Bovine Lactoferrin Counteracts Toll-Like Receptor Mediated Activation Signals in Antigen Presenting Cells

Lactoferrin (LF), a key element in mammalian immune system, plays pivotal roles in host defence against infection and excessive inflammation. Its protective effects range from direct antimicrobial activities against a large panel of microbes, including bacteria, viruses, fungi and parasites, to antinflammatory and anticancer activities. In this study, we show that monocyte-derived dendritic cells (MD-DCs) generated in the presence of bovine LF (bLF) fail to undergo activation by up-modulating CD83, co-stimulatory and major histocompatibility complex molecules, and cytokine/chemokine secretion. Moreover, these cells are weak activators of T cell proliferation and retain antigen uptake activity. Consistent with an impaired maturation, bLF-MD-DC primed T lymphocytes exhibit a functional unresponsiveness characterized by reduced expression of CD154 and impaired expression of IFN-γ and IL-2. The observed imunosuppressive effects correlate with an increased expression of molecules with negative regulatory functions (i.e. immunoglobulin-like transcript 3 and programmed death ligand 1), indoleamine 2,3-dioxygenase, and suppressor of cytokine signaling-3. Interestingly, bLF-MD-DCs produce IL-6 and exhibit constitutive signal transducer and activator of transcription 3 activation. Conversely, bLF exposure of already differentiated MD-DCs completely fails to induce IL-6, and partially inhibits Toll-like receptor (TLR) agonist-induced activation. Cell-specific differences in bLF internalization likely account for the distinct response elicited by bLF in monocytes versus immature DCs, providing a mechanistic base for its multiple effects. These results indicate that bLF exerts a potent anti-inflammatory activity by skewing monocyte differentiation into DCs with impaired capacity to undergo activation and to promote Th1 responses. Overall, these bLF-mediated effects may represent a strategy to block excessive DC activation upon TLR-induced inflammation, adding further evidence for a critical role of bLF in directing host immune function

Overexpression of the Mitochondrial T3 Receptor p43 Induces a Shift in Skeletal Muscle Fiber Types

In previous studies, we have characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor and consequently stimulating mitochondrial activity and mitochondrial biogenesis. We have established the involvement of this T3 pathway in the regulation of in vitro myoblast differentiation.We have generated mice overexpressing p43 under control of the human α-skeletal actin promoter. In agreement with the previous characterization of this promoter, northern-blot and western-blot experiments confirmed that after birth p43 was specifically overexpressed in skeletal muscle. As expected from in vitro studies, in 2-month old mice, p43 overexpression increased mitochondrial genes expression and mitochondrial biogenesis as attested by the increase of mitochondrial mass and mt-DNA copy number. In addition, transgenic mice had a body temperature 0.8°C higher than control ones and displayed lower plasma triiodothyronine levels. Skeletal muscles of transgenic mice were redder than wild-type animals suggesting an increased oxidative metabolism. In line with this observation, in gastrocnemius, we recorded a strong increase in cytochrome oxidase activity and in mitochondrial respiration. Moreover, we observed that p43 drives the formation of oxidative fibers: in soleus muscle, where MyHC IIa fibers were partly replaced by type I fibers; in gastrocnemius muscle, we found an increase in MyHC IIa and IIx expression associated with a reduction in the number of glycolytic fibers type IIb. In addition, we found that PGC-1α and PPARδ, two major regulators of muscle phenotype were up regulated in p43 transgenic mice suggesting that these proteins could be downstream targets of mitochondrial activity. These data indicate that the direct mitochondrial T3 pathway is deeply involved in the acquisition of contractile and metabolic features of muscle fibers in particular by regulating PGC-1α and PPARδ

Anticancer effects of lactoferrin: underlying mechanisms and future trends in cancer therapy

Lactoferrin has been widely studied over the last 70 years, and its role in diverse biological functions is now well known and generally accepted by the scientific community. Usually, alterations of the lactoferrin gene in cells are associated with an increased incidence of cancer. Several studies suggest that exogenous treatment with lactoferrin and its derivatives can efficiently inhibit the growth of tumors and reduce susceptibility to cancer. None of these studies, however, reported a consistent outcome with regard to the mechanisms underlying the anticancer effects of lactoferrin. In this review, the association of lactoferrin with cancer is thoroughly discussed, from lactoferrin gene expression to the potential use of lactoferrin in cancer therapy. Lactoferrin cytotoxicity against several cancers is reported to occur in distinct ways under different conditions, namely by cell membrane disruption, apoptosis induction, cell cycle arrest, and cell immunoreaction. Based on these mechanisms, new strategies to improve the anticancer effects of the lactoferrin protein and/or its derivatives are proposed. The potential for lactoferrin in the field of cancer research (including as a chemotherapeutic agent in cancer therapy) is also discussed.Funding. Financial support was received from the Erasmus Mundus External Cooperation Window (Y), the Strategic Project PEst-OE/EQB/LA0023/2013, and the Fundacao para a Ciencia e a Tecnologia (project reference RECI/BBB-EBI/0179/2012; project no. FCOMP-01-0124-FEDER-027462)

Green Sturgeon Physical Habitat Use in the Coastal Pacific Ocean

The green sturgeon (Acipenser medirostris) is a highly migratory, oceanic, anadromous species with a complex life history that makes it vulnerable to species-wide threats in both freshwater and at sea. Green sturgeon population declines have preceded legal protection and curtailment of activities in marine environments deemed to increase its extinction risk. Yet, its marine habitat is poorly understood. We built a statistical model to characterize green sturgeon marine habitat using data from a coastal tracking array located along the Siletz Reef near Newport, Oregon, USA that recorded the passage of 37 acoustically tagged green sturgeon. We classified seafloor physical habitat features with high-resolution bathymetric and backscatter data. We then described the distribution of habitat components and their relationship to green sturgeon presence using ordination and subsequently used generalized linear model selection to identify important habitat components. Finally, we summarized depth and temperature recordings from seven green sturgeon present off the Oregon coast that were fitted with pop-off archival geolocation tags. Our analyses indicated that green sturgeon, on average, spent a longer duration in areas with high seafloor complexity, especially where a greater proportion of the substrate consists of boulders. Green sturgeon in marine habitats are primarily found at depths of 20–60 meters and from 9.5–16.0°C. Many sturgeon in this study were likely migrating in a northward direction, moving deeper, and may have been using complex seafloor habitat because it coincides with the distribution of benthic prey taxa or provides refuge from predators. Identifying important green sturgeon marine habitat is an essential step towards accurately defining the conditions that are necessary for its survival and will eventually yield range-wide, spatially explicit predictions of green sturgeon distribution