Marine organisms represent a highly diverse reserve of bioactives which could aid in the treatment of a wide range of diseases, including various musculoskeletal conditions. Osteoporosis in ...particular would benefit from a novel and effective marine-based treatment, due to its large disease burden and the inefficiencies of current treatment options. Osteogenic bioactives have been isolated from many marine organisms, including nacre powder derived from molluscan shells and fucoidan-the sulphated polysaccharide commonly sourced from brown macroalgae. Such extracts and compounds are known to have a range of osteogenic effects, including stimulation of osteoblast activity and mineralisation, as well as suppression of osteoclast resorption. This review describes currently known soluble osteogenic extracts and compounds from marine invertebrates and algae, and assesses their preclinical potential.
Abdominal aortic aneurysm is a dynamic vascular disease characterized by inflammatory cell invasion and extracellular matrix degradation. Damage to elastin in the extracellular matrix results in ...release of elastin-derived peptides (EDPs), which are chemotactic for inflammatory cells such as monocytes. Their effect on macrophage polarization is less well known. Proinflammatory M1 macrophages initially are recruited to sites of injury, but, if their effects are prolonged, they can lead to chronic inflammation that prevents normal tissue repair. Conversely, anti-inflammatory M2 macrophages reduce inflammation and aid in wound healing. Thus, a proper M1/M2 ratio is vital for tissue homeostasis. Abdominal aortic aneurysm tissue reveals a high M1/M2 ratio in which proinflammatory cells and their associated markers dominate. In the current study, in vitro treatment of bone marrow-derived macrophages with EDPs induced M1 macrophage polarization. By using C57BL/6 mice, Ab-mediated neutralization of EDPs reduced aortic dilation, matrix metalloproteinase activity, and proinflammatory cytokine expression at early and late time points after aneurysm induction. Furthermore, direct manipulation of the M1/M2 balance altered aortic dilation. Injection of M2-polarized macrophages reduced aortic dilation after aneurysm induction. EDPs promoted a proinflammatory environment in aortic tissue by inducing M1 polarization, and neutralization of EDPs attenuated aortic dilation. The M1/M2 imbalance is vital to aneurysm formation.
OBJECTIVE—Abdominal aortic aneurysms are inflammatory in nature and are associated with some risk factors that also lead to atherosclerotic occlusive disease, most notably smoking. The purpose of our ...study was to identify differential cytokine expression in patients with abdominal aortic aneurysm and those with atherosclerotic occlusive disease. Based on this analysis, we further explored and compared the mechanism of action of IL (interleukin)-1β versus TNF-α (tumor necrosis factor-α) in abdominal aortic aneurysm formation.
APPROACH AND RESULTS—IL-1β was differentially expressed in human plasma with lower levels detected in patients with abdominal aortic aneurysm compared with matched atherosclerotic controls. We further explored its mechanism of action using a murine model and cell culture. Genetic deletion of IL-1β and IL-1R did not inhibit aneurysm formation or decrease MMP (matrix metalloproteinase) expression. The effects of IL-1β deletion on M1 macrophage polarization were compared with another proinflammatory cytokine, TNF-α. Bone marrow-derived macrophages from IL-1β and TNF-α mice were polarized to an M1 phenotype. TNF-α deletion, but not IL-1β deletion, inhibited M1 macrophage polarization. Infusion of M1 polarized TNF-α macrophages inhibited aortic diameter growth; no inhibitory effect was seen in mice infused with M1 polarized IL-1β macrophages.
CONCLUSIONS—Although IL-1β is a proinflammatory cytokine, its effects on aneurysm formation and macrophage polarization differ from TNF-α. The differential effects of IL-1β and TNF-α inhibition are related to M1/M2 macrophage polarization and this may account for the differences in clinical efficacy of IL-1β and TNF-α antibody therapies in management of inflammatory diseases.
OBJECTIVE:Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired ...inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined.
APPROACH AND RESULTS:Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3−, CD19−, Ly6G−) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow–derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL interleukin-1β, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow–derived macrophages and wound macrophages. This demonstrated decreased expression of Mll1, an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow–derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in MLL1 compared with nonseptic controls.
CONCLUSIONS:These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1–mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.
Ignition delay times were measured in a constant volume spray combustion chamber for four compounds considered as surrogates for fatty-acid methyl/ethyl ester biodiesel fuels. Experiments were ...performed for methyl decanoate, ethyl nonanoate, methyl 9-decenoate, and methyl 5-decenoate for characterization of the derived cetane number (DCN) and temperature-dependent spray ignition delay of these compounds under conditions relevant to low-temperature combustion engines (625–820 K and 2.14 and 4.0 MPa). The low-temperature reactivity of these compounds, from least reactive to most reactive at the DCN condition (818 K and 2.14 MPa), was determined to be: methyl 5-deceonate (DCN = 33.6), methyl 9-decenoate (DCN = 40.0), ethyl nonanoate (DCN = 50.2), and methyl decanoate (DCN = 52.5). Experimental results for temperature dependent ignition delay are compared to prior shock tube results and show the same order of reactivity with quantitatively similar differences in ignition delay for the C10 methyl esters, illustrating that spray ignition delay and DCN correlate to homogenous chemical kinetic reactivity for fuels with similar physical properties. Comparisons of measured DCNs with the statistical group contribution model of Dahmen and Marquardt (Energy and Fuels 2015, 29, 5781–5801) show good agreement for the influence of double bonds on reactivity for the C10 methyl esters studied.
Toll-like receptor (TLR) activation has been implicated in acetaminophen (APAP)-induced hepatotoxicity. Herein, we hypothesize that TLR3 activation significantly contributed to APAP-induced liver ...injury. In fasted wildtype (WT) mice, APAP caused significant cellular necrosis, edema, and inflammation in the liver, and the de novo expression and activation of TLR3 was found to be necessary for APAP-induced liver failure. Specifically, liver tissues from similarly fasted TLR3-deficient (tlr3(-/-) ) mice exhibited significantly less histological and biochemical evidence of injury after APAP challenge. Similar protective effects were observed in WT mice in which TLR3 was targeted through immunoneutralization at 3 h post-APAP challenge. Among three important death ligands (i.e. TNFα, TRAIL, and FASL) known to promote hepatocyte death after APAP challenge, TNFα was the only ligand that was significantly reduced in APAP-challenged tlr3(-/-) mice compared with APAP-challenged WT controls. In vivo studies demonstrated that TLR3 activation contributed to TNFα production in the liver presumably via F4/80(+) and CD11c(+) immune cells. In vitro studies indicated that there was cooperation between TNFα and TLR3 in the activation of JNK signaling in isolated and cultured liver epithelial cells (i.e. nMuLi). Moreover, TLR3 activation enhanced the expression of phosphorylated JNK in APAP injured livers. Thus, the current study demonstrates that TLR3 activation contributes to APAP-induced hepatotoxicity.
Macrophages are critical immune cells for the clearance of microbial pathogens and cellular debris from peripheral tissues. Macrophage inflammatory responses are governed by gene expression patterns, ...and these patterns are often subject to epigenetic control. Chromatin modifications, such as histone methylation, regulate gene accessibility in macrophages, and macrophage polarization is governed in part by the expression and function of chromatin-modifying enzymes. The histone methyltransferase mixed-lineage leukemia 1 (MLL1) preferentially modifies lysine residue 4 on the unstructured protein tail of histone H3. MLL1 expression and function have been shown to be governed by signal transduction pathways that are activated by inflammatory stimuli, such as NF-κB. Therefore, we sought to investigate the role of MLL1 in mediating macrophage inflammatory responses. Bone marrow-derived macrophages from mice with a targeted MLL1 gene knockout (Lys2-Cre
MLL1
) exhibited decreased proinflammatory gene expression with concurrent decreases in activating histone methylation. However, MLL1-deficient macrophages also exhibited increased phagocytic and bacterial killing activity in vitro. RNA profiling of MLL1-knockout macrophages identified numerous genes involved with inflammatory responses whose expression was altered in response to TLR ligands or proinflammatory cytokines, including STAT4. STAT4-dependent cytokines, such as type I IFNs were able to drive MLL1 expression in macrophages, and MLL1-knockout macrophages exhibited decreased activating histone methylation in the STAT4 promoter. These results implicate an important role for MLL1-dependent epigenetic regulation of macrophage antimicrobial functions.
ABSTRACT
Introduction
Battlefield-related wound infections are a significant source of morbidity among combat casualties. Seasonality of these infections was demonstrated in previous conflicts (e.g., ...Korea) but has not been described with trauma-related health care–associated infections from the war in Afghanistan.
Methods
The study population included military personnel wounded in Afghanistan (2009-2014) medevac’d to Landstuhl Regional Medical Center and transitioned to participating military hospitals in the United States with clinical suspicion of wound infections and wound cultures collected ≤7 days post-injury. Analysis was limited to the first wound culture from individuals. Infecting isolates were collected from skin and soft-tissue infections, osteomyelitis, and burn soft-tissue infections. Data were analyzed by season (winter December 1-February 28/29, spring March 1-May 31, summer June 1-August 31, and fall September 1-November 30).
Results
Among 316 patients, 297 (94.0%) sustained blast injuries with a median injury severity score and days from injury to initial culture of 33 and 3.5, respectively. Although all patients had a clinical suspicion of a wound infection, a diagnosis was confirmed in 198 (63%) patients. Gram-negative bacilli (59.5% of 316) were more commonly isolated from wound cultures in summer (68.1%) and fall (67.1%) versus winter (43.9%) and spring (45.1%; P < .001). Multidrug-resistant (MDR) Gram-negative bacilli (21.8%) were more common in summer (21.8%) and fall (30.6%) versus winter (7.3%) and spring (19.7%; P = .028). Findings were similar for infecting Gram-negative bacilli (72.7% of 198)—summer (79.5%) and fall (83.6%; P = .001)—and infecting MDR Gram-negative bacilli (27.3% of 198)—summer (25.6%) and fall (41.8%; P = .015). Infecting anaerobes were more common in winter (40%) compared to fall (11%; P = .036). Gram-positive organisms were not significantly different by season.
Conclusion
Gram-negative bacilli, including infecting MDR Gram-negative bacilli, were more commonly recovered in summer/fall months from service members injured in Afghanistan. This may have implications for empiric antibiotic coverage during these months.
Planet formation occurs around a wide range of stellar masses and stellar system architectures
. An improved understanding of the formation process can be achieved by studying it across the full ...parameter space, particularly towards the extremes. Earlier studies of planets in close-in orbits around high-mass stars have revealed an increase in giant planet frequency with increasing stellar mass
until a turnover point at 1.9 solar masses (M
), above which the frequency rapidly decreases
. This could potentially imply that planet formation is impeded around more massive stars, and that giant planets around stars exceeding 3 M
may be rare or non-existent. However, the methods used to detect planets in small orbits are insensitive to planets in wide orbits. Here we demonstrate the existence of a planet at 560 times the Sun-Earth distance from the 6- to 10-M
binary b Centauri through direct imaging. The planet-to-star mass ratio of 0.10-0.17% is similar to the Jupiter-Sun ratio, but the separation of the detected planet is about 100 times wider than that of Jupiter. Our results show that planets can reside in much more massive stellar systems than what would be expected from extrapolation of previous results. The planet is unlikely to have formed in situ through the conventional core accretion mechanism
, but might have formed elsewhere and arrived to its present location through dynamical interactions, or might have formed via gravitational instability.
Heart failure (HF) professionals are managing an older population with multiple, often interconnected comorbidities. The average age of the HF patient has increased substantially and many have a ...number of comorbidities. For the older HF patient, diligent planning of care has the potential to reduce hospitalization, improve quality of life and mortality; nevertheless, this vital component is often overlooked. Frailty, cachexia, sarcopenia, and cognitive impairment are all common in the older HF patient and require special care considerations. Many older HF patients live for many years with troublesome symptoms that could be better addressed through the incorporation of a palliative approach to care. Effective care plans can help patients maximize their health potential through both lifestyle and pharmacological interventions. However, current evidence remains scarce on what constitutes an optimal plan, therefore further studies are urgently needed. We review the care that could be implemented for the complex older HF patient with comorbidities.
PDF
