Search Results (170)

Background: Pain is a complex phenomenon characterized by unpleasant experiences with profound heterogeneity influenced by biological, psychological, and social factors. According to the National Health Interview Survey, 50.2 million U.S. adults (20.5%) experience pain on most days, with the annual cost of prescription medication for pain reaching approximately USD 17.8 billion. Theranostic pain nanomedicine therefore emerges as an attractive analgesic strategy with the potential for increased efficacy, reduced side-effects, and treatment personalization. Theranostic nanomedicine combines drug delivery and diagnostic features, allowing for real-time monitoring of analgesic efficacy in vivo using molecular imaging. However, clinical translation of these nanomedicines are challenging due to complex manufacturing methodologies, lack of standardized quality control, and potentially high costs. Quality by Design (QbD) can navigate these challenges and lead to the development of an optimal pain nanomedicine. Our lab previously reported a macrophage-targeted perfluorocarbon nanoemulsion (PFC NE) that demonstrated analgesic efficacy across multiple rodent pain models in both sexes. Here, we report PFC-free, biphasic nanoemulsions formulated with a biocompatible and non-immunogenic plant-based coconut oil loaded with a COX-2 inhibitor and a clinical-grade, indocyanine green (ICG) near-infrared fluorescent (NIRF) dye for parenteral theranostic analgesic nanomedicine. Methods: Critical process parameters and material attributes were identified through the FMECA (Failure, Modes, Effects, and Criticality Analysis) method and optimized using a 3 × 2 full-factorial design of experiments. We investigated the impact of the oil-to-surfactant ratio (w/w) with three different surfactant systems on the colloidal properties of NE. Small-scale (100 mL) batches were manufactured using sonication and microfluidization, and the final formulation was scaled up to 500 mL with microfluidization. The colloidal stability of NE was assessed using dynamic light scattering (DLS) and drug quantification was conducted through reverse-phase HPLC. An in vitro drug release study was conducted using the dialysis bag method, accompanied by HPLC quantification. The formulation was further evaluated for cell viability, cellular uptake, and COX-2 inhibition in the RAW 264.7 macrophage cell line. Results: Nanoemulsion droplet size increased with a higher oil-to-surfactant ratio (w/w) but was no significant impact by the type of surfactant system used. Thermal cycling and serum stability studies confirmed NE colloidal stability upon exposure to high and low temperatures and biological fluids. We also demonstrated the necessity of a solubilizer for long-term fluorescence stability of ICG. The nanoemulsion showed no cellular toxicity and effectively inhibited PGE2 in activated macrophages. Conclusions: To our knowledge, this is the first instance of a celecoxib-loaded theranostic platform developed using a plant-derived hydrocarbon oil, applying the QbD approach that demonstrated COX-2 inhibition. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

Introduction: Leptospirosis is an under-recognized zoonosis that affects both tropical and temperate regions. While it is often associated with exposure to contaminated water or infected animals, its presentation and epidemiology in Mediterranean countries remain incompletely understood. This retrospective cohort study investigates the clinical and epidemiological profile of leptospirosis in Crete, Greece, a region where data are scarce. Methods: All adult patients with laboratory-confirmed leptospirosis admitted to three major public hospitals in Crete, Greece, between January 2019 and December 2023 were included in the analysis. Diagnosis was made through serologic testing along with compatible clinical symptoms. Results: A total of 17 patients were included. Their median age was 48 years, with a predominance of males (70.6%). Notably, more than half of the patients had no documented exposure to classic risk factors such as rodents or standing water. Clinical presentations were varied but commonly included fever, fatigue, acute kidney injury, and jaundice. Of the patients who underwent imaging, most showed hepatomegaly. The median delay from symptom onset to diagnosis was 11 days, underscoring the diagnostic challenge in non-endemic areas. Ceftriaxone was the most frequently administered antibiotic (76.5%), often in combination with tetracyclines or quinolones. Despite treatment, three patients (17.6%) died, all presenting with severe manifestations such as ARDS, liver failure, or shock. A concerning increase in cases was noted in 2023. Conclusions: Leptospirosis can present with severe and potentially fatal outcomes even in previously healthy individuals and in regions not traditionally considered endemic. The relatively high mortality and disease frequency noted emphasize the importance of maintaining a high index of suspicion. Timely diagnosis and appropriate antimicrobial therapy are essential to improving patient outcomes. Additionally, the need for enhanced public health awareness, diagnostic capacity, and possibly environmental surveillance to control this neglected but impactful disease better, should be emphasized. Full article

Background/Objectives: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer’s disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (Aβ) accumulation. Methods: Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against Aβ fibrils. Dissociation of Aβ fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. Results: In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated Aβ fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. Conclusions: Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer’s disease through effective modulation of Aβ pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation. Full article

The abdomen is a key region in small animal veterinary practice, with the middle and caudal sections housing various organ systems that are susceptible to dysfunction, necessitating medical intervention or surgery. Sectional imaging techniques like CT and MRI are commonly used in small mammals, but no studies have focused on rodent abdomen. This study aimed to correlate micro-CT and MRI images of the middle and caudal abdominal regions with corresponding anatomical sections in Syrian hamsters (SHs), which are popular pets and experimental models. Ten healthy male SHs were used, and anatomical structures from frozen sections were compared with corresponding MCT and MRI images. Clinically relevant structures identified in anatomical sections were discernible on MCT and MRI scans. The key findings include the presence of glandular and non-glandular stomachs, the stomach and cecum primarily located on the left side, the absence of ampulla coli, sacculus rotundus, and cecal appendix, and sacculation of the colon, as well as the jejunum, mainly on the right side. The vesicular, coagulating, and prostate glands were also present, and the right kidney did not extend to the last thoracic vertebra. The results were similar to abdominal anatomical and radiologic studies in rats, mice, and guinea pigs, regardless of the rat’s and mice’s sacculated cecum and the guinea pig’s glandular stomach. However, significant differences were observed compared to the rabbit abdomen’s sectional anatomy and CT findings. This study highlights the diagnostic value of MCT and MRI in SHs and provides a valuable reference for interpreting cross-sectional abdominal images in SHs. Full article

Background: In addition to behavioral and biochemical abnormalities, a parafunction associated with temporomandibular joint disorders (TMDs) resulted in stress-induced depression in rats. Exploring how chronic stress influences molar wear in rodents provides insights into the understanding of depression, TMD, and oral health. This study aimed to conduct a three-dimensional (3D) analysis of first molar wear in an animal model of depression by comparing molar attrition and cusp variation between stressed male rats and control groups. Methods: After obtaining a validated model of depression in male rats, we obtained 3D scans of lower molars to analyze wear patterns. The 3D analysis was applied to quantify cusps’ volume and the difference in first molar cusp morphological structure. The data were then compared to identify significant morphological differences between groups side by side. Results: The analysis revealed the reduction of cusps’ volume in the depression groups. Rats exposed to depression exhibited significantly greater occlusal table wear than their control counterparts (p < 0.05). Conclusions: As dentistry moves towards greater digital imaging, understanding the impact of psychological factors on TMD becomes increasingly necessary. This study shows that stress-induced depression in rats can result in significant tooth wear, as investigated using a 3D dental scanner. Full article

Early-onset heart failure is a major treat to healthy aging individuals with HIV-1 infection. Women with HIV-1 infection (WLWH) are especially vulnerable and develop heart failure with preserved ejection fraction (HFpEF), of which left ventricular diastolic dysfunction, vascular deficits, myocardial infarction, and fibrosis are major components. HIV-infected rodent models that exhibit these pathophysiological features remain under-reported, and this has left a void in our understanding of their molecular causes and therapeutic strategies to blunt its development. Here, we show that female NOD.Cg-Prkdc^scidIl2rgt^m1Wjl/SzJ humanized mice (Hu-mice) infected with HIV-1_ADA and treated for 13 weeks with dolutegravir (DTG)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) develop progressive diastolic dysfunction with preserved ejection fraction (E:A ratio, E:e′, IVRT, left atrial volume and global longitudinal strain increased by 32.1 ± 5.1%, 28.2 ± 5.6%, 100.2 ± 12.6%, 26.6 ± 4.2% and 32.5 ± 4.3%, respectively). In vivo photoacoustic imaging revealed a 30.4 ± 6.8% reduction in saturated oxygenated hemoglobin in the anterior wall of the heart. The ex vivo analysis of hearts showed a reduction in density of perfused microvessels/ischemia (30.6 ± 6.2%) with fibrosis (20.2 ± 1.2%). The HIF-1α level was increased 2.6 ± 0.5-fold, while inflammation-induced serum semicarbazide amine oxidase and glycolysis byproduct methylglyoxal increased 2-fold and 2.1-fold, respectively. Treating H9C2 cardiac myocytes with DTG, FTC and TDF dose-dependently increased expression of HIF-1α. These data show that HIV-infected Hu-mice treated with DTG/TDF/FTC for thirteen weeks develop cardiac diastolic dysfunction, with vascular deficits, ischemia, and fibrosis like those reported in women living with HIV-1 infection (WLWH). They also show that DTG, TDF, and FTC treatment can increase total HIF-1α in H9C2 cells. Full article

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, presenting a significant global healthcare challenge due to its rising incidence, association with increased morbidity and mortality, and economic burden. This arrhythmia is driven by a complex interplay of electrical, structural, and autonomic remodelling, compounded by genetic predisposition, systemic inflammation, and oxidative stress. Despite advances in understanding its pathophysiology, AF management remains suboptimal, with ongoing debates surrounding rhythm control, rate control, and anticoagulation strategies. Animal models have been instrumental in elucidating AF mechanisms, facilitating preclinical research, and advancing therapeutic development. This review critically evaluates the role of animal models in studying AF, emphasizing their utility in exploring electrical, structural, and autonomic remodelling. It highlights the strengths and limitations of various models, from rodents to large animals, in replicating human AF pathophysiology and advancing translational research. Emerging approaches, including optogenetics, advanced imaging, computational modelling, and tissue engineering, are reshaping AF research, bridging the gap between preclinical and clinical applications. We also briefly discuss ethical considerations, the translational challenges of animal studies and future directions, including integrative multi-species approaches, omics technologies and personalized computational models. By addressing these challenges and addressing emerging methodologies, this review underscores the importance of refining experimental models and integrating innovative technologies to improve AF management and outcomes. Full article

Background: Anesthesia can significantly impact positron emission tomography (PET) neuroimaging in preclinical studies. Therefore, understanding these effects is crucial for accurate interpretation of the results. In this experiment, we investigate the effect of [¹⁸F]-labeled glucose analog fluorodeoxyglucose ([¹⁸F]FDG) uptake in the brains of rats anesthetized with two commonly used anesthetics for rodents: isoflurane, an inhalation anesthetic, and Hypnorm–Dormicum, a combination injection anesthetic. Materials and Methods: Female adult Sprague Dawley rats were randomly assigned to one of two anesthesia groups: isoflurane or Hypnorm–Dormicum. The rats were submitted to dynamic [¹⁸F]FDG PET scan. The whole brain [¹⁸F]FDG standard uptake value (SUV) and the brain voxel-based analysis were performed. Results: The dynamic [¹⁸F]FDG data revealed that the brain SUV was 38% lower in the isoflurane group after 40 min of image (2.085 ± 0.3563 vs. 3.369 ± 0.5577, p = 0.0008). In voxel-based analysis between groups, the maps collaborate with SUV data, revealing a reduction in [¹⁸F]FDG uptake in the isoflurane group, primarily in the cortical regions, with additional small increases observed in the midbrain and cerebellum. Discussion and Conclusions: The observed differences in [¹⁸F]FDG uptake in the brain may be attributed to variations in metabolic activity. These results underscore the necessity for careful consideration of anesthetic choice and its impact on neuroimaging outcomes in future research. Full article

Background: Rodents severely damage the ecological environment of grasslands, and rodent mounds of different ages require distinct management strategies. Understanding the age of these mounds aids in formulating targeted restoration measures, which can enhance grassland productivity and biodiversity. Current surveys of rodent mounds rely on ground exposure and mound height to determine their age, which is time-consuming and labor-intensive. Remote sensing methods can quickly and easily identify the distribution of rodent mounds. Existing remote sensing images use ground exposure and mound height for identification but do not distinguish between mounds of different ages, such as one-year-old and two-year-old mounds. According to the existing literature, rodent mounds of different ages exhibit significant differences in vegetation structure, soil background, and plant diversity. Utilizing a combination of vegetation indices and hyperspectral data to determine the age of rodent mounds aims to provide a better method for extracting rodent hazard information. This experiment investigates and analyzes the age, distribution, and vegetation characteristics of rodent mounds, including total coverage, height, biomass, and diversity indices such as Patrick, Shannon–Wiener, and Pielou. Spectral data of rodent mounds of different ages were collected using an Analytical Spectral Devices field spectrometer. Correlation analysis was conducted between vegetation characteristics and spectral vegetation indices to select key indices, including NDVI₆₇₀, NDVI₇₀₅, EVI, TCARI, Ant, and SR. Multiple stepwise regression and Random Forest (RF) inversion models were established using vegetation indices, and the most suitable model was selected through comparison. Random Forest modeling was conducted to classify plateau zokor rat mounds of different ages, using both vegetation characteristic indicators and vegetation indices for comparison. The rodent mound classification models established using vegetation characteristic indicators and vegetation indices through Random Forest could distinguish rodent mounds of different ages, with out-of-bag error rates of 36.96% and 21.74%, respectively. The model using vegetation indices performed better. Conclusions: (1) Rodent mounds play a crucial ecological role in alpine meadow ecosystems by enhancing plant diversity, biomass, and the stability and vitality of the ecosystem. (2) The vegetation indices SR and TCARI are the most influential in classifying rodent mounds. (3) Incorporating vegetation indices into Random Forest modeling facilitates a precise and robust remote sensing interpretation of rodent mound ages, which is instrumental for devising targeted restoration strategies. Full article

Conventional strategies aimed at mitigating beam-hardening artifacts in computed tomography (CT) can be categorized into two main approaches: (1) postprocessing following conventional reconstruction and (2) iterative reconstruction incorporating a beam-hardening model. While the former fails in low-dose and/or limited-data cases, the latter substantially increases computational cost. Although deep learning-based methods have been proposed for several cases of limited-data CT, few works in the literature have dealt with beam-hardening artifacts, and none have addressed the problems caused by randomly selected projections and a highly limited span. We propose the deep learning-based prior image constrained (PICDL) framework, a hybrid method used to yield CT images free from beam-hardening artifacts in different limited-data scenarios based on the combination of a modified version of the Prior Image Constrained Compressed Sensing (PICCS) algorithm that incorporates the L2 norm (L2-PICCS) with a prior image generated from a preliminary FDK reconstruction with a deep learning (DL) algorithm. The model is based on a modification of the U-Net architecture, incorporating ResNet-34 as a replacement of the original encoder. Evaluation with rodent head studies in a small-animal CT scanner showed that the proposed method was able to correct beam-hardening artifacts, recover patient contours, and compensate streak and deformation artifacts in scenarios with a limited span and a limited number of projections randomly selected. Hallucinations present in the prior image caused by the deep learning model were eliminated, while the target information was effectively recovered by the L2-PICCS algorithm. Full article

The lanthanide series elements are transition metals used as critical components of electronics, as well as rechargeable batteries, fertilizers, antimicrobials, contrast agents for medical imaging, and diesel fuel additives. With the surge in their utilization, lanthanide metals are being found more in our environment. However, little is known about the health effects associated with lanthanide exposure. Epidemiological studies as well as studies performed in rodents exposed to lanthanum (La) suggest neurological damage, learning and memory impairment, and disruption of neurotransmitter signaling, particularly in serotonin and dopamine pathways. Unfortunately, little is known about the neurological effects of heavier lanthanides. As dysfunctions of serotonergic and dopaminergic signaling are implicated in multiple neurological conditions, including Parkinson’s disease, depression, generalized anxiety disorder, and post-traumatic stress disorder, it is of utmost importance to determine the effects of La and other lanthanides on these neurotransmitter systems. We therefore hypothesized that early-life exposure of light [La (III) or cerium (Ce (III))] or heavy [erbium (Er (III)) or ytterbium (Yb (III))] lanthanides in Caenorhabditis elegans could cause dysregulation of serotonergic and dopaminergic signaling upon adulthood. Serotonergic signaling was assessed by measuring pharyngeal pump rate, crawl-to-swim transition, as well as egg-laying behaviors. Dopaminergic signaling was assessed by measuring locomotor rate and egg-laying and swim-to-crawl transition behaviors. Treatment with La (III), Ce (III), Er (III), or Yb (III) caused deficits in serotonergic or dopaminergic signaling in all assays, suggesting both the heavy and light lanthanides disrupt these neurotransmitter systems. Concomitant with dysregulation of neurotransmission, all four lanthanides increased reactive oxygen species (ROS) generation and decreased glutathione and ATP levels. This suggests increased oxidative stress, which is a known modifier of neurotransmission. Altogether, our data suggest that both heavy and light lanthanide series elements disrupt serotonergic and dopaminergic signaling and may affect the development or pharmacological management of related neurological conditions. Full article

Background/Objectives: Small molecules that interfere with the interaction between acetylated protein tails and the tandem bromodomains of BET (bromodomain and extra-terminal) family proteins are pivotal in modulating immune/inflammatory and neoplastic diseases. This study aimed to develop a novel PET imaging tracer, [¹¹C]GSK023, that targets the N-terminal bromodomain (BD1) of BET family proteins with high selectivity and potency, thereby enriching the chemical probe toolbox for epigenetic imaging. Methods: [¹¹C]GSK023, a radio-chemical probe, was designed and synthesized to specifically target the BET BD1. In vivo PET imaging evaluations were conducted on rodents, focusing on the tracer’s distribution and binding specificity in various tissues. Blocking studies were performed to confirm the probe’s selectivity and specificity. Results: The evaluations revealed that [¹¹C]GSK023 demonstrated good uptake in peripheral organs with limited brain penetration. Further blocking studies confirmed the probe’s high binding specificity and selectivity for the BET BD1 protein, underscoring its potential utility in epigenetic imaging. Conclusions: The findings suggest that [¹¹C]GSK023 is a promising PET probe for imaging the BET BD1 protein, offering the potential to deepen our understanding of the roles of BET bro-modomains in disease and their application in clinical settings to monitor disease progression and therapeutic responses. Full article

Background/Objectives: The microphthalmia-associated transcription factor (Mitf) has been found to play an important role in eye development, structure, and function. The Mitf gene is responsible for controlling cellular processes in a range of cell types, contributing to multiple eye development processes. In this review, we survey what is now known about the impact of Mitf on eye structure and function in retinal disorders. Several mutations in the human and mouse Mitf gene are now known, and the effects of these on eye phenotype are addressed. We discuss the importance of Mitf in regulating ion transport across the retinal pigment epithelium (RPE) and the vasculature of the eye. Methods: The literature was searched using the PubMed, Scopus, and Google Scholar databases. Fundus and Optical Coherence Tomography (OCT) images from mice were obtained with a Micron IV rodent imaging system. Results: Defects in neural-crest-derived melanocytes resulting from any Mitf mutations lead to hypopigmentation in the eye, coat, and inner functioning of the animals. While many Mitf mutations target RPE cells in the eye, fewer impact osteoclasts at the same time. Some of the mutations in mice lead to microphthalmia, and ultimately vision loss, while other mice show a normal eye size; however, the latter, in some cases, show hypopigmentation in the fundus and the choroid is depigmented and thickened, and in rare cases Mitf mutations lead to progressive retinal degeneration. Conclusions: The Mitf gene has an impact on the structure and function of the retina and its vasculature, the RPE, and the choroid in the adult eye. Full article

Iron redistribution in the intestine after total body irradiation is an established phenomenon. However, in the literature, there are no reports about the use of X-ray fluorescence microscopy or equivalent techniques to generate semi-quantitative 2D maps of iron in sectioned intestine samples from irradiated mice. In this work, we used X-ray fluorescence microscopy (XFM) to map the elemental content of iron as well as phosphorus, sulfur, calcium, copper and zinc in tissue sections of the small intestine from eight-week-old BALB/c male mice that developed gastrointestinal acute radiation syndrome (GI-ARS) in response to exposure to 8 Gray of gamma rays. Seven days after irradiation, we found that the majority of the iron is localized as hot spots in the intercellular regions of the area surrounding crypts and stretching between the outer perimeter of the intestine and the surface cell layer of villi. In addition, this study represents our current efforts to develop elemental cell classifiers that could be used for the automated generation of regions of interest for analyses of X-ray fluorescence maps. Once developed, such a tool will be instrumental for studies of effects of radiation and other toxicants on the elemental content in cells and tissues. While XFM studies cannot be conducted on living organisms, it is possible to envision future scenarios where XFM imaging of single cells sloughed from the human (or rodent) intestine could be used to follow up on the progression of GI-ARS. Full article