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Hypothalamic mTORC1 signaling is involved in nutrient sensing. Neurons that express the agouti-related protein (AgRP) are activated by food restriction and integrate interoceptive and exteroceptive signals to control food intake, energy expenditure, and other metabolic responses. To determine whether mTORC1 signaling in AgRP neurons is necessary for regulating energy and glucose homeostasis, especially in situations of negative energy balance, mice carrying ablation of the Raptor gene exclusively in AgRP-expressing cells were generated. AgRPΔRaptor mice showed no differences in body weight, fat mass, food intake, or energy expenditure; however, a slight improvement in glucose homeostasis was observed compared to the control group. When subjected to 5 days of food restriction (40% basal intake), AgRPΔRaptor female mice lost less lean body mass and showed a blunted reduction in energy expenditure, whereas AgRPΔRaptor male mice maintained a higher energy expenditure compared to control mice during the food restriction and 5 days of refeeding period. AgRPΔRaptor female mice did not exhibit the food restriction-induced increase in serum corticosterone levels. Finally, although hypothalamic fasting- or refeeding-induced Fos expression showed no differences between the groups, AgRPΔRaptor mice displayed increased hyperphagia during refeeding. Thus, some metabolic and neuroendocrine responses to food restriction are disturbed in AgRPΔRaptor mice.
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Ingestión de Alimentos , Diana Mecanicista del Complejo 1 de la Rapamicina , Neuronas , Animales , Femenino , Masculino , Ratones , Proteína Relacionada con Agouti/metabolismo , Ingestión de Alimentos/fisiología , Glucosa/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Neuronas/metabolismoRESUMEN
Introduction: The tumor microenvironment (TME) of glioblastoma (GB) is characterized by an increased infiltration of immunosuppressive cells that attenuate the antitumor immune response. The participation of neutrophils in tumor progression is still controversial and a dual role in the TME has been proposed. In this study, we show that neutrophils are reprogrammed by the tumor to ultimately promote GB progression. Methods: Using in vitro and in vivo assays, we demonstrate the existence of bidirectional GB and neutrophil communication, directly promoting an immunosuppressive TME. Results and discussion: Neutrophils have shown to play an important role in tumor malignancy especially in advanced 3D tumor model and Balb/c nude mice experiments, implying a time- and neutrophil concentration-dependent modulation. Studying the tumor energetic metabolism indicated a mitochondria mismatch shaping the TME secretome. The given data suggests a cytokine milieu in patients with GB that favors the recruitment of neutrophils, sustaining an anti-inflammatory profile which is associated with poor prognosis. Besides, glioma-neutrophil crosstalk has sustained a tumor prolonged activation via NETs formation, indicating the role of NFκB signaling in tumor progression. Moreover, clinical samples have indicated that neutrophil-lymphocyte ratio (NLR), IL-1ß, and IL-10 are associated with poor outcomes in patients with GB. Conclusion: These results are relevant for understanding how tumor progression occurs and how immune cells can help in this process.
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Glioblastoma , Neutrófilos , Animales , Ratones , Ratones Desnudos , Transducción de Señal , Inmunidad , Microambiente TumoralRESUMEN
Although the exact mechanism of the pathogenesis of coronavirus SARS-CoV-2 (COVID-19) is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the level of inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red photobiomodulation (PBM) as an attractive therapy to downregulate the cytokine storm caused by COVID-19 in a zebrafish model. RT-qPCR analyses and protein-protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that recombinant Spike protein (rSpike) was responsible for generating systemic inflammatory processes with significantly increased levels of pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a and coa1) mRNA markers, with a pattern similar to those observed in COVID-19 cases in humans. On the other hand, PBM treatment was able to decrease the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most-impacted metabolic pathways between PBM and the rSpike treated groups were related to steroid metabolism, immune system, and lipid metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19 and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials can commence.
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COVID-19 , Animales , Humanos , Pez Cebra/metabolismo , SARS-CoV-2/metabolismo , Síndrome de Liberación de Citoquinas , Citocinas/metabolismo , ARN Mensajero , Proteínas de la Membrana , Proteínas MitocondrialesRESUMEN
Chronic kidney disease (CKD) has been recognized as a significant global health problem due to being an important contributor to morbidity and mortality. Inflammation is the critical event that leads to CKD development orchestrated by a complex interaction between renal parenchyma and immune cells. Particularly, the crosstalk between tubular epithelial cells (TECs) and macrophages is an example of the critical cell communication in the kidney that drives kidney fibrosis, a pathological feature in CKD. Metabolism dysregulation of TECs and macrophages can be a bridge that connects inflammation and fibrogenesis. Currently, some evidence has reported how cellular lipid disturbances can affect kidney disease and cause tubulointerstitial fibrosis highlighting the importance of investigating potential molecules that can restore metabolic parameters. Vitamin D (VitD) is a hormone naturally produced by mammalian cells in a coordinated manner by the skin, liver, and kidneys. VitD deficiency or insufficiency is prevalent in patients with CKD, and serum levels of VitD are inversely correlated with the degree of kidney inflammation and renal function. Proximal TECs and macrophages produce the active form of VitD, and both express the VitD receptor (VDR) that evidence the importance of this nutrient in regulating their functions. However, whether VitD signaling drives physiological and metabolism improvement of TECs and macrophages during kidney injury is an open issue to be debated. In this review, we brought to light VitD as an important metabolic modulator of lipid metabolism in TECs and macrophages. New scientific approaches targeting VitD e VDR signaling at the cellular metabolic level can provide a better comprehension of its role in renal physiology and CKD progression.
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a broad spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients in a cohort of 231 individuals, of which 161 were COVID-19 patients (72 with mild, 61 moderate, and 28 with severe disease) and 70 were healthy controls. Dysregulated IgG and IgA autoantibody signatures, characterized mainly by elevated concentrations, occurred predominantly in patients with moderate or severe COVID-19 infection. Autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations while stratifying COVID-19 severity as indicated by random forest and principal component analyses. Furthermore, while young versus elderly COVID-19 patients showed only slight differences in autoantibody levels, elderly patients with severe disease presented higher IgG autoantibody concentrations than young individuals with severe COVID-19. This work maps the intersection of COVID-19 and autoimmunity by demonstrating the dysregulation of multiple autoantibodies triggered during SARS-CoV-2 infection. Thus, this cross-sectional study suggests that SARS-CoV-2 infection induces autoantibody signatures associated with COVID-19 severity and several autoantibodies that can be used as biomarkers of COVID-19 severity, indicating autoantibodies as potential therapeutical targets for these patients.
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Enfermedades Autoinmunes , COVID-19 , Anciano , Humanos , Autoanticuerpos , Estudios Transversales , SARS-CoV-2 , Inmunoglobulina GRESUMEN
OBJECTIVE: Astrocytes play a significant role in the pathology of multiple sclerosis (MS). Nevertheless, for ethical reasons, most studies in these cells were performed using the Experimental Autoimmune Encephalomyelitis model. As there are significant differences between human and mouse cells, we aimed here to better characterize astrocytes from patients with MS (PwMS), focusing mainly on mitochondrial function and cell metabolism. METHODS: We obtained and characterized induced pluripotent stem cell (iPSC)-derived astrocytes from three PwMS and three unaffected controls, and performed electron microscopy, flow cytometry, cytokine and glutamate measurements, gene expression, in situ respiration, and metabolomics. We validated our findings using a single-nuclei RNA sequencing dataset. RESULTS: We detected several differences in MS astrocytes including: (i) enrichment of genes associated with neurodegeneration, (ii) increased mitochondrial fission, (iii) increased production of superoxide and MS-related proinflammatory chemokines, (iv) impaired uptake and enhanced release of glutamate, (v) increased electron transport capacity and proton leak, in line with the increased oxidative stress, and (vi) a distinct metabolic profile, with a deficiency in amino acid catabolism and increased sphingolipid metabolism, which have already been linked to MS. INTERPRETATION: Here we describe the metabolic profile of iPSC-derived astrocytes from PwMS and validate this model as a very powerful tool to study disease mechanisms and to perform non-invasive drug targeting assays in vitro. Our findings recapitulate several disease features described in patients and provide new mechanistic insights into the metabolic rewiring of astrocytes in MS, which could be targeted in future therapeutic studies. ANN NEUROL 2022;91:652-669.
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Células Madre Pluripotentes Inducidas , Esclerosis Múltiple , Animales , Astrocitos/metabolismo , Ácido Glutámico/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Mitocondrias/metabolismo , Esclerosis Múltiple/patologíaRESUMEN
Despite the significant increase in the generation of SARS-CoV-2 contaminated domestic and hospital wastewater, little is known about the ecotoxicological effects of the virus or its structural components in freshwater vertebrates. In this context, this study evaluated the deleterious effects caused by SARS-CoV-2 Spike protein on the health of Danio rerio, zebrafish. We demonstrated, for the first time, that zebrafish injected with fragment 16 to 165 (rSpike), which corresponds to the N-terminal portion of the protein, presented mortalities and adverse effects on liver, kidney, ovary and brain tissues. The conserved genetic homology between zebrafish and humans might be one of the reasons for the intense toxic effects followed inflammatory reaction from the immune system of zebrafish to rSpike which provoked damage to organs in a similar pattern as happen in severe cases of COVID-19 in humans, and, resulted in 78,6% of survival rate in female adults during the first seven days. The application of spike protein in zebrafish was highly toxic that is suitable for future studies to gather valuable information about ecotoxicological impacts, as well as vaccine responses and therapeutic approaches in human medicine. Therefore, besides representing an important tool to assess the harmful effects of SARS-CoV-2 in the aquatic environment, we present the zebrafish as an animal model for translational COVID-19 research.
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COVID-19 , Glicoproteína de la Espiga del Coronavirus , Animales , Femenino , Humanos , SARS-CoV-2 , Pez CebraRESUMEN
Psychological stress predisposes our body to several disorders. Understanding the cellular and molecular mechanisms involved in the physiological responses to psychological stress is essential for the success of therapeutic applications. New studies show, by using in vivo inducible Cre/loxP-mediated approaches in combination with pharmacological blockage, that sympathetic nerves, activated by psychological stress, induce brown adipocytes to produce IL-6. Strikingly, this cytokine promotes gluconeogenesis in hepatocytes, that results in the decline of tolerance to inflammatory organ damage. The comprehension arising from this research will be crucial for the handling of many inflammatory diseases. Here, we review recent advances in our comprehension of the sympathetic nerve-adipocyte axis in the tissue microenvironment.
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Adipocitos/metabolismo , Estrés Psicológico/metabolismo , Sistema Nervioso Simpático/metabolismo , Animales , Humanos , Interleucina-6/metabolismo , Microambiente TumoralRESUMEN
Histone deacetylases (HDACs) are enzymes that regulate several processes, such as transcription, cell proliferation, differentiation and development. HDACs are classified as either Zn2+ -dependent or NAD+ -dependent enzymes. Over the years, experimental and clinical evidence has demonstrated that HDAC modulation is a critical process in neurodegenerative and psychiatric disorders. Nevertheless, most of the studies have focused on the role of Zn2+ -dependent HDACs in the development of these diseases, although there is growing evidence showing that the NAD+ -dependent HDACs, known as sirtuins, are also very promising targets. This possibility has been strengthened by reports of decreased levels of NAD+ in CNS disorders, which can lead to alterations in sirtuin activation and therefore result in increased pathology. In this review, we discuss the role of sirtuins in neurodegenerative and neuropsychiatric disorders as well the possible rationale for them to be considered as pharmacological targets in future therapeutic interventions. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.
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Sirtuinas , Histona Desacetilasas , Humanos , NADRESUMEN
Virus-like particles (VLPs) are a versatile, safe, and highly immunogenic vaccine platform. Recently, there are developmental vaccines targeting SARS-CoV-2, the causative agent of COVID-19. The COVID-19 pandemic affected humanity worldwide, bringing out incomputable human and financial losses. The race for better, more efficacious vaccines is happening almost simultaneously as the virus increasingly produces variants of concern (VOCs). The VOCs Alpha, Beta, Gamma, and Delta share common mutations mainly in the spike receptor-binding domain (RBD), demonstrating convergent evolution, associated with increased transmissibility and immune evasion. Thus, the identification and understanding of these mutations is crucial for the production of new, optimized vaccines. The use of a very flexible vaccine platform in COVID-19 vaccine development is an important feature that cannot be ignored. Incorporating the spike protein and its variations into VLP vaccines is a desirable strategy as the morphology and size of VLPs allows for better presentation of several different antigens. Furthermore, VLPs elicit robust humoral and cellular immune responses, which are safe, and have been studied not only against SARS-CoV-2 but against other coronaviruses as well. Here, we describe the recent advances and improvements in vaccine development using VLP technology.
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Dendritic Cells (DCs) direct either cellular immune response or tolerance. The crotoxin (CTX) and its CB subunit (phospholipase A2) isolated from Crotalus durissus terrificus rattlesnake venom modulate the DC maturation induced by a TLR4 agonist. Here, we analyzed the potential effect of CTX and CB subunit on the functional ability of DCs to induce anti-ovalbumin (OVA) immune response. Thus, CTX and CB inhibited the maturation of OVA/LPS-stimulated BM-DCs from BALB/c mice, which means inhibition of costimulatory and MHC-II molecule expression and proinflammatory cytokine secretion, accompanied by high expression of ICOSL, PD-L1/2, IL-10 and TGF-ß mRNA expression. The addition of CTX and CB in cultures of BM-DCs incubated with ConA or OVA/LPS inhibited the proliferation of CD3+ or CD4+T cells from OVA-immunized mice. In in vitro experiment of co-cultures of purified CD4+T cells of DO11.10 mice with OVA/LPS-stimulated BM-DCs, the CTX or CB induced lowest percentage of Th1 and Th2 and CTX induced increase of Treg cells. In in vivo, CTX and CB induced lower percentage of CD4+IFNγ+ and CD4+IL-4+ cells, as well as promoted CD4+CD25+IL-10+ population in OVA/LPS-immunized mice. CTX in vivo also inhibited the maturation of DCs. Our findings demonstrate that the modulatory action of CTX and CB on DCs interferes with the generation of adaptive immunity and, therefore contribute for the understanding of the mechanisms involved in the generation of cellular immunity, which can be useful for new therapeutic approaches for immune disorders.
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Proliferación Celular/efectos de los fármacos , Crotoxina/farmacología , Citocinas/inmunología , Células Dendríticas/inmunología , Fosfolipasas A2/farmacología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Crotalus , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
Periodontitis is an inflammatory disease induced by a dysbiotic oral microbiome. Probiotics of the genus Bifidobacterium may restore the symbiotic microbiome and modulate the immune response, leading to periodontitis control. We evaluated the effect of two strains of Bifidobacterium able to inhibit Porphyromonas gingivalis interaction with host cells and biofilm formation, but with distinct immunomodulatory properties, in a mice periodontitis model. Experimental periodontitis (P+) was induced in C57Bl/6 mice by a microbial consortium of human oral organisms. B. bifidum 1622A [B+ (1622)] and B. breve 1101A [B+ (1101)] were orally inoculated for 45 days. Alveolar bone loss and inflammatory response in gingival tissues were determined. The microbial consortium induced alveolar bone loss in positive control (P + B-), as demonstrated by microtomography analysis, although P. gingivalis was undetected in oral biofilms at the end of the experimental period. TNF-α and IL-10 serum levels, and Treg and Th17 populations in gingiva of SHAM and P + B- groups did not differ. B. bifidum 1622A, but not B. breve 1101A, controlled bone destruction in P+ mice. B. breve 1101A upregulated transcription of Il-1ß, Tnf-α, Tlr2, Tlr4, and Nlrp3 in P-B+(1101), which was attenuated by the microbial consortium [P + B+(1101)]. All treatments downregulated transcription of Il-17, although treatment with B. breve 1101A did not yield such low levels of transcripts as seen for the other groups. B. breve 1101A increased Th17 population in gingival tissues [P-B+ (1101) and P + B+ (1101)] compared to SHAM and P + B-. Administration of both bifidobacteria resulted in serum IL-10 decreased levels. Our data indicated that the beneficial effect of Bifidobacterium is not a common trait of this genus, since B. breve 1101A induced an inflammatory profile in gingival tissues and did not prevent alveolar bone loss. However, the properties of B. bifidum 1622A suggest its potential to control periodontitis.
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Cholesterol-ester transfer protein (CETP) plays a role in atherosclerosis, the inflammatory response to endotoxemia and in experimental and human sepsis. Functional alterations in lipoprotein (LP) metabolism and immune cell populations, including macrophages, occur during sepsis and may be related to comorbidities such as chronic obstructive pulmonary disease (COPD). Macrophages are significantly associated with pulmonary emphysema, and depending on the microenvironment, might exhibit an M1 or M2 phenotype. Macrophages derived from the peritoneum and bone marrow reveal CETP that contributes to its plasma concentration. Here, we evaluated the role of CETP in macrophage polarization and elastase-induced pulmonary emphysema (ELA) in human CETP-expressing transgenic (huCETP) (line 5203, C57BL6/J background) male mice and compared it to their wild type littermates. We showed that bone marrow-derived macrophages from huCETP mice reduce polarization toward the M1 phenotype, but with increased IL-10. Compared to WT, huCETP mice exposed to elastase showed worsened lung function with an increased mean linear intercept (Lm), reflecting airspace enlargement resulting from parenchymal destruction with increased expression of arginase-1 and IL-10, which are M2 markers. The cytokine profile revealed increased IL-6 in plasma and TNF, and IL-10 in bronchoalveolar lavage (BAL), corroborating with the lung immunohistochemistry in the huCETP-ELA group compared to WT-ELA. Elastase treatment in the huCETP group increased VLDL-C and reduced HDL-C. Elastase-induced pulmonary emphysema in huCETP mice promotes lung M2-like phenotype with a deleterious effect in experimental COPD, corroborating the in vitro result in which CETP promoted M2 macrophage polarization. Our results suggest that CETP is associated with inflammatory response and influences the role of macrophages in COPD.
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Proteínas de Transferencia de Ésteres de Colesterol/fisiología , Macrófagos/metabolismo , Enfisema Pulmonar/inmunología , Animales , Arginasa/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Proteínas de Transferencia de Ésteres de Colesterol/deficiencia , Proteínas de Transferencia de Ésteres de Colesterol/genética , Interleucina-10/metabolismo , Recuento de Leucocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Elastasa Pancreática/efectos adversos , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/inducido químicamente , Enfisema Pulmonar/genéticaRESUMEN
The phenotypes of allergic airway diseases are influenced by the interplay between host genetics and the gut microbiota, which may be modulated by probiotics. We investigated the probiotic effects on allergic inflammation in A/J and C57BL/6 mice. C57BL/6 mice had increased gut microbiota diversity compared to A/J mice at baseline. Acetate producer probiotics differentially modulated and altered the genus abundance of specific bacteria, such as Akkermansia and Allistipes, in mouse strains. We induced airway inflammation followed by probiotic treatment and found that only A/J mice exhibited decreased inflammation, and the beneficial effects of probiotics in A/J mice were partially due to acetate production. To understand the relevance of microbial composition colonization in the development of allergic diseases, we implanted female C57BL/6 mice with A/J embryos to naturally modulate the microbial composition of A/J mice, which increased gut microbiota diversity and reduced eosinophilic inflammation in A/J. These data demonstrate the central importance of microbiota to allergic phenotype severity. Video Abstract.
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Microbioma Gastrointestinal , Probióticos , Animales , Femenino , Inflamación , Ratones , Ratones Endogámicos C57BL , Sistema RespiratorioRESUMEN
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic ß cells. We show here that the protein NOD-like receptor family pyrin domain containing 1 (NLRP1) has a key role in the pathogenesis of mouse and human T1D. More specifically, downregulation of NLRP1 expression occurs during T helper 17 (Th17) differentiation, alongside greater expression of several molecules related to Th17 cell differentiation in a signal transducers and activators of transcription 3 (STAT3)-dependent pathway. These changes lead to a consequent increase in interleukin 17 (IL-17) production within the pancreas and higher incidence of diabetes in streptozotocin (STZ)-injected mice. Finally, in patients with T1D and a SNP (rs12150220) in NLRP1, there is a robust decrease in IL-17 levels in serum and in memory Th17 cells from peripheral blood mononuclear cells. Our results demonstrate that NLRP1 acts as a negative regulator of the Th17 cell polarization program, making it an interesting target for intervention during the early stages of T1D.
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Enfermedades Autoinmunes/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/genética , Proteínas NLR/metabolismo , Células Th17/inmunología , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , RatasRESUMEN
Coronaviruses gained public attention during the severe acute respiratory syndrome (SARS) outbreak in East Asia in 2003 and spread of Middle Eastern respiratory syndrome (MERS) in 2012. Direct human-to-human contact and droplet are the main methods of transmission. Viral stability in aerosols on different surfaces supports evidence on indirect viral acquisition from fomites through the mucous membranes of the mouth, nose, and eyes. Given the pandemic circumstances, the level of evidence in COVID-19 and ophthalmology regarding eye infection, conjunctival transmission, and viral shedding through tears is insufficient. Presently, conjunctival transmission of coronaviruses has not been confirmed and remains controversial. Considering the physiology of the lacrimal system and ocular surface, the eyes are considered an immunoprotective site, with several antiviral molecules and anti-inflammatory proteins. Nevertheless, they represent an interface with the exterior world and face daily putative aggressors. Understanding the host's ocular surface immunological and protective environment is crucial to clarify the potential of the conjunctiva as an entry route for SARS-CoV-2 and as part of this viral infection. We will discuss hypothetical ocular surface transmission mechanisms and related counterarguments addressed to both angiotensin-converting enzyme 2 receptors found on the conjunctival and corneal epithelia and lactoferrin, lysozyme, lipocalin and secretory IgA levels in the tear film. Hopefully, we will promote better understanding of this organ in COVID-19 infection and the potential transmission route that can be helpful in setting recommendations on best practices and protective guidelines to mitigate the disease spread.
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Teenagers generally present mild to no symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present report, we present the case of a 14-year-old boy with Angelman syndrome (AS) who presented with severe COVID-19 symptoms. He spent 20 days in the ICU with elevated inflammatory biomarkers (C-reactive protein and D-dimer) and increased peaks of neutrophil-to-lymphocyte ratio, which is uncommon for teenagers diagnosed with COVID-19. Although he showed physiological instability, he was able to produce neutralizing antibodies, suggesting a functional immune response. The literature concerning the immune response to infections in patients with AS is still poor, and to our knowledge, this was the first report of a patient with AS diagnosed with COVID-19. As such, the present study may alert other patients with AS or other rare diseases that they lack a competent immune response and could suffer severe consequences of SARS-CoV-2 infection.
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Dendritic Cells (DCs) direct either cellular immune response or tolerance. The crotoxin (CTX) and its CB subunit (phospholipase A2) isolated from Crotalus durissus terrificus rattlesnake venom modulate the DCs maturation induced by a TLR4 agonist. Here, we analyzed the potential effect of CTX and CB subunit on the functional ability of DCs to induce anti-ovalbumin (OVA) immune response. Thus, CTX and CB inhibited the maturation of OVA/LPS-stimulated BM-DCs from BALB/c mice, which means inhibition of costimulatory and MHC-II molecules expression and proinflammatory cytokines secretion, accompanied by high expression of ICOSL, PD-L1/2, IL-10 and TGF-β mRNA expression. The addition of CTX and CB in cultures of BM-DCs incubated with ConA or OVA/LPS inhibited the proliferation of CD3+ or CD4+T cells from OVA-immunized mice. In in vitro experiment of co-cultures of purified CD4+T cells of DO11.10 mice with OVA/LPS-stimulated BM-DCs, the CTX or CB induced lowest percentage of Th1 and Th2 and CTX induced increase of Treg cells. In in vivo, CTX and CB induced lower percentage of CD4+IFNγ+ and CD4+IL-4+ cells, as well as promoted CD4+CD25+IL-10+ population in OVA/LPS-immunized mice. CTX in vivo also inhibited the maturation of DCs. Our findings demonstrate that the modulatory action of CTX and CB on DCs interferes with the generation of adaptive immunity and, therefore contribute for the understanding of the mechanisms involved in the generation of cellular immunity, which can be useful for new therapeutic approaches for immune disorders.
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Palmitoleic acid (POA, 16:1n-7) is a lipokine that has potential nutraceutical use to treat non-alcoholic fatty liver disease. We tested the effects of POA supplementation (daily oral gavage, 300 mg/Kg, 15 days) on murine liver inflammation induced by a high fat diet (HFD, 59% fat, 12 weeks). In HFD-fed mice, POA supplementation reduced serum insulin and improved insulin tolerance compared with oleic acid (OA, 300 mg/Kg). The livers of POA-treated mice exhibited less steatosis and inflammation than those of OA-treated mice with lower inflammatory cytokine levels and reduced toll-like receptor 4 protein content. The anti-inflammatory effects of POA in the liver were accompanied by a reduction in liver macrophages (LM, CD11c+; F4/80+; CD86+), an effect that could be triggered by peroxisome proliferator activated receptor (PPAR)-γ, a lipogenic transcription factor upregulated in livers of POA-treated mice. We also used HFD-fed mice with selective deletion of PPAR-γ in myeloid cells (PPAR-γ KOLyzCre+) to test whether the beneficial anti-inflammatory effects of POA are dependent on macrophages PPAR-γ. POA-mediated improvement of insulin tolerance was tightly dependent on myeloid PPAR-γ, while POA anti-inflammatory actions including the reduction in liver inflammatory cytokines were preserved in mice bearing myeloid cells deficient in PPAR-γ. This overlapped with increased CD206+ (M2a) cells and downregulation of CD86+ and CD11c+ liver macrophages. Moreover, POA supplementation increased hepatic AMPK activity and decreased expression of the fatty acid binding scavenger receptor, CD36. We conclude that POA controls liver inflammation triggered by fat accumulation through induction of M2a macrophages independently of myeloid cell PPAR-γ.