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Cinnamaldehyde (CNM) is an essential-oil component with reported anti-infective, anti-inflammatory, and healing effects, making it an interesting compound for the treatment of wound infection. Herein, we evaluated the effects of topical administration of CNM in experimental wounds infected by Staphylococcus aureus. Swiss mice (n = 12/group) were randomly allocated into three groups (CON: animals with uninfected lesions; Sa: animals with untreated infected lesions; Sa + CNM: animals with infected wounds and treated with CNM). Excisional lesions (64 mm2) were induced at the dorsal area followed by the addition of S. aureus (80 µL of a 1.5 × 108 CFU/mL bacterial suspension). The wounds were treated with CNM (200 µg/wound/day) or vehicle (2% DMSO) for 10 days. Skin samples were taken on the 3rd or 10th treatment day for quantification of inflammatory mediators, bacterial load, immunophenotyping, and histological analysis. The treatment with CNM improved the healing process and attenuated the severity of skin lesions infected by S. aureus. These effects were associated with significant decreases in bacterial loads in CNM-treated wounds. The levels of neutrophils, TNF-α, IL-6, NO, and VEGF were decreased in the lesions treated with CNM. Taken together, these data provide further evidence of the effectiveness of CNM for the treatment of skin infections.
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Infecções Estafilocócicas , Infecção dos Ferimentos , Camundongos , Animais , Staphylococcus aureus , Cicatrização , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/patologia , Infecção dos Ferimentos/tratamento farmacológicoRESUMO
Rheumatoid arthritis (RA) is characterized by inflammation of one or more joints, and affects ~1% of the adult population worldwide. Sulforaphane (SFN) is a natural compound that has been suggested as an antioxidant. Here, SFN's effects were evaluated in a murine mono-arthritis model. Mono-arthritis was induced in mice by a single intra-articular injection of Complete Freund's Adjuvant (CFA-10 µg/joint, in 10 µL) into the ipsilateral joint. The contralateral joint received an equal volume of PBS. On the 4th day post-joint inflammation induction, animals received either SFN (10 mg/kg) or vehicle (3% DMSO in saline), intraperitoneally (i.p.), twice a day for 3 days. Joint swelling and secondary mechanical allodynia and hyperalgesia were evaluated over 7 days post-CFA. After this period, animals were culled and their blood and synovial fluid samples were collected for analysis of cell populations, cytokine release and thioredoxin reductase (TrxR) activity. Knee joint samples were also collected for histology. SFN reduced joint swelling and damage whilst increasing the recruitment of Ly6C⺠and Ly6G⺠cells to CFA-injected joints. SFN-treated animals presented down-regulation of CD11b and CD62L on synovial fluid Ly6G⺠cells. Synovial fluid samples obtained from CFA-injected joints and plasma samples of SFN-treated mice presented higher levels of IL-6 and increased activity of TrxR, in comparison with controls. These results indicate that SFN reduces knee joint damage by modulating cell activation/migration to the joints, cytokine production and increasing the activity of TrxR, and therefore, may represent an alternative treatment to joint inflammation.
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Artrite Experimental/etiologia , Artrite Experimental/patologia , Adjuvante de Freund/efeitos adversos , Isotiocianatos/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Histocitoquímica , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Leucócitos/metabolismo , Leucócitos/patologia , Camundongos , Fenótipo , SulfóxidosRESUMO
Plant-derived products have played a fundamental role in the development of new therapeutic agents. This study aimed to analyze antimicrobial, antibiofilm, cytotoxicity and antiproliferative potentials of the extract and fractions from leaves of Himatanthusdrasticus, a plant from the Apocynaceae family. After harvesting, H. drasticus leaves were macerated and a hydroalcoholic extract (HDHE) and fractions were prepared. Antimicrobial tests, such as agar-diffusion, Minimum Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) were carried out against several bacterial species. Staphylococcus aureus, Pseudomonas aeruginosa, Listeria monocytogenes and Klebsiella pneumoniae were inhibited by at least one extract or fraction in the agar-diffusion assay (inhibition halos from 12 mm to 30 mm). However, the lowest MIC value was found for HDHE against K. pneumoniae. In addition, HDHE and its fractions were able to inhibit biofilm formation at sub-inhibitory concentrations (780 µg/mL and 1.56 µg/mL). As the best activities were found for HDHE, we selected it for further assays. HDHE was able to increase ciprofloxacin (CIP) activity against K. pneumoniae, displaying synergistic (initial concentration CIP + HDHE: 2 µg/mL + 600 µg/mL and 2.5 µg/mL + 500 µg/mL) and additive effects (CIP + HDHE: 3 µg/mL + 400 µg/mL). This action seems to be associated with the alteration in bacterial membrane permeability induced by HDHE (as seen by propidium iodide labeling). This extract was non-toxic for red blood cell or human peripheral blood mononuclear cells (PBMCs). Additionally, it inhibited the lipopolysaccharide-induced proliferation of PBMCs. The following compounds were detected in HDHE using HPLC-ESI-MS analysis: plumieride, plumericin or isoplumericin, rutin, quercetin and derivatives, and chlorogenic acid. Based on these results we suggest that compounds from H. drasticus have antimicrobial and antibiofilm activities against K. pneumoniae and display low cytotoxicity and anti-proliferative action in PBMC stimulated with lipopolysaccharide.
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Anti-Infecciosos/química , Apocynaceae/química , Biofilmes/efeitos dos fármacos , Flavonoides/química , Furanos/química , Iridoides/química , Folhas de Planta/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Biofilmes/crescimento & desenvolvimento , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciprofloxacina/farmacologia , Combinação de Medicamentos , Sinergismo Farmacológico , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Furanos/isolamento & purificação , Furanos/farmacologia , Iridoides/isolamento & purificação , Iridoides/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/fisiologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/fisiologia , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologiaRESUMO
Thousands of people suffer from severe malaria every year. The innate immune response plays a determinant role in host's defence to malaria. Transient receptor potential vanilloid 1 (TRPV1) modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. We investigated the effects of capsazepine, a TRPV1 antagonist, in malaria. C57BL/6 mice received 10(5) red blood cells infected with Plasmodium berghei ANKA intraperitoneally. Noninfected mice were used as controls. Capsazepine or vehicle was given intraperitoneally for 6 days. Mice were culled on day 7 after infection and blood and spleen cell phenotype and activation were evaluated. Capsazepine decreased circulating but not spleen F4/80(+)Ly6G(+) cell numbers as well as activation of both F4/80(+)and F4/80(+)Ly6G(+) cells in infected animals. In addition, capsazepine increased circulating but not spleen GR1(+) and natural killer (NK) population, without interfering with natural killer T (NKT) cell numbers and blood NK and NKT activation. However, capsazepine diminished CD69 expression in spleen NKT but not NK cells. Infection increased lipid peroxidation and the release of TNFα and IFNγ, although capsazepine-treated group exhibited lower levels of lipid peroxidation and TNFα. Capsazepine treatment did not affect parasitaemia. Overall, TRPV1 antagonism modulates the innate immune response to malaria.
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Capsaicina/análogos & derivados , Plasmodium berghei/patogenicidade , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Capsaicina/uso terapêutico , Citometria de Fluxo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei/imunologiaRESUMO
OBJECTIVE AND DESIGN: Among the options for treatment of diseases affecting the respiratory system, especially asthma, drug delivering systems for intranasal application represent an important therapeutic approach at the site of inflammation. The present study aimed to evaluate the therapeutic effect of biodegradable microparticles formed by poly lactic-co-glycolic acid (PLGA) containing encapsulated pomegranate extract on a murine model of asthma. MATERIAL: The extract was acquired from the leaves of P. granatum and characterized qualitatively by HPLC. A w/o/w emulsion solvent extraction-evaporation method was chosen to prepare the microparticles containing pomegranate encapsulated extract (MP). TREATMENT: OVA-sensitized BALB/c mice were used as asthma model and treated with dexamethasone and P. granatum extract in solution form or encapsulated into microparticles. RESULTS: MP were able to inhibit leukocytes' recruitment to bronchoalveolar fluid, especially, eosinophils, decreasing cytokines (IL-1ß and IL-5) and protein levels in the lungs. CONCLUSIONS: This approach can be used as an alternative/supplementary therapy based on the biological effects of P. granatum for managing inflammatory processes, especially those with pulmonary complications.
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Anti-Inflamatórios/administração & dosagem , Asma/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Lythraceae , Extratos Vegetais/administração & dosagem , Animais , Anti-Inflamatórios/química , Asma/imunologia , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Portadores de Fármacos/química , Feminino , Ácido Láctico/química , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Fitoterapia , Extratos Vegetais/química , Folhas de Planta , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
Rheumatoid arthritis (RA) is a painful inflammatory disease of the joints which affects a considerable proportion of the world population, mostly women. If not adequately treated, RA patients can become permanently disabled. Importantly, not all the patients respond to the available anti-rheumatic therapies, which also present diverse side effects. In this context, monitoring of treatment response is pivotal to avoid unnecessary side effects and costs towards an ineffective therapy. Herein, we performed a pilot study to investigate the potential use of flow cytometry and attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy as measures to identify responders and non-responders to leflunomide, a disease-modifying drug used in the treatment of RA patients. The evaluation of peripheral blood CD62L+ polymorphonuclear cell numbers and ATR-FTIR vibrational modes in plasma were able to discriminate responders to leflunomide (LFN) three-months after therapy has started. Overall, the results indicate that both flow cytometry and ATR-FTIR can potentially be employed as additional measures to monitor early treatment response to LFN in RA patients.
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Psoriasis (PS) is a chronic skin inflammation. Up to 30% of the patients with PS develop psoriatic arthritis (PsA), a condition characterized by inflammatory arthritis that affects joints or entheses. Although there is mounting evidence for a critical role of interleukin-23 (IL-23) signaling in the pathogenesis of both PS and PsA, it remains unclear whether IL-23-induced skin inflammation drives joint disease. Here, we show that mice expressing increased levels of IL-23 in the skin (K23 mice) develop a PS-like disease that is characterized by acanthosis, parakeratosis, hyperkeratosis, and inflammatory infiltrates in the dermis. Skin disease preceded development of PsA, including enthesitis, dactylitis, and bone destruction. The development of enthesitis and dactylitis was not due to high circulating levels of IL-23, as transgenic animals and controls had similar levels of this cytokine in circulation. IL-22, a downstream cytokine of IL-23, was highly increased in the serum of K23 mice. Although IL-22 deficiency did not affect skin disease development, IL-22 deficiency aggravated the PsA-like disease in K23 mice. Our results demonstrate a central role for skin expressed IL-23 in the initiation of PS and on pathogenic processes leading to PsA.
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Artrite Psoriásica/genética , Interleucina-23/genética , Psoríase/genética , Pele/imunologia , Animais , Artrite Psoriásica/imunologia , Feminino , Humanos , Interleucina-23/imunologia , Interleucinas/genética , Interleucinas/imunologia , Masculino , Camundongos , Psoríase/imunologia , Interleucina 22RESUMO
We have used a novel conditional transgenic system to study the mechanisms of angioproliferation induced by viral G protein-coupled receptor (vGPCR), the constitutively active chemokine receptor encoded by human herpesvirus 8 (HHV8, also known as Kaposi sarcoma herpesvirus). Using this system, we were able to control temporal expression of vGPCR and to monitor its expression in situ via the use of the surrogate marker LacZ. Upon treatment with doxycycline (DOX), cells expressing vGPCR and LacZ (vGPCR/LacZ(+) cells) progressively accumulated in areas where angioproliferation was observed. Sorted vGPCR/LacZ(+) cells from angiogenic lesions expressed markers characteristic of endothelial progenitor cells, produced angiogenic factors, and proliferated in vitro. Prolonged treatment of transgenic mice with DOX led to development of tumors in the skin of ears, tail, nose, and paws. vGPCR/LacZ(+) cells were frequent in early lesions but scarce within these tumors. Finally, transfer of vGPCR/LacZ(+) cells into Rag1(-/-) mice treated with DOX led to angioproliferation and, with time, to development of tumors containing both vGPCR/LacZ(+) and vGPCR/LacZ(-) cells. Taken together, these results indicate that vGPCR triggers angioproliferation directly and suggest a novel role for this molecule in the pathogenesis of Kaposi sarcoma.
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Células Endoteliais/virologia , Herpesvirus Humano 8/metabolismo , Receptores de Quimiocinas/fisiologia , Animais , Proliferação de Células , Doxiciclina/farmacologia , Células Endoteliais/citologia , Óperon Lac , Camundongos , Camundongos Transgênicos , Neovascularização Patológica , Receptores de Quimiocinas/químicaRESUMO
Importance: Malaria during pregnancy is associated with adverse events for the fetus and newborn, but the association of malaria during pregnancy with the head circumference of the newborn is unclear. Objective: To investigate the association of malaria during pregnancy with fetal head growth. Design, Setting, and Participants: Two cohort studies were conducted at the general maternity hospital of Cruzeiro do Sul (Acre, Brazil) in the Amazonian region. One cohort study prospectively enrolled noninfected and malaria-infected pregnant women who were followed up until delivery, between January 2013 and April 2015. The other cohort study was assembled retrospectively using clinical and malaria data from all deliveries that occurred between January 2012 and December 2013. Data analyses were conducted from January to August 2017 and revised in November 2018. Clinical data from pregnant women and anthropometric measures of their newborns were evaluated. A total of 600 pregnant women were enrolled through volunteer sampling (prospective cohort study), and 4697 pregnant women were selected by population-based sampling (retrospective cohort study). After application of exclusion criteria, data from 251 (prospective cohort study) and 232 (retrospective cohort study) malaria-infected and 158 (prospective cohort study) and 3650 (retrospective cohort study) noninfected women were evaluated. Exposure: Malaria during pregnancy. Main Outcomes and Measures: The primary end point was the incidence of altered head circumference in newborns delivered from malaria-infected mothers compared with that from noninfected mothers. Secondary end points included measures of placental pathology relative to newborn head circumference. Results: In total, 4291 maternal-child pairs were analyzed. Among 409 newborns in the prospective cohort study, the mothers of 251 newborns had malaria during pregnancy, infected with Plasmodium vivax, Plasmodium falciparum, or both. Among 3882 newborns in the retrospective cohort study, 232 were born from mothers that had malaria during pregnancy. The prevalence of newborns with a small head (19 [30.7%] in the prospective cohort study and 30 [36.6%] in the retrospective cohort study) and the prevalence of microcephaly among newborns (5 [8.1%] in the prospective cohort study and 6 [7.3%] in the retrospective cohort study) were higher among newborns from women infected with P falciparum during pregnancy. Multivariate logistic regression analyses revealed that P falciparum infection during pregnancy represented a significant risk factor for the occurrence of small head circumference in newborns (prospective cohort study: odds ratio, 3.15; 95% CI, 1.52-6.53; P = .002; retrospective cohort study: odds ratio, 1.91; 95% CI, 1.21-3.04; P = .006). Placental pathologic findings corroborated this association, with more syncytial nuclear aggregates and inflammatory infiltrates occurring in placentas of newborns born with decreased head circumference. Conclusions and Relevance: This study indicates that falciparum malaria during pregnancy is associated with decreased head circumference in newborns, which is in turn associated with evidence of placental malaria.
Assuntos
Cabeça/anatomia & histologia , Malária Falciparum/fisiopatologia , Exposição Materna/efeitos adversos , Complicações Infecciosas na Gravidez/epidemiologia , Adulto , Brasil/epidemiologia , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Gravidez , Prevalência , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Severe wounds result in large lesions and/or loss of function of the affected areas. The treatment of wounds has challenged health professionals due to its complexity, especially in patients with chronic diseases (such as diabetes), and the presence of pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. Taking this into consideration, the development of new therapies for wound healing requires immediate attention. Ethnopharmacological studies performed in different countries have shown the use of several plants from the Asteraceae family as wound-healing agents. Evidences gained from the traditional medicine have opened new ways for the development of novel and more efficient therapies based on the pharmacological properties of these plants. In this article, we discuss the literature data on the use of Asteraceae plants for the treatment of wounds, based on the ethnopharmacological relevance of each plant. Special attention was given to studies showing the mechanisms of action of Asteraceae-derived compounds and clinical trials. Ageratina pichinchensis (Kunth) R.M. King and H. Rob. and Calendula officinalis L. preparations/compounds were found to show good efficacy when assessed in clinical trials of complicated wounds, including venous leg ulcers and foot ulcers of diabetic patients. The compounds silibinin [from Silybum marianum (L.) Gaertn.] and jaceosidin (from Artemisia princeps Pamp.) were identified as promising compounds for the treatment of wounds. Overall, we suggest that Asteraceae plants represent important sources of compounds that may act as new and efficient healing products.
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OBJECTIVE: This randomized double-blind clinical trial compared tooth sensitivity (TS), bleaching efficacy, and cytokine levels after applying in-office bleaching treatments containing 15% and 35% hydrogen peroxide (HP15% and HP35%, respectively). METHODS: Twenty-five volunteers were randomly assigned to receive HP15% or HP35% treatment. The bleaching agent was applied in three 15-min applications per session. Two bleaching sessions were separated by a 1-week interval. The participants scored TS using a visual analog scale and numerical rating scale. Bleaching efficacy was determined by subjective and objective methods. Gingival crevicular fluid was collected from three jaws sites per patient for the analysis of fluid volume. Flow cytometry was used to analyze gingival crevicular fluid levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor, and interferon-gamma. All measurements were obtained before and after bleaching. All data were statistically analyzed (α=0.05). RESULTS: The absolute risk and intensity of TS was higher for HP35% than for HP15% (p>0.002). One month post-bleaching, HP35% produced more bleaching than HP15% (p=0.02). However patient perception (p=0.06) and patient satisfaction (p=0.53) with regard to bleaching were not significantly different. No significant differences existed in the gingival fluid volume (p>0.38) or in any cytokine level (p>0.05) for either HP concentration. CONCLUSION: Treatment: with HP35% is more effective than HP15%, but generates a greater risk and intensity of TS. No inflammatory changes occurred despite the difference in the HP concentrations. CLINICAL SIGNIFICANCE: Hydrogen peroxide at a lower concentration (e.g., 15%) should be considered a good treatment alternative for in-office bleaching because the higher concentration for in-office bleaching generates a greater risk and intensity of TS for patients.
Assuntos
Sensibilidade da Dentina/etiologia , Líquido do Sulco Gengival/química , Peróxido de Hidrogênio/efeitos adversos , Clareadores Dentários/efeitos adversos , Clareamento Dental/efeitos adversos , Adolescente , Adulto , Análise de Variância , Citocinas/análise , Método Duplo-Cego , Gengiva/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/administração & dosagem , Luz/efeitos adversos , Satisfação do Paciente , Clareadores Dentários/administração & dosagem , Descoloração de Dente/terapia , Resultado do Tratamento , Escala Visual Analógica , Voluntários , Adulto JovemRESUMO
Thioredoxin plays an essential role in bacterial antioxidant machinery and virulence; however, its regulatory actions in the host are less well understood. Reduced human Trx activates transient receptor potential canonical 5 (TRPC5) in inflammation, but there is no evidence of whether these receptors mediate bacterial thioredoxin effects in the host. Importantly, TRPC5 can form functional complexes with other subunits such as TRPC4. Herein, E. coli-derived thioredoxin induced mortality in lipopolysaccharide- (LPS-) injected mice, accompanied by reduction of leukocyte accumulation, regulation of cytokine release into the peritoneum, and impairment of peritoneal macrophage-mediated phagocytosis. Dual TRPC4/TRPC5 blockade by ML204 increased mortality and hypothermia in thioredoxin-treated LPS mice but preserved macrophage's ability to phagocytose. TRPC5 deletion did not alter body temperature but promoted additional accumulation of peritoneal leukocytes and inflammatory mediator release in thioredoxin-administered LPS mice. Thioredoxin diminished macrophage-mediated phagocytosis in wild-type but not TRPC5 knockout animals. TRPC5 ablation did not affect LPS-induced responses. However, ML204 caused mortality associated with exacerbated hypothermia and decreased peritoneal leukocyte numbers and cytokines in LPS-injected mice. These results suggest that bacterial thioredoxin effects under LPS stimuli are mediated by TRPC4 and TRPC5, shedding light on the additional mechanisms of bacterial virulence and on the pathophysiological roles of these receptors.
Assuntos
Escherichia coli/química , Lipopolissacarídeos/toxicidade , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Canais de Cátion TRPC/metabolismo , Tiorredoxinas/uso terapêutico , Animais , Peróxido de Hidrogênio/metabolismo , Indóis/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Piperidinas/toxicidade , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Canais de Cátion TRPC/antagonistas & inibidores , Virulência/efeitos dos fármacosRESUMO
Patients with rheumatoid arthritis (RA) suffer from pain and joint disability. The transient receptor potential ankyrin 1 (TRPA1) channel expressed on sensory neurones and non-neuronal cells mediates pain transduction and inflammation and it has been implicated in RA. However, there is little information on the contribution of TRPA1 for human disease. Here, we investigated the expression of TRPA1 on peripheral blood leukocytes and the circulating levels of its endogenous activators 4-hydroxynonenal (4-HNE) and hydrogen peroxide (H2O2) in RA patients treated or not with the anti-rheumatic leflunomide (LFN) or the anti-TNFα adalimumab (ADA). We also assessed whether TRPA1 expression correlates with joint pain and disability, in addition to the immune changes in RA. TRPA1 expression on peripheral blood leukocytes correlated with pain severity and disability. TRPA1 levels on these cells were associated with the numbers of polymorphonuclear and the activation of CD14+ cells. No correlations were found between the lymphocyte population and TRPA1 expression, pain or disability. Patients recently diagnosed with RA expressed increased levels of TRPA1 on their leukocytes whilst treatment with either LFN or ADA down-regulated this receptor probably by reducing the numbers of polymorphonuclears and the activation of CD14+ cells. We suggest that the activation levels of CD14+ cells, the numbers of PMNs in the peripheral blood and the expression of TRPA1 on peripheral blood leukocytes correlate with RA progression, affecting joint pain sensitivity and loss of function.
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In the face of increasing bacterial resistance to antibiotics currently in use, the search for new antimicrobial agents has received a boost in recent years, with natural products playing an important role in this field. In fact, several methods have been proposed to investigate the antibacterial activities of natural products. However, given that the ultimate aim is future therapeutic use as novel drugs, it is extremely necessary to elucidate their modes of action, stating the molecular effects in detail, and identifying their targets in the bacterial cell. This review analyzes the application of "omics technologies" to understand the antibacterial mechanisms of bioactive natural products, to stimulate research interest in this area and promote scientific collaborations. Some studies have been specifically highlighted herein by examining their procedures and results (targeted proteins and metabolic pathways). These approaches have the potential to provide new insights into our comprehension of antimicrobial resistance/susceptibility, creating new perspectives for the struggle against bacteria, and leading to the development of novel products in the future.
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Mechanisms involved in severe P. vivax malaria remain unclear. Parasite polymorphisms, parasite load and host cytokine profile may influence the course of infection. In this study, we investigated the influence of circumsporozoite protein (CSP) polymorphisms on parasite load and cytokine profile in patients with vivax malaria. A cross-sectional study was carried out in three cities: São Luís, Cedral and Buriticupu, Maranhão state, Brazil, areas of high prevalence of P. vivax. Interleukin (IL)-2, IL-4, IL-10, IL-6, IL-17, tumor necrosis factor alpha (TNF-α, interferon gamma (IFN-γ and transforming growth factor beta (TGF-ß were quantified in blood plasma of patients and in supernatants from peripheral blood mononuclear cell (PBMC) cultures. Furthermore, the levels of cytokines and parasite load were correlated with VK210, VK247 and P. vivax-like CSP variants. Patients infected with P. vivax showed increased IL-10 and IL-6 levels, which correlated with the parasite load, however, in multiple comparisons, only IL-10 kept this association. A regulatory cytokine profile prevailed in plasma, while an inflammatory profile prevailed in PBMC culture supernatants and these patterns were related to CSP polymorphisms. VK247 infected patients showed higher parasitaemia and IL-6 concentrations, which were not associated to IL-10 anti-inflammatory effect. By contrast, in VK210 patients, these two cytokines showed a strong positive correlation and the parasite load was lower. Patients with the VK210 variant showed a regulatory cytokine profile in plasma, while those infected with the VK247 variant have a predominantly inflammatory cytokine profile and higher parasite loads, which altogether may result in more complications in infection. In conclusion, we propose that CSP polymorphisms is associated to the increase of non-regulated inflammatory immune responses, which in turn may be associated with the outcome of infection.
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Citocinas/sangue , Variação Genética , Malária Vivax/epidemiologia , Malária Vivax/patologia , Carga Parasitária , Plasmodium vivax/genética , Proteínas de Protozoários/genética , Adolescente , Adulto , Animais , Brasil/epidemiologia , Células Cultivadas , Criança , Pré-Escolar , Cidades/epidemiologia , Estudos Transversais , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Plasmodium vivax/isolamento & purificação , Adulto JovemRESUMO
Cinnamaldehyde is a natural essential oil suggested to possess anti-bacterial and anti-inflammatory properties; and to activate transient receptor potential ankyrin 1 (TRPA1) channels expressed on neuronal and non-neuronal cells. Here, we investigated the immunomodulatory effects of cinnamaldehyde in an in vivo model of systemic inflammatory response syndrome (SIRS) induced by lipopolysaccharide. Swiss mice received a single oral treatment with cinnamaldehyde 1 h before LPS injection. To investigate whether cinnamaldehyde effects are dependent on TRPA1 activation, animals were treated subcutaneously with the selective TRPA1 antagonist HC-030031 5 min prior to cinnamaldehyde administration. Vehicle-treated mice were used as controls. Cinnamaldehyde ameliorated SIRS severity in LPS-injected animals. Diminished numbers of circulating mononuclear cells and increased numbers of peritoneal mononuclear and polymorphonuclear cell numbers were also observed. Cinnamaldehyde augmented the number of peritoneal Ly6C(high) and Ly6C(low) monocyte/macrophage cells in LPS-injected mice. Reduced levels of nitric oxide, plasma TNFα and plasma and peritoneal IL-10 were also detected. Additionally, IL-1ß levels were increased in the same animals. TRPA1 antagonism by HC-030031 reversed the changes in the number of circulating and peritoneal leukocytes in cinnamaldehyde-treated animals, whilst increasing the levels of peritoneal IL-10 and reducing peritoneal IL-1ß. Overall, cinnamaldehyde modulates SIRS through TRPA1-dependent and independent mechanisms.
Assuntos
Acroleína/análogos & derivados , Macrófagos/efeitos dos fármacos , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Canais de Potencial de Receptor Transitório/metabolismo , Acetanilidas/farmacologia , Acroleína/uso terapêutico , Animais , Movimento Celular/efeitos dos fármacos , Cinnamomum zeylanicum/imunologia , Modelos Animais de Doenças , Feminino , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Camundongos , Gravidez , Purinas/farmacologia , Canal de Cátion TRPA1RESUMO
Aiming to clarify the role of endogenous interleukin-12 (IL-12) in protective immunity against blood stages of Plasmodium chabaudi chabaudi (AS), we evaluated the course of infection in IL-12p40 gene knockout (IL-12p40KO) and wild-type (WT) C57BL/6 mice, focusing (1) on the ability of T cells to develop adequate type 1 responses and (2) on the potentiality of macrophages to respond to parasites, interferon-gamma (IFN-gamma), or both. We observed that IL-12p40KO mice develop significantly higher parasitemias during the acute infection, although mice from both groups clear the parasites within a month and similarly eliminate a secondary challenge. Thus, fully protective immunity to P. c. chabaudi can be generated in the absence of IL-12. However, this cytokine may promote parasite control during the early phase of infection. The increased acute parasitemia of IL-12p40KO mice was associated with both impaired IFN-gamma and nitric oxide (NO) response by spleen cells. Because stimulation with recombinant IFN-gamma (rIFN-gamma) failed to improve the NO response in IL-12p40KO macrophages, we investigated whether these cells have an intrinsic defect. Analysis of peritoneal macrophages revealed that IL-12p40KO cells produce higher levels of transforming growth factor-beta1 (TGF-beta1) compared with WT cells and respond to infected erythrocytes or rIFN-gamma by releasing little NO. Moreover, IL-12p40KO macrophages had a severely impaired ability to internalize opsonized infected erythrocytes, suggesting that the low effector profile assumed by these cells may compromise antibody-mediated immunity. Taken together, our results support the idea that the absence of IL-12p40 not only affects IFN-gamma production but also has deep consequences in macrophage effector functions that may contribute to exacerbation of the early phase of P. c. chabaudi malaria.
Assuntos
Interleucina-12/deficiência , Macrófagos/imunologia , Malária/sangue , Malária/imunologia , Parasitemia/imunologia , Animais , Interferon gama/biossíntese , Interferon gama/farmacologia , Interleucina-12/genética , Interleucina-12/fisiologia , Linfócitos/imunologia , Malária/fisiopatologia , Camundongos , Camundongos Knockout , Óxido Nítrico/fisiologia , Parasitemia/sangue , Parasitemia/fisiopatologia , Fagocitose , Proteínas Recombinantes , Baço/imunologia , Fatores de TempoRESUMO
Challenge of 1-yr Trypanosoma cruzi chronically infected mice with trypomastigotes results in a consistent reduction of parasite dissemination that correlates with spleen activation and increase in the anti-T. cruzi effector immune mechanisms. That is, parasite challenge results not only in elimination of the inoculum but also in a drastic decrease in basal subpatent parasitemia levels as revealed by transferring blood samples to immunosuppressed mice. Parasite elimination correlated with (1) a brief and intense burst in the ability of spleen cells to produce interferon-gamma, (2) an increase in total IgG2a-producing spleen cells, (3) higher parasite-specific IgG2a serum levels, and (4) an accumulation of non-B, non-T class II+ cells in the spleen. Furthermore, challenged, chronically infected mice had increased numbers of B, CD4+, and CD8+ large spleen cells. Besides reinforcing the activation of protective Th1 effector mechanisms, challenge with T. cruzi also induced Th2 effector molecules, such as interleukin (IL)-10 and IL-4, and IL-4-dependent IgG1. Our results are the first evidence that the immune system of T. cruzi chronically infected mice can be optimized in its ability to restrict parasite dissemination, opening the possibility that therapeutic vaccination could be used to reduce the parasite load and pathology of patients with chronic Chagas' disease.
Assuntos
Doença de Chagas/imunologia , Parasitemia/imunologia , Baço/imunologia , Trypanosoma cruzi/imunologia , Animais , Anticorpos Antiprotozoários/sangue , Doença Crônica , Citocinas/biossíntese , Feminino , Hospedeiro Imunocomprometido/imunologia , Imunoglobulinas/biossíntese , Imunoglobulinas/sangue , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos A , Baço/citologiaRESUMO
Langerhans cells (LCs) are the dendritic cells (DCs) of the epidermis, forming one of the first hematopoietic lines of defense against skin pathogens. In contrast to other DCs, LCs arise from hematopoietic precursors that seed the skin before birth. However, the origin of these embryonic precursors remains unclear. Using in vivo lineage tracing, we identify a first wave of yolk sac (YS)-derived primitive myeloid progenitors that seed the skin before the onset of fetal liver hematopoiesis. YS progenitors migrate to the embryo proper, including the prospective skin, where they give rise to LC precursors, and the brain rudiment, where they give rise to microglial cells. However, in contrast to microglia, which remain of YS origin throughout life, YS-derived LC precursors are largely replaced by fetal liver monocytes during late embryogenesis. Consequently, adult LCs derive predominantly from fetal liver monocyte-derived cells with a minor contribution of YS-derived cells. Altogether, we establish that adult LCs have a dual origin, bridging early embryonic and late fetal myeloid development.
Assuntos
Células de Langerhans/citologia , Fígado/citologia , Fígado/embriologia , Monócitos , Saco Vitelino/citologia , Saco Vitelino/embriologia , Fatores Etários , Animais , Linhagem da Célula , Feminino , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Células Progenitoras Mieloides , Gravidez , Pele/citologia , Pele/embriologia , Células-TroncoRESUMO
One of the main unresolved questions in solid organ transplantation is how to establish indefinite graft survival that is free from long-term treatment with immunosuppressive drugs and chronic rejection (i.e., the establishment of tolerance). The failure to achieve this goal may be related to the difficulty in identifying the phenotype and function of the cell subsets that participate in the induction of tolerance. To address this issue, we investigated the suppressive roles of recipient myeloid cells that may be manipulated to induce tolerance to transplanted hearts in mice. Using depleting mAbs, clodronate-loaded liposomes, and transgenic mice specific for depletion of CD11c+, CD11b+, or CD115+ cells, we identified a tolerogenic role for CD11b+CD115+Gr1+ monocytes during the induction of tolerance by costimulatory blockade with CD40L-specific mAb. Early after transplantation, Gr1+ monocytes migrated from the bone marrow into the transplanted organ, where they prevented the initiation of adaptive immune responses that lead to allograft rejection and participated in the development of Tregs. Our results suggest that mobilization of bone marrow CD11b+CD115+Gr1+ monocytes under sterile inflammatory conditions mediates the induction of indefinite allograft survival. We propose that manipulating the common bone marrow monocyte progenitor could be a useful clinical therapeutic approach for inducing transplantation tolerance.