Vedelkoefoed9955

Exposure to phosphine (PH3) presents with a host of diverse, non-specific symptoms that span multiple organ systems and is characterized by a high mortality rate. While a comprehensive mechanism for PH3 poisoning remains inconclusive, prior studies have implicated cardiac failure and circulatory compromise as potential pathways central to PH3-induced mortality. In this study, milrinone (MLR), a phosphodiesterase-3 inhibitor used to treat cardiac failure, was investigated as a potential countermeasure for PH3 poisoning. Lethality, physiological responses, and behavioral changes were evaluated in telemetrized female rats pretreated with water (sham) or one of three doses of MLR (40, 200, or 600 μg/kg) and exposed to PH3 (660 ppm for 25-40 min; 16,500-26,400 ppm × min). Animals receiving prophylactic administration of 600 μg/kg of MLR had nominally improved survivability compared to sham animals, although median lethal concentration-time and time of death did not differ substantially between treatment groups. Changes in respiration and behavior induced by PH3 appeared largely unaffected by MLR pretreatment, regardless of dose. Conversely, MLR pretreatment alleviated some aspects of PH3-induced cardiac function impairment, with slight dose-dependent effects observed for cardiac contractility, mean arterial pressure, and QRS duration. Together, these results illustrate the importance of circulatory compromise in PH3 poisoning and highlight the potential viability of MLR as a potential countermeasure option or part of a countermeasure regimen when administered prophylactically at 600 μg/kg.Aortic dissection (AD) is a life-threatening disease featured by the dissection of intimal layer and the formation of a blood-filled false lumen within the aortic wall. Recent studies revealed that the formation and progression of AD lesions is closely related to vascular inflammation and macrophage infiltration. However, the potential efficacy of anti-inflammatory therapy on the prevention and treatment of AD has not been extensively investigated. Herein, we proposed a biomimetic anti-inflammatory liposome (PM/TN-CCLP) co-loaded with curcumin and celecoxib (CC), modified with cell-penetrating TAT-NBD fusion peptide (TN), and further camouflaged by isolated macrophage plasma membrane (PM), as a potential nanotherapy for AD. In vitro results showed that PM/TN-CCLP exhibited low cytotoxicity and elevated cellular uptake by inflammatory macrophages, and prominently inhibited the transendothelial migration, inflammatory responses and ROS generation of macrophages. Moreover, the PM/TN-CCLP treatment significantly prevented the H2O2-induced smooth muscle cell apoptosis. In vivo experiments were performed on the acute and chronic AD mouse models, respectively. The results verified the elevated accumulation of PM-camouflaged liposome at the aorta lesions. Further, the anti-inflammatory liposomes, especially PM/TN-CCLP, could reduce the rupture rate of dissection, prevent the loss of elastic fibers, and reduce MMP-9 expression as well as macrophage infiltration in the aortic lesions. Notably, as compared with free drugs and TN-CCLP, the PM/TN-CCLP treatment displayed the longest survival period along with the minimal aortic injury on both acute and chronic AD mice. Taken together, the present study suggested that the macrophage-biomimetic anti-inflammatory nanotherapy would be a promising strategy for the prevention and therapy of aortic dissection.Delivery of therapeutic peptides upon oral administration is highly desired and investigations report that the cell-penetrating peptide (CPP) penetratin and its analogues shuffle and penetramax show potential as carriers to enhance insulin delivery. Exploring this, the specific aim of the present study was to understand the impact that their complexation with a lipidated or non-lipidated therapeutic cargo would have on the delivery, to evaluate the effect of differences in membrane interactions in vitro and in vivo, as well as to deduce the mode of action leading to enhanced delivery. Fundamental biophysical aspects were studied by a range of orthogonal methods. Transepithelial permeation of therapeutic peptide was evaluated using the Caco-2 cell culture model supplemented with epithelial integrity measurements, real-time assessment of the carrier peptide effects on cell viability and on mode of action. Pharmacokinetic and pharmacodynamic (PK/PD) parameters were evaluated following intestinal administration td cargo permeation points towards enhancement via the paracellular route in the tight epithelium. This is different from the anticipated belief being that it is the cell-penetrating capability that facilitate transepithelial cargo permeation via a transcellular route.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Despite the gold standard treatment combining surgical resection, radiation and adjuvant plus concomitant chemotherapy with the alkylating agent temozolomide (TMZ), the prognosis remains poor (5-year survival rate<10%). Over the last three decades, a vast array of drug delivery systems (DDS) have been developed for the local treatment of GBM, with the majority of the characterization being undertaken in pre-clinical models. We aimed to gain an overview of the potential efficacy of such local delivery systems in comparison to the systemic drug administration.

In this paper, a systematic search of Pubmed, Web of Science, and Scopus was performed using pre-determined search terms. Studies were assessed for eligibility based on specific inclusion and exclusion criteria. A total of fifteen publications were included for analysis of local vs systemic group median survival, tumor volume and adverse events, with five brought forward for a meta-analysis.

The majority of studies showed local delivery to be more efficacious than systemic administration, regardless of the drug, animal model, type of DDS used, or duration of the study. The meta-analysis also showed that the mean difference between median survival ratios was statistically significantly in favor of local delivery.

Preclinical evidence shows that there is a firm rationale for further developing DDS for local therapeutic delivery to GBM and other brain cancers.

Preclinical evidence shows that there is a firm rationale for further developing DDS for local therapeutic delivery to GBM and other brain cancers.Wildlife ecotourism can offer a source of revenue which benefits local development and conservation simultaneously. However, habituation of wildlife for ecotourism can cause long-term elevation of glucocorticoid hormones, which may suppress immune function and increase an animal's vulnerability to disease. selleckchem We have previously shown that western lowland gorillas (Gorilla gorilla gorilla) undergoing habituation in Dzanga-Sangha Protected Areas, Central African Republic, have higher fecal glucocorticoid metabolite (FGCM) levels than both habituated and unhabituated gorillas. Here, we tested the relationship between FGCM levels and strongylid infections in the same gorillas. If high FGCM levels suppress the immune system, we predicted that FGCM levels will be positively associated with strongylid egg counts and that gorillas undergoing habituation will have the highest strongylid egg counts, relative to both habituated and unhabituated gorillas. We collected fecal samples over 12 months in two habituated gorilla groups, one group undergoing habituation and completely unhabituated gorillas. We established FGCM levels and fecal egg counts of Necator/Oesophagostomum spp. and Mammomonogamus sp. Controlling for seasonal variation and age-sex category in strongylid infections we found no significant relationship between FGCMs and Nectator/Oesophagostomum spp. link2 or Mammomonogamus sp. egg counts in a within group comparison in either a habituated group or a group undergoing habituation. However, across groups, egg counts of Nectator/Oesophagostomum spp. were lowest in unhabituated animals and highest in the group undergoing habituation, matching the differences in FGCM levels among these gorilla groups. Our findings partially support the hypothesis that elevated glucocorticoids reduce a host's ability to control the extent of parasitic infections, and show the importance of non-invasive monitoring of endocrine function and parasite infection in individuals exposed to human pressure including habituation process and ecotourism.Today, hydrogels opened new windows to the high-tech due to their amazing features. Thus, we applied hydrogel nanocomposite (HNC) made of tragacanth gum (a kind of polysaccharide) and CaCO3 nanoparticles to remove methylene blue dye (MBD) from the water solution. We used nonlinear and linear isotherms and kinetics as well as thermodynamics to uncover the adsorption mechanism. The results showed that the hydrogel could remove 80% of MBD. link3 Besides, the linear form of the pseudo-second-order kinetic model fits well with the results, showing chemical interactions. We found that this process follows both Sips and Redlich-Peterson models by applying nonlinear and linear isotherm models. The maximum adsorption capacities from nonlinear and linear Sips were 1401 and 2145 mg/g, respectively. Based on the thermodynamic equations, the adsorption of MBD onto HNC was physiochemical and exothermic. According to the phenomenological calculations, diffusion from the bulk (or film diffusion, Df = 1.2 × 10-8 cm2/s) is the primary mechanism.Hemopexin, a high affinity heme-binding protein is widely involved in variety physiological and pathological processes. It is an important acute phase response protein, and is important in regulating the inflammatory response. In this study, the open reading frame of Nile tilapia hemopexin (OnHpx) gene was amplified. The expression pattern of OnHpx in natural and bacterial challenged tilapia tissues were analyzed through RT-qPCR. The results indicated the OnHpx was most abundant in liver, and increased significantly in liver, spleen, head kidney and peripheral blood after bacterial challenge. Furthermore, the OnHpx mRNA was also significantly up-regulated in monocytes/macrophages and hepatocytes under the stimulation of S. agalactiae or A. hydrophila. In addition, the recombinant OnHpx protein could effectively reduce the bacteria proliferation and alleviate the inflammatory reaction caused by bacteria. Moreover, the (r)OnHpx also regulated the respiratory burst of monocytes/macrophages and played an important role in the antioxidant process. To our knowledge, these results provide the first evidence on the antibacterial and anti-inflammatory response mechanism of Hpx in early vertebrates. This brings new insights about the understanding of the evolutionary origins and ancient roles of the Hpx in the innate immune defense.Heparan sulfate (HS) is involved in many biological activities, including the biogenesis and uptake of exosomes, which are related to the occurrence and development of tumors. This study investigated the role of HS analogues (heparin, low molecular weight heparin, and 6-O-desulfated heparin) in modulating exosome secretion, composition and functions. Exosomes derived from B16F10 cells exposed to different HS analogues were isolated and characterized by TEM, western blotting and Nanosight analyses. The number, size and protein cargo of exosomes secreted by HS analogues-induced B16F10 cells were detected. The findings indicated the reduced tumor-derived exosome secretion and protein cargo as reflected by lower levels of CD63, TSG101, heparinase and IL-6 in exosomes derived from heparin-induced B16F10 cells as compared with 6-O-desulfated heparin-induced tumor cells. Further functional assays demonstrated that exosomes from tumor cells exposed to heparin weakened tumor proliferation, migration and invasion most significantly among various exosomes derived from B16F10 cells treated with different HS analogues.