence suggests that some of the actions of the thyroid hormone receptors could be secondary to regulation of stem/progenitor cell function. Here we will also include the latest knowledge on the role of these receptors in proliferation and differentiation of embryonic and adult stem cells. GENERAL SIGNIFICANCE: The thyroid hormone receptors are potent regulators of proliferation and differentiation of many cell types. This can explain the important role of the thyroid hormones and their receptors in key processes such as growth, development, tissue homeostasis or cancer. This article is part of a Special Issue entitled Thyroid hormone signalling.

Basophil activation after nonsteroidal anti-inflammatory drugs stimulation in patients with immediate hypersensitivity reactions to these drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in allergic reactions of which two main types exist: IgE-mediated and crossintolerance. The diagnosis of crossintolerance reactions is often based on the drug provocation test. The potential value of the basophil activation test (BAT) was evaluated using different basophil markers in the diagnosis of patients with crossintolerance to NSAIDs and cutaneous symptoms. We studied 46 patients with crossintolerance to NSAIDs and 45 tolerant controls. BAT was performed with acetyl salicylic acid, paracetamol, diclofenac, dipyrone, naproxen, and ibuprofen at four different concentrations using CD193 and CD203c as basophil markers and CD63 as activation marker. We compared BAT results using CD193⁺ or CD193⁺ CD203c⁺ for basophil selection and found a significant increase in the stimulation index when using CD193⁺ CD203c⁺ in both patients and controls (P = 0.004 and P = 0.017, respectively). Selection of living cells only produced an increase in basophil stimulation in patients for both CD193⁺ and CD193⁺ CD203c⁺ (P < 0.001 for both), whereas in controls there was no change with CD193⁺ and a decrease with CD193⁺ CD203c⁺ (P = 0.001). We found that CD193⁺ CD203c⁺ increased the percentage of positive cases in patients and controls when compared with CD193⁺. When excluding dead cells, there was an increase of 21.7% in patients and 10% in controls. These results indicate that using CD193⁺ CD203⁺, excluding dead cells, is the best approach for BAT although this test is not recommended for the diagnosis of patients with crossintolerance to NSAIDs owing to its low sensitivity and specificity.

Fluoroquinolone photodegradation influences specific basophil activation.

Fluoroquinolones (FQs) are photoreactive drugs, but it is not known whether laboratory light exposure can influence the induction of photoproducts and modify in vitro test results. The basophil activation test (BAT) has proven to be useful for evaluating immunoglobulin E (IgE)-mediated hypersensitivity to FQs, with a higher percentage of positive responders with ciprofloxacin (CIP) than with moxifloxacin (MOX). We studied the effect of laboratory light on CIP and MOX degradation, and drug-protein conjugate formation, and its influence on the BAT for evaluating IgE-mediated hypersensitivity to FQs. The results showed an important decrease in fluorescence emission intensity under light compared to dark conditions for MOX, and that BAT positivity was lower in light (17.9%) than in dark (35.7%) conditions. No changes were found for CIP in either fluorescence emission intensity or BAT results (46.4% in both conditions). We can conclude that light exposure is a critical factor in BAT results when photolabile drugs like MOX are used. Therefore, light is important when interpreting in vitro results.

Receptors of thyroid hormones.

The important physiological actions of the thyroid hormones are mediated by binding to nuclear thyroid hormone receptors (TRs), encoded by two genes TRalpha and TRbeta. These receptors act as hormone-dependent transcription factors by binding to DNA motifs located in the regulatory regions of target genes and recruiting coregulators (coactivators and corepresors), which alter chromatin structure. Novel thyromimetics have been developed that bind preferentially TRbeta could be used for treatment of hyperlipidemia and obesity. TRbeta gene mutations cause resistance to thyroid hormones (RTH), characterized by inappropriately high thyroid-stimulating hormone (TSH) levels due to lack of feedback inhibition of thyroid hormones on the hypothalamus and pituitary gland, and to reduced sensitivity of other TRbeta target tissues to thyroid hormones. Very recently, patients heterozygous for TRalpha mutations have been identified. These patients exhibit clinical symptoms of hypothyroidism in TRalpha target tissues such as intestine or hearth and near normal circulating TSH and thyroid hormone levels.

Acute liver failure secondary to malignant infiltration: A single center experience.

Acute liver failure (ALF) requires early and very precise treatment decisions for a diagnosis that is not often easy and may lead to erroneous decisions. Accordingly, we undertook a review of ALF secondary to malignant infiltration given the rarity of the condition, plus its singularity and therapeutic implications. This review should aid in establishing future frameworks for action. Analyze cases of ALF secondary to malignant infiltration in our center during the last 5 years and review the literature. We undertook a retrospective review of all cases of ALF due to malignant infiltration in our center between January 2015 and December 2019. Data were recorded on demographic characteristics, clinical presentation, type of tumor, diagnostic techniques used, treatment and evolution. We also undertook a literature review on the subject and compared the results. AFL secondary to malignant infiltration was diagnosed in five patients, four women and one man with a median age 58 years. The most common clinical presentation was jaundice. Three cases were due to infiltration by hematological tumors (non-Hodgkin lymphoma and histiocytosis), one a cholangiocarcinoma and one lung cancer. In all cases a liver biopsy was required for diagnosis, this being conclusive in four cases; diagnosis in the non-conclusive case was by analysis of the hepatectomy sample after transplantation. Three patients died due to AFL in a mean of 13.8 days, another died 5 months after diagnosis as a consequence of the tumor while the patient with a diagnosis of non-Hodgkin lymphoma and transplant recipient remains alive after a follow-up of 6 years and after receiving chemotherapy. AFL due to malignant infiltration is a very unusual condition but with a high rate of mortality. It requires a rapid and precise diagnosis given the relevant treatment options.

The thyroid hormone enhances mouse embryonic fibroblasts reprogramming to pluripotent stem cells: role of the nuclear receptor corepressor 1.

Introduction: Pluripotent stem cells can be generated from somatic cells by the Yamanaka factors Oct4, Sox2, Klf4 and c-Myc. Methods: Mouse embryonic fibroblasts (MEFs) were transduced with the Yamanaka factors and generation of induced pluripotent stem cells (iPSCs) was assessed by formation of alkaline phosphatase positive colonies, pluripotency gene expression and embryod bodies formation. Results: The thyroid hormone triiodothyronine (T3) enhances MEFs reprogramming. T3-induced iPSCs resemble embryonic stem cells in terms of the expression profile and DNA methylation pattern of pluripotency genes, and of their potential for embryod body formation and differentiation into the three major germ layers. T3 induces reprogramming even though it increases expression of the cyclin kinase inhibitors p21 and p27, which are known to oppose acquisition of pluripotency. The actions of T3 on reprogramming are mainly mediated by the thyroid hormone receptor beta and T3 can enhance iPSC generation in the absence of c-Myc. The hormone cannot replace Oct4 on reprogramming, but in the presence of T3 is possible to obtain iPSCs, although with low efficiency, without exogenous Klf4. Furthermore, depletion of the corepressor NCoR (or Nuclear Receptor Corepressor 1) reduces MEFs reprogramming in the absence of the hormone and strongly decreases iPSC generation by T3 and also by 9cis-retinoic acid, a well-known inducer of reprogramming. NCoR depletion also markedly antagonizes induction of pluripotency gene expression by both ligands. Conclusions: Inclusion of T3 on reprogramming strategies has a potential use in enhancing the generation of functional iPSCs for studies of cell plasticity, disease and regenerative medicine.

Plant hormesis: Revising of the concepts of biostimulation, elicitation and their application in a sustainable agricultural production.

Current research in basic and applied knowledge of plant science has aimed to unravel the role of the interaction between environmental factors and the genome in the physiology of plants to confer the ability to overcome challenges in a climate change scenario. Evidence shows that factors causing environmental stress (stressors), whether of biological, chemical, or physical origin, induce eustressing or distressing effects in plants depending on the dose. The latter suggests the induction of the "hormesis" phenomenon. Sustainable crop production requires a better understanding of hormesis, its basic concepts, and the input variables to make its management feasible. This implies that acknowledging hormesis in plant research could allow specifying beneficial effects to effectively manage environmental stressors according to cultivation goals. Several factors have been useful in this regard, which at low doses show beneficial eustressing effects (biostimulant/elicitor), while at higher doses, they show distressing toxic effects. These insights highlight biostimulants/elicitors as tools to be included in integrated crop management strategies for reaching sustainability in plant science and agricultural studies. In addition, compelling evidence on the inheritance of elicited traits in plants unfolds the possibility of implementing stressors as a tool in plant breeding.

The thyroid hormone receptors as modulators of skin proliferation and inflammation.

We have analyzed the role of the thyroid hormone receptors (TRs) in epidermal homeostasis. Reduced keratinocyte proliferation is found in interfollicular epidermis of mice lacking the thyroid hormone binding isoforms TRα1 and TRß (KO mice). Similar results were obtained in hypothyroid animals, showing the important role of the liganded TRs in epidermal proliferation. In addition, KO and hypothyroid animals display decreased hyperplasia in response to 12-O-tetradecanolyphorbol-13-acetate. Both receptor isoforms play overlapping functional roles in the skin because mice lacking individually TRα1 or TRß also present a proliferative defect but not as marked as that found in double KO mice. Defective proliferation in KO mice is associated with reduction of cyclin D1 expression and up-regulation of the cyclin-dependent kinase inhibitors p19 and p27. Paradoxically, ERK and AKT activity and expression of downstream targets, such as AP-1 components, are increased in KO mice. Increased p65/NF-κB and STAT3 phosphorylation and, as a consequence, augmented expression of chemokines and proinflammatory cytokines is also found in these animals. These results show that thyroid hormones and their receptors are important mediators of skin proliferation and demonstrate that TRs act as endogenous inhibitors of skin inflammation, most likely due to interference with AP-1, NF-κB, and STAT3 activation.

Vinyl-triphenylamine dyes, a new family of switchable fluorescent probes for targeted two-photon cellular imaging: from DNA to protein labeling.

On the basis of our previous work on vinyl-triphenylamine derived DNA fluorophores we explored the structure space around this core by coupling it to diverse cationic, anionic and zwitterionic groups in the aim of targeting different classes of biomolecules. In parallel core modifications were performed to optimize the photophysical properties (quantum yield, two-photon absorption). The resulting water soluble π-conjugated molecules are called TP dyes and display an exceptional combination of optical properties: high two-photon absorption cross-section, high photostability, no self-quenching, and switchable fluorescence emission when bound to a biopolymer matrix. The linear and nonlinear optical properties of the TP dyes were studied in vitro in presence of DNA and in presence of a model protein (human serum albumin) using complementary absorption and fluorescence spectroscopy characterization tools. Structure modifications enabled to switch from DNA probes (cationic TP-pyridinium series) to protein probes (anionic TP-rhodanine series) without affecting the optical properties. Finally most TP compounds appear cell-permeant and show an intracellular localization consistent with their in vitro target specificity.