RESUMO
Abstract Acute pancreatitis (AP) is a life-unpleasant situation with contradictory and inadequate treatments. In this regard, the present study evaluated the effect of the possible pretreatment of lipase-pancreatin on L-arginine-induced AP. Forty adult mice were selected and divided into five groups: I) control group, II and III) AP groups (i.p.) receiving L-arginine of 2×300 and 2×400 mg/100 g body weight (b.w.), IV) AP (2×300 L-arginine) group + pancreatin (mice were i.p. injected by 350 U-lipase), and V) AP (2×400 L-arginine) group + pancreatin (mice were i.p. injected by 350 U-lipase). All AP groups displayed a significant increase in serum levels of ALT, AST, TBARS, and TNF-alpha compared to the control group. Moreover, pancreatic tissue edema, inflammation, and vacuolization of acinar cells were significantly higher in the untreated L-arginine group compared to the control and pancreatin groups. Conversely, the diameter of pancreatic islets significantly declined after induction of pancreatitis compared with control and pancreatin groups. Pancreatin treatment can be used in pancreatic dysfunction, however, this medicine showed no protective effect against L-arginine-induced AP in the mouse model.
Assuntos
Animais , Masculino , Camundongos , Pancreatite/induzido quimicamente , Pancreatina/efeitos adversos , Fator de Necrose Tumoral alfa/agonistas , Células Acinares/classificaçãoRESUMO
The main aim of this investigation was to study the regulatory roles of let-7b and miR-155-3p on the expression of inflammation-associated genes in monocytes, macrophages, and lipopolysaccharide (LPS)-activated macrophages (AcM). A second goal was to analyze the potential modulatory roles of different fatty acids, including oleic, palmitic, eicosapentaenoic (EPA), and docosahexaenoic (DHA), on the expression of these miRNAs in the three cell types. This hypothesis was tested in human acute monocytic leukemia cells (THP-1), which were differentiated into macrophages with 2-O-tetradecanoylphorbol-13-acetate (TPA) and further activated with LPS for 24 h. Monocytes, macrophages, and AcM were transfected with a negative control, or mimics for miR-155-3p and miR-let-7b-5p. The expression of both miRNAs and some proinflammatory genes was analyzed by qRT-PCR. Interestingly, let-7b mimic reduced the expression of IL6 and TNF in monocytes, and SERPINE1 expression in LPS-activated macrophages. However, IL6, TNF, and SERPINE1 were upregulated in macrophages by let-7b mimic. IL6 expression was higher in the three types of cells after transfecting with miR-155-3p mimic. Similarly, expression of SERPINE1 was increased by miR-155-3p mimic in monocytes and macrophages. However, TLR4 was downregulated by miR-155-3p in monocytes and macrophages. Regarding the effects of the different fatty acids, oleic acid increased the expression of let-7b in macrophages and AcM and also increased the expression of miR-155 in monocytes when compared with DHA but not when compared with non-treated cells. Overall, these results suggest anti- and proinflammatory roles of let-7b and miR-155-3p in THP-1 cells, respectively, although these outcomes are strongly dependent on the cell type. Noteworthy, oleic acid might exert beneficial anti-inflammatory effects in immune cells (i.e., non-activated and LPS-activated macrophages) by upregulating the expression of let-7b.
Assuntos
Ácidos Graxos não Esterificados/metabolismo , Regulação da Expressão Gênica , Macrófagos/metabolismo , MicroRNAs/metabolismo , Monócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/metabolismo , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/agonistas , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , MicroRNAs/química , Monócitos/imunologia , Ácido Oleico/metabolismo , Inibidor 1 de Ativador de Plasminogênio/agonistas , Inibidor 1 de Ativador de Plasminogênio/química , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA/metabolismo , Células THP-1 , Acetato de Tetradecanoilforbol/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/agonistas , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Visceral leishmaniasis is a fatal parasitic neglected disease affecting 1.5 million people worldwide. Based on a drug repositioning approach, the aim of this work was to investigate the in vitro immunomodulatory potential of buparvaquone (BPQ) and to establish a safe regimen to evaluate the in vivo efficacy of BPQ entrapped by negatively charged nanoliposomes (BPQ-LP) in Leishmania infantum-infected hamsters. Small-angle X-ray scattering, dynamic light scattering, and the ζ-potential were applied in order to study the influence of BPQ on the liposome structure. Our data revealed that BPQ was located in the polar-apolar interface, snorkeling the polar region, and protected against aggregation inside the lipophilic region. The presence of BPQ also decreased the Z-average hydrodynamic diameter and increased the surface charge. Compared to intravenous and intramuscular administration, a subcutaneous route was a more effective route for BPQ-LP; at 0.4 mg/kg, BPQ-LP reduced infection in the spleen and liver by 98 and 96%, respectively. Treatment for 5 days resulted in limited efficacy, but 10 days of treatment resulted in an efficacy similar to that of a 15-day regimen. The nanoliposomal drug was highly effective, with a mean 50% effective dose of 0.25 mg/kg, reducing the parasite load in bone marrow by 80%, as detected using quantitative PCR analysis. In addition, flow cytometry studies showed that BPQ upregulated cytokines as tumor necrosis factor, monocyte chemoattractant protein 1, interleukin-10 (IL-10), and IL-6 in Leishmania-infected macrophages, eliminating the parasites via a nitric oxide-independent mechanism. This new formulation proved to be a safe and effective treatment for murine leishmaniasis that could be a useful candidate against visceral leishmaniasis.
Assuntos
Antiprotozoários/farmacologia , Fatores Imunológicos/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Lipossomos/química , Macrófagos/efeitos dos fármacos , Naftoquinonas/farmacologia , Administração Cutânea , Animais , Antiprotozoários/química , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/parasitologia , Quimiocina CCL2/agonistas , Quimiocina CCL2/biossíntese , Cricetinae , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Fatores Imunológicos/química , Interleucina-10/agonistas , Interleucina-10/biossíntese , Interleucina-6/agonistas , Interleucina-6/biossíntese , Leishmania infantum/crescimento & desenvolvimento , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Lipossomos/farmacocinética , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/parasitologia , Macrófagos/imunologia , Macrófagos/parasitologia , Masculino , Camundongos , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Naftoquinonas/química , Carga Parasitária , Baço/efeitos dos fármacos , Baço/imunologia , Baço/parasitologia , Eletricidade Estática , Fator de Necrose Tumoral alfa/agonistas , Fator de Necrose Tumoral alfa/biossínteseRESUMO
La psoriasis es una enfermedad crónica que afecta al 1%-2% de la población, produce importante deterioro de la calidad de vida y puede asociarse a complicaciones metabólicas y articulares severas. Existen múltiples agentes sistémicos para el manejo de los casos moderado-severos; sin embargo, la mayoría no puede utilizarse de manera continua o prolongada y los estudios han demostrado que un alto porcentaje de pacientes está disconforme con sus tratamientos. Los agentes biológicos representan una poderosa herramienta en el tratamiento de la psoriasis; no obstante, los riesgos asociados y sus costos hacen necesario restringir su uso. Debido a estas consideraciones, diferentes sociedades dermatológicas en el mundo han desarrollado guías clínicas de consenso para el manejo de estos agentes en psoriasis. El presente artículo resume las recomendaciones de las sociedades Alemana (2007), Americana (2008), Española (2009) y Británica (2009) de Dermatología y los principales ensayos clínicos de cada uno de los agentes biológicos disponibles para el tratamiento de la psoriasis, y pretende entregar algunas directrices para la utilización de estos agentes en el medio nacional.
Psoriasis is a chronic disease that affects 1%-2% of the population, causes serious deterioration in the quality of life and may be associated with severe metabolic and joint complications. There are numerous systemic agents for the management of moderate-severe cases, however, most of them cannot be used in a continuous or prolonged way, and studies have shown a high percentage of dissatisfaction with those treatments. Biologics represent a powerful tool in the treatment of psoriasis, however, associated risks and costs make it necessary to restrict their use. Because of this, different dermatological societies around the world have developed clinical guidelines for the management of these agents in psoriasis. This article summarizes the recommendations of the German (2007), American (2008), Spanish (2009) and British (2009) Dermatology Societies, as well as the main clinical trials of biologics for the treatment of Psoriasis, and attempts to provide some guidelines for the use of these agents in our country.