Microcurrent wave alleviates mouse intracranial arterial dolichoectasia development.

Intracranial arterial dolichoectasia (IADE) is associated with the interaction of hypertension and inflammation, and microcurrent can be effective in hypertension. Therefore, this study aimed to investigate the therapeutic effect of microcurrent electrical stimulation in a mouse IADE model. This study randomly categorized 20 mice into five groups: group 1-C (healthy control), group 2-D (IADE model), group 3-M + D (microcurrent administration before nephrectomy and until brain surgery), group 4-D + M (microcurrent administration for 4 weeks following brain surgery), and group 5-M (microcurrent administration for 4 weeks). Cerebral artery diameter and thickness and cerebral arterial wall extracellular matrix components were assessed. Among the five groups, group 2-D showed significantly higher cerebral arterial wall diameter (117.79 ± 17.05 µm) and proportion of collagen (42.46 ± 14.12%) and significantly lower arterial wall thickness (9.31 ± 2.26 µm) and proportion of smooth muscle cell (SMC) and elastin in the cerebral arterial wall (SMC: 38.05 ± 10.32%, elastin: 11.11 ± 6.97%). Additionally, group 4-D + M exhibited a non-significantly lower diameter (100.28 ± 25.99 µm) and higher thickness (12.82 ± 5.17 µm). Group 5-M demonstrated no evidence of toxicity in the liver and brain. The pilot study revealed that microcurrent is effective in preventing IADE development, although these beneficial effects warrant further investigation.

Dual anticancer and antibacterial activity of fluorescent naphthoimidazolium salts.

Cancer has emerged as a significant global health challenge, ranking as the second leading cause of death worldwide. Moreover, cancer patients frequently experience compromised immune systems, rendering them susceptible to bacterial infections. Combining anticancer and antibacterial properties in a single drug could lead to improved overall treatment outcomes and patient well-being. In this context, the present study focused on a series of hydrophilic naphthoimidazolium salts with donor groups (NI-R), aiming to create dual-functional agents with antibacterial and anticancer activities. Among these compounds, NI-TPA demonstrated notable antibacterial activity, particularly against drug-resistant bacteria, with MIC value of 7.8 µg mL-1. Furthermore, NI-TPA exhibited the most potent cytotoxicity against four different cancer cell lines, with an IC50 range of 0.67-2.01 µg mL-1. The observed high cytotoxicity of NI-TPA agreed with molecular docking and dynamic simulation studies targeting c-Met kinase protein. Additionally, NI-TPA stood out as the most promising candidate for two-photo excitation, fluorescence bioimaging, and localization in lysosomes. The study findings open new avenues for the design and development of imidazolium salts that could be employed in phototheranostic applications for cancer treatment and bacterial infections.

Transferrin-Conjugated Melittin-Loaded L-Arginine-Coated Iron Oxide Nanoparticles for Mitigating Beta-Amyloid Pathology of the 5XFAD Mouse Brain.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases and a major contributor to dementia. Although the cause of this condition has been identified long ago as aberrant aggregations of amyloid and tau proteins, effective therapies for it remain elusive. The complexities of drug development for AD treatment are often compounded by the impermeable blood-brain barrier and low-yield brain delivery. In addition, the use of high drug concentrations to overcome this challenge may entail side effects. To address these challenges and enhance the precision of delivery into brain regions affected by amyloid aggregation, we proposed a transferrin-conjugated nanoparticle-based drug delivery system. The transferrin-conjugated melittin-loaded L-arginine-coated iron oxide nanoparticles (Tf-MeLioNs) developed in this study successfully mitigated melittin-induced cytotoxicity and hemolysis in the cell culture system. In the 5XFAD mouse brain, Tf-MeLioNs remarkably reduced amyloid plaque accumulation, particularly in the hippocampus. This study suggested Tf-LioNs as a potential drug delivery platform and Tf-MeLioNs as a candidate for therapeutic drug targeting of amyloid plaques in AD. These findings provide a foundation for further exploration and advancement in AD therapeutics.

Gadolinium-Cyclic 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid-Click-Sulfonyl Fluoride for Probing Serine Protease Activity in Magnetic Resonance Imaging.

Serine protease is linked to a wide range of diseases, prompting the development of robust, selective, and sensitive protease assays and sensing methods. However, the clinical needs for serine protease activity imaging have not yet been met, and the efficient in vivo detection and imaging of serine protease remain challenging. Here, we report the development of the gadolinium-cyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-click-Sulfonyl Fluoride (Gd-DOTA-click-SF) MRI contrast agent targeting serine protease. The HR-FAB mass spectrum confirmed the successful formation of our designed chelate. The molar longitudinal relaxivity (r1) of the Gd-DOTA-click-SF probe (r1 = 6.82 mM-1 s-1) was significantly higher than that of Dotarem (r1 = 4.63 mM-1 s-1), in the range of 0.01-0.64 mM at 9.4 T. The in vitro cellular study and the transmetallation kinetics study showed that the safety and stability of this probe are comparable to those of conventional Dotarem. Ex vivo abdominal aortic aneurysm (AAA) MRI revealed that this probe has a contrast-agent-to-noise ratio (CNR) that is approximately 51 ± 23 times greater than that of Dotarem. This study of superior visualization of AAA suggests that it has the potential to detect elastase in vivo and supports the feasibility of probing serine protease activity in T1-weighted MRI.

Melittin-loaded Iron Oxide Nanoparticles Prevent Intracranial Arterial Dolichoectasia Development through Inhibition of Macrophage-mediated Inflammation.

Rationale: In intracranial arterial dolichoectasia (IADE) development, the feedback loop between inflammatory cytokines and macrophages involves TNF-α and NF-κB signaling pathways and leads to subsequent MMP-9 activation and extracellular matrix (ECM) degeneration. In this proof-of-concept study, melittin-loaded L-arginine-coated iron oxide nanoparticle (MeLioN) was proposed as the protective measure of IADE formation for this macrophage-mediated inflammation and ECM degeneration. Methods: IADE was created in 8-week-old C57BL/6J male mice by inducing hypertension and elastase injection into a basal cistern. Melittin was loaded on the surface of ION as a core-shell structure (hydrodynamic size, 202.4 nm; polydispersity index, 0.158). Treatment of MeLioN (2.5 mg/kg, five doses) started after the IADE induction, and the brain was harvested in the third week. In the healthy control, disease control, and MeLioN-treated group, the morphologic changes of the cerebral arterial wall were measured by diameter, thickness, and ECM composition. The expression level of MMP-9, CD68, MCP-1, TNF-α, and NF-κB was assessed from immunohistochemistry, polymerase chain reaction, and Western blot assay. Results: MeLioN prevented morphologic changes of cerebral arterial wall related to IADE formation by restoring ECM alterations and suppressing MMP-9 expression. MeLioN inhibited MCP-1 expression and reduced CD68-positive macrophage recruitments into cerebral arterial walls. MeLioN blocked TNF-α activation and NF-κB signaling pathway. In the Sylvian cistern, co-localization was found between the CD68-positive macrophage infiltrations and the MeLioN distributions detected on Prussian Blue and T2* gradient-echo MRI, suggesting the role of macrophage harboring MeLioN. Conclusions: The macrophage infiltration into the arterial wall plays a critical role in the MMP-9 secretion. MeLioN, designed for ION-mediated melittin delivery, effectively prevents IADE formation by suppressing macrophage-mediated inflammations and MMP activity. MeLioN can be a promising strategy preventing IADE development in high-risk populations.

Faster Region-Based Convolutional Neural Network in the Classification of Different Parkinsonism Patterns of the Striatum on Maximum Intensity Projection Images of [18F]FP-CIT Positron Emission Tomography.

The aim of this study was to compare the performance of a deep-learning convolutional neural network (Faster R-CNN) model to detect imaging findings suggestive of idiopathic Parkinson's disease (PD) based on [18F]FP-CIT PET maximum intensity projection (MIP) images versus that of nuclear medicine (NM) physicians. The anteroposterior MIP images of the [18F]FP-CIT PET scan of 527 patients were classified as having PD (139 images) or non-PD (388 images) patterns according to the final diagnosis. Non-PD patterns were classified as overall-normal (ONL, 365 images) and vascular parkinsonism with definite defects or prominently decreased dopamine transporter binding (dVP, 23 images) patterns. Faster R-CNN was trained on 120 PD, 320 ONL, and 16 dVP pattern images and tested on the 19 PD, 45 ONL, and seven dVP patterns images. The performance of the Faster R-CNN and three NM physicians was assessed using receiver operating characteristics curve analysis. The difference in performance was assessed using Cochran's Q test, and the inter-rater reliability was calculated. Faster R-CNN showed high accuracy in differentiating PD from non-PD patterns and also from dVP patterns, with results comparable to those of NM physicians. There were no significant differences in the area under the curve and performance. The inter-rater reliability among Faster R-CNN and NM physicians showed substantial to almost perfect agreement. The deep-learning model accurately differentiated PD from non-PD patterns on MIP images of [18F]FP-CIT PET, and its performance was comparable to that of NM physicians.

Sex Difference in Mortality for Premature and Low Birth Weight Neonates: A Systematic Review.

OBJECTIVE: Advances in neonatology have made possible the survival of neonates with lower gestational ages and birth weights. Nevertheless, findings remain of a sex difference in mortality for premature and low birth weight (LBW) neonates with male sex often associated with poorer outcome (the "male disadvantage"). Through literature review, this article will seek clarification of the existing evidence regarding the association between sex and mortality at discharge from neonatal intensive care units (NICUs) for premature and LBW neonates. METHODS: A systematic review was conducted in Medline and Google Scholar with subsequent search of study reference lists. RESULTS: The database search yielded 349 articles and an additional 11 were identified from study reference lists. A final 32 studies were reviewed. Of these, 26 studies demonstrated worse male mortality outcome and 6 studies reported no sex difference in mortality. CONCLUSION: The majority of reviewed studies found poorer male mortality outcome. A small number of studies maintained a null association between sex and mortality. This indicates male premature and LBW neonates experience higher risk of mortality by discharge compared with females, an observation which may inform clinical decision making in the NICU.