Pouched Mouse Research Articles

Neuro-Immunomodulatory Potential of Nanoenabled 4D Bioprinted Microtissue for Cartilage Tissue Engineering.

Cartilage defects trigger post-traumatic inflammation, leading to a catabolic metabolism in chondrocytes and exacerbating cartilage degradation. Current treatments aim to relieve pain but fail to target the inflammatory process underlying osteoarthritis (OA)progression. Here, a human cartilage microtissue (HCM) nanoenabled with ibuprofen-loaded poly(lactic-co-glycolic acid) nanoparticles (ibu-PLGA NPs) is 4D-bioprinted to locally mitigate inflammation and impair nerve sprouting. Under an in vitro inflamed environment, the nanoenabled HCM exhibits chondroprotective potential by decreasing the interleukin (IL)1β and IL6 release, while sustaining extracellular matrix (ECM) production. In vivo, assessments utilizing the air pouch mouse model affirm the nanoenabled HCM non-immunogenicity. Nanoenabled HCM-derived secretomes do not elicit a systemic immune response and decrease locally the recruitment of mature dendritic cells and the secretion of multiple inflammatory mediators and matrix metalloproteinases when compared to inflamed HCM condition. Notably, the nanoenabled HCM secretome has no impact on the innervation profile of the skin above the pouch cavity, suggesting a potential to impede nerve growth. Overall, HCM nanoenabled with ibu-PLGA NPs emerges as a potent strategy to mitigate inflammation and protect ECM without triggering nerve growth, introducing an innovative and promising approach in the cartilage tissue engineering field.

Biomineralized Nanoscavenger Abrogates Proinflammatory Macrophage Polarization and Induces Neutrophil Clearance through Reverse Migration during Gouty Arthritis.

The deposition of monosodium urate (MSU) crystals induces the overexpression of reactive oxygen species (ROS) and proinflammatory cytokines in residential macrophages, further promoting the infiltration of inflammatory leukocytes in the joints of gouty arthritis. Herein, a peroxidase-mimicking nanoscavenger was developed by forming manganese dioxide over albumin nanoparticles loaded with an anti-inflammatory drug, indomethacin (BIM), to block the secretion of ROS and COX2-induced proinflammatory cytokines in the MSU-induced gouty arthritis model. In the MSU-induced arthritis mouse model, the BIM nanoparticles alleviated joint swelling, which is attributed to the abrogation of ROS and inflammatory cytokine secretions from proinflammatory macrophages that induces neutrophil infiltration and fluid building up in the inflammation site. Further, the BIM nanoparticle treatment reduced the influx of macrophages and neutrophils in the injured region by blocking migration and inducing reverse migration in the zebrafish larva tail amputation model as well as in MSU-induced peritonitis and air pouch mouse models. Overall, the current strategy of employing biomineralized nanoscavengers for arthritis demonstrates clinical significance in dual blocking of peroxides and COX2 to prevent influx of inflammatory cells into the sites of inflammation.

ZnO nanoparticles attenuate polymer-wear-particle induced inflammatory osteolysis by regulating the MEK-ERK-COX-2 axis

Background/ObjectivesAdvanced thermoplastic materials, such as polyether-ether-ketone (PEEK) and highly cross-linked polyethylene (HXLPE), have been increasingly used as orthopaedic implant materials. Similar to other implants, PEEK-on-HXLPE prostheses produce debris from polymer wear that may activate the immune response, which can cause osteolysis, and ultimately implant failure. In this study, we examined whether the anti-inflammatory properties of zinc oxide nanoparticles (ZnO NPs) could attenuate polymer wear particle-induced inflammation.MethodsRAW264.7 ​cells were cultured with PEEK or PE particles and gradient concentrations of ZnO NPs. Intracellular mRNA expression and protein levels of pro-inflammatory factors TNF-α, IL-1β, and IL-6 were detected. An air pouch mouse model was constructed to examine the inflammatory response and expression of pro-inflammatory factors in vivo. Furthermore, an osteolysis rat model was used to evaluate the activation of osteoclasts and destruction of bone tissue induced by polymer particles with or without ZnO NPs. Protein expression of the MEK-ERK-COX-2 pathway was also examined by western blotting to elucidate the mechanism underlying particle-induced anti-inflammatory effects.ResultsZnO NPs (≤50 ​nm, 5 ​μg/mL) showed no obvious cytotoxicity and attenuated PEEK or PE particle-induced inflammation and inflammatory osteolysis by reducing MEK and ERK phosphorylation and decreasing COX-2 expression.ConclusionZnO NPs (≤50 ​nm, 5 ​μg/mL) attenuated polymer wear particle-induced inflammation via regulation of the MEK-ERK-COX-2 axis. Further, ZnO NPs reduced bone tissue damage caused by particle-induced inflammatory osteolysis.The translational potential of this articlePolymer wear particles can induce inflammation and osteolysis in the body after arthroplasty. ZnO NPs attenuated polymer particle-induced inflammation and inflammatory osteolysis. Topical use of ZnO NPs and blended ZnO NP/polymer composites may provide promising approaches for inhibiting polymer wear particle-induced inflammatory osteolysis, thus expanding the range of polymers used in joint prostheses.

Quantifying the nutritional and income loss caused by crop raiding in a rural African subsistence farming community in South Africa.

Globally, crop damage by wildlife contributes to food insecurity through the direct loss of food and income. We investigated the calories lost and the potential economic impact of crop raiding at subsistence homesteads abutting the Hluhluwe Game Reserve, and assessed mitigation measures to combat crop raiding. We quantified the seasonal loss of calories (kJ/g) of four common crops, namely, beetroot, common bean, maize, and spinach, and determined the seasonal potential income loss. We used a stratified sampling approach to sample the homesteads. We found that season, crop type and the interaction between season and crop type predicted relative calorie loss and potential income loss, with the highest income loss recorded for spinach in the dry season. Significant differences were found for the potential income loss for all crop types in the wet season, and for the interaction between the crop types (maize, spinach) and the wet season. Farm slope was also a significant predictor of the relative calorie loss. Crop raiding animals, crops raided and distance of farms from the reserve all had a significant effect on the choice of mitigation measures of farmers. The highest relative calorie loss was for maize during the dry season, which could affect the subsistence farmers by reducing their daily calorie intake. This has an impact on their food security, especially during the dry season. Moreover, the most preferred mitigation measure used by farmers can have opportunity costs. These results have important implications for food security policies and practices.

A pharmacological approach assessing the role of mast cells in insulin infusion site inflammation.

Background Extending the lifespan of subcutaneous insulin administration sets and infusion pumps requires overcoming unreliable insulin delivery induced by dermal reactions. All commercially available insulin formulations contain insulin phenolic preservatives (IPP), which stabilize the insulin molecule but result in unwanted cell and tissue toxicity. Mast cells, which are the first line of defense once the epithelium is breached, are particularly abundant beneath the skin surface. Thus, we hypothesize a sequence of events initiated by device insertion that activates skin mast cells (MC) that subsequently trigger neutrophil and monocyte/macrophage recruitment. The ensuing inflammatory response compromises effective insulin infusion therapy. Methods We employed a non-genetic, pharmacological approach to MC membrane stabilization using Cromolyn sodium (CS), which inhibits MC degranulation. These studies were conducted in our modified air pouch mouse model using non-diabetic and streptozotocin induced diabetic mice. We evaluated the impact of systemic CS through intraperitoneal injections, as well as the impact of local CS through co-infusion, on infusion catheter insertion and IPP-induced inflammation. Results CS at a concentration of 50mg/kg minimized inflammation triggered in response to insulin phenolic preservatives present in standard insulin formulations. The resultant degree of tissue inflammation was comparable to that observed with saline injections. Conclusion Targeting MC has the potential to extend the longevity of insulin infusion sets by mitigating the inflammatory response. Future studies should be directed at employing other MC models, such as newer Cre/loxP mouse strains, to confirm the sentinel role of MC in insulin infusion therapy.

Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone.

Microsomal PGE synthase-1 (mPGES-1), the inducible synthase that catalyses the terminal step in PGE2 biosynthesis, is of high interest as therapeutic target to treat inflammation. Inhibition of mPGES-1 is suggested to be safer than traditional NSAIDs, and recent data demonstrate anti-constrictive effects on vascular tone, indicating new therapeutic opportunities. However, there is a lack of potent mPGES-1 inhibitors lacking interspecies differences for conducting in vivo studies in relevant preclinical disease models. Potency was determined based on the reduction of PGE2 formation in recombinant enzyme assays, cellular assay, human whole blood assay, and air pouch mouse model. Anti-inflammatory properties were assessed by acute paw swelling in a paw oedema rat model. Effect on vascular tone was determined with human ex vivo wire myography. We report five new mPGES-1 inhibitors (named 934, 117, 118, 322, and 323) that selectively inhibit recombinant human and rat mPGES-1 with IC50 values of 10-29 and 67-250 nM respectively. The compounds inhibited PGE2 production in a cellular assay (IC50 values 0.15-0.82 μM) and in a human whole blood assay (IC50 values 3.3-8.7 μM). Moreover, the compounds blocked PGE2 formation in an air pouch mouse model and reduced acute paw swelling in a paw oedema rat model. Human ex vivo wire myography analysis showed reduced adrenergic vasoconstriction after incubation with the compounds. These mPGES-1 inhibitors can be used as refined tools in further investigations of the role of mPGES-1 in inflammation and microvascular disease.

378 Induced psoriasis-like inflammation in an air pouch mouse model

Human psoriasis is a complex autoimmune skin disease, affecting a significant number of the global population. The initiation pathway comprises the differentiation and infiltration of Th17 cells into the skin and is characterized by the production of IL-17A and IL-17F cytokines. This results in a downstream cascade of events, including an exacerbated inflammatory response. In order to establish a more simplified mechanistic mouse model of psoriasis inflammation, we utilized the 6-day air pouch mouse model and aimed for the induction of a psoriasis-like inflammation by injecting a cocktail of inflammatory triggers into the air pouch cavity. The combination of anti-CD3 and IL-23 with or without IL-1β resulted in significantly increased IL-17A and IL-17F intra-pouch levels, and triggered a downstream production of the CXCL1 chemokine. The produced cytokines were detectable even 72 hours post-induction. In addition, TCRβ was downregulated on the cell surface of CD4 and CD8 positive T cells, indicating intra-pouch T cell activation. The presence of anti-CD3 seemed to be important for the increased production of the IL-17 cytokines, even at low concentrations. Furthermore, anti-CD3 induced CD3 positive cell migration into the subcutis and the lining tissue surrounding the air pouch cavity. In conclusion, the induced air pouch mouse model can mirror the IL-23/IL-17 axis of psoriasis-like inflammation.

Searching for cover: soil enrichment and herbivore exclusion, not fire, enhance African savanna small‐mammal abundance

AbstractLarge mammalian herbivores (LMH) are known to suppress populations of small mammals in African savanna ecosystems; whether this suppression is driven by depletion of nutrients and food resources, or of cover, is poorly understood. Cattle management creates scattered, persistent, nutrient‐enriched areas (glades). Similarly, prescribed fire may enhance forage nutrition of burned patches. Both enriched microhabitats attract wild and domestic LMH and are fertilized by their wastes, but removal of vegetative cover by LMH or fire may negate the benefits of enhanced nutrition to risk‐averse small‐mammal species or individuals. We used replicated LMH exclusion experiments on red sandy loam and black‐cotton clay soils, and a multi‐scale burn experiment on black cotton to examine abundance, diversity, and biomass of small mammals across sites varying in vegetation cover and enrichment. Small‐mammal species composition varied dramatically among habitats. Species diversity and density on red sands were roughly double that of black cotton soils. Small‐mammal densities and diversity were dramatically greater inside LMH exclosures; maximal densities occurred inside fenced, nutrient‐rich, tall‐grass glades. Small‐mammal density was similar between black‐cotton burn sites and unburned matrix habitat but was significantly greater on unburned than burned patches within the burn sites. Burned patches contained less grassy cover up to 50 months post‐burn, although vegetation differences diminished following significant rains. Mice captured on burned patches traveled farther but were not heavier than mice captured on unburned patches. Small mammals were nearly 20‐fold more abundant on totally fenced glades than matrix habitat on both soils and ninefold more abundant on fenced bushland (non‐glades) on red sands. Unfenced glades supported intermediate densities in black cotton but lower densities in red sands because of close cropping by LMH. Total small‐mammal biomass tended to be greater on red sands (though mean body mass was greater on black cotton for two common species), within exclosures, and on glades. Both the grass rat and pouched mouse reached maximal densities within glade LMH exclosures on both soils. This and the positive association of small‐mammal densities with grass height and dead‐stem density suggest loss of cover is a primary driver of large‐herbivore suppression of certain savanna small mammals.

Impacts of large mammals on movements of the pouched mouse (Saccostomus mearnsi) in central Kenya

AbstractPopulations of large wild mammals are declining worldwide, while the abundance of livestock is increasing. The absence of large mammals frequently leads to increases in the abundance of small mammals such as rodents, but little is known about how the loss of large mammals affects the behaviour of small mammals. To investigate this question, we analysed long‐term data collected at the Kenya Long‐term Exclosure Experiment, which excludes different combinations of large mammals from a savannah ecosystem in central Kenya. We investigated the effects of excluding large mammals, both wild and domestic, on the movements of the pouched mouse (Saccostomus mearnsi), the most common species of small mammal in this habitat. Mice moved ~20% more in the presence of wildlife, but their movements were not significantly affected by the presence of cattle. An index of intraspecific contacts between mice was higher at higher mouse densities, and these high densities were more likely when wildlife and cattle were absent. The results suggest that the absence of large mammals led to higher densities of small mammals, which resulted in a greater probability of intraspecific contacts, despite lower average movement distances.

Anti-inflammatory effect of Allium hookeri on carrageenan-induced air pouch mouse model.

Inflammation is a commonly observed immune reaction, and rheumatoid arthritis is a particularly severe inflammatory disease. In this study, we used an air pouch mouse model to evaluate the anti-inflammatory potential of Allium hookeri, which has both been used as a culinary material and a traditional medicine in south-eastern Asia for many years. Allium hookeri suppressed typical symptoms of inflammation, such as condensation of the air pouch membrane, and inhibited the expression of several inducible proinflammatory cytokines such as IL-1β, IL-6, IL-13, and TNF-α. In order to determine the molecules modulating the inflammatory effect of carrageenan treatment, the components in Allium hookeri were analyzed by GC-MS, and linoleic acid, which have anti-inflammatory effect, was detected. From the results, we concluded that the anti-inflammatory effect of Allium hookeri might be attributed to linoleic acid, which could be promising candidates for anti-inflammatory drugs that have no adverse effects.

Antimicrobial and Anti-Inflammatory Effects of Ethanol Extract of Corylopsis coreana Uyeki Flos.

Background:Corylopsis coreana Uyeki (Hamamelidaceae) is a medicinal plant cultivated in Northeast Asia. Previously, we have reported that an ethanol extract of Corylopsis coreana Uyeki flos (ECCF) contains four active compounds with antioxidant activity.Objective:The aim of this study was to investigate the antimicrobial spectrum against infectious bacteria and anti-inflammatory effect of ECCF in a mouse model of acute local inflammation.Materials and Methods:In vitro antimicrobial susceptibility was evaluated using standard plate assay technique. Antimicrobial activities (minimum inhibitory concentration, MIC; μg/mL) were determined with the serial dilution method. In vivo anti-inflammatory activity was studied using a mouse model of carrageenan-induced air pouch inflammation.Results:The ECCF showed antimicrobial activities against general bacteria and drug-resistant bacteria including Staphylococcus aureus, Micrococcus luteus ATCC 9341, Mycrobacterium smegmatis ATCC 9341, Mycrobacterium smegmatis ATCC 9341, Salmonella typhimrium KCTC 1925, and nine methicillin-resistant Staphylococcus aureus strains, with MIC values ranging from 250 to 1000 μg/mL. In in vivo mouse model, inflammatory morphologic changes observed in the air pouch membrane were restored to its normal condition by the ECCF treatment. Moreover, the ECCF significantly reduced exudate volumes, protein contents, inflammatory cell counts, and pro-inflammatory cytokine levels in the exudates recovered from air pouches of the mouse model. Flavonoids in the ECCF were found to contain bergenin, quercitrin, and quercetin with reported anti-inflammatory activity via suppressing tumor necrosis factor-α production.Conclusion:To the best of our knowledge, this is the first report to demonstrate the antimicrobial and anti-inflammatory activities of ECCF. Our results suggest that the ECCF might potentially serve as an alternative or complementary medicine for treating inflammatory diseases caused by microbial infection.SUMMARY ECCF showed antimicrobial activity against infectious bacteria and multidrug-resistant strains.ECCF exhibited anti-inflammatory activity in a carrageenan-induced air pouch mouse model.ECCF contained several active constituents such as bergenin, quercitrin, and quercetin. Abbreviations used: Corylopsis coreana CCF: Uyeki flos, ECCF: ethanol extract of CCF

Evolutionary history and species diversity ofAfrican pouched mice (Rodentia:Nesomyidae:Saccostomus)

We explore diversity ofAfrican pouched mice, genusSaccostomus(Rodentia,Nesomyidae), by sampling molecular and morphological variation across their continental‐scale distribution in southern and easternAfrican savannahs and woodlands. Both mitochondrial (cytochrome b) and nuclearDNA(IRBP,RAG1) as well as skull morphology confirm the distinction between two recognized species,S. campestrisandS. mearnsi, with disjunct distribution in theZambezian andSomali–Maasai bioregions, respectively. Molecular dating suggests the divergence of these taxa occurred in theEarlyPliocene, 3.9 Ma before present, whereas the deepest divergences within each of them are only as old as 2.0 Ma forS. mearnsiand 1.4 Ma forS. campestris. Based on cytochrome b phylogeny, we defined five clades (three withinS. campestris, two inS. mearnsi) whose species status was considered in the light of nuclearDNAmarkers and morphology. We conclude thatS. campestrisgroup consists of two subspeciesS. campestris campestris(Peters, 1846; comprising two cytochrome b clades) andS. campestris mashonae(deWinton, 1897) that are moderately differentiated, albeit distinct inIRBPand skull form. They likely hybridize to a limited extent along theKafue–ZambeziRivers.Saccostomus mearnsigroup consists of two species,S. mearnsi(Heller, 1910) andS. umbriventer(Miller, 1910), that are markedly differentiated in both nuclear markers and skull form and may possibly co‐occur in south‐westernKenya and north‐easternTanzania. Analysis of historical demography suggests both subspecies ofS. campestrisexperienced population expansion dated to theLastGlacial. In the present range ofS. campestrisgroup, the distribution modelling suggests a moderate fragmentation of suitable habitats during the last glacial cycle, whereas in the range ofS. mearnsigroup it predicts substantial shifts of its occurrence in the same period.

Large wildlife removal drives immune defence increases in rodents

Summary Anthropogenic disturbances involving land use change, climate disruption, pollution and invasive species have been shown to impact immune function of wild animals. These immune changes have direct impacts on the fitness of impacted animals and, also, potentially indirect effects on other species and on ecological processes, notably involving the spread of infectious disease. Here, we investigate whether the selective loss of large wildlife can also drive changes in immune function of other consumer species. Using a long‐standing large‐scale exclosure experiment in East Africa, we investigated the effects of selective removal of large wildlife on multiple measures of immune function in the dominant small rodent in the system, the East African pouched mouse, Saccostomus mearnsi. We find support for a general increase in immune function in landscapes where large wildlife has been removed, but with some variation across immune parameters. These changes may be mediated in part by increased pathogen pressure in plots where large wildlife has been removed due to major increases in rodent density in such plots, but other factors such as changes in food resources are also likely involved. Overall, our research reveals that the elimination of large‐bodied wildlife – now recognized as another major form of global anthropogenic change – may have cascading effects on immune health, with the potential for these effects to also impact disease dynamics in ecological communities.

Cascading Consequences of the Loss of Large Mammals in an African Savanna

African savannas are home to an abundant and diverse assemblage of wild herbivores, but the very grasses that sustain these wild herds also make savannas attractive to humans and their livestock. We used the Kenya Long-term Exclosure Experiment to investigate the ecological effects of different combinations of native and domestic grazers. The experimental removal of large grazing mammals set into motion a cascade of consequences, beginning with the doubling in abundance of a small grazing mammal, the pouched mouse (Saccostomus mearnsi). The presence of abundant mice attracted venomous snakes such as the olive hissing snake (Psammophis mossambicus); devastated seedlings of the dominant tree (Acacia drepanolobium); and doubled the abundance of fleas, which potentially increased the risk of transmission of flea-borne pathogens. Together, these results show the potential for the loss of large mammals to have cryptic consequences for African savannas, with important and often undesirable repercussions for humans.

Therapeutic potentials of naringin on polymethylmethacrylate induced osteoclastogenesis and osteolysis, in vitro and in vivo assessments

Wear debris associated periprosthetic osteolysis represents a major pathological process associated with the aseptic loosening of joint prostheses. Naringin is a major flavonoid identified in grapefruit. Studies have shown that naringin possesses many pharmacological properties including effects on bone metabolism. The current study evaluated the influence of naringin on wear debris induced osteoclastic bone resorption both in vitro and in vivo. The osteoclast precursor cell line RAW 264.7 was cultured and stimulated with polymethylmethacrylate (PMMA) particles followed by treatment with naringin at several doses. Tartrate resistant acid phosphatase (TRAP), calcium release, and gene expression profiles of TRAP, cathepsin K, and receptor activator of nuclear factor-kappa B were sequentially evaluated. PMMA challenged murine air pouch and the load bearing tibia titanium pin-implantation mouse models were used to evaluate the effects of naringin in controlling PMMA induced bone resorption. Histological analyses and biomechanical pullout tests were performed following the animal experimentation. The in vitro data clearly demonstrated the inhibitory effects of naringin in PMMA induced osteoclastogenesis. The naringin dose of 10 μg/mL exhibited the most significant influence on the suppression of TRAP activities. Naringin treatment also markedly decreased calcium release in the stimulated cell culture medium. The short-term air pouch mouse study revealed that local injection of naringin ameliorated the PMMA induced inflammatory tissue response and subsequent bone resorption. The long-term tibia pin-implantation mouse model study suggested that daily oral gavage of naringin at 300 mg/kg dosage for 30 days significantly alleviated the periprosthetic bone resorption. A significant increase of periprosthetic bone volume and regaining of the pin stability were found in naringin treated mice. Overall, this study suggests that naringin may serve as a potential therapeutic agent to treat wear debris associated osteolysis.

Daily energy expenditure in the pouched mouse (Saccostomus campestris Peters 1896)

ABSTRACT Previous studies of the pouched mouse (Saccostomus campestris) have revealed that during reproduction there is no increase in food consumption, although resting energy demands, measured by respirometry, increase substantially. One explanation for this anomalous situation is that these mice may routinely use torpor to compensate their energy budgets. We measured the daily energy expenditure of eleven individual pouched mice over three consecutive days using the doubly-labelled water technique. The mice were housed in cages where they had free access to food and water, at an average temperature of 26.5 °C, and exposed to a natural photoperiod (February Pretoria). There was a large day-to-day variation in energy expenditure within each individual. The coefficient of variation in daily energy demand averaged 24.5%. By comparing the correlation of estimates for consecutive and nonconsecutive days we established that this variation was not a consequence of errors in the isotopic technique. The scaling ...

Cross-Reactivity of Secondary Antibodies against African Rodents and Application for Sero-Surveillance

A total of 466 rodents were captured in the Republic of Zambia from 2006 to 2010. Based on morphological observations and phylogenetic analyses of mitochondrial gene sequences, rodents were divided into 10 groups consisting of 39 Rattus rodents, 263 multimammate rats, 18 other Murinae rodents, 95 gerbils, 11 pouched mice, 1 giant-pouched rat, 38 fat mice and 1 dormouse. Rodent antibodies except that from Rattus were examined for their cross-reactivity to commercially available antibody detection reagents. Anti-mouse immunoglobulin G (IgG) was most cross-reactive to heterologous antibodies including multimammate rat, gerbil, pouched mouse and fat mouse. Thus, anti-mouse IgG would be a useful detection tool in serological examination of the Zambian rodent population. Preliminary sero-surveillance for plague, leptospirosis and hantavirus infection was performed by ELISA.

Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion

AimsActivation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid-independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo.Methods and resultsPhysiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor κB (NF-κB) mediated apoCIII-induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-κB activation. Furthermore, in the aorta of hypercholesterolaemic Ldlr−/− mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect.ConclusionsThese findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII.

Strong hybrid viability between two widely divergent chromosomal forms of the pouched mouse

A large degree of karyotypic diversity in the pouched mouse Saccostomus campestris, ranging from 2n=28 to 2n=46, is mostly due to centric fusions. The taxon comprises a complex of cryptic species, of which the 2n=32 and 2n=46 karyotypes represent two different species. Crossbreeding pure 2n=32 and pure 2n=46 karyotypes up to the F3 hybrid generation yielded F1 hybrids with 39 chromosomes, seven of which were unpaired. Unpaired chromosomes ranged in size from very long to short. We measured the growth rate, testis structure and litter size of these crosses and did not find any indication that the F1, F2 or F3 generations exhibit any degree of hybrid disadvantage or hybrid breakdown. The interpretation of these results is strongly affected by the species concept used, but weakens the conclusions of several other authors that S. campestris in southern Africa comprises a complex of cryptic species.

Effects of the removal of large herbivores on fleas of small mammals

The removal of large herbivorous mammals can cause dramatic increases in the densities of small mammals. These small mammals are hosts for a variety of ectoparasites, many of which are important pathogens of human diseases such as plague and murine typhus. It is thus valuable from a human health perspective to understand if large herbivore removals can indirectly affect ectoparasite numbers and thus potentially alter disease risk. To make this determination, we experimentally excluded large herbivores and measured the number of fleas present on the numerically dominant small mammal, the pouched mouse, Saccostomus mearnsi. Removing large herbivores nearly doubled S. mearnsi density, while the percentage of mice infested with fleas (prevalence) and the average number of fleas per sampled mouse (intensity) remained constant. The net effect of doubling the number of mice via the removal of large herbivores was a near doubling in the number of fleas present in the study habitat. Because these fleas also parasitize humans and can serve as disease vectors, this work empirically demonstrates a potential mechanism by which ecosystem alterations could affect human risk for zoonotic diseases.