RESUMO
Alzheimer's disease (AD) is a progressively debilitating neurodegenerative condition primarily affecting the elderly. Emerging research suggests that microRNAs (miRNAs) play a role in the development of AD. This study investigates the impact of miR-107-5p on neurological damage, oxidative stress, and immune responses in AD. We utilized APP/PS1 mice as AD mouse models and C57BL/6 J mice as controls. AD mice received treatment with agomir miR-107-5p (to overexpress miR-107-5p) or BAY11-7082 (an NF-κB pathway inhibitor). We evaluated learning and memory abilities through the Morris water maze test. Histopathological changes, hippocampal neuron distribution, and apoptosis were assessed using hematoxylin-eosin, Nissl, and TUNEL staining. Reactive oxygen species (ROS) levels, amyloid-Aß (Aß1-40/42) contents, and inflammatory factors (TNF-α, IL-6, IL-1ß) in hippocampal tissues were measured using ROS kits and enzyme-linked immunosorbent assay (ELISA). Microglial activation in hippocampal tissues was observed under a fluorescence microscope. miR-107-5p's binding to TLR4 was predicted via the TargetScan database and confirmed through a dual-luciferase assay. miR-107-5p expression, along with TLR4, APOE, and TREM2 in hippocampal tissue homogenate, and NF-κB p65 protein expression in the nucleus and cytoplasm were assessed via RT-qPCR and Western blot. Overexpression of miR-107-5p ameliorated hippocampal neurological damage, oxidative stress, and immune responses. This was evidenced by improved enhanced learning/memory abilities, reduced Aß1-40 and Aß1-42 levels, diminished neuronal injuries, decreased ROS and TNF-α, IL-6, and IL-1ß levels, increased APOE and TREM2 levels, and suppressed microglial activation. miR-107-5p directly targeted and inhibited TLR4 expression, leading to reduced nuclear translocation of NF-κB p65 in the NF-κB pathway. Inhibition of the NF-κB pathway similarly improved neurological damage, oxidative stress, and immune response in AD mice. miR-107-5p exerts its beneficial effects by suppressing the TLR4/NF-κB pathway, ultimately ameliorating neurological damage, oxidative stress, and immune responses in AD mice.
Assuntos
Doença de Alzheimer , MicroRNAs , Animais , Humanos , Camundongos , Doença de Alzheimer/genética , Apolipoproteínas E/metabolismo , Imunidade , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio , Transdução de Sinais/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Melatonin, historically recognized for its primary role in regulating circadian rhythms, has expanded its influence particularly due to its wide range of biological activities. It has firmly established itself in cancer research. To highlight its versatility, we delved into how melatonin interacts with key signaling pathways, such as the Wnt/ß-Catenin, PI3K, and NF-κB pathways, which play foundational roles in tumor development and progression. Notably, melatonin can intricately modulate these pathways, potentially affecting various cellular functions such as apoptosis, metastasis, and immunity. Additionally, a comprehensive review of current clinical studies provides a dual perspective. These studies confirm melatonin's potential in cancer management but also underscore its inherent limitations, particularly its limited bioavailability, which often relegates it to a supplementary role in treatments. Despite this limitation, there is an ongoing quest for innovative solutions and current advancements include the development of melatonin derivatives and cutting-edge delivery systems. By synthesizing the past, present, and future, this review provides a detailed overview of melatonin's evolving role in oncology, positioning it as a potential cornerstone in future cancer therapeutics.
Assuntos
Melatonina , Neoplasias , Humanos , Melatonina/uso terapêutico , Melatonina/metabolismo , Transdução de Sinais , Biologia , Neoplasias/tratamento farmacológicoRESUMO
Background: Stereotactic radiosurgery (SRS) treatment planning requires accurate delineation of brain metastases, a task that can be tedious and time-consuming. Although studies have explored the use of convolutional neural networks (CNNs) in magnetic resonance imaging (MRI) for automatic brain metastases delineation, none of these studies have performed clinical evaluation, raising concerns about clinical applicability. This study aimed to develop an artificial intelligence (AI) tool for the automatic delineation of single brain metastasis that could be integrated into clinical practice. Methods: Data from 426 patients with postcontrast T1-weighted MRIs who underwent SRS between March 2007 and August 2019 were retrospectively collected and divided into training, validation, and testing cohorts of 299, 42, and 85 patients, respectively. Two Gamma Knife (GK) surgeons contoured the brain metastases as the ground truth. A novel 2.5D CNN network was developed for single brain metastasis delineation. The mean Dice similarity coefficient (DSC) and average surface distance (ASD) were used to assess the performance of this method. Results: The mean DSC and ASD values were 88.34%±5.00% and 0.35±0.21 mm, respectively, for the contours generated with the AI tool based on the testing set. The DSC measure of the AI tool's performance was dependent on metastatic shape, reinforcement shape, and the existence of peritumoral edema (all P values <0.05). The clinical experts' subjective assessments showed that 415 out of 572 slices (72.6%) in the testing cohort were acceptable for clinical usage without revision. The average time spent editing an AI-generated contour compared with time spent with manual contouring was 74 vs. 196 seconds, respectively (P<0.01). Conclusions: The contours delineated with the AI tool for single brain metastasis were in close agreement with the ground truth. The developed AI tool can effectively reduce contouring time and aid in GK treatment planning of single brain metastasis in clinical practice.
RESUMO
Two new monoterpenoid indole alkaloids, named taberibogines E and F (1 and 2), together with three known ones (3-5) were isolated from the stems of Tabernaemontana bovina Lour (Apocynaceae). Their structures including absolute configurations were elucidated from a combination of NMR and HRESIMS data and NMR calculations as well as DP4+ probability analyses. Compounds 1 and 2 exhibited inhibitory effects on LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages.
RESUMO
A novel monoterpenoid indole alkaloid, melognine (1) possessing an unprecedented skeleton with a 6/6/5/5/6/6 hexatomic rearranged ring system was isolated from the stems of Melodinus fusiformis. The structure with absolute configuration of 1 was established by extensive spectroscopic analyses and quantum ECD calculations. Melognine showed significant cytotoxicity on human breast cancer BT549 cells with an IC50 value of 1.49 µM by MTT assay. Further mechanism of action study indicated that melognine demonstrated the ability to induce apoptosis by activation of caspase-3 and p53, and downregulation of Bcl-2 in BT549 cells.
Assuntos
Apocynaceae , Apoptose/efeitos dos fármacos , Alcaloides de Triptamina e Secologanina , Apocynaceae/química , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Monoterpenos/isolamento & purificação , Monoterpenos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química , Alcaloides de Triptamina e Secologanina/isolamento & purificação , Alcaloides de Triptamina e Secologanina/farmacologiaRESUMO
Two new butenolides, balanolides A (1) and B (1), were isolated from the aerial parts of the parasitic plant Balanophora fungosa. Their structures were established by comprehensive spectroscopic analysis and quantum chemical ECD calculation. The new butenolides were evaluated for their inhibitory effects against nitric oxide (NO) production in LPS-induced RAW 264.7 macrophage cells. Compounds 1 and 2 displayed moderate anti-inflammatory activity with IC50values of 11.8 and 12.9 µM, respectively.
Assuntos
4-Butirolactona/análogos & derivados , Anti-Inflamatórios/farmacologia , Balanophoraceae/química , 4-Butirolactona/farmacologia , Animais , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Óxido Nítrico/biossíntese , Extratos Vegetais/química , Células RAW 264.7RESUMO
Four new aspidosperma-type alkaloids, melosuavines J-M (1-4) were isolated from the leaves of Melodinus suaveolens. Their structures with absolute configurations were elucidated by extensive HRESIMS and NMR spectroscopic analysis, as well as ECD calculations and Mosher's method. Their cytotoxic activities against four human cancer cell lines were also evaluated.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apocynaceae/química , Folhas de Planta/química , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , China , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologiaRESUMO
An effective method was developed for the preparative separation and purification of monoterpenoid indole alkaloid epimers from Ervatamia yunnanensis Tsiang using a combination of pH-zone-refining counter-current chromatography and preparative high-performance liquid chromatography. With this method, two pairs of MIA epimers including ervatamine (72 mg, 1), 20-epi-ervatamine (27 mg, 4), dregamine (95 mg, 2), tabernaemontanine (129 mg, 3), along with two MIAs, apparicine (112 mg, 5) and isovoacangine (15 mg, 6), were successfully purified from 2.1 g crude extract of E. yunnanensis, each with a purity of over 95% as determined by HPLC. The structures of the MIAs were identified by ESI-MS, 1D, and 2D NMR.
Assuntos
Ascomicetos/química , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular , SolventesRESUMO
A new bisindole alkaloid, melosuavine I (1) possessing an aspidosperma-aspidosperma dimeric skeleton, was isolated from the leaves of Melodinus suaveolens. The structure with absolute configuration of 1 was elucidated by a combination of MS, NMR and computational methods. MTT assays indicated that 1 exhibited significant cytotoxicity on human breast cancer BT549 cells with an IC50 value of 0.89⯵M. Further study showed that 1 inhibited BT549 cell proliferation by inducing apoptosis through activation of caspase 3 and p53, and down-regulation of Bcl-2.