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Malignant melanoma tends to aggressively metastasize, resulting in it being a potentially lethal form of skin cancer with high mortality rates. The advanced stages of melanoma have a very poor prognosis because of the high tendency for metastasis, and there is therefore, a strong desire to develop efficient technology for the early detection of melanoma. The benzamide structure, which contains aromatic ring and amine group, exhibits a high affinity for melanin, making it a promising agent for targeting melanoma in diagnostic and therapeutic applications. In this study, we synthesized a fluorinated benzamide derivative and chelated it with the radioisotope 68Ga to detect melanoma on positron emission tomography (PET) imaging, and then evaluated its biological properties. We synthesized the new probe 2,2',2,"2"'-(2-(4-(3-(2-((2-(5-fluoropicolinamido)ethyl)(methyl)amino)ethyl)thioureido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (MI-0202C1) for melanoma imaging from 5-fluoropyridine-2-carboxylic acid and conjugated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for chelation with 68Ga. The radiochemical yield and radiochemical purity of the 68Ga chelation complex were confirmed by radio-thin layer chromatography (radio TLC). In vitro cellular uptake of 68Ga-MI-0202C1 was verified in B16F10 cells (murine melanoma). In vivo distribution and small animal PET studies were conducted on mice bearing B16F10 xenografts. The MI-0202C1 was chelated with 68Ga at 90°C for 10 min at pH 5, resulting in a radiochemical yield and radiochemical purity of over 95%. The cellular uptake of 68Ga-MI-0202C1 over 60 min was higher in a group treated with L-tyrosine (2 mM) than in a non-treated group, indicating selective uptake of melanin. 68Ga-MI-0202C1 successfully visualized B16F10 xenografts in microPET imaging performed at 30 and 60 min after intravenous injection, suggesting that 68Ga-MI-0202C1 has considerable potential as a diagnostic probe for melanoma. [ABSTRACT FROM AUTHOR] more...

Brain ischemia, a condition in which the brain is deprived of blood flow, can lead to a stroke due to blocked or unstable blood vessels. Global cerebral ischemia (GCI), characterized by an interruption in blood flow, deprives the brain of oxygen and nutrients, producing reactive oxygen species (ROS) that trigger cell death, which kills nerve cells. Microplastics (MPs), tiny environmental pollutants, can enter the human body through contaminated food, water, disposable items, cosmetics, and more. Once in the brain, MPs can increase neuroinflammation by overstimulating inflammatory factors such as microglia. MPs can also damage neurons by scratching myelin and microtubules, slowing signal transduction, causing cognitive impairment, and leading to neuronal death. Furthermore, microtubule damage may result in the release of phosphorylated tau proteins, potentially linked to Alzheimer's disease. We hypothesized that MPs could exacerbate neuroinflammation and microtubule destruction after GCI, leading to increased neuronal death. To test this hypothesis, we administered MPs (0.5 µm) orally at a dose of 50 mg/kg before and after inducing GCI. Staining techniques such as Fluoro-Jade B (FJB), ionized calcium-binding adaptor molecule 1 (Iba-1), cluster of differentiation 68 (CD68), myelin basic protein (MBP), and microtubule-associated protein 2 (MAP2) were used, along with Western blot analysis for interleukin-6 (IL-6), TNF-α, tau-5, and phospho-tau (S396) to evaluate the effects of MPs on neuronal cell death, neuroinflammation, and microtubule destruction. The results showed that MP accumulation significantly increased neuroinflammation, microtubule disruption, and neuronal cell death in the GCI-MP group compared to the GCI-vehicle group. Therefore, this study suggests that MP accumulation in daily life may contribute to the exacerbation of the disease, potentially leading to severe neuronal cell death after GCI. [ABSTRACT FROM AUTHOR] more...

Epilepsy, a chronic neurological disorder, is triggered by various insults, including traumatic brain injury and stroke. Acid sphingomyelinase (ASMase), an enzyme that hydrolyzes sphingomyelin into ceramides, is implicated in oxidative stress, neuroinflammation, and neuronal apoptosis. Ceramides, which have pro-apoptotic properties, contribute to oxidative damage and lysosomal dysfunction, exacerbating neuronal injury. This study investigates the role of ASMase in epilepsy, hypothesizing that seizure activity upregulates ASMase, increasing ceramide levels, DNA damage, and neuronal apoptosis. We employed a pilocarpine-induced rat seizure model and examined the effects of imipramine, an ASMase inhibitor, administered intraperitoneally (10 mg/kg) for four weeks post-seizure induction. Histological and cognitive analyses showed that while imipramine did not prevent early neuronal death within the first week, it significantly reduced markers of neuronal apoptosis by four weeks. Imipramine also promoted hippocampal neurogenesis and preserved cognitive function, which is often impaired following seizures. These findings suggest that ASMase inhibition could mitigate neuronal apoptosis and improve cognitive recovery after seizures. Imipramine may serve as a promising therapeutic strategy for epilepsy-associated neuronal damage and cognitive deficits. Further studies should delineate the molecular mechanisms of ASMase inhibition and evaluate its long-term efficacy in addressing epilepsy-related neurodegeneration and functional impairments. [ABSTRACT FROM AUTHOR] more...

Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways crucial for brain development and the pathophysiology of neurological disorders. Among the 11 PDE subtypes, PDE4 and PDE5 are particularly significant due to their regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling, respectively, which are vital for learning, memory, and neuroprotection. This review synthesizes current evidence on the roles of PDE4 and PDE5 in neurological health and disease, focusing on their regulation of second messenger pathways and their implications for brain function. Elevated PDE4 activity impairs synaptic plasticity by reducing cAMP levels and protein kinase A (PKA) activity, contributing to cognitive decline, acute brain injuries, and neuropsychiatric conditions such as bipolar disorder and schizophrenia. Similarly, PDE5 dysregulation disrupts nitric oxide (NO) signaling and protein kinase G (PKG) pathways, which are involved in cerebrovascular homeostasis, recovery after ischemic events, and neurodegenerative processes in Alzheimer's, Parkinson's, and Huntington's diseases. PDE4 and PDE5 are promising therapeutic targets for neurological disorders. Pharmacological modulation of these enzymes offers potential to enhance cognitive function and mitigate pathological mechanisms underlying brain injuries, neurodegenerative diseases, and psychiatric disorders. Further research into the regulation of PDE4 and PDE5 will advance therapeutic strategies for these conditions. [ABSTRACT FROM AUTHOR] more...

Non-invasive imaging techniques employing biomarkers with high selectivity for inflammation are essential not only for the early diagnosis and prevention of chronic inflammatory diseases but also for guiding appropriate drug therapy and enabling real-time evaluation of anti-inflammatory drug efficacy. In this study, we conjugated radioactive zirconium to sorbitol, a compound that can selectively target inflammation, and evaluated its inflammation-specific uptake and potential for assessing anti-inflammatory treatment efficacy in a mouse inflammation model. Pharmacokinetic analysis demonstrated that radiolabeled sorbitol achieved maximal uptake in inflamed tissues within 1 h. Positron emission tomography imaging further confirmed its utility in monitoring therapeutic effects during anti-inflammatory drug treatment. Our findings suggest that [89Zr]DTPA-sorbitol is a promising radioprobe for targeting rapid systemic inflammation, particularly in tissues demonstrating minimal non-specific uptake, such as the brain, heart, and lung tissues. Additionally, it holds significant potential for the in vivo evaluation of anti-inflammatory drug efficacy. [ABSTRACT FROM AUTHOR] more...

Complex regional pain syndrome (CRPS) is a chronic pain syndrome characterized by intense hyperalgesia and allodynia, with an unclear etiology and limited definitive treatments. This case involves a 23-year-old female patient who developed CRPS following a simple hand laceration from wine glass shards. After initial primary closure, the patient developed scar contracture at the thumb metacarpophalangeal crease, accompanied by erythema, warmth, heaviness, and hypersensitivity throughout the hand, leading to a CRPS diagnosis. A multidisciplinary approach, including anesthesiology and rehabilitation, confirmed nerve adhesion from scar contracture. Surgical intervention successfully released the adhered scar tissue, fascia, and nerve, followed by rehabilitation therapy. The patient's functional recovery took nearly 6 months. This case highlights that CRPS can result from minor injuries due to scar-induced nerve entrapment and emphasizes the importance of early diagnosis and interdisciplinary treatment for gradual recovery. [ABSTRACT FROM AUTHOR] more...

A deployable reflector antenna (DR-A) is a structure that can be stored in a large-diameter Synthetic Aperture Radar (SAR) antenna and be mounted onto a launch vehicle. Considering the performance of the launch vehicle, it is necessary to develop a lightweight, high-performance antenna structure. The solid-type deployable reflector antenna is composed of a number of unit main reflectors. To reduce the weight of the antenna, a lightweight main reflector must be developed. In this paper, following "Development of Deployable Reflector Antenna for the SAR Satellite (Part 1)", the manufacturing and qualification of the main reflector using honeycomb sandwich composites are described. Four types of composite main reflectors were manufactured with variables in the manufacturing process. The manufacturing variables include the curing process of the structure, the application of an adhesive film between the sheet and the core, and the venting path inside of the sandwich core. After manufacturing the main reflector, we performed weight measurements, non-destructive testing (NDT), surface error measurement using a Coordinate Measurement Machine (CMM), and modal testing for each type of composite main reflector. Through the research and development process, we found that a perforated hole is necessary when excluding the adhesive film during bonding of an aramid core and a CFRP sheet, and a lightweight composite reflector could be developed through this process. We selected the main reflector with the best performance and developed a composite main reflector that can be applied to satellites. [ABSTRACT FROM AUTHOR] more...

The Y2O3-stabilized ZrO2 (YSZ)/ceria bi-layer electrolyte is a key component in recent solid oxide fuel cells and electrolyzers. An industrially viable route for its effective implementation involves reduced-temperature co-sintering; however, this is a multistep process, often requiring precise control due to the poor sinterability of conventional gadolinia-doped ceria (GDC). Here we demonstrate a bi-layer electrolyte in a single-step 1250 °C co-sintering with Sm0.2Ce0.8O2−δ (SDC) as a key solution, and verify the performance of the resultant bi-layer electrolyte in a Ni–YSZ fuel electrode supported cell. This approach, proven to be scalable, delivers a satisfactory cell performance, such as a fuel cell power density of ∼2.15 W cm−2 and a steam electrolysis current density of ∼2.95 A cm−2 at 800 °C. Even without adding the Fe2O3 aid to SDC, the YSZ/SDC electrolyte remains reasonably dense, free from resistive phases, and exhibits a higher interdiffusion conductivity than that of the benchmark YSZ/GDC. Furthermore, the strategic addition of Fe2O3 improves the shrinkage compatibility of YSZ and SDC, enhancing the integrity of the bi-layer structure. The optimal electrolytes show a remarkable stability across 300 h of typical fuel cell operation. These results suggest important strategic modifications in bi-layer electrolyte compositions and processing. [ABSTRACT FROM AUTHOR] more...

Loss of the inner blood–retinal barrier (BRB) integrity is a main feature of ocular diseases such as diabetic macular edema. However, there is a lack of clarity on how inner BRB function is modulated within the diabetic retina. The current study examined whether eucalyptol inhibited inner BRB destruction and aberrant retinal angiogenesis in 33 mM glucose-exposed human retinal microvascular endothelial (RVE) cells and db/db mice. This study further examined the molecular mechanisms underlying endothelial dysfunction including retinal endoplasmic reticulum (ER) stress and angiopoietin (Ang)/Tie axis in conjunction with vascular endothelial growth factor (VEGF). Eucalyptol is a naturally occurring monoterpenoid and an achiral aromatic component of many plants including eucalyptus leaves. Nontoxic eucalyptol reduced the production of amyloid-β (Aβ) protein in glucose-loaded RVE cells and in diabetic mice. This natural compound blocked apoptosis of Aβ-exposed RVE cells in diabetic mouse eyes by targeting ER stress via the inhibition of PERK-eIF2α-ATF4-CHOP signaling. Eucalyptol promoted activation of the Ang-1/Tie-2 pathway and dual inhibition of Ang-2/VEGF in Aβ-exposed RVE cells and in diabetic eyes. Supply of eucalyptol reversed the induction of junction proteins in glucose/Aβ-exposed RVE cells within the retina and reduced permeability. In addition, oral administration of eucalyptol reduced vascular leaks in diabetic retinal vessels. Taken together, these findings clearly show that eucalyptol inhibits glucose-induced Aβ-mediated ER stress and manipulates Ang signaling in diabetic retinal vessels, which ultimately blocks abnormal angiogenesis and loss of inner BRB integrity. Therefore, eucalyptol provides new treatment strategies for diabetes-associated RVE defects through modulating diverse therapeutic targets including ER stress, Ang-1/Tie-2 signaling, and Ang-2/VEGF. [ABSTRACT FROM AUTHOR] more...

Introduction Mitochondria generate ATP by oxidative phosphorylation. This involves a redox reaction whereby electrons are transferred by the electron transport chain (ETC). Electrons are donated by nicotinamide adenine dinucleotide (NADH) [...], Mitochondria affect cellular functions alone or in cooperation with other cellular organelles. Recent research has demonstrated the close relationship of mitochondria with the endoplasmic reticulum (ER), both at the physical and the functional level. In an effort to define the combined effect of mitochondrial dysfunction (MD) and ER stress in the proinflammatory activities of macrophages, the human macrophage-like monocytic leukemia cell line THP-1 was treated with mitochondrial electron transport chain (ETC) blockers, and changes in the cellular responses upon stimulation by interferon (IFN)-[gamma] were analyzed. Inducing mitochondrial dysfunction (MD) with ETC blockers resulted in suppression of IFN-induced activation of JAK1 and STAT1/3, as well as the expression of STAT1-regulated genes. In addition, experiments utilizing pharmacological modulators of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and liver kinase B1 (LKBl)-deficient HeLa cells demonstrated that these suppressive effects are mediated by the LKB1-AMPK pathway. Treatment with pharmacological inhibitors of ER stress sensors failed to affect these processes, thus indicating that involvement of ER stress is not required. These results indicate that MD, induced by blocking the ETC, affects IFN-induced activation of JAK-STAT and associated inflammatory changes in THP-1 cells through the LKB1-AMPK pathway independently of ER stress. Key words: macrophage, inflammation, mitochondrial dysfunction, ER stress, JAK-STAT, AMPK. Les mitochondries affectent les fonctions cellulaires, seules ou en coopération avec d'autres organites cellulaires. La recherche récente a démontré une étroite relation entre la mitochondrie et le réticulum endoplasmique (RE), tant sur le plan physique que fonctionnel. Dans le but de définir les effets combinés de la dysfonction mitochondriale (DM) et du stress du RE sur les activités proinflammatoires des macrophages, la lignée cellulaire monocytique humaine de type macrophage THP-1 a été traitée avec des bloqueurs de la chaîne de transport d'électrons (CTE), et les changements des réponses cellulaires en réponse à une stimulation par l'interféron (IFN)-_ ont été analysés. L'induction de la dysfonction mitochondriale par les bloqueurs de la CTE donnait lieu à la suppression de l'activation de JAK1 et de STAT1/3 induite par l'IFN, de même que de l'expression des gènes régulés par STAT1. De plus, des expériences réalisées avec des modulateurs pharmacologiques de la protéine kinase activée par l'adénosine 5=-monophosphate (AMP) (AMPK) et des cellules HeLa déficientes en kinase B1 du foie (LKB1) ont démontré que ces effets suppresseurs sont médiés par la voie LKB1-AMPK. Un traitement avec des inhibiteurs pharmacologiques de détecteurs du stress du RE n'affectait pas ces processus, indiquant alors que l'implication du stress du RE n'est pas requise. Ces résultats indiquent que la dysfonction mitochondriale induite par le blocage de la CTE affecte l'activation de JAK-STAT induite par l'IFN et les changements inflammatoires associés chez les cellules THP1 par l'intermédiaire de la voie LKB1-AMPK de manière indépendante du stress du RE. [Traduit par la Rédaction] Mots-clés : macrophage, inflammation, dysfonction mitochondriale, stress du RE, JAK-STAT, AMPK. more...