Peptídeos antimicrobianos de mamíferos: potencial e limitações para o tratamento de infecções por Staphylococcus aureus.

Antimicrobial peptides (AMPs) are small molecules produced by virtually all living organisms as a part of the innate immune system. They present a broad spectrum antimicrobial activity against a myriad of microorganisms, but also anti-inflammatory, immunomodulatory and antitumor effects, among others. Therefore, it was our objective to compile and analyze the current information about natural and synthetic AMPs, regarding their general mechanisms of action, potentials, and limitations for clinical use, especially for the treatment of Staphylococcus aureus infections. Furthermore, we intended to briefly discuss new routes of administration and the emergence of bacterial resistance to AMPs. To do so, two databases, PubMed and Scopus, and the keywords “Staphylococcus aureus”, “antimicrobial peptide” and “novel antibiotics” were used, and the articles were filtered by the English language for the period between 2011 and 2016. We found that AMPs possess different properties, with characteristic antimicrobial activities and secondary effects. Moreover, we also pointed some modifications that could be used to design new AMPs and different routes of administration that could be used to improve AMP capacity or to adapt it to a specific purpose, such as preventing biofilm formation in catheters or treating a specific disease. On the other hand, they also present limitations that include: development of bacterial resistance, cytotoxicity, and reduced stability, sometimes lower efficacy when compared to the actual treatment, high costs of production and also some inconsistent results between articles, which we believe that may be related to differences in methods and/or strains of S. aureus investigated.Peptídeos antimicrobianos (AMPs) são pequenas moléculas conservadas evolutivamente e encontradas virtualmente em todos os organismos vivos como parte de sua imunidade inata. Eles possuem um amplo espectro de atividade antimicrobiana contra diversos microrganismos, mas também ação anti-inflamatória, imunomodulatória, antitumoral, dentre outros efeitos. Desse modo, nosso objetivo foi compilar e analisar as informações mais atuais sobre AMPs naturais e sintéticos, considerando seus mecanismos gerais de ação, bem como seu potencial e limitações para uso clínico, especialmente no tratamento de infecções por Staphylococcus aureus. Além disso, discutimos brevemente o uso de novas vias de administração e a possibilidade do desenvolvimento de resistência bacteriana aos AMPs. Para tanto, foram usadas duas bases de dados, PubMed e Scopus e os descritores “Staphylococcus aureus”, “peptídeos antimicrobianos” e “novos antibióticos”. Os artigos foram filtrados para a língua inglesa e foram selecionadas publicações entre 2011 e 2016. Os resultados foram em sua maioria compatíveis com o que se obteve em revisões prévias, a saber, que existe uma grande variedade de AMPs, cada qual com características, atividades antimicrobianas e efeitos secundários específicos. Ademais, também foram apontadas modificações que podem ser usadas para o planejamento de novos AMPs e diferentes vias de administração que podem ser usadas para aprimorar os potenciais de um AMP, ou adaptá-lo para um propósito específico, como a prevenção de formação de biofilmes em cateteres ou no tratamento de uma doença específica. Por outro lado, eles também possuem limitações, que incluem: desenvolvimento de resistência bacteriana, citotoxicidade e reduzida estabilidade, eventualmente baixa eficácia quando comparados ao tratamento atual, elevados custos de produção, e mesmo inconsistências de resultados entre artigos, o que acreditamos estar relacionado a diferenças no método e/ou a cepa de S. aureus usados

Obesidade: uma abordagem inflamatória e microbiana

Obesity is closely linked to an inflammatory state, being considered a complex metabolic pathology. Hypercaloric diets alter the composition of intestinal microbiota, and the change in the proportion of bacteria from the Bacteroidetes and Firmicutes phyla is one of the most known consequences. This change causes the production of specific immune system metabolites, inducing an inflammatory state which is responsible for aggravating some diseases. The hypercaloric diet represents a risk factor for obesity and diabetes mellitus, diseases linked by the concept of lipotoxicity, and the inflammatory state also contributes to the onset and to the progression of cardiovascular diseases. In this article, we aim to study obesity from the immunological and microbiological perspective, addressing the consequences of hypercaloric diets on the inflammatory state and microbiota. In addition, to analyze the role of microbiome change in prevalent diseases like diabetes mellitus and cardiovascular diseases, pointing out potential therapeutic approaches.A obesidade está intimamente ligada ao estado inflamatório, sendo considerada uma patologia metabólica complexa. Dietas hipercalóricas alteram a composição da microbiota intestinal, sendo a mudança da proporção de bactérias dos filos Bacteroidetes e Firmicutes uma das consequências mais conhecidas.  Essa mudança determina a produção de metabólitos específicos do sistema imune, induzindo estado inflamatório responsável pelo agravamento de uma série de doenças. A dieta hipercalórica representa um fator de risco para a obesidade e para o diabetes mellitus, doenças interligadas pelo conceito de lipotoxicidade, e o estado inflamatório também contribui para o aparecimento e para a progressão de doenças cardiovasculares. Com esse artigo, objetivamos estudar a obesidade pela perspectiva imunológica e microbiológica, abordando as consequências de dietas hipercalóricas sobre o estado inflamatório e a sobre a microbiota. Ademais, associar a mudança no microbioma a doenças prevalentes como o diabetes mellitus e as doenças cardiovasculares, apontando abordagens terapêuticas potenciais

Image_2_AIM2 as a putative target in acute kidney graft rejection.jpeg

Acute rejection (AR) is a process triggered via the recognition of grafted organ-derived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and meta-analysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival.</p

Table_3_AIM2 as a putative target in acute kidney graft rejection.xlsx

Acute rejection (AR) is a process triggered via the recognition of grafted organ-derived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and meta-analysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival.</p

Table_1_AIM2 as a putative target in acute kidney graft rejection.xlsx

Acute rejection (AR) is a process triggered via the recognition of grafted organ-derived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and meta-analysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival.</p

Table_2_AIM2 as a putative target in acute kidney graft rejection.xlsx

Acute rejection (AR) is a process triggered via the recognition of grafted organ-derived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and meta-analysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival.</p

Image_4_AIM2 as a putative target in acute kidney graft rejection.jpeg

Acute rejection (AR) is a process triggered via the recognition of grafted organ-derived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and meta-analysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival.</p

Image_6_AIM2 as a putative target in acute kidney graft rejection.jpeg

Acute rejection (AR) is a process triggered via the recognition of grafted organ-derived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and meta-analysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival.</p