RESUMO
Aims: Pre-existing conditions, such as age, hypertension, obesity, and diabetes, constitute known risk factors for severe COVID-19. However, the impact of prediabetes mellitus (PDM) on COVID-19 severity is less clear. This study aimed to evaluate the influence of PDM in the acute and long-term phases of COVID-19. Materials and methods: We compared inflammatory mediators, laboratory and clinical parameters and symptoms in COVID-19 patients with prediabetes (PDM) and without diabetes (NDM) during the acute phase of infection and at three months post-hospitalization. Results: Patients with PDM had longer hospital stays and required intensive care unit admission more frequently than NDM. Upon hospitalization, PDM patients exhibited higher serum levels of interleukin 6 (IL-6), which is related to reduced partial pressure of oxygen (PaO2) in arterial blood, oxygen saturation (SpO2) and increased COVID-19 severity. However, at three months after discharge, those with PDM did not exhibit significant alterations in laboratory parameters or residual symptoms; however, PDM was observed to influence the profile of reported symptoms. Conclusions: PDM seems to be associated with increased risk of severe COVID-19, as well as higher serum levels of IL-6, which may constitute a potential biomarker of severe COVID-19 risk in affected patients. Furthermore, while PDM correlated with more severe acute-phase COVID-19, no long-term worsening of sequelae was observed.
Assuntos
COVID-19 , Diabetes Mellitus , Interleucina-6/biossíntese , Estado Pré-Diabético , COVID-19/complicações , Hospitalização , Humanos , Estado Pré-Diabético/complicaçõesRESUMO
Curcumin and its analogues exhibited anti-inflammatory activity in different experimental models. Recently, we synthesized (2E,3E)-3-buten-2-one-4-(4-hydroxy-3-methoxyphenyl)-2-(4-(4-methoxyphenyl)-2-thiazolyl)hydrazone (RI75), a curcumin analogue with a thiazolyl hydrazone moiety. In the present study, we investigated the effects induced by RI75 in different models of inflammation and pain in mice, as well as some underlying mechanisms. Pre-treatment with RI75 (40 mg/kg, intraperitoneal; i.p.) or curcumin (40 mg/kg, i.p.) reduced the mechanical allodynia and paw edema induced by intraplantar (i.pl) injection of carrageenan. RI75 antiallodynic activity was reduced by pre-treatment with naltrexone (5 and 10 mg/kg, i.p.) and cyproheptadine (10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, i.p.). In a model of neuropathic pain, a single i.p. administration of RI75 (40 mg/kg) or curcumin (40 mg/kg) attenuated the ongoing mechanical allodynia induced by repeated administrations of paclitaxel. Pre-treatment with RI75 (40 mg/kg, i.p.) or curcumin (40 mg/kg, i.p.) also reduced tumor necrosis factor-α and interleukin-6 production and myeloperoxidase activity induced by carrageenan. The results of the present study demonstrate that RI75, a synthetic curcumin analogue, exhibits antiallodynic and antiedematogenic activities. Activation of opioidergic and serotonergic mechanisms and reduced production of inflammatory mediators and neutrophil recruitment may underlie RI75 activities.
Assuntos
Curcumina , Hiperalgesia , Interleucina-6 , Neuralgia , Fator de Necrose Tumoral alfa , Animais , Curcumina/análogos & derivados , Curcumina/farmacologia , Modelos Animais de Doenças , Edema/tratamento farmacológico , Edema/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Camundongos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Acute ischemic stroke is associated with pulmonary complications, and often dexmedetomidine and propofol are used to decrease cerebral metabolic rate. However, it is unknown the immunomodulatory actions of dexmedetomidine and propofol on brain and lungs during acute ischemic stroke. The effects of dexmedetomidine and propofol were compared on perilesional brain tissue and lung damage after acute ischemic stroke in rats. Further, the mean amount of both sedatives was directly evaluated on alveolar macrophages and lung endothelial cells primarily extracted 24-h after acute ischemic stroke. In twenty-five Wistar rats, ischemic stroke was induced and after 24-h treated with sodium thiopental (STROKE), dexmedetomidine and propofol. Dexmedetomidine, compared to STROKE, reduced diffuse alveolar damage score [median(interquartile range); 12(7.8-15.3) vs. 19.5(18-24), p = 0.007)], bronchoconstriction index [2.28(2.08-2.36) vs. 2.64(2.53-2.77), p = 0.006], and TNF-α expression (p = 0.0003), while propofol increased VCAM-1 expression compared to STROKE (p = 0.0004). In perilesional brain tissue, dexmedetomidine, compared to STROKE, decreased TNF-α (p = 0.010), while propofol increased VCAM-1 compared to STROKE (p = 0.024). In alveolar macrophages and endothelial cells, dexmedetomidine decreased IL-6 and IL-1ß compared to STROKE (p = 0.002, and p = 0.040, respectively), and reduced IL-1ß compared to propofol (p = 0.014). Dexmedetomidine, but not propofol, induced brain and lung protection in experimental acute ischemic stroke.
Assuntos
Encéfalo/efeitos dos fármacos , Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , AVC Isquêmico/tratamento farmacológico , Pulmão/efeitos dos fármacos , Propofol/administração & dosagem , Animais , Isquemia Encefálica/prevenção & controle , Dexmedetomidina/efeitos adversos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Hipnóticos e Sedativos/efeitos adversos , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Propofol/efeitos adversos , Ratos , Ratos Wistar , Tiopental , Fator de Necrose Tumoral alfa/biossíntese , Molécula 1 de Adesão de Célula Vascular/biossínteseRESUMO
BACKGROUND: Cold temperatures can aggravate pulmonary diseases and promote pulmonary arterial hypertension (PAH); however, the underlying mechanism has not been fully explored. AIM: To explore the effect of chronic cold exposure on the production of inflammatory cytokines and microRNAs (miRNAs) in a monocrotaline (MCT)-induced PAH model. METHODS: Male Sprague Dawley rats were divided into a Control (23.5 ± 2 °C), Cold (5.0 ± 1 °C for ten days), MCT (60 mg/kg body weight i.p.), and MCT + Cold (ten days of cold exposure after 3 weeks of MCT injection). Hemodynamic parameters, right ventricle (RV) hypertrophy, and pulmonary arterial medial wall thickness were determined. IL-1ß, IL-6, and TNF-α levels were determined using western blotting. miR-21-5p and -3p, miR-146a-5p and -3p, and miR-155-5p and -3p and plasma extracellular vesicles (EVs) and mRNA expression of Cd68, Cd163, Bmpr2, Smad5, Tgfbr2, and Smad3 were determined using RT-qPCR. RESULTS: The MCT + Cold group had aggravated RV hypertrophy hemodynamic parameters, and pulmonary arterial medial wall thickness. In lungs of the MCT + Cold, group the protein levels of TNF-α, IL-1ß, and IL-6 were higher than those in the MCT group. The mRNA expression of Cd68 and Cd163 were higher in the MCT + Cold group. miR-146a-5p and miR-155-5p levels were higher in the plasma EVs and lungs of the MCT + Cold group. Cold exposure promoted a greater decrease in miR-21-5p, Bmpr2, Smad5, Tgfbr2, and Smad3 mRNA expression in lungs of the MCT + Cold group. CONCLUSION: Cold exposure aggravates MCT-induced PAH with an increase in inflammatory marker and miRNA levels in the plasma EVs and lungs.
Assuntos
Temperatura Baixa/efeitos adversos , Citocinas/biossíntese , MicroRNAs/biossíntese , Hipertensão Arterial Pulmonar/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Animais , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Pulmão/metabolismo , Pulmão/patologia , Masculino , Hipertensão Arterial Pulmonar/patologia , Ratos , Ratos Sprague-DawleyRESUMO
During pregnancy, Toxoplasma gondii can triggers serious manifestations and potentially affect the fetal development. In this scenario, differences in susceptibility of trophoblast cells to T. gondii infection might be evaluated in order to establish new therapeutic approaches capable of interfering in the control of fetal infection by T. gondii. This study aimed to evaluate the susceptibility of cytotrophoblast, syncytiotrophoblast and extravillous trophoblast cells to T. gondii infection. Our data demonstrate that HTR-8/SVneo cells (extravillous trophoblast cells) present higher susceptibility to T. gondii infection when compared to syncytiotrophoblast and cytotrophoblast cells, whereas syncytiotrophoblast was the cell type more resistant to the parasite infection. Also, cytotrophoblast and syncytiotrophoblast cells produced significantly more IL-6 than HTR-8/SVneo cells. On the other hand, HTR-8/SVneo cells showed higher ERK1/2 phosphorylation than cytotrophoblast and syncytiotrophoblast cells. ERK1/2 inhibition reduced T. gondii infection and increased IL-6 production in HTR-8/SVneo cells. Thus, it is plausible to conclude that the greater susceptibility of HTR-8/SVneo cells to infection by T. gondii is related to a higher ERK1/2 phosphorylation and lower levels of IL-6 in these cells compared to other cells, suggesting that these mediators may be important to favor the parasite infection in this type of trophoblastic population.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Gigantes/patologia , Interleucina-6/biossíntese , Toxoplasmose/patologia , Trofoblastos/patologia , Trofoblastos/parasitologia , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Suscetibilidade a Doenças , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Humanos , Fosforilação , Regulação para CimaRESUMO
Systemic embolization has been reported in up to 40% of patients with left atrial myxoma, half of them with cerebral involvement. However, development of intracerebral embolization associated with parenchymal seeding of the myxoma emboli is an extremely rare complication, with only 36 histologically diagnosed cases reported in the published literature. We describe a 69-year-old woman who arrived at the emergency service with hemiparesis associated with drug-resistant epilepsy and a medical history of resection of a left atrial myxoma 10 months previously. Cranial computed tomography revealed multiple large lesions of heterogeneous density and cystic components in the occipital lobes and posterior fossa parenchyma. Histopathological analyses after stereotactic biopsy of the occipital lesion revealed infiltrative myxoma cells with benign histological findings and uniform expression of calretinin similar to that of the primary cardiac myxoma. Additional immunohistochemical studies confirmed brain parenchymal seeding of the myxoma cells with strong expression of interleukin-6 (IL-6) and focal expression of matrix metalloproteinases-2 (MMP-2). Here, we discuss the clinicopathological features of intracerebral embolization of left atrial myxomas associated with progressive parenchymal seeding of the tumor emboli and the potential pathogenic role of IL-6 and MMPs.
Assuntos
Neoplasias Cardíacas/metabolismo , Interleucina-6/biossíntese , Embolia Intracraniana/metabolismo , Metaloproteinase 2 da Matriz/biossíntese , Mixoma/metabolismo , Inoculação de Neoplasia , Idoso , Feminino , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/cirurgia , Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/cirurgia , Humanos , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/cirurgia , Mixoma/diagnóstico por imagem , Mixoma/cirurgiaRESUMO
Photobiomodulation (PBM) therapy is used to stimulate cell proliferation and metabolism, as well as reduce inflammatory cytokine synthesis, which plays a main role in the long-term stability of implants. This study assessed the response of gingival fibroblasts cultured on titanium (Ti) and zirconia (ZrO2), submitted to PBM and exposed to lipopolysaccharide (LPS). Cells seeded on Ti and ZrO2 were irradiated (InGaAsP; 780 nm, 25 mW) 3 times, using 0.5, 1.5, and 3.0 J/cm2 doses, and exposed to Escherichia coli LPS (1 µg/mL). After 24 h, cell viability (alamarBlue, n = 8), interleukin 6 (IL-6) and 8 (IL-8) synthesis (ELISA, n = 6), and IL-6 and vascular endothelial growth factor (VEGF) gene expression (qPCR, n = 5) were assessed and statistically analyzed (one-way ANOVA, α = 0.05). Cell morphology was evaluated by fluorescence microscopy. Increased cell viability occurred in all groups cultured on Ti compared with that of the control, except for cells exposed to LPS. Fibroblasts cultured on ZrO2 and LPS-exposed exhibited reduced viability. PBM at 3.0 J/cm2 and 1.5 J/cm2 downregulated the IL-6 synthesis by fibroblasts seeded on Ti and ZrO2, as well as IL-8 synthesis by cells seeded on ZrO2. Fibroblasts seeded on both surfaces and LPS-exposed showed increased IL-6 gene expression; however, this activity was downregulated when fibroblasts were irradiated at 3.0 J/cm2. Enhanced VEGF gene expression by cells seeded on Ti and laser-irradiated (3.0 J/cm2). Distinct patterns of cytoskeleton occurred in laser-irradiated cells exposed to LPS. Specific parameters of PBM can biomodulate the inflammatory response of fibroblasts seeded on Ti or ZrO2 and exposed to LPS.
Assuntos
Escherichia coli/metabolismo , Fibroblastos/efeitos da radiação , Gengiva/citologia , Lipopolissacarídeos/farmacologia , Terapia com Luz de Baixa Intensidade , Titânio/farmacologia , Zircônio/farmacologia , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/biossíntese , Adulto JovemRESUMO
Extracellular vesicles (EVs) are lipid bilayered compartments released by virtually all living cells, including fungi. Among the diverse molecules carried by fungal EVs, a number of immunogens, virulence factors and regulators have been characterised. Within EVs, these components could potentially impact disease outcomes by interacting with the host. From this perspective, we previously demonstrated that EVs from Candida albicans could be taken up by and activate macrophages and dendritic cells to produce cytokines and express costimulatory molecules. Moreover, pre-treatment of Galleria mellonella larvae with fungal EVs protected the insects against a subsequent lethal infection with C. albicans yeasts. These data indicate that C. albicans EVs are multi-antigenic compartments that activate the innate immune system and could be exploited as vaccine formulations. Here, we investigated whether immunisation with C. albicans EVs induces a protective effect against murine candidiasis in immunosuppressed mice. Total and fungal antigen-specific serum IgG antibodies increased by 21 days after immunisation, confirming the efficacy of the protocol. Vaccination decreased fungal burden in the liver, spleen and kidney of mice challenged with C. albicans. Splenic levels of cytokines indicated a lower inflammatory response in mice immunised with EVs when compared with EVs + Freund's adjuvant (ADJ). Higher levels of IL-12p70, TNFα and IFNγ were detected in mice vaccinated with EVs + ADJ, while IL-12p70, TGFß, IL-4 and IL-10 were increased when no adjuvants were added. Full protection of lethally challenged mice was observed when EVs were administered, regardless the presence of adjuvant. Physical properties of the EVs were also investigated and EVs produced by C. albicans were relatively stable after storage at 4, -20 or -80°C, keeping their ability to activate dendritic cells and to protect G. mellonella against a lethal candidiasis. Our data suggest that fungal EVs could be a safe source of antigens to be exploited in vaccine formulations.
Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Vesículas Extracelulares/imunologia , Animais , Anticorpos Antifúngicos/sangue , Antígenos de Fungos/imunologia , Candidíase/prevenção & controle , Temperatura Baixa , Citocinas/sangue , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Vacinas Fúngicas/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Interleucina-6/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Mariposas/imunologia , Mariposas/microbiologia , VacinaçãoRESUMO
We recently reported, for the first time, the expression and regulation of the PDZ polarity proteins Scrib and Dlg1 in human APCs, and also described the viral targeting of these proteins by NS1 of influenza A virus in human dendritic cells (DCs). Scrib plays an important role in reactive oxygen species (ROS) production in MÏs and uropod formation and migration in T cells, while Dlg1 is important for T cell downstream activation after Ag recognition. Nevertheless, the functions of these proteins in human DCs remain unknown. Here, we knocked-down the expression of both Scrib and Dlg1 in human DCs and then evaluated the expression of co-stimulatory molecules and cytokine production during maturation. We demonstrated that Scrib is necessary for adequate CD86 expression, while Dlg1 is important for CD83 up-regulation and IL-6 production upon maturation, suggesting that Scrib and Dlg1 participate in separate pathways in DCs. Additionally, both proteins are required for adequate IL-12 production after maturation. Furthermore, we showed that the inefficient maturation of DCs induced by Scrib or Dlg1 depletion leads to impaired T cell activation. Our results revealed the previously unknown contribution of Scrib and Dlg1 in human DCs pivotal functions, which may be able to impact innate and adaptive immune response.
Assuntos
Apresentação de Antígeno , Células Dendríticas/imunologia , Proteína 1 Homóloga a Discs-Large/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Imunidade Adaptativa , Antígenos CD/biossíntese , Antígenos CD/genética , Antígeno B7-2/biossíntese , Antígeno B7-2/genética , Células Cultivadas , Citocinas/biossíntese , Citocinas/genética , Proteína 1 Homóloga a Discs-Large/antagonistas & inibidores , Proteína 1 Homóloga a Discs-Large/genética , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata , Imunoglobulinas/biossíntese , Imunoglobulinas/genética , Interleucina-12/metabolismo , Interleucina-6/biossíntese , Interleucina-6/genética , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Densidade Pós-Sináptica/fisiologia , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Regulação para Cima , Antígeno CD83RESUMO
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint damage, and it may present with comorbidities at the systemic level. The Th1/Th2/Th17 CD4+ lymphocyte imbalance produces inflammatory cytokines, which begin to act, injuring joint tissue. Atorvastatin is a cholesterol- lowering drug with a range of biological effects including anti-inflammatory potential. Patients with rheumatoid arthritis who used statins exhibited clinical improvement. However, the mechanism is not fully understood. Therefore, we aimed to evaluate the RA immunomodulatory activity of atorvastatin. METHODS: Peripheral blood mononuclear cells (PBMCs) of RA patients and healthy donors were exposed to atorvastatin in different concentrations following a cytotoxicity assay. Th1, Th2, and Th17 cytokines profiles were evaluated in the culture supernatant by cytometric bead array (CBA). Data were analyzed using the Wilcoxon test, and differences were considered significant when p < 0.05. RESULTS: Atorvastatin showed no toxicity at the tested doses in RA PBMC cultures, and at 10µM, it showed the most significant results, reducing IL-17A (p = 0.002), TNF (p = 0.002), and IL-6 (p = 0.008) supernatant levels. The outcomes also revealed that only patients with more severe disease activity and those sensitive to corticoid treatments were responders to atorvastatin in vitro. CONCLUSION: These findings suggest the potential immunomodulatory action of atorvastatin as a mechanism in rheumatoid arthritis treatment.