Respiratory diseases remain challenging to treat, with current efforts primarily focused on managing symptoms rather than maintaining overall lung health. Traditional treatment methods, such as oral or parenteral administration of antiviral, antibacterial, and anti-inflammatory drugs, face limitations. These include difficulty in delivering therapeutic agents to pathogens residing deep in the airways and the risk of severe side effects due to high systemic drug concentrations. The growing threat of drug-resistant pathogens further complicates infection management. The lung's large surface area offers an attractive target for inhalation-based drug delivery. Nanoparticles (NP) enable uniform and sustained drug distribution across the alveolar network, overcoming challenges posed by complex lung anatomy. Recent breakthroughs in nanorobots (NR) have demonstrated precise navigation through biological environments, delivering therapies directly to affected lung areas with enhanced accuracy. Nanotechnology has also shown promise in treating lung cancer, with nanoparticles engineered to overcome biological barriers, improve drug solubility, and enable controlled drug release. This review explores the progress of NP and NR in addressing challenges in pulmonary drug delivery. These innovations allow targeted delivery of nucleic acids, drugs, or peptides to the pulmonary epithelium with unprecedented accuracy, offering significant potential for improving therapeutic effectiveness in respiratory disorders.

Serotonin (5-HT) plays an extensive role during pregnancy in regulating both the placental physiology and embryonic/fetal development. The uptake of 5-HT into cells is central to the control of local concentrations of 5-HT near its molecular targets. Here, we investigated the mechanisms of 5-HT uptake into human primary placental cells and cord blood platelets, all isolated immediately after birth. Trophoblasts and cord blood platelets showed 5-HT uptake with similar Michaelis constant (Km) values (~0.6 μM), typical of the high-affinity serotonin transporter (SERT). The uptake of 5-HT into trophoblasts was efficiently inhibited by various SERT-targeting drugs. In contrast, the uptake of 5-HT into feto-placental endothelial cells was not inhibited by a SERT blocker and showed a Km value (~782 μM) in the low-affinity range. Consistent with this, SERT mRNAs were abundant in term trophoblasts but sparse in feto-placental endothelial cells, whereas the opposite was found for the low-affinity plasma membrane monoamine transporter (PMAT) mRNAs. Organic cation transporter (OCT) 1, 2, and 3 mRNAs were absent or sparse in both cell types. In summary, the results demonstrate, for the first time, the presence of functional 5-HT uptake systems in feto-placental endothelial cells and fetal platelets, cells that are in direct contact with fetal blood plasma. The data also highlight the sensitivity to various psychotropic drugs of 5-HT transport into trophoblasts facing the maternal blood. The multiple, high-, and low-affinity systems present for the cellular uptake of 5-HT underscore the importance of 5-HT homeostasis at the maternal–fetal interface.

Oxysterols are oxidized cholesterol derivatives whose systemic levels are found elevated in pregnancy disorders such as gestational diabetes mellitus (GDM). Oxysterols act through various cellular receptors and serve as a key metabolic signal, coordinating inflammation. GDM is a condition of low-grade chronic inflammation accompanied by altered inflammatory profiles in the mother, placenta and fetus. Higher levels of two oxysterols, namely 7-ketocholesterol (7-ketoC) and 7β-hydroxycholesterol (7β-OHC), were observed in fetoplacental endothelial cells (fpEC) and cord blood of GDM offspring. In this study, we tested the effects of 7-ketoC and 7β-OHC on inflammation and investigated the underlying mechanisms involved. Primary fpEC in culture treated with 7-ketoC or 7β-OHC, induced the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) signaling, which resulted in the expression of pro-inflammatory cytokines (IL-6, IL-8) and intercellular cell adhesion molecule-1 (ICAM-1). Liver-X receptor (LXR) activation is known to repress inflammation. Treatment with LXR synthetic agonist T0901317 dampened oxysterol-induced inflammatory responses. Probucol, an inhibitor of LXR target gene ATP-binding cassette transporter A-1 (ABCA-1), antagonized the protective effects of T0901317, suggesting a potential involvement of ABCA-1 in LXR-mediated repression of inflammatory signaling in fpEC. TLR-4 inhibitor Tak-242 attenuated pro-inflammatory signaling induced by oxysterols downstream of the TLR-4 inflammatory signaling cascade. Taken together, our findings suggest that 7-ketoC and 7β-OHC contribute to placental inflammation through the activation of TLR-4. Pharmacologic activation of LXR in fpEC decelerates its shift to a pro-inflammatory phenotype in the presence of oxysterols.

As opposed to adults, high-density lipoprotein (HDL) is the main cholesterol carrying lipoprotein in fetal circulation. The major HDL receptor, scavenger receptor class B type I (SR-BI), contributes to local cholesterol homeostasis. Arterial endothelial cells (ECA) from human placenta are enriched with cholesterol compared to venous endothelial cells (ECV). Moreover, umbilical venous and arterial plasma cholesterol levels differ markedly. We tested the hypothesis that the uptake of HDL-cholesteryl esters differs between ECA and ECV because of the differential expression of SR-BI. We aimed to identify the key regulators underlying these differences and the functional consequences. Immunohistochemistry was used for visualization of SR-BI in situ. ECA and ECV were isolated from the chorionic plate of human placenta and used for RT-qPCR, Western Blot, and HDL uptake assays with ³H- and ¹²⁵I-labeled HDL. DNA was extracted for the methylation profiling of the SR-BI promoter. SR-BI regulation was studied by exposing ECA and ECV to differential oxygen concentrations or shear stress. Our results show elevated SR-BI expression and protein abundance in ECA compared to ECV in situ and in vitro. Immunohistochemistry demonstrated that SR-BI is mainly expressed on the apical side of placental endothelial cells in situ, allowing interaction with mature HDL circulating in the fetal blood. This was functionally linked to a higher increase of selective cholesterol ester uptake from fetal HDL in ECA than in ECV, and resulted in increased cholesterol availability in ECA. SR-BI expression on ECV tended to decrease with shear stress, which, together with heterogeneous immunostaining, suggests that SR-BI expression is locally regulated in the placental vasculature. In addition, hypomethylation of several CpG sites within the SR-BI promoter region might contribute to differential expression of SR-BI between chorionic arteries and veins. Therefore, SR-BI contributes to a local cholesterol homeostasis in ECA and ECV of the human feto-placental vasculature.

Background: Accumulation of amyloid beta (Aβ) and tau proteins have for decades been thought to be central in the pathogenesis of Alzheimer’s disease (AD). More recently, a plethora of evidence emerged that links metabolic dysfunctions such as obesity, type 2 diabetes (T2D), and dyslipidemia with the pathophysiology of AD. In this study, we investigated the effects of streptozocin and high fat diet (HFD) induced T2D on lipid and amyloid beta metabolism in APPxhQC transgenic mice and their wild‐type littermates.Method: APPxhQC mice were generated by crossbreeding APP_SL with hQC mice. As controls wild‐type littermates were used. APP_SL mice express human APP751 with the Swedish and the London mutation on a C57Bl/6RccHsd background. hQC mice express human glutaminyl cyclase (QC) enzyme on B6CBAF1/J background. Plasma lipids (triglycerides and cholesterol) and liver function enzymes (aspartate aminotransferase and alanine transaminase, ALT and ALT, respectively) were determined by ELISA. Brain concentrations of soluble and insoluble Aβ _1‐38, _1‐40 and _1‐42 peptides were determined using an immunosorbent assay (Mesoscale discovery immunosorbent assay) while pGlu Aβ_1‐42 was measured by ELISA. Hepatic mRNA expression levels of genes involved in cholesterol efflux and lipid metabolism were determined by quantitative real time polymerase chain reaction (qRT‐PCR).Result: T2D induced increased concentrations of plasma cholesterol as well as AST and ALT levels. The magnitudes, however, were dependent on sex and genotype and were statistically significant in female wild‐type mice, while a similar pattern was observed in APPxhQC transgenes. These increased plasma concentrations were accompanied by a down‐regulation of hepatic gene expression levels of LRP1, ABCA1, PPARα, PBC1β, and NEP that were statistically significant in female wild‐type mice, while a similarly pattern was observed in APPxhQC transgenic mice. More interestingly, T2D provoked a progressive shift of brain Aβ _1‐38 and _1‐40 from soluble to insoluble forms in male APPxhQC mice and a significant increase of pyroglutamate modified Aβ _1‐42 in female mice.Conclusion: T2D in APPxhQC mice provokes a shift from soluble to large insoluble polymers of Aβ in the brain, corroborates the deteriorating role of T2D in the progression of AD