ST258-K. pneumoniae (ST258-KP) strains, the most widespread multidrug-resistant hospital-acquired pathogens, belong to at least two clades differing in a 215 Kb genomic region that includes the cluster of capsule genes. To investigate the effects of the different capsular phenotype on host-pathogen interactions, we studied representatives of ST258-KP clades, KKBO-1 and KK207-1, for their ability to activate monocytes and myeloid dendritic cells from human immune competent hosts. The two ST258-KP strains strongly induced the production of inflammatory cytokines. Significant differences between the strains were found in their ability to induce the production of IL-1β: KK207-1/clade I was much less effective than KKBO-1/clade II in inducing IL-1β production by monocytes and dendritic cells. The activation of NLRP3 inflammasome pathway by live cells and/or purified capsular polysaccharides was studied in monocytes and dendritic cells. We found that glibenclamide, a NLRP3 inhibitor, inhibits more than 90% of the production of mature IL-1β induced by KKBO1 and KK207-1. KK207-1 was always less efficient compared to KKBO-1 in: a) inducing NLRP3 and pro-IL-1β gene and protein expression; b) in inducing caspase-1 activation and pro-IL-1β cleavage. Capsular composition may play a role in the differential inflammatory response induced by the ST258-KP strains since capsular polysaccharides purified from bacterial cells affect NLRP3 and pro-IL-1β gene expression through p38MAPK- and NF-κB-mediated pathways. In each of these functions, capsular polysaccharides from KK207-1 were significantly less efficient compared to those purified from KKBO-1. On the whole, our data suggest that the change in capsular phenotype may help bacterial cells of clade I to partially escape innate immune recognition and IL-1β-mediated inflammation.
These results demonstrate that the spontaneous formation of protein coronas on NPs represents a possible approach to fast, easy, cost-effective DCs stimulation.
Background:
Obesity represents the second preventable mortality cause worldwide,
and is very often associated with type 2 Diabetes Mellitus (T2DM). The first line treatment
is lifestyle modification to weight-loss, but for those who fail to achieve the goal or have
difficulty in maintaining achieved results, pharmacological treatment is needed. Few drugs are
available today, because of their side effects.
Objective:
We aim to review actual pharmacological management of obese patients, highlighting
differences between Food and Drug Administration - and European Medicine
Agency-approved molecules, and pointing out self-medications readily obtainable and widely
distributed.
Methods:
Papers on obesity, weight loss, pharmacotherapy, self- medication and diet-aid
products were selected using Medline. Research articles, systematic reviews, clinical trials
and meta-analyses were screened.
Results:
Anti-obesity drugs with central mechanisms, such as phentermine and lorcaserin, are
available in USA, but not in Europe. Phentermine/topiramate and naltrexone/bupropion combinations
are now available, even though the former is still under investigation from EMA.
Orlistat, with peripheral mechanisms, represents the only drug approved for weight reduction
in adolescents. Liraglutide has been approved at higher dose for obesity. Anti-obesity drugs,
readily obtainable from the internet, include crude-drug products and supplements for which
there is often a lack of compliance to national regulatory standards.
Conclusion:
Mechanisms of weight loss drugs include the reduction of energy intake or the
increase in energy expenditure and sense of satiety as well as the decrease of hunger or the
reduction in calories absorption. Few drugs are approved, and differences exist between USA
and Europe. Moreover, herbal medicines and supplements often sold on the internet and
widely used by obese patients, present a risk of adverse effects.
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