RESUMO
The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn(2+) and Zn(2+) with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn(2+) sequestration. The asymmetry of the CP heterodimer creates a single Mn(2+)-binding site from six histidine residues, which distinguishes CP from all other Mn(2+)-binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn(2+) and Zn(2+) being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn(2+) sequestration. These data establish the importance of Mn(2+) sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.
Assuntos
Imunidade Inata , Complexo Antígeno L1 Leucocitário/química , Complexo Antígeno L1 Leucocitário/imunologia , Manganês/metabolismo , Substituição de Aminoácidos , Sítios de Ligação , Calgranulina A/química , Calgranulina A/genética , Calgranulina A/imunologia , Calgranulina B/química , Calgranulina B/genética , Calgranulina B/imunologia , Cristalografia por Raios X , Histidina/química , Interações Hospedeiro-Patógeno/imunologia , Humanos , Complexo Antígeno L1 Leucocitário/genética , Complexo Antígeno L1 Leucocitário/farmacologia , Modelos Moleculares , Mutagênese Sítio-Dirigida , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/imunologia , Zinco/metabolismoRESUMO
OBJECTIVE: Weight gain and metabolic disturbances are growing side effects of a modern antipsychotic therapy. Different programs were developed to reduce them. This article gives an overview of existing and evaluated programs. METHODS: A literature research was made through PubMed. Relevant reviews and intervention studies were identified. RESULTS: Studies with the main outcome variable of weight reductions are numerous, even randomised controlled trials. Short-term weight loss under antipsychotic treatment is possible, but there is still a lack of long-term studies. Life style interventions, which include e. g. physical exercise, are not that common. Also, interventions such as wellness-activities, which contribute by means of adequate motivation strategies to an enhancement of the general well-being, are still missing. Present results turned out to be positive. CONCLUSIONS: Further programs which exceed weight management are required. There is necessity for more studies with consistent outcome variables and methods, especially long-term programs.