Orange Juice and Hesperidin Promote Differential Innate Immune Response in Macrophages ex vivo

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Inhibition of Nitric Oxide and Tumour Necrosis Factor-alpha Production in Peritoneal Macrophages by Aspergillus nidulans Melanin

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Hypusine Modification of the Ribosome-binding Protein eIF5A, a Target for New Anti-Inflammatory Drugs: Understanding the Action of the Inhibitor GC7 on a Murine Macrophage Cell Line

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis

Although melatonin is mainly produced by the pineal gland, an increasing number of extra-pineal sites of melatonin synthesis have been described. We previously demonstrated the existence of bidirectional communication between the pineal gland and the immune system that drives a switch in melatonin production from the pineal gland to peripheral organs during the mounting of an innate immune response. In the present study, we show that acute neuroinflammation induced by lipopolysaccharide (LPS) injected directly into the lateral ventricles of adult rats reduces the nocturnal peak of melatonin in the plasma and induces its synthesis in the cerebellum, though not in the cortex or hippocampus. This increase in cerebellar melatonin content requires the activation of nuclear factor kappa B (NF-κB), which positively regulates the expression of the key enzyme for melatonin synthesis, arylalkylamine N-acetyltransferase (AA-NAT). Interestingly, LPS treatment led to neuronal death in the hippocampus and cortex, but not in the cerebellum. This privileged protection of cerebellar cells was abrogated when G-protein-coupled melatonin receptors were blocked by the melatonin antagonist luzindole, suggesting that the local production of melatonin protects cerebellar neurons from LPS toxicity. This is the first demonstration of a switch between pineal and extra-pineal melatonin production in the central nervous system following a neuroinflammatory response. These results have direct implications concerning the differential susceptibility of specific brain areas to neuronal death.

Terpinen-4-ol and alpha-terpineol (tea tree oil components) inhibit the production of IL-1 beta, IL-6 and IL-10 on human macrophages

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Citral and eugenol modulate DNA damage and pro-inflammatory mediator genes in murine peritoneal macrophages

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

TNF alpha contributes for attenuating both Y(397)FAK and Y(416)Src phosphorylations in osteoblasts

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Morphological effects of bacterial compounds on the testes of Eupemphix nattereri (Anura)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Phenotypic and functional evaluations of peripheral blood monocytes from chronic-form paracoccidioidomycosis patients before and after treatment

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Synergistic Anti-Inflammatory Activity of the Antimicrobial Peptides Human Beta-Defensin-3 (hBD-3) and Cathelicidin (LL-37) in a Three-Dimensional Co-Culture Model of Gingival Epithelial Cells and Fibroblasts

Given the spread of antibiotic resistance in bacterial pathogens, antimicrobial peptides that can also modulate the immune response may be a novel approach for effectively controlling periodontal infections. In the present study, we used a three-dimensional (3D) co-culture model of gingival epithelial cells and fibroblasts stimulated with Aggregatibacter actinomycetemcomitans lipopolysaccharide (LPS) to investigate the anti-inflammatory properties of human beta-defensin-3 (hBD-3) and cathelicidin (LL-37) and to determine whether these antimicrobial peptides can act in synergy. The 3D co-culture model composed of gingival fibroblasts embedded in a collagen matrix overlaid with gingival epithelial cells had a synergistic effect with respect to the secretion of IL-6 and IL-8 in response to LPS stimulation compared to fibroblasts and epithelial cells alone. The 3D co-culture model was stimulated with non-cytotoxic concentrations of hBD-3 (10 and 20 mu M) and LL-37 (0.1 and 0.2 mu M) individually and in combination in the presence of A. actinomycetemcomitans LPS. A multiplex ELISA assay was used to quantify the secretion of 41 different cytokines. hBD-3 and LL-37 acted in synergy to reduce the secretion of GRO-alpha, G-CSF, IP-10, IL-6, and MCP-1, but only had an additive effect on reducing the secretion of IL-8 in response to A. actinomycetemcomitans LPS stimulation. The present study showed that hBD-3 acted in synergy with LL-37 to reduce the secretion of cytokines by an LPS-stimulated 3D model of gingival mucosa. This combination of antimicrobial peptides thus shows promising potential as an adjunctive therapy for treating inflammatory periodontitis.

Determinação de adenosina deaminase, fator de necrose tumoral-alfa e interleucina-1 em gestantes portadoras de pré-eclâmpsia

Preeclampsia is a specific disorder of pregnancy, characterized by arterial hypertension and proteinuria detected after 20 weeks of gestation. This pathology is associated with hyperuricemia, higher levels of pro-inflammatory cytokines, enhanced leukocyte activation and oxidative stress. Adenosine deaminase (ADA) is an enzyme present in all human tissues and, it is involved with the maturation of the immune system. Although its function is not fully understood, ADA is considered an indicator of cellular inflammation and, its increased serum concentration is observed in inflammatory diseases, such as tuberculosis and rheumatoid arthritis. This study aimed to assess serum ADA levels in preeclamptic patients (PE) compared with normotensive pregnant (NT) and non-pregnant women (NP), and to correlate these values with TNF-α and IL-1β production. Ninety pregnant women were included: 60 were pre-eclamptic and 30 were normotensive matched for gestational age. As control group 20 healthy non-pregnant women matched with pregnant for age were included. Peripheral blood mononuclear cells (PMMC) obtained from the three groups studied were cultured with or without lipopolysaccharide (LPS) for 18h at 37oC, and TNF-α and IL-1β production was assessed in the supernatant of cultures by enzyme immunoassay (ELISA). ADA plasmatic concentration was determined by colorimetric method. The results show that ADA plasma levels were significantly higher in PE group compared with NT and NP groups. A positive correlation between ADA and uric acid levels was detected in preeclamptic women. There was no significant difference in relation to ADA levels when PE patients were classified in early and late-onset PE. The endogenous production of IL-1β and TNF-α by PBMC was significantly higher in PE group than in NT and NP women, showing the activation state of these cells in PE. LPS induced...(Complete abstract click electronic access below)

Efeito da silibinina sobre o fator de transcrição nuclear-kB e produção de citocinas inflamatórias por células mononucleares de gestantes portadoras de pré-eclâmpsia

Pre-eclampsia (PE) is a complication of human pregnancy characterized by hypertension and proteinuria after 20 weeks of gestation. Its incidence varies from 5% to 7% of pregnancies and is a major cause of morbidity and maternal and fetal mortality. This is a multisystemic disease, with focus on vascular dysfunction and is closely related to the exacerbated activation of the immune system. In addition to increased activation of monocytes and granulocytes, there is an elevated production of proinflammatory cytokines in pregnant women with PE. The nuclear transcription factor-kB (NF-kB) is present in the cells of the immune system and is responsible for transcription of genes related to inflammation. Whereas the PE is associated with intense inflammatory response, the use of substances modulating the activity of NF-kB factor could be useful in alleviating the inflammation present in these patients. Silibinin is the main component of silymarin, a polyphenolic extract obtained from fruits and seeds of Sylibum marianum with potent hepatoprotective, anti-inflammatory and anti-fibrotic activities. The silibinin mechanism of action includes the ability to inhibit NF-kB activation and, consequently, its migration to the nucleus. The objective of this study was to assess whether silibinin modulates the activity of NF-kB and the production of inflammatory cytokines in mononuclear cells of patients with PE. We evaluated 34 pregnant women with PE, 20 normotensive pregnant women (GN) and 15 non-pregnant women (NG). Peripheral blood mononuclear cells (PBMC) were obtained from those groups of women and cultured in the presence or absence of silibinin (5 uM or 50 uM) and stimulated or not with lipopolysaccharide (LPS) for 18 h to obtain supernatant for determination of tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1β) by enzyme immunoassay (ELISA). The cells were...(Complete abstract click electronic access below)

Associação entre expressão de receptores TLR2 e TLR4 e produção de TNF-alpha e IL-10 por monócitos de gestantes portadoras de pré-eclâmpsia

Preeclampsia (PE) is a pregnancy specific syndrome characterized by a systemic inflammatory response, with higher intensity than that observed in normal pregnancy. Cells of the immune system, such as monocytes and granulocytes are endogenously activated and secrete high levels of free radicals and inflammatory cytokines. The objective of this study was to assess the activation state of monocytes from pregnant women with preeclampsia by endogenous expression of TLR2 e TLR4 receptors and to correlate the expression of TLR2 and TLR4 on monocytes surface of pregnant women with PE with the production of tumor necrosis factor-alpha (TNF- and interleukin-10 (IL-10) by these cells stimulated or not with peptidoglycan (PG) and lipopolysaccharide (LPS), as agonists agents of TLR2 and TLR4, respectively. We evaluated 15 pregnant women with PE, 15 normotensive pregnant women (NT) and 15 non-pregnant (NP). Peripheral blood monocytes were incubates in the presence or absence of LPS or PG. The supernatant obtained after 18h of culture was aspirated and used for TNF- and IL-10 determination by enzyme immunoassay (ELISA). The endogenous expression of TLR2 and TLR4 receptors was evaluated by flow cytometry. Our results showed significant highly concentrations of TNF- and TLR4 expression in monocytes of preeclamptic women when compared with NT and NP. Normal pregnant women presented higher levels of IL-10 in comparison with PE and NP groups. TLR2 expression was similar in the three groups studied. Therefore, our study highlights the important role of TLR4 in PE and the consequent high production of TNF- by monocytes of these patients, as well as the potential mechanism involving low levels of IL-10 in the pathophysiology of the disease. These observations demonstrate the strong link between the pathology of PE and the immune system of these patients

Efeito protetor da proteína anti-inflamatória Galectina-1 sobre o processo de uveíte induzida pelo inflamógeno lipopolissacarídeo

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Anti-inflammatory effect of MAPK phosphatase-1 local gene transfer in inflammatory bone loss

Alveolar bone loss associated with periodontal diseases is the result of osteoclastogenesis induced by bacterial pathogens. The mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is a critical negative regulator of immune response as a key phosphatase capable of dephosphorylating activated MAPKs. In this study, rat macrophages transduced with recombinant adenovirus (Ad.)MKP-1 specifically dephosphorylated activated MAPKs induced by lipopolysaccharide (LPS) compared with control cells. Bone marrow macrophages from MKP-1 knockout (KO) mice exhibited higher interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and select chemokine compared with wild-type (WT) mice when stimulated by LPS. In addition, bone marrow cultures from MKP-1 KO mice exhibited significantly more osteoclastogenesis induced by LPS than when compared with WT mice. Importantly, MKP-1 gene transfer in bone marrow cells of MKP-1 KO mice significantly decreased IL-6, IL-10, TNF-α and chemokine levels, and formed fewer osteoclasts induced by LPS than compared with control group of cells. Furthermore, MKP-1 gene transfer in an experimental periodontal disease model attenuated bone resorption induced by LPS. Histological analysis confirmed that periodontal tissues transduced with Ad. MKP-1 exhibited less infiltrated inflammatory cells, less osteoclasts and less IL-6 than compared with rats of control groups. These studies indicate that MKP-1 is a key therapeutic target to control of inflammation-induced bone loss.