Discovery medicine最新文献

Background: Epilepsy is a prevalent neurological disorder characterized by transient brain dysfunction due to abnormal neuronal discharges. Oxidative stress is strongly correlated with epilepsy onset and progression and is a critical factor in triggering seizures. Therefore, antioxidants may serve as effective anti-seizure treatments. Cerium oxide nanoparticles (CNP), which have antioxidant properties and function as nano-enzymes, may offer neuroprotective and therapeutic benefits for epilepsy. This study aims to investigate the effects of CNP on epilepsy.

Methods: We established a pilocarpine (PILO)-induced epilepsy rat model to assess the effects of pretreatment with different doses of CNP on epileptic behavioral changes, electroencephalographic activity, and nuclear factor erythroid 2-related factor 2 (NRF2) signaling in rats.

Results: In brief, a dose of 2.5 mg/kg CNP prolonged the latency of PILO-induced seizures in rats (p < 0.05), reduced the severity of seizures (p < 0.05), and decreased the 24-h mortality rate (p < 0.01). Additionally, CNP also extended the latency of epileptiform discharges (p < 0.01) and significantly decreased the average energy density of electroencephalographic activity (p < 0.0001). It inhibited seizure-induced lipid peroxidation (p < 0.001) and increased superoxide dismutase (p < 0.05) and catalase activities (p < 0.01). Furthermore, pretreatment with CNP elevated the expression of NRF2 and NADPH:quinone oxidoreductase 1 (NQO1) in antioxidative stress pathways (p < 0.05) and reduced neuronal necrosis and degeneration in CA1 and CA3 regions (p < 0.05).

Conclusions: CNP exhibits anti-epileptic and neuroprotective effects in PILO-induced epilepsy. This protective effect is likely due to the enhancement of the NRF2 signaling pathway, which regulates antioxidant enzymes, improves neuronal defense mechanisms against oxidative stress, and reduces seizure-induced neuronal damage.

Eyelid ptosis, characterized by the drooping of the upper eyelid, can significantly impair vision and aesthetics. Surgical repair is often necessary, and the choice between the anterior and posterior approaches is crucial for optimal outcomes. This review compares these two techniques based on efficacy, safety, and recovery. The anterior approach, typically involving an external incision along the eyelid crease, allows direct access to the levator muscle or aponeurosis for resection or advancement. This method is particularly advantageous in cases of aponeurotic ptosis where direct visualization is often necessary. Benefits include enhanced control over eyelid height and contour, with the potential for superior cosmetic outcomes due to hidden incisions. However, the anterior approach carries a higher risk of complications such as hematoma, infection, and scarring, necessitating careful patient selection and surgical expertise. Conversely, the posterior approach, involving an internal incision through the conjunctiva, is less invasive and avoids external scars. This technique is predominantly used for mild to moderate ptosis, especially in patients with preserved levator function. It targets Müller's muscle, which is less traumatic and associated with a shorter recovery time and lower complication rates. The posterior approach is favored for its simplicity and reduced risk profile, though it offers limited visualization and may not be suitable for all ptosis types. In conclusion, both the anterior and posterior approaches to eyelid ptosis repair have distinct advantages and limitations. The choice of technique should be individualized, considering factors such as the severity of ptosis, patient anatomy, desired outcomes, and potential risks. A thorough preoperative assessment and discussion of patient expectations are essential to achieving the best surgical results.

Bone is an important connective tissue involved in the movement and mechanical support of the body. Its homeostasis refers to the equilibrium between bone formation by osteoblasts and bone resorption by osteoclasts. Hematopoietic progenitor cells are shared by bone and immune cells, and the skeletal system is extensively innervated by an extensive nerve network. The immune, endocrine and nervous systems synthesize and secrete cytokines, hormones and neurotransmitters, respectively, which regulate physiological processes involved in bone homeostasis. Hormones such as gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, testosterone, insulin, thyroxine, parathyroid hormone (PTH), calcitonin, etc., regulate bone formation and resorption. Tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (interleukin (IL)-1,3,4,6,10,17,18,23,27) regulate the function of osteoblasts and osteoclasts as well as the bone microenvironment. The skeleton is innervated by sympathetic, parasympathetic and sensory nerve fibers that release neurotransmitters/factors such as serotonin, nerve growth factor, neuropeptide Y, substance P, norepinephrine and acetylcholine, which interact with various cells in the bone. Sclerostin, osteopontin, osteoprotegerin, osteocalcin, prostaglandin E2 and receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK) are some of the important proteins released by osteoblasts, osteocytes and osteoclasts that regulate osteoblastogenesis, osteoclastogenesis and angiogenesis and are also involved in pathological conditions. Further research is needed to establish links between the skeleton and other tissues and to gain additional insights into the etiology of degenerative diseases and the drug development process. The aim of this minireview is therefore to understand the composition of bone and the maintenance of bone homeostasis through three coordinates, namely the endocrine, nervous and immune systems.

Background: Osteoporosis is a common systemic metabolic disease, leading to increased bone fragility and risk of fractures. Research has shown that Adenosine triphosphate (ATP) synthase, H+transporting, mitochondrial F1 complex, alpha subunit 1 (ATP5A1), a crucial component in ATP production, is inhibited in dexamethasone (DEX)-induced osteoblasts. Therefore, this study aimed to investigate the molecular mechanism underlying the inhibitory impact of DEX on osteogenic differentiation in rat bone marrow mesenchymal stem cells (BMSCs).

Methods: Rat BMSCs were treated with varying concentrations of DEX for 14 days, followed by subsequent analyses. The expression levels of calpastatin (CAST), calpain 1 (CAPN1), and ATP5A1 were assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting analyses. Furthermore, osteogenic marker proteins and ATP activity were evaluated employing Western blotting analysis and enzyme-linked immunosorbent assay (ELISA). Moreover, to determine the regulatory role of DEX on the CAST-CAPN1 axis, overexpression plasmids for CAST (oe-CAST) and CAPN1 (oe-CAPN1) were constructed. Additionally, osteogenic differentiation and ATP activity in BMSCs were analyzed using qRT-PCR, Western blotting, Alizarin Red S staining, and ELISA.

Results: With increasing concentrations of DEX, the expression of the CAST-CAPN1-ATP5A1 axis in BMSCs was significantly altered (p < 0.05). DEX downregulated the levels of osteogenic markers, including Runt-Related Transcription Factor 2 (RUNX2), alkaline phosphatase (ALP), and osteopontin (OPN), while reducing ATP activity (p < 0.05). However, oe-CAST partially mitigated the inhibitory effects of DEX on osteogenic differentiation and ATP activity (p < 0.05). In contrast, oe-CAPN1 exacerbated the effects of DEX and reversed the regulatory impact of CAST (p < 0.05).

Conclusion: DEX inhibits osteogenic differentiation and reduces ATP activity in BMSCs by modulating the CAST-CAPN1 axis.

Aim: The NLR family pyrin domain containing 3-associated autoinflammatory disease (NLRP3-AID) is a rare and heterogeneous hereditary inflammatory disorder caused by variants in the NLRP3 gene on chromosome 1q44. This condition encompasses a broad spectrum of clinical phenotypes, including urticarial rash, fever, ocular disorders, hearing loss, and musculoskeletal and central nervous system (CNS) involvement. This study reports the clinical features and newly identified NLRP3 gene variants in two Chinese Han patients with NLRP3-AID presenting with leukoencephalopathy.

Case presentation: The study includes two adult male patients aged 25 and 24 years. Both patients experienced recurrent fevers with elevated C-reactive protein levels during febrile episodes, which normalized during asymptomatic intervals. Elevated cerebrospinal fluid protein levels and magnetic resonance imaging (MRI) findings of intracranial calcification and white matter damage were observed in both cases. Genetic testing revealed novel heterozygous NLRP3 variants: p.L798M in Patient 1 and p.K829T in Patient 2. Both patients received treatment with adalimumab and canakinumab, resulting in significant clinical improvement.

Results: The clinical and genetic features of two NLRP3-AID patients were characterized. Functional studies demonstrated overactivation of the NLRP3 inflammasome in these patients.

Conclusions: Neurological involvement in NLRP3-AID patients is variable. This study expands the clinical spectrum of CNS damage in NLRP3-AID to include intracranial calcification and leukoencephalopathy. Additionally, two novel NLRP3 variants, L798M and K829T, were identified and associated with the disease.

Background: Miltefosine, an alkylphosphocholine, affects lipid metabolism and cell signaling by interacting with cell membranes. In this study, we aim to demonstrate the effect of miltefosine (hexadecylphosphocholine (HePC)) on the alterations of the membrane lipid content of human lung adenocarcinoma (A549) cells and normal human umbilical vein endothelial cells (HUVECs) in respect to the reduction of their membrane fluidity and metastatic potential of the cancer cells.

Methods: To study lateral diffusion in cell membranes, we employed membrane labeling with fusogenic liposomes followed by fluorescence recovery after photobleaching (FRAP) analysis. Cell viability was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay; total cholesterol and sphingomyelin were measured using commercially available kits.

Results: Miltefosine inhibited cell growth and increased the total cholesterol in both cell lines (p < 0.05 for HUVEC and p < 0.01 for A549). Sphingomyelin levels were not significantly altered in A549 cells, but in HUVECs HePC caused a decrease in sphingomyelin (p < 0.05). Miltefosine treatment of A549 cells reduced the membrane diffusion coefficient (p < 0.001), which was associated with an increased half-time of fluorescent recovery (p < 0.05) measured by FRAP. These changes reflect a significant reduction in membrane fluidity in the cancer cells. In contrast, miltefosine induced a milder response in HUVECs, attenuating the diffusion coefficient (p < 0.05) but not affecting the half-time of fluorescent recovery. As a result, the reduction in membrane fluidity in HUVECs was less pronounced.

Conclusion: Miltefosine induces a decrease in membrane fluidity of cancer cells, and this effect was related to decreased cell viability and total cholesterol levels. Miltefosine may be an effective antitumor agent and has great potential as an adjuvant therapy in the future.

The integration of biological therapies, including biologics and biosimilars, into the medical practice has transformed the management of numerous chronic inflammatory, autoimmune, and oncological conditions. However, these treatments can pose challenges in oral and maxillofacial surgery due to their potential effects on wound healing, infection risk, and immune responses. This article reviews the most commonly used biological agents and provides safety recommendations for managing patients on biological therapies undergoing oral surgical procedures, such as tooth extractions (including multiple and surgical extractions), implant placement, periodontal and soft tissue surgeries, and the removal of non-cancerous or cancerous growths in the oral cavity. Key considerations include the oral complications associated with biologic treatments, preoperative risk assessment, perioperative timing of biologic administration, and postoperative monitoring to minimize complications. While several professional organizations have issued recommendations on the perioperative management of biological agents, there is currently no specific guidance tailored to dental or oral surgical procedures. This paper aims to explore the existing literature and recommendations regarding the use of biologics in the perioperative period.

This review aims to explore the current methods and advancements in nail permeation, with a focus on the potential of ultrashort pulse lasers to enhance drug delivery. The treatment of nail diseases, such as onychomycosis, is particularly challenging due to the dense structure of nails, which hinders drug permeation. We reviewed traditional methods that are used to enhance drug penetration; however, these methods are often limited by discomfort, infection risks, and inadequate drug permeability. Laser therapy offers a novel perspective in enhancing transungual drug delivery by creating channels on the nail surface without damaging the nail root or bed, thus improving drug absorption. However, common lasers (such as CO₂ lasers) may increase the target temperature beyond the thermal denaturation threshold, thus causing thermal damage to the nail bed and underlying tissues. This can also induce cracks and tissue debris, thus potentially spreading fungal pathogens in cases of onychomycosis. We specifically noted the potential of ultrashort pulsed lasers, which operate in the femtosecond range, to produce high peak power with minimal thermal damage to surrounding tissues. These lasers can create micropores on the nail plate via cold ablation, thus making them promising tools for improving the treatment of nail diseases. However, experimental data on this method are limited, and further studies, including histological research, are needed to validate its effectiveness in enhancing local drug permeability. This represents both a challenge and an opportunity for advancing nail disease treatments.

Background: MicroRNAs (miRNAs) are linked to asthma progression. In this study, we aimed to decipher the functional role of miR-140 and delineate its link to the mechanism behind the progression of asthma.

Methods: BALB/c mice were divided into four groups, designated as control, asthma, Agomir negative control (NC), and Agomir group. In vitro model of asthma using transforming growth factor-beta 1 (TGF-β1)-treated 16HBE cells, and cells transfected with glycogen synthase kinase 3β (GSK3β) overexpression plasmid or Agomir miR-140. Real-time quantitative polymerase chain reaction (RT-qPCR) was to test miR-140 abundance. Hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) of lung tissues for examining their histopathological changes. Enzyme-linked immunosorbent assay (ELISA) and in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were to test inflammatory factors levels and cell apoptosis, respectively. B-cell lymphoma 2 (Bcl-2), GSK3β, cleaved caspase-3 and Bcl-2 associated X protein (BAX) protein levels were evaluated using Western blotting. GSK3β expression was also detected using immunohistochemistry (IHC). RNA immunoprecipitation (RIP) and dual-luciferase reporter assay were to verify the correlation between GSK3β and miR-140.

Results: Both the asthma mice and TGF-β1-treated 16HBE cells exhibited decreased miR-140 level and increased protein expression of GSK3β (p < 0.001). Compared with the asthma mice, overexpression of miR-140 significantly relieved airway inflammation and reduced cell apoptosis (p < 0.001). Targeted relationship existed between GSK3β and miR-140, and the overexpression of miR-140 dramatically repressed the level of GSK3β in asthma group and TGF-β1-treated 16HBE cells (p < 0.001). Nevertheless, the suppressive impacts of miR-140 overexpression were hindered by GSK3β upregulation in TGF-β1-treated 16HBE cells (p < 0.01 or p < 0.001).

Conclusions: miR-140 mitigates airway inflammation and represses apoptosis in asthma by targeting and regulating GSK3β.

Background: Trophoblast cell surface antigen 2 (TROP2) is a promising target for various cancers, including breast cancer. The development of noninvasive techniques for assessing TROP2 expression in tumors holds considerable importance. This study aims to explore the efficacy of machine learning models based on multi-b-value diffusion-weighted imaging (DWI) using the stretched-exponential model (SEM) for predicting TROP2 expression in breast cancer in nude mouse models.

Materials and methods: Thirty-two nude mouse breast cancer models were subjected to 1.5T magnetic resonance imaging (MRI). Using the freely available software package FireVoxe, we extracted the distribution diffusion coefficient (DDC) and water molecule diffusion heterogeneity index (α) values from SEM, along with histogram parameters of DDC and α maps. TROP2 expression was identified by immunohistochemical staining, with integrated optical density (IOD) quantifying the expression levels. Mice were categorized into high and low TROP2 expression groups based on the median IOD. Key imaging parameters were selected to establish three machine learning models: extreme gradient boosting (XGBoost) classifier, logistic regression, and adaptive boosting (AdaBoost) classifier. We compared the models using the area under the curve (AUC) of the receiver operating characteristic (ROC) on a validation set to determine the superior model. The dataset was split into a training set (28 cases) and a test set (4 cases). The selected model was trained to optimize its performance. We evaluated the models' predictive accuracy in estimating TROP2 expression using AUC, calibration curve, and decision curve analysis (DCA).

Results: Thirty-eight imaging parameters, including DDC, α value, and 36 histogram parameters, were extracted per sample. Using these, we identified eight key imaging parameters for constructing the machine learning models. The validation set AUC values for the XGBoost, logistic regression, and AdaBoost models were 0.828, 0.639, and 0.728, respectively, with XGBoost demonstrating superior prediction performance. In the training set, XGBoost achieved an AUC of 1, sensitivity of 0.911, specificity of 1, and accuracy of 0.954; each of these values was 1 in the test set. Cross-validation yielded an AUC of 0.689, sensitivity of 0.567, specificity of 0.567, and accuracy of 0.580. The calibration curve's Brier score was 0.044, indicating proximity to the ideal curve. DCA indicated favorable net benefits within a risk threshold range of 20-90%.

Conclusions: Machine learning models based on SEM show promise for predicting TROP2 expression in breast cancer in nude mouse models. Among the models, XGBoost demonstrated outstanding performance, suggesting its potential for clinical applications.