RESUMO
Visceral adiposity is a risk factor for severe COVID-19, and a link between adipose tissue infection and disease progression has been proposed. Here we demonstrate that SARS-CoV-2 infects human adipose tissue and undergoes productive infection in fat cells. However, susceptibility to infection and the cellular response depends on the anatomical origin of the cells and the viral lineage. Visceral fat cells express more ACE2 and are more susceptible to SARS-CoV-2 infection than their subcutaneous counterparts. SARS-CoV-2 infection leads to inhibition of lipolysis in subcutaneous fat cells, while in visceral fat cells, it results in higher expression of pro-inflammatory cytokines. Viral load and cellular response are attenuated when visceral fat cells are infected with the SARS-CoV-2 gamma variant. A similar degree of cell death occurs 4-days after SARS-CoV-2 infection, regardless of the cell origin or viral lineage. Hence, SARS-CoV-2 infects human fat cells, replicating and altering cell function and viability in a depot- and viral lineage-dependent fashion.
Assuntos
COVID-19 , SARS-CoV-2 , Tecido Adiposo , Enzima de Conversão de Angiotensina 2 , Citocinas , HumanosRESUMO
OBJECTIVE: To evaluate the oral health-related quality of life (OHRQoL) of individuals with rheumatoid arthritis (RA) in comparison with individuals with no RA. METHOD: A cross-sectional study was carried out with 112 individuals distributed into two groups. Group 1 (G1) consisted of 42 RA individuals and group 2 (G2) consisted of 70 individuals without RA. Participants' OHRQoL was assessed by means of the long form of the Oral Health Impact Profile (OHIP). The OHIP has 49 questions distributed across seven domains: functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability, and handicap. The overall score ranges between 0 and 196. A higher score denotes a greater negative impact on OHRQoL. All participants underwent oral examination for the evaluation of clinical variables. Sociodemographic and oral behavior variables were also collected. Data analysis included descriptive statistics, Mann-Whitney test, and regression analysis. RESULTS: Individuals in G1 presented higher OHIP overall score (p = 0.006) than G2 individuals. G1 individuals also presented higher scores in the functional limitation (p = 0.003) and the physical disability (p = 0.005) domains than G2 individuals. Individuals with RA (p = 0.044), individuals who brushed their teeth less often (p = 0.019), and those with a higher number of decayed, missing, and filled teeth (DMFT) (p = 0.038) presented a significantly higher OHIP-49 overall score (more negative perception of their OHRQoL) than individuals without RA, individuals who brushed their teeth more often, and those with a lower DMFT. CONCLUSION: RA individuals had a more negative perception of their OHRQoL compared with individuals with no RA.
Assuntos
Artrite Reumatoide/complicações , Saúde Bucal , Periodontite/complicações , Qualidade de Vida , Adulto , Estudos de Casos e Controles , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Epidemiologic studies have highlighted the association of environmental factors with the development and progression of autoimmune and chronic inflammatory diseases. Among the environmental factors, smoking has been associated with increased susceptibility and poor prognosis in rheumatoid arthritis (RA). However, the immune and molecular mechanism of smoking-induced arthritis aggravation remains unclear. The transcription factor aryl hydrocarbon receptor (AHR) regulates the generation of Th17 cells, CD4 T cells linked the development of autoimmune diseases. AHR is activated by organic compounds including polycyclic aromatic hydrocarbons (PAHs), which are environmental pollutants that are also present in cigarette smoke. In this study, we investigated the role of AHR activation in the aggravation of experiment arthritis induced by exposure to cigarette smoke. METHODS: Mice were exposed to cigarette smoke during the developmental phase of antigen-induced arthritis and collagen-induced arthritis to evaluate the effects of smoking on disease development. Aggravation of articular inflammation was assessed by measuring neutrophil migration to the joints, increase in articular hyperalgesia and changes in the frequencies of Th17 cells. In vitro studies were performed to evaluate the direct effects of cigarette smoke and PAH on Th17 differentiation. We also used mice genetically deficient for AHR (Ahr KO) and IL-17Ra (Il17ra KO) to determine the in vivo mechanism of smoking-induced arthritis aggravation. RESULTS: We found that smoking induces arthritis aggravation and increase in the frequencies of Th17 cells. The absence of IL-17 signaling (Il17ra KO) conferred protection to smoking-induced arthritis aggravation. Moreover, in vitro experiments showed that cigarette smoke can directly increase Th17 differentiation of T cells by inducing AHR activation. Indeed, Ahr KO mice were protected from cigarette smoke-induced arthritis aggravation and did not display increase in TH17 frequencies, suggesting that AHR activation is an important mechanism for cigarette smoke effects on arthritis. Finally, we demonstrate that PAHs are also able to induce arthritis aggravation. CONCLUSIONS: Our data demonstrate that the disease-exacerbating effects of cigarette smoking are AHR dependent and environmental pollutants with AHR agonist activity can induce arthritis aggravation by directly enhancing Th17 cell development.
Assuntos
Artrite Experimental/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Fumaça/efeitos adversos , Células Th17/metabolismo , Animais , Artrite Experimental/etiologia , Artrite Experimental/genética , Compostos Azo/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Pirazóis/farmacologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Nicotiana/químicaRESUMO
Neuronal stimulation is an emerging field in modern medicine to control organ function and reestablish physiological homeostasis during illness. The nervous system innervates most of the peripheral organs and provides a fine tune to control the immune system. Most of these studies have focused on vagus nerve stimulation and the physiological, cellular and molecular mechanisms regulating the immune system. Here, we review the new results revealing afferent vagal signaling pathways, immunomodulatory brain structures, spinal cord-dependent circuits, neural and non-neural cholinergic/catecholaminergic signals and their respective receptors contributing to neuromodulation of inflammation in rheumatoid arthritis. These new neuromodulatory networks and structures will allow the design of innovative bioelectronic or pharmacological approaches for safer and low-cost treatment of arthritis and related inflammatory disorders.
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AIM: The objective was to evaluate the effects of nitric oxide (NO) and hydrogen sulfide (H2S) donors and possible interactions between these two systems in modulating gastric function. METHODS: Mice received saline, sodium nitroprusside (SNP), or sodium hydrosulfite (NaHS), and after 1 h, the animals were killed for immunofluorescence analysis of CSE or eNOS expressions, respectively. Other groups received saline, SNP, NaHS, Lawesson's reagent (H2S donor), PAG + SNP, L-NAME, L-NAME + NaHS, or L-NAME + Lawesson's reagent. Then, the gastric secretions (mucous and acid), gastric blood flow, gastric defense against ethanol, and gastric motility (gastric emptying and gastric contractility) were evaluated. RESULTS: SNP and NaHS increased the expression of CSE or eNOS, respectively. SNP or Lawesson's reagent did not alter gastric acid secretion but increased mucus production, and these effects reverted with PAG and L-NAME treatment, respectively. SNP or NaHS increased gastric blood flow and protected the gastric mucosa against ethanol injury, and these effects reverted with PAG and L-NAME treatments, respectively. SNP delayed gastric emptying when compared with saline, and PAG partially reversed this effect. NaHS accelerate gastric emptying, and L-NAME partially reversed this effect. SNP and NaHS alone induced gastric fundus and pylorus relaxation. However, pretreatment with PAG or L-NAME reversed these relaxant effects only in the pylorus but not in the gastric fundus. CONCLUSION: NO and H2S interact in gastric physiological functions, and this "cross-talk" is important in the control of mucus secretion, gastric blood flow, gastric mucosal defense, and gastric motility, but not in the control of basal gastric acid secretion.
Assuntos
Cistationina gama-Liase/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Nitroprussiato/farmacologia , Estômago/efeitos dos fármacos , Sulfetos/farmacologia , Alcinos/farmacologia , Animais , Depressores do Sistema Nervoso Central/farmacologia , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/metabolismo , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Etanol/farmacologia , Imunofluorescência , Ácido Gástrico/metabolismo , Fundo Gástrico/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Glicina/análogos & derivados , Glicina/farmacologia , Fluxometria por Laser-Doppler , Masculino , Malondialdeído/metabolismo , Camundongos , Muco/efeitos dos fármacos , Muco/metabolismo , Contração Muscular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Piloro/efeitos dos fármacos , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional , Estômago/irrigação sanguíneaRESUMO
OBJECTIVE: We investigated the anti-inflammatory activity of strontium ranelate (SR) in arthritis models. MATERIALS AND METHODS: Rats received 1 mg zymosan (Zy) or saline intra-articularly. Other groups were subjected to anterior cruciate ligament transection in the right knee, as an osteoarthritis (OA) model, or a sham procedure. Joint pain was assessed using the articular incapacitation and paw-pressure tests. Cell influx and cytokines were measured in joint exudates. TREATMENT: Groups received either SR (30-300 mg/kg per os) or saline. RESULTS: SR dose-dependently and significantly inhibited joint pain in both Zy and OA models, while not altering cell influx. Naloxone administration significantly reversed SR analgesia. SR significantly reduced levels of Interleukin-1ß and tumor necrosis factor-α in Zy arthritis, whereas those of cytokine-induced neutrophil chemoattractant (CINC)-1 were not altered. CONCLUSIONS: SR provides analgesia in arthritis that is associated to inhibition of the release of inflammatory cytokines into inflamed joints. This effect is abrogated by administration of the opioid antagonist naloxone.
Assuntos
Analgésicos não Narcóticos/uso terapêutico , Citocinas/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Receptores Opioides/efeitos dos fármacos , Tiofenos/uso terapêutico , Animais , Artralgia/tratamento farmacológico , Quimiocina CXCL1/metabolismo , Relação Dose-Resposta a Droga , Injeções Intra-Articulares , Interleucina-1beta/metabolismo , Articulações/patologia , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Osteoartrite/patologia , Medição da Dor , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 µg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.
Assuntos
Colecistocinina/uso terapêutico , Endotoxemia/tratamento farmacológico , Hipotensão/prevenção & controle , Mediadores da Inflamação/sangue , Choque Séptico/tratamento farmacológico , Animais , Aorta/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Colecistocinina/antagonistas & inibidores , Colecistocinina/sangue , Colecistocinina/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Endotoxemia/sangue , Endotoxemia/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Interleucina-10/sangue , Ácido Láctico/sangue , Lipopolissacarídeos , Fígado/enzimologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/biossíntese , Proglumida/farmacologia , Ratos , Ratos Wistar , Choque Séptico/sangue , Choque Séptico/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Vasopressinas/sangueRESUMO
The aim of the present study was to evaluate the potential antinociceptive and toxicity of Canavalia boliviana lectin (CboL) using different methods in mice. The role of carbohydrate-binding sites was also investigated. CboL given to mice daily for 14 days at doses of 5 mg/kg did not cause any observable toxicity. CboL (1, 5, and 10 mg/kg) administered to mice intravenously inhibited abdominal constrictions induced by acetic acid and the two phases of the formalin test. In the hot plate and tail immersion tests, the same treatment of CboL induced significant increase in the latency period. In the hot plate test, the effect of CboL (5 mg/kg) was reversed by naloxone (1 mg/kg), indicating the involvement of the opioid system. In the open-field and rota-rod tests, the CboL treatment did not alter animals' motor function. These results show that CboL presents antinociceptive effects of both central and peripheral origin, involving the participation of the opioid system via lectin domain.
Assuntos
Analgésicos/farmacologia , Canavalia/química , Dor/tratamento farmacológico , Lectinas de Plantas/farmacologia , Analgésicos/administração & dosagem , Analgésicos/toxicidade , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Medição da Dor , Lectinas de Plantas/administração & dosagem , Lectinas de Plantas/toxicidade , SementesRESUMO
BACKGROUND: Obesity has become a global epidemic and bariatric surgery is one of the therapeutic tools to deal with it. Postoperative complications can occur, such as staple line dehiscence and anastomotic leaks, leading to increased patient mortality. The diagnosis of these complications is frequently difficult. The objective of the present study was to determine whether peritoneal and systemic cytokines could early detect those complications. METHODS: All patients who underwent open Roux-en-Y gastric bypass from February 2007 to August 2008 were prospectively evaluated. Blood and peritoneal effluent from the drain were collected for the determination of cytokine levels. We also evaluated the clinical signs and the leukograms of the patients. RESULTS: A total of 107 obese patients were studied. Ninety patients had no complications; 17 had at least one infectious complication which include five cases of staple line dehiscence. Until the third postoperative day, the vital signs and the leukogram did not predict the onset of infectious complications, but the cytokines (interleukin-1beta and interleukin-6) were early markers of these complications. CONCLUSION: Cytokines are good predictors of poor postoperative evolution in bariatric surgery since peritoneal cytokines diagnose better these infectious complications even before changes in blood count and before the occurrence of clinical manifestations.
Assuntos
Cirurgia Bariátrica/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Deiscência da Ferida Operatória/etiologia , Infecção da Ferida Cirúrgica/diagnóstico , Adulto , Biomarcadores/sangue , Feminino , Humanos , Interleucina-1/sangue , Interleucina-6/sangue , Masculino , Peritonite/imunologia , Complicações Pós-Operatórias/prevenção & controle , Infecção da Ferida Cirúrgica/prevenção & controle , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangueRESUMO
In the present study, the participation of the Na(V)1.8 sodium channel was investigated in the development of the peripheral pro-nociceptive state induced by daily intraplantar injections of PGE(2) in rats and its regulation in vivo by protein kinase A (PKA) and protein kinase C epsilon (PKCvarepsilon) as well. In the prostaglandin E(2) (PGE(2))-induced persistent hypernociception, the Na(V)1.8 mRNA in the dorsal root ganglia (DRG) was up-regulated. The local treatment with dipyrone abolished this persistent hypernociception but did not alter the Na(V)1.8 mRNA level in the DRG. Daily intrathecal administrations of antisense Na(V)1.8 decreased the Na(V)1.8 mRNA in the DRG and reduced ongoing persistent hypernociception. Once the persistent hypernociception had been abolished by dipyrone, but not by Na(V)1.8 antisense treatment, a small dose of PGE(2) restored the hypernociceptive plateau. These data show that, after a period of recurring inflammatory stimuli, an intense and prolonged nociceptive response is elicited by a minimum inflammatory stimulus and that this pro-nociceptive state depends on Na(V)1.8 mRNA up-regulation in the DRG. In addition, during the persistent hypernociceptive state, the PKA and PKCvarepsilon expression and activity in the DRG are up-regulated and the administration of the PKA and PKCvarepsilon inhibitors reduce the hypernociception as well as the Na(V)1.8 mRNA level. In the present study, we demonstrated that the functional regulation of the Na(V)1.8 mRNA by PKA and PKCvarepsilon in the primary sensory neuron is important for the development of the peripheral pro-nociceptive state induced by repetitive inflammatory stimuli and for the maintenance of the behavioral persistent hypernociception.