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Scientific Reports Jun 2024Mononuclear phagocytes (MNP), including macrophages and dendritic cells form an essential component of primary responses to environmental hazards and toxic exposures....
Mononuclear phagocytes (MNP), including macrophages and dendritic cells form an essential component of primary responses to environmental hazards and toxic exposures. This is particularly important in disease conditions such as asthma and allergic airway disease, where many different cell types are present. In this study, we differentiated CD34+ haematopoietic stem cells towards different populations of MNP in an effort to understand how different cell subtypes present in inflammatory disease microenvironments respond to the common allergen house dust mite (HDM). Using single cell mRNA sequencing, we demonstrate that macrophage subtypes MC and MLC display different patterns of gene expression after HDM challenge, noted especially for the chemokines CXCL5, CXCL8, CCL5 and CCL15. MLC alternatively activated macrophages displayed the greatest changes in expression, while neutrophil and monocyte populations did not respond. Further work investigated how pollutant diesel exhaust particles could modify these transcriptional responses and revealed that CXC but not CC type chemokines were further upregulated. Through the use of diesel particles with adsorbed material removed, we suggest that soluble pollutants on these particles are the active constituents responsible for the modifying effects on HDM. This study highlights that environmental exposures may influence tissue responses dependent on which MNP cell type is present, and that these should be considerations when modelling such events in vitro. Understanding the nuanced responsiveness of different immune cell types to allergen and pollutant exposure also contributes to a better understanding of how these exposures influence the development and exacerbation of human disease.
Topics: Animals; Pyroglyphidae; Humans; Phagocytes; Macrophages; Allergens; Vehicle Emissions; Hematopoietic Stem Cells; Dendritic Cells; Gene Expression Regulation
PubMed: 38902328
DOI: 10.1038/s41598-024-64783-1 -
Traffic Injury Prevention Jun 2024The objective of this study was to describe fatal pedestrian injury patterns in youth aged 15 to 24 years old and correlate them with motor vehicle collision (MVC)...
OBJECTIVE
The objective of this study was to describe fatal pedestrian injury patterns in youth aged 15 to 24 years old and correlate them with motor vehicle collision (MVC) dynamics and pedestrian kinematics using data from medicolegal death investigations of MVCs occurring in the current Canadian motor vehicle (MV) fleet.
METHODS
Based on a systematic literature review, MVC-pedestrian injuries were collated in an injury data collection form (IDCF). The IDCF was coded using the Abbreviated Injury Scale (AIS) 2015 revision. The AIS of the most frequent severe injury was noted for individual body regions. The Maximum AIS (MAIS) was used to define the most severe injury to the body overall and by body regions (MAISBR). This study focused on serious to maximal injuries (AIS 3-6) that had an increasing likelihood of causing death. The IDCF was used to extract collision and injury data from the Office of the Chief Coroner for Ontario (OCCO) database of postmortem examinations done at the Provincial Forensic Pathology Unit (PFPU) in Toronto, Canada, and other provincial facilities between 2013 and 2019. Injury data were correlated with data about the MVs and MV dynamics and pedestrian kinematics.The study was approved by the Western University Health Science Research Ethics Board (Project ID: 113440; Lawson Health Research Institute Approval No. R-19-066).
RESULTS
There were 88 youth, including 54 (61.4%) males and 34 (38.6%) females. Youth pedestrians comprised 13.1% (88/670) of all autopsied pedestrians. Cars ( = 25/88, 28.4%) were the most frequent type of vehicle in single-vehicle impacts, but collectively vehicles with high hood edges (i.e., greater distance between the ground and hood edge) were in the majority. Forward projection ( = 34/88, 38.6%) was the most frequent type of pedestrian kinematics. Regardless of the type of vehicle, there was a tendency in most cases for the median MAISBR ≥ 3 to involve the head and thorax. A similar trend was seen in most of the pedestrian kinematics involving the various frontal impacts. Of the 88 cases, at least 63 (71.6%) were known to be engaged in risk-taking behaviors (e.g., activity on roadway). At least 12 deaths were nonaccidental (8 suicides and 4 homicides). Some activities may have been impairment related, because 26/63 (41.3%) pedestrians undertaking risk-taking behavior on the roadway were impaired. Toxicological analyses revealed that over half of the cases (47/88, 53.4%) tested positive for a drug that could have affected behavior. Ethanol was the most common. Thirty-one had positive blood results.
CONCLUSION
A fatal dyad of head and thorax trauma was observed for pedestrians struck by cars. For those pedestrians hit by vehicles with high hood edges, which were involved in the majority of cases, a fatal triad of injuries to the head, thorax, and abdomen/retroperitoneum was observed. Most deaths occurred from frontal collisions and at speeds more than 35 km/h.
PubMed: 38900934
DOI: 10.1080/15389588.2024.2351603 -
Nanomedicine (London, England) Jun 2024Exosomes, a category of extracellular vesicle (EV), are phospholipid bilayer structures ranging from 30 to 150 nm, produced by various organisms through the endosomal... (Review)
Review
Exosomes, a category of extracellular vesicle (EV), are phospholipid bilayer structures ranging from 30 to 150 nm, produced by various organisms through the endosomal pathway. Recent studies have established the utilization of exosomes as nanocarriers for drug distribution across various therapeutic areas including cancer, acute liver injury, neuroprotection, oxidative stress, inflammation, etc. The importance of plant-derived exosomes and exosome vesicles derived from mammalian cells or milk, loaded with potent plant bioactives for various therapeutic indications are discussed along with insights into future perspectives. Moreover, this review provides a detailed understanding of exosome biogenesis, their composition, classification, stability of different types of exosomes, and different routes of administration along with the standard techniques used for isolating, purifying, and characterizing exosomes.
PubMed: 38900607
DOI: 10.1080/17435889.2024.2354159 -
European Journal of Nuclear Medicine... Jun 2024
Correction to: HER2-directed antibodies, affibodies and nanobodies as drug-delivery vehicles in breast cancer with a specific focus on radioimmunotherapy and radioimmunoimaging.
PubMed: 38900309
DOI: 10.1007/s00259-024-06792-w -
RSC Pharmaceutics Jun 2024A mucus gel layer lines the luminal surface of tissues throughout the body to protect them from infectious agents and particulates. As a result, nanoparticle drug...
A mucus gel layer lines the luminal surface of tissues throughout the body to protect them from infectious agents and particulates. As a result, nanoparticle drug delivery systems delivered to these sites may become trapped in mucus and subsequently cleared before they can reach target cells. As such, optimizing the properties of nanoparticle delivery vehicles, such as their surface chemistry and size, is essential to improving their penetration through the mucus barrier. In previous work, we developed a mucin-based hydrogel that has viscoelastic properties like that of native mucus which can be further tailored to mimic specific mucosal tissues and disease states. Using this biomimetic hydrogel system, a 3D-printed array containing synthetic mucus barriers was created that is compatible with a 96-well plate enabling its use as a high-throughput screening platform for nanoparticle drug delivery applications. To validate this system, we evaluated several established design parameters to determine their impact on nanoparticle penetration through synthetic mucus barriers. Consistent with the literature, we found nanoparticles of smaller size and coated with a protective PEG layer more efficiently penetrated through synthetic mucus barriers. In addition, we evaluated a mucolytic (tris(2-carboxyethyl) phosphine, TCEP) for use as a permeation enhancer for mucosal drug delivery. In comparison to -acetyl cysteine (NAC), we found TCEP significantly improved nanoparticle penetration through a disease-like synthetic mucus barrier. Overall, our results establish a new high-throughput screening approach using synthetic mucus barrier arrays to identify promising nanoparticle formulation strategies for drug delivery to mucosal tissues.
PubMed: 38899149
DOI: 10.1039/d3pm00057e -
Biology of Sex Differences Jun 2024Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and...
BACKGROUND
Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A (TxA) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment.
METHODS
Pregnant Sprague-Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O) or hypoxia (11% O) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence.
RESULTS
Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels.
CONCLUSIONS
Prenatal hypoxia increased TxA vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring.
Topics: Animals; Female; Rats, Sprague-Dawley; Pregnancy; Vasoconstriction; Male; Prenatal Exposure Delayed Effects; Thromboxane A2; Sex Characteristics; Antioxidants; Nitric Oxide; Mesenteric Arteries; Rats; Hypoxia; Fetal Hypoxia; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
PubMed: 38898532
DOI: 10.1186/s13293-024-00627-x -
Molecular Neurobiology Jun 2024Alzheimer's Disease is a degenerative neurological condition which leads to a decline in memory and cognitive function. Chlorogenic Acid (CGA) presents properties...
Alzheimer's Disease is a degenerative neurological condition which leads to a decline in memory and cognitive function. Chlorogenic Acid (CGA) presents properties including neuroprotective, antioxidant and anti-inflammatory. The aim of this study was to examine the impact of CGA on cognitive impairments, neuroinflammation and neuronal damage in mice submitted to an experimental model of Sporadic Alzheimer Disease (SAD) induced by intracerebroventricular administration of streptozotocin (ICV-STZ). Male Swiss mice received bilateral ICV-STZ injections (3 mg/Kg) on days 1 and 3. The treatment with CGA (5 mg/Kg, orally) or vehicle (water, orally), was initiated and continued for 26 days, starting 2 h after the second induction procedure. At first, there was no change in serum glucose levels after SAD induction. ICV-STZ induces impairments in aversive, recognition, and spatial memory, while CGA treatment significantly alleviated these memory deficits. Furthermore, locomotor activity, working memory, and anxiety-related activities remained unaffected by the treatments. CGA treatment protects against ICV-STZ-induced increase in the nitrite/nitrate and TBARS levels. ICV-STZ induced a reduction in viable cells, depletion of BDNF, and triggered astrogliosis and microgliosis in the cortex and hippocampus. Treatment with CGA preserves viable cell count in the prefrontal cortex, CA1, and CA3 regions of the hippocampus. Additionally, it prevented BDNF depletion in the prefrontal cortex and hippocampus (CA1, CA3, and DG regions), and mitigated astrogliosis and microgliosis in the prefrontal cortex and hippocampus (CA1, CA3, and DG regions). These findings indicate the neuroprotective effects of CGA, underscoring their potential as therapeutic agents or adjuncts in the treatment of SAD.
PubMed: 38898198
DOI: 10.1007/s12035-024-04299-x -
International Journal of Toxicology Jun 2024The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13...
The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUC and C at Day 91) was greater in males than females, suggesting sex differences. AUC and C at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed T and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively.
PubMed: 38897632
DOI: 10.1177/10915818241261631 -
Journal of Pharmaceutical Sciences Jun 2024Since eyedrops have conventionally been formulated in aqueous vehicles, ocular pharmacokinetic studies are generally performed using aqueous buffers to identify...
Since eyedrops have conventionally been formulated in aqueous vehicles, ocular pharmacokinetic studies are generally performed using aqueous buffers to identify physicochemical properties of the drug and the vehicles that influence drug absorption. In recent years, biocompatible lipophilic vehicles are increasingly finding application in ocular drug delivery; however, the mechanism of drug penetration from these non-aqueous vehicles is poorly understood. This study aims to compare ocular penetration of the model lipophilic drug curcumin when incorporated into lipophilic vehicles. To elucidate whether intrinsic solubility in the lipophilic vehicle influences ocular penetration, a curcumin solution and suspension were prepared in medium chain triglycerides (MCT) and squalane, respectively. Ocular penetration and distribution of curcumin from both vehicles was compared and evaluated qualitatively and quantitatively ex vivo. Significantly greater and faster penetration was observed from the squalane suspension than from the MCT solution in all ocular tissues. Our results suggest that the ability of lipophilic drugs to partition out of lipophilic vehicles and into cell membranes, rather than their intrinsic solubility in the lipophilic vehicle, determines the rate and extent of their ocular penetration.
PubMed: 38897564
DOI: 10.1016/j.xphs.2024.06.011 -
Molecules (Basel, Switzerland) May 2024Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques,... (Review)
Review
Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques, the dose escalation required to enhance tumor control is limited due to the inevitable toxicity to the surrounding healthy tissue. Therefore, the local enhancement of dosing in tumor sites can provide the necessary means to improve the treatment modality. In recent years, the emergence of nanotechnology has facilitated a unique opportunity to increase the efficacy of radiotherapy treatment. The application of high-atomic-number (Z) nanoparticles (NPs) can augment the effects of radiotherapy by increasing the sensitivity of cells to radiation. High-Z NPs can inherently act as radiosensitizers as well as serve as targeted delivery vehicles for radiosensitizing agents. In this work, the therapeutic benefits of high-Z NPs as radiosensitizers, such as their tumor-targeting capabilities and their mechanisms of sensitization, are discussed. Preclinical data supporting their application in radiotherapy treatment as well as the status of their clinical translation will be presented.
Topics: Humans; Radiation-Sensitizing Agents; Neoplasms; Nanoparticles; Animals; Radiotherapy
PubMed: 38893315
DOI: 10.3390/molecules29112438