Acetaminophen (APAP) is usually safe when administrated in therapeutic doses; however, APAP overdose can lead to severe liver injury. APAP can cause direct hepatocyte damage, and stimulates an ...inflammatory response leading to oxidative stress. Supressor of Cytokine Signaling (SOCS) 2 modulates cytokine and growth factor signaling, and plays a role in the regulation of hepatic cellular processes. Our study evaluated the role of SOCS2 in APAP liver injury. The administration of a toxic dose (600 mg/kg) of APAP caused significant liver necrosis in WT mice. In SOCS2
mice, there was significantly more necrosis, neutrophil recruitment, and expression of the neutrophil-active chemokine CXCL-1. Expression of proinflammatory cytokines, such as TNF-α and IL-6, was elevated, while expression of anti-inflammatory cytokines, IL-10 and TGF-β, was diminished.
, SOCS2
hepatocytes expressed more p-NF-kB and produced more ROS than WT hepatocytes when exposed to APAP. SOCS2
hepatocytes were more sensitive to cell death in the presence of IL-6 and hydrogen peroxide. The administration of catalase
and
resulted in a pronounced reduction of cells/mice death and necrosis in the SOCS2
group. We have demonstrated that SOCS2 has a protective role in the liver by controlling pro-oxidative and inflammatory mechanisms induced by APAP.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T ...cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental Trypanosoma cruzi infection. The relevance of AhR for the outcome of T. cruzi infection is not known and was investigated here. We infected wild-type (WT) mice and AhR knockout (AhR KO) mice with T. cruzi (Y strain) and determined levels of parasitemia, myocardial inflammation and fibrosis, expression of AhR/cytokines/suppressor of cytokine signaling (SOCS) (spleen/heart), and production of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO(-)) (spleen). AhR expression was increased in the heart of infected WT mice. Infected AhR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an anticipated increased immune response characterized by increased levels of inflammatory cytokines and reduced expression of SOCS2 and SOCS3 in the heart. In vitro, AhR deficiency caused impairment in parasite replication and decreased levels of ROS production. In conclusion, AhR influences the development of murine Chagas disease by modulating ROS production and regulating the expression of key physiological regulators of inflammation, SOCS1 to -3, associated with the production of cytokines during experimental T. cruzi infection.
Current chemical therapies for Chagas Disease (CD) lack ability to clear Trypanosoma cruzi (Tc) parasites and cause severe side effects, making search for new strategies extremely necessary. We ...evaluated the action of Tityus serrulatus venom (TsV) components during Tc infection. TsV treatment increased nitric oxide and pro-inflammatory cytokine production by Tc-infected macrophages (MØ), decreased intracellular parasite replication and trypomastigotes release, also triggering ERK1/2, JNK1/2 and p38 activation. Ts7 demonstrated the highest anti-Tc activity, inducing high levels of TNF and IL-6 in infected MØ. TsV/Ts7 presented synergistic effect on p38 activation when incubated with Tc antigen. KPP-treatment of MØ also decreased trypomastigotes releasing, partially due to p38 activation. TsV/Ts7-pre-incubation of Tc demonstrated a direct effect on parasite decreasing MØ-trypomastigotes releasing. In vivo KPP-treatment of Tc-infected mice resulted in decreased parasitemia. Summarizing, this study opens perspectives for new bioactive molecules as CD-therapeutic treatment, demonstrating the TsV/Ts7/KPP-trypanocidal and immunomodulatory activity during Tc infection.
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•TsV induces inflammatory mediators inhibiting T. cruzi replication in host cells.•TsV components have a direct effect in T. cruzi differentiation.•The mechanism of TsV-trypanocidal activity involve MAPKs signaling in host cells.•Ts14-derived tripeptide (KPP) retain the trypanocidal activity in vitro and in vivo.•KPP a potential candidate to design drugs for Chagas disease treatment.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor initially identified as the receptor for dioxin. Almost half a century after its discovery, AHR is now recognized as a ...receptor for multiple physiological ligands, with important roles in health and disease. In this review, we discuss the role of AHR in the gut-brain axis and its potential value as a therapeutic target for immune-mediated diseases.
Tumor-associated macrophages (TAMs) play an important role in the immune response to cancer, but the mechanisms by which the tumor microenvironment controls TAMs and T cell immunity are not ...completely understood. Here we report that kynurenine produced by glioblastoma cells activates aryl hydrocarbon receptor (AHR) in TAMs to modulate their function and T cell immunity. AHR promotes CCR2 expression, driving TAM recruitment in response to CCL2. AHR also drives the expression of KLF4 and suppresses NF-κB activation in TAMs. Finally, AHR drives the expression of the ectonucleotidase CD39 in TAMs, which promotes CD8
T cell dysfunction by producing adenosine in cooperation with CD73. In humans, the expression of AHR and CD39 was highest in grade 4 glioma, and high AHR expression was associated with poor prognosis. In summary, AHR and CD39 expressed in TAMs participate in the regulation of the immune response in glioblastoma and constitute potential targets for immunotherapy.
An increasing number of innovative therapies have emerged in the field of wound healing. Nanostructured systems have been used to improve wound healing at different stages. The drug itself may be ...formulated at a nanoscale such that it can function as its own “carrier” or nanomaterials may be used as drug delivery vehicles. The present work covers the latest advancements on innovative nano‐based organic and inorganic materials. These novel drug delivery systems possess high stability, large surface area and tunable compositions and have demonstrated their wound‐healing properties using in vitro and in vivo models. Key areas in the development of new systems for wound care are the assessment of biological compatibility, the evaluation of anti‐microbial activity and the in vivo efficacy assessment using full‐thickness skin models. Due to the multifactorial nature of chronic wound occurrence robust models should support the investigation of new materials in order to elucidate mechanisms involved in the sequence of physiologic processes that take place at wound healing. Although several nanoparticles have been successfully tested both in vitro and in vivo, researchers are still investigating the approaches to implementing large scale production of nanotechnological platforms to wound healing treatments.
Several nanomaterials have been employed in wound healing in each type of healing phase (Hemostasis, Inflammation, Proliferation, Remodeling). The rationale for using each material strongly depends on the phase but also the duration of the therapeutic effect, dose, deepness and mechanism of action. NPs, nanoparticles.
Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive ...investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.
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•A multidisciplinary approach to study effects of environmental factors on astrocytes•Linuron boosts IRE1α-XBP1 signaling in astrocytes via Sigmar1•Astrocytic IRE1α-XBP1 signaling promotes CNS inflammation in EAE•IRE1α-XBP1 signaling is activated in astrocytes in multiple sclerosis
An environmental trigger, the herbicide linuron boosts astrocyte pathogenic activities in the context of CNS inflammation by activating IRE1α-XBP1 signaling in mice and, potentially, multiple sclerosis patients.
Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including microcephaly, known as congenital ZIKV syndrome. The identification of host factors involved in ZIKV replication may guide ...efficacious therapeutic interventions. In genome-wide transcriptional studies, we found that ZIKV infection triggers aryl hydrocarbon receptor (AHR) activation. Specifically, ZIKV infection induces kynurenine (Kyn) production, which activates AHR, limiting the production of type I interferons (IFN-I) involved in antiviral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia (PML) protein, which limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains in vitro and also suppressed replication of the related flavivirus dengue. Finally, AHR inhibition with a nanoparticle-delivered AHR antagonist or an inhibitor developed for human use limited ZIKV replication and ameliorated newborn microcephaly in a murine model. In summary, we identified AHR as a host factor for ZIKV replication and PML protein as a driver of anti-ZIKV intrinsic immunity.
Obstructive sleep apnea (OSA) is a disorder characterized by obstructive apneas, hypopneas, and/or arousals related to respiratory effort caused by repetitive collapse of the upper airway during ...sleep. Left untreated, or with poor adherence to treatment, is likely to lead to negative outcomes, especially cardiac or cerebrovascular diseases. Our objective was to investigate age as a potential factor that may interfere with adherence to treatment with automatic positive airway pressure (APAP).
This is a cross-sectional study on 1151 patients with OSA and we analyzed the adherence data of all patients who had been on APAP for at least six months during the period from July 1, 2019 to December 31, 2020 at Centro de Medicina do Sono. Spearman correlation was used in the bivariate analysis and to determine the factors associated with APAP adherence, a logistic regression was performed.
Of 1151 patients included, 780 patients were men (67.1%) and the majority was under 65 years (59.4%). APAP adherence was higher in older age groups (p<0.001) and in patients with a higher AHI (p < 0.001), no differences were observed with regards to gender. In the multivariable regression analysis, the main factors associated with adherence were age group over 65 years (OR = 2.435; 95% CI = 1.862-3.185), AHI 15-30/h (OR = 1.733; 95% CI = 1.242-2.416), and AHI > 30/h (OR = 3.406; 95% CI = 2.426-4.782).
Patients older than 65 years have better adherence to APAP than younger ones and with moderate but especially severe AHI have better adherence than those with the milder form of the disease.
Squaraine dyes are a family of compounds known for their relevant photophysical and photochemical properties potentially useful as photosensitizing agents. Since pyridines have been introduced into ...the skeleton of several families of compounds to enhance their pharmacological activity, and this approach had not yet been performed on squaraines, novel dyes derived from benzeindole functionalized with picolyl- and dipicolylamine and N-ethyl and -hexyl chains were designed and synthesized. After being fully characterized, their interaction with human albumin was in vitro and in silico evaluated. Dyes were further assessed for their phototoxicity activity, and the most interesting ones were studied regarding cell localization and induction of morphological cell changes, genotoxicity, apoptosis and cell cycle arrest. The molecules with N-ethyl chains showed the greatest in vitro light-dependent cytotoxic effects, particularly the zwitterionic squaraine dye and the one bearing a single pyridine unit, which also exhibited a more significant interaction with human albumin. Phenotypically, the cells incubated with these squaraines became smaller and rounded after irradiation, the effects varying with the tested concentration. Genotoxic effects were observed even without irradiation, being more evident for the N-ethyl picolylamine-derived dye. The fluorescence emitted by Rhodamine 123 largely coincided with that emitted by the dyes, suggesting that they are found preferentially in mitochondria. After irradiation, an increase in the subG1 population was verified by propidium iodide-staining analysis by flow cytometry, indicative of cell death by apoptosis.
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•Picolyl- and dipicolylamine-functionalized benzeindole squaraines were prepared.•All the compounds exhibited absorption within the “phototherapeutic window”.•Squaraine dyes exhibited worthy affinity and interaction with human serum albumin.•N-ethyl picolylamine-bearing and zwitterionic dyes presented high photoselectivity.•Morphology, localization, genotoxicity, and subG1/cell cycle studies were achieved.
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