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Liposomes have been extensively adopted in drug delivery systems with clinically approved formulations. However, hurdles remain in terms of loading multiple components and precisely controlling their release. Herein, we report a vesosomal carrier composed of liposomes encapsulated inside the core of another liposome for the controlled and sustained release of multiple contents. The inner liposomes are made of lipids with different compositions and are co-encapsulated with a photosensitizer. Upon induction of reactive oxygen species (ROS), the contents of the liposomes are released, with each type of liposome displaying distinct kinetics due to the variance in lipid peroxidation for differential structural deformation. In vitro experiments demonstrated immediate content release from ROS-vulnerable liposomes, followed by sustained release from ROS-nonvulnerable liposomes. Moreover, the release trigger was validated at the organismal level using Caenorhabditis elegans. This study demonstrates a promising platform for more precisely controlling the release of multiple components.
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Portadores de Fármacos , Lipossomos , Lipossomos/química , Preparações de Ação Retardada/farmacologia , Espécies Reativas de Oxigênio , Sistemas de Liberação de MedicamentosRESUMO
Cancer is a major global public health concern that affects both industrialized and developing nations. Current cancer chemotherapeutic options are limited by side effects, but plant-derived alternatives and their derivatives offer the possibilities of enhanced treatment response and reduced side effects. A plethora of recently published articles have focused on treatments based on cannabinoids and cannabinoid analogs and reported that they positively affect healthy cell growth and reverse cancer-related abnormalities by targeting aberrant tumor microenvironments (TMEs), lowering tumorigenesis, preventing metastasis, and/or boosting the effectiveness of chemotherapy and radiotherapy. Furthermore, TME modulating systems are receiving much interest in the cancer immunotherapy field because it has been shown that TMEs have significant impacts on tumor progression, angiogenesis, invasion, migration, epithelial to mesenchymal transition, metastasis and development of drug resistance. Here, we have reviewed the effective role of cannabinoids, their analogs and cannabinoid nano formulations on the cellular components of TME (endothelial cells, pericytes, fibroblast and immune cells) and how efficiently it retards the progression of carcinogenesis is discussed. The article summarizes the existing research on the molecular mechanisms of cannabinoids regulation of the TME and finally highlights the human studies on cannabinoids' active interventional clinical trials. The conclusion outlines the need for future research involving clinical trials of cannabinoids to demonstrate their efficacy and activity as a treatment/prevention for various types of human malignancies.
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Canabinoides , Neoplasias , Humanos , Canabinoides/farmacologia , Células Endoteliais , Transição Epitelial-Mesenquimal , Neoplasias/tratamento farmacológico , Microambiente Tumoral , Ensaios Clínicos como AssuntoRESUMO
Peroxisome proliferator-activated receptor (PPAR)-γ has been implicated as a key player in the regulation of adiponectin levels via both transcriptional and posttranscriptional mechanisms. Herein, we show that PPAR-γ interacts with human antigen R (HuR) and that the PPAR-γ-HuR complex dissociates following activation of PPAR-γ by rosiglitazone, a specific ligand of PPAR-γ. This rosiglitazone-dependent dissociation of HuR from PPAR-γ leads to nucleocytoplasmic shuttling of HuR and its binding to the 3'-UTR of adiponectin mRNA. PPAR-γ with H321A and H447A double mutation (PPAR-γH321/447A), a mutant lacking ligand-binding activity, impaired HuR dissociation from the PPAR-γ-HuR complex, resulting in reduced nucleocytoplasmic shuttling, even in the presence of rosiglitazone. Consequently, rosiglitazone up-regulated adiponectin levels by modulating the stability of adiponectin mRNA, whereas these effects were abolished by HuR ablation or blocked in cells expressing the PPAR-γH321/447A mutant, indicating that the interaction of PPAR-γ and HuR is a critical event during adiponectin expression. Taken together, the findings demonstrate a novel mechanism for regulating adiponectin expression at the posttranscriptional level and suggest that ligand-mediated activation of PPAR-γ to interfere with interaction of HuR could offer a therapeutic strategy for inflammation-associated diseases that involve decreased adiponectin mRNA stability.-Hwang, J. S., Lee, W. J., Hur, J., Lee, H. G., Kim, E., Lee, G. H., Choi, M.-J., Lim, D.-S., Paek, K. S., Seo, H. G. Rosiglitazone-dependent dissociation of HuR from PPAR-γ regulates adiponectin expression at the posttranscriptional level.
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Adiponectina/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , PPAR gama/metabolismo , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , Rosiglitazona/farmacologia , Adiponectina/genética , Animais , Linhagem Celular , Humanos , Ligantes , Ligação Proteica , Transcrição GênicaRESUMO
Dopamine plays a crucial role in controlling reproduction in eels, and its action is mediated through D2-type dopamine receptors. D2A and D2B receptors in the Japanese eel Anguilla japonica were cloned and characterized in the present study. Attention (daily expression patterns in the brain and endogenous regulation) was paid to D2B receptor because it is considered to play a crucial role in eel reproduction. The cDNAs of D2A and D2B receptors had open reading frames comprising 456 and 454 amino acid residues, respectively, which were phylogenetically clustered with those of other teleost species. Both receptors were highly expressed in the brain. D2B receptor transcript levels exhibited high day/low night variation in the midbrain and pituitary, suggesting that its transcription in these tissues is regulated in a daily manner, possibly under influence of melatonin. Intraperitoneal injection of dopamine downregulated D2B receptor transcription significantly in the midbrain and moderately in the pituitary within 1â¯h, but upregulated its transcription in the forebrain. Co-injection of dopamine with its antagonist (domperidone) reversed the effect of dopamine in the pituitary and forebrain, but not in the midbrain, suggesting that the effect of dopamine on D2B receptor transcription differs among brain regions. The same treatment with melatonin resulted in decreased D2B receptor transcription in the midbrain. These findings indicate that dopamine and melatonin have key roles in the daily variation in D2B receptor transcription in the brain of Japanese eel, and that they are related to a daily base secretion of hormones in the hypothalamic-pituitary-gonadal axis in this species.
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Anguilla/genética , Encéfalo/metabolismo , Relógios Circadianos , Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Melatonina/farmacologia , Receptores de Dopamina D2/genética , Anguilla/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Dopaminérgicos/farmacologia , Japão , Masculino , Filogenia , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Receptores de Dopamina D2/metabolismoRESUMO
Ginsenosides are active components found abundantly in ginseng which has been used as a medicinal herb to modify disease status for thousands of years. However, the pharmacological activity of ginsenoside Re in the neuronal system remains to be elucidated. Neuroprotective activity of ginsenoside Re was investigated in SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA) to induce cellular injury. Ginsenoside Re significantly inhibited 6-OHDA-triggered cellular damage as judged by analysis of tetrazolium dye reduction and lactose dehydrogenase release. In addition, ginsenoside Re induced the expression of the antioxidant protein glutathione peroxidase 4 (GPX4) but not catalase, glutathione peroxidase 1, glutathione reductase, or superoxide dismutase-1. Furthermore, upregulation of GPX4 by ginsenoside Re was mediated by phosphoinositide 3-kinase and extracellular signal-regulated kinase but not by p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. Ginsenoside Re also suppressed 6-OHDA-triggered cellular accumulation of reactive oxygen species and peroxidation of membrane lipids. The GPX4 inhibitor (1S,3R)-RSL3 reversed ginsenoside Re-mediated inhibition of cellular damage in SH-SY5Y cells exposed to 6-OHDA, indicating that the neuronal activity of ginsenoside Re is due to upregulation of GPX4. These findings suggest that ginsenoside Re-dependent upregulation of GPX4 reduces oxidative stress and thereby alleviates 6-OHDA-induced neuronal damage.
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Ginsenosídeos/farmacologia , Oxidopamina/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Catalase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1/metabolismo , Glutationa Peroxidase GPX1RESUMO
This study shows that taurine and ginsenoside Rf act synergistically to increase the expression of brain-derived neurotrophic factor (BDNF) in SH-SY5Y human neuroblastoma cells in a dose- and time-dependent manner. The increase of BDNF mRNA by taurine and ginsenoside Rf was markedly attenuated by inhibitors of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. In addition, taurine and ginsenoside Rf protected cells from corticosterone-induced BDNF suppression and reduced cell viability and lactate dehydrogenase release. The results from this study showed that combined treatment with both taurine and ginsenoside Rf enhanced BDNF expression and protected cells against corticosterone-induced damage.
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Fator Neurotrófico Derivado do Encéfalo/biossíntese , Corticosterona/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/farmacologia , Proteínas de Neoplasias/biossíntese , Neuroblastoma/metabolismo , Taurina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologiaRESUMO
Peroxisome proliferator-activated receptor (PPAR) δ is a promising therapeutic target in metabolic and inflammatory disorders. However, its role in oncogenesis is controversial, and its therapeutic potential remains to be determined. In our study, we show that ligand-activated PPARδ forms a complex with the proto-oncogene product c-Myc. The interaction of PPARδ with c-Myc affected the transcriptional activity of c-Myc and the expression of its target genes. The PPARδ-dependent regulation of c-Myc activity was associated with decreased tumorigenicity in breast cancer cells. Administration of the PPARδ ligand GW501516 inhibited tumor growth in xenograft model mice bearing MDA-MB-231 cells stably expressing wild-type PPARδ, but not those expressing dominant-negative PPARδ, by interfering with c-Myc function through protein-protein interaction. Our results indicating that PPARδ forms an antitumorigenic complex with c-Myc in the presence of ligand suggest a potential role of PPARδ in breast cancer development.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , PPAR delta/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tiazóis/farmacologia , Células A549 , Animais , Linhagem Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Ligantes , Células MCF-7 , Células PC12 , Proto-Oncogene Mas , RNA Interferente Pequeno/metabolismo , RatosRESUMO
The cancer stem cell (CSC) hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs) have been used as antimicrobial, disinfectant, and antitumor agents. However, there is no study reporting the effects of AgNPs on ovarian cancer stem cells (OvCSCs). In this study, we investigated the cytotoxic effects of AgNPs and their mechanism of causing cell death in A2780 (human ovarian cancer cells) and OvCSCs derived from A2780. In order to examine these effects, OvCSCs were isolated and characterized using positive CSC markers including aldehyde dehydrogenase (ALDH) and CD133 by fluorescence-activated cell sorting (FACS). The anticancer properties of the AgNPs were evaluated by assessing cell viability, leakage of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and mitochondrial membrane potential (mt-MP). The inhibitory effect of AgNPs on the growth of ovarian cancer cells and OvCSCs was evaluated using a clonogenic assay. Following 1-2 weeks of incubation with the AgNPs, the numbers of A2780 (bulk cells) and ALDHâº/CD133⺠colonies were significantly reduced. The expression of apoptotic and anti-apoptotic genes was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Our observations showed that treatment with AgNPs resulted in severe cytotoxicity in both ovarian cancer cells and OvCSCs. In particular, AgNPs showed significant cytotoxic potential in ALDHâº/CD133⺠subpopulations of cells compared with other subpopulation of cells and also human ovarian cancer cells (bulk cells). These findings suggest that AgNPs can be utilized in the development of novel nanotherapeutic molecules for the treatment of ovarian cancers by specific targeting of the ALDHâº/CD133⺠subpopulation of cells.
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Nanopartículas Metálicas/química , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/patologia , Prata/farmacologia , Antígeno AC133/metabolismo , Aldeído Desidrogenase/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Fatores de Tempo , Ensaio Tumoral de Célula-TroncoRESUMO
Graphene oxide (GO) is a monolayer of carbon atoms that form a dense honeycomb structure, consisting of hydroxyl and epoxide functional groups on the two accessible sides and carboxylic groups at the edges. In contrast, graphene is a two-dimensional sheet of sp2-hybridized carbon atoms packed into a honeycomb lattice. Graphene has great potential for use in biomedical applications due to its excellent physical and chemical properties. In this study, we report a facile and environmentally friendly approach for the synthesis of reduced graphene oxide (rGO) using uric acid (UA). The synthesized uric acid-reduced graphene oxide (UA-rGO) was fully characterized by ultraviolet-visible (UV-Vis) absorption spectra, X-ray diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared (FTIR), scanning electron microscopy (SEM), and Raman spectroscopy. GO and UA-rGO induced a dose-dependent decrease in cell viability and induced cytotoxicity in human ovarian cancer cells. The results from this study suggest that UA-rGO could cause apoptosis in mammalian cells. The toxicity of UA-rGO is significantly higher than GO. Based on our findings, UA-rGO shows cytotoxic effects against human ovarian cancer cells, and its synthesis is environmentally friendly. UA-rGO significantly inhibits cell viability by increasing lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, activation of caspase-3, and DNA fragmentation. This is the first report to describe the comprehensive effects of UA-rGO in ovarian cancer cells. We believe that the functional aspects of newly synthesized UA-rGO will provide advances towards various biomedical applications in the near future.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Grafite/química , Grafite/farmacologia , Óxidos/química , Animais , Caspase 3/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Grafite/síntese química , Humanos , Espécies Reativas de Oxigênio , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Propriedades de Superfície , Difração de Raios XRESUMO
The purpose of this study was to design and synthesize Palladium nanoparticles (PdNPs) using an environmentally friendly approach and evaluate the in vitro efficacy of PdNPs in human ovarian cancer A2780 cells. Ultraviolet-Visible (UV-Vis) spectroscopy was used to monitor the conversion of Pd(II) ions to Pd(0)NPs. X-ray diffraction (XRD) revealed the crystallinity of the as-synthesized PdNPs and Fourier transform infrared spectroscopy (FTIR) further confirmed the role of the leaf extract of Evolvulus alsinoides as a reducing and stabilizing agent for the synthesis of PdNPs. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) showed that the average size of the NPs was 5 nm. After a 24-h exposure to PdNPs, cell viability and light microscopy assays revealed the dose-dependent toxicity of the PdNPs. Furthermore, the dose-dependent cytotoxicity of the PdNPs was confirmed by lactate dehydrogenase (LDH), increased reactive oxygen species (ROS) generation, activation of PdNPs-induced autophagy, impairment of mitochondrial membrane potential (MMP), enhanced caspase-3 activity, and detection of TUNEL-positive cells. Our study demonstrates a single, simple, dependable and green approach for the synthesis of PdNPs using leaf extracts of Evolvulus alsinoides. Furthermore, the in vitro efficacy of PdNPs in human ovarian cancer cells suggests that it could be an effective therapeutic agent for cancer therapy.
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Antineoplásicos/síntese química , Nanopartículas/química , Paládio/química , Antineoplásicos/farmacologia , Autofagia , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Convolvulaceae/química , Ensaios de Seleção de Medicamentos Antitumorais , Química Verde , Humanos , L-Lactato Desidrogenase/metabolismo , Paládio/farmacologia , Tamanho da Partícula , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo , Substâncias Redutoras/químicaRESUMO
BACKGROUND: Graphene is the 2D form of carbon that exists as a single layer of atoms arranged in a honeycomb lattice and has attracted great interest in the last decade in view of its physical, chemical, electrical, elastic, thermal, and biocompatible properties. The objective of this study was to synthesize an environmentally friendly and simple methodology for the preparation of graphene using a recombinant enhanced green fluorescent protein (EGFP). RESULTS: The successful reduction of GO to graphene was confirmed using UV-vis spectroscopy, and FT-IR. DLS and SEM were employed to demonstrate the particle size and surface morphology of GO and EGFP-rGO. The results from Raman spectroscopy suggest the removal of oxygen-containing functional groups from the surface of GO and formation of graphene with defects. The biocompatibility analysis of GO and EGFP-rGO in human embryonic kidney (HEK) 293 cells suggests that GO induces significant concentration-dependent cell toxicity in HEK cells, whereas graphene exerts no adverse effects on HEK cells even at a higher concentration (100 µg/mL). CONCLUSIONS: Altogether, our findings suggest that recombinant EGFP can be used as a reducing and stabilizing agent for the preparation of biocompatible graphene. The novelty and originality of this work is that it describes a safe, simple, and environmentally friendly method for the production of graphene using recombinant enhanced green fluorescent protein. Furthermore, the synthesized graphene shows excellent biocompatibility with HEK cells; therefore, biologically synthesized graphene can be used for biomedical applications. To the best of our knowledge, this is the first and novel report describing the synthesis of graphene using recombinant EGFP.
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Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Grafite/química , Grafite/toxicidade , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/toxicidade , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
In this paper, a comprehensive exploration is undertaken to elucidate the utilization of Spiking Neural Networks (SNNs) within the biomedical domain. The investigation delves into the experimentally validated advantages of SNNs in comparison to alternative models like LSTM, while also critically examining the inherent limitations of SNN classifiers or algorithms. SNNs exhibit distinctive advantages that render them particularly apt for targeted applications within the biomedical field. Over time, SNNs have undergone extensive scrutiny in realms such as neuromorphic processing, Brain-Computer Interfaces (BCIs), and Disease Diagnosis. Notably, SNNs demonstrate a remarkable affinity for the processing and analysis of biomedical signals, including but not limited to electroencephalogram (EEG), electromyography (EMG), and electrocardiogram (ECG) data. This paper initiates its exploration by introducing some of the biomedical applications of EMG, such as the classification of hand gestures and motion decoding. Subsequently, the focus extends to the applications of SNNs in the analysis of EEG and ECG signals. Moreover, the paper delves into the diverse applications of SNNs in specific anatomical regions, such as the eyes and noses. In the final sections, the paper culminates with a comprehensive analysis of the field, offering insights into the advantages, disadvantages, challenges, and opportunities introduced by various SNN models in the realm of healthcare and biomedical domains. This holistic examination provides a nuanced perspective on the potential transformative impact of SNN across a spectrum of applications within the biomedical landscape.
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In early gastric cancer (EGC), the presence of lymph node metastasis (LNM) is a crucial factor for determining the treatment options. Endoscopic resection is used for treatment of EGC with minimal risk of LNM. However, owing to the lack of definitive criteria for identifying patients who require additional surgery, some patients undergo unnecessary additional surgery. Considering that histopathologic patterns are significant factor for predicting lymph node metastasis in gastric cancer, we aimed to develop a machine learning algorithm which can predict LNM status using hematoxylin and eosin (H&E)-stained images. The images were obtained from several institutions. Our pipeline comprised two sequential approaches including a feature extractor and a risk classifier. For the feature extractor, a segmentation network (DeepLabV3+) was trained on 243 WSIs across three datasets to differentiate each histological subtype. The risk classifier was trained with XGBoost using 70 morphological features inferred from the trained feature extractor. The trained segmentation network, the feature extractor, achieved high performance, with pixel accuracies of 0.9348 and 0.8939 for the internal and external datasets in patch level, respectively. The risk classifier achieved an overall AUC of 0.75 in predicting LNM status. Remarkably, one of the datasets also showed a promising result with an AUC of 0.92. This is the first multi-institution study to develop machine learning algorithm for predicting LNM status in patients with EGC using H&E-stained histopathology images. Our findings have the potential to improve the selection of patients who require surgery among those with EGC showing high-risk histological features.
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Basella alba, a green leafy vegetable with remarkable nutraceutical potential is widely used since ancient times to maintain a healthy colon. This plant has been investigated for its medicinal potential due to the increase in young adult cases of colorectal cancer each year. This study was accomplished to investigate Basella alba methanolic extract (BaME) antioxidant and anticancer properties. BaME consisted of a substantial amount of both phenolic and flavonoid compounds which exhibited significant antioxidant reactivity. Both colon cancer cell lines experienced a cell cycle arrest at the G0/G1 phase after receiving treatment with BaME, which inhibited pRb and cyclin D1 and raised p21 expression levels. This was associated with the survival pathway molecule inhibition and downregulation of E2F-1. The results of the current investigation confirm that BaME inhibits CRC cell survival and expansion. To conclude, the bioactive principles in the extract act as potential antioxidants and antiproliferative agents against colorectal cancer.
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ETHNOPHARMACOLOGICAL RELEVANCE: Red clover (Trifolium pratense L.) is a traditional Chinese medicine and use as herbal medicine which has the effects of regulating menopausal symptoms, heart problem, inflammatory disease, psoriasis and cognitive deficits. In previous reported, the studies of red clover were mainly focused on clinical practice. the pharmacological functions of red clover not fully elucidated. AIM OF THE STUDY: To identify the molecules that regulate ferroptosis, we examined whether red clover (Trifolium pratense L.) extracts (RCE) affected ferroptosis induced by chemical treatment or cystine/glutamate antiporter (xCT) deficiency. MATERIALS AND METHODS: Cellular models for ferroptosis were induced by erastin/Ras-selectiv lethal 3 (RSL3) treatment or xCT deficiency in mouse embryonic fibroblasts (MEFs). Intracellular iron and peroxidized lipid levels were determined using Calcein-AM and BODIPY-C11 fluorescence dyes, respectively. Protein and mRNA were quantified by Western blot and real-time polymerase chain reaction, respectively. RNA sequencing analysis was performed on xCT-/- MEFs. RESULTS: RCE significantly suppressed ferroptosis induced by both erastin/RSL3 treatment and xCT deficiency. The anti-ferroptotic effects of RCE correlated to ferroptotic phenotypic changes such as cellular iron accumulation and lipid peroxidation in cellular ferroptosis models. Importantly, RCE affected levels of iron metabolism-related proteins including iron regulatory protein 1, ferroportin 1 (FPN1), divalent metal transporter 1, and transferrin receptor. RNA sequencing analysis of xCT-/- MEFs identified that expression of cellular defense genes was upregulated, while expression of cell death-related genes was downregulated, by RCE. CONCLUSION: RCE potently suppressed ferroptosis triggered both by erastin/RSL3 treatment and xCT deficiency by modulating cellular iron homeostasis. This is the first report that RCE has therapeutic potential in diseases associated with ferroptotic cell death, particularly ferroptosis induced by dysregulation of cellular iron metabolism.
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Trifolium , Animais , Camundongos , Trifolium/metabolismo , Linhagem Celular Tumoral , Fibroblastos/metabolismo , Morte Celular , Ferro/metabolismo , HomeostaseRESUMO
Zinc finger protein (ZFP) 251 is a member of the C2H2 ZFP family containing a Krüppel-associated box domain that might mainly act as a transcriptional repressor. However, its cellular function remains largely unknown. Here, we discovered that ZFP251 deficiency caused glucose intolerance in mice. This phenotype was associated with impaired insulin signaling due to hypertrophic changes in white adipose tissue (WAT). Gene ontology analysis revealed that ZFP251 deficiency affected the expression of genes associated with adipocyte differentiation and lipid and fatty acid metabolism. Consistent with in vivo results, hypertrophic changes were observed in Zfp251 knockdown (KD) 3T3-L1 adipocytes. In addition, Zfp251 KD 3T3-L1 preadipocytes exhibited cell cycle arrest in G0/G1 phase, leading to impaired differentiation into mature adipocytes, upon which abnormal mitotic clonal expansion and reduced expression of adipogenic markers were exhibited. These results suggest that ZFP251 deficiency causes impaired adipogenesis and adipocyte hypertrophy, leading to dysfunction of WAT.
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Adipócitos , Adipogenia , Animais , Camundongos , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/genética , Diferenciação Celular/genética , Glucose/metabolismo , Hipertrofia/metabolismo , Dedos de ZincoRESUMO
T cells expressing chimeric antigen receptors (CAR-T cells) have shown unprecedented clinical responses against hematological malignancies. However, some patients relapse after CAR-T cell therapy due to antigen-negative escape variants. Additionally, CAR-T cell therapies showed limited clinical efficacy in solid tumors with high antigen heterogeneity. To overcome this, we metabolically labeled the glycans on cancer cells to redirect CAR-T cell cytotoxicity regardless of the endogenous antigen expression status of the cancer cells. We found that modifying cancer cells with N-azidoacetylmannosamine and bicyclo[6.1.0]non-4-yne-fluorescein isothiocyanate can elicit selective and durable cytotoxicity of anti-FITC CAR-T cells. Furthermore, we demonstrated that dinitrophenyl-conjugated sialic acid (Sia-DNP) generated DNP-modified glycans on cancer cells in situ that could be effectively targeted by anti-DNP CAR-T cells to eradicate established tumors in xenograft models. Our study illustrates that metabolic glycan labeling using unnatural sugars can be combined with CAR-T cell therapy to provide novel cancer immunotherapy for solid tumors that lack viable target antigens.
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Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/metabolismo , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/metabolismo , Linfócitos T/metabolismo , Imunoterapia Adotiva/efeitos adversos , Imunoterapia , Ensaios Antitumorais Modelo de Xenoenxerto , Receptores de Antígenos de Linfócitos TRESUMO
Prostate cancer (PC) is one of the most common cancers in males and the fifth leading reason of death. Age, ethnicity, family history, and genetic defects are major factors that determine the aggressiveness and lethality of PC. The African population is at the highest risk of developing high-grade PC. It can be challenging to distinguish between low-risk and high-risk patients due to the slow progression of PC. Prostate-specific antigen (PSA) is a revolutionary discovery for the identification of PC. However, it has led to an increase in over diagnosis and over treatment of PC in the past few decades. Even if modifications are made to the standard PSA testing, the specificity has not been found to be significant. Our understanding of PC genetics and proteomics has improved due to advances in different fields. New serum, urine, and tissue biomarkers, such as PC antigen 3 (PCA3), have led to various new diagnostic tests, such as the prostate health index, 4K score, and PCA3. These tests significantly reduce the number of unnecessary and repeat biopsies performed. Chemotherapy, radiotherapy, and prostatectomy are standard treatment options. However, newer novel hormone therapy drugs with a better response have been identified. Androgen deprivation and hormonal therapy are evolving as new and better options for managing hormone-sensitive and castration-resistant PC. This review aimed to highlight and discuss epidemiology, various risk factors, and developments in PC diagnosis and treatment regimens.
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Emerging evidence shows that peroxisome proliferator-activated receptor delta (PPARδ) plays a pivotal role in cellular aging. However, its function in retinal disease processes such as hyperglycemia-associated diabetic retinopathy is unclear. Here, we demonstrate that PPARδ inhibits premature senescence of retinal pigment epithelial (RPE) cells induced by high glucose (HG) through SIRT1 upregulation. A specific ligand GW501516-activation of PPARδ suppressed premature senescence and production of reactive oxygen species induced by HG in ARPE-19 cells, a spontaneously arising human RPE cell line. These effects were accompanied by the regulation of the premature senescence-associated genes p53, p21, and SMP-30. Furthermore, GW501516-activated PPARδ almost completely abolished the effects of HG treatment on the formation of phosphorylated H2A histone family member X (γ-H2A.X) foci, a molecular marker of aging. These inhibitory effects of GW501516 were significantly reversed in ARPE-19 cells stably expressing small hairpin RNA targeting PPARδ. Notably, GW501516 significantly increased the mRNA and protein levels of SIRT1, indicating that GW501516-activated PPARδ exerted its beneficial effects through SIRT1. In addition, GW501516 restored HG-suppressed SIRT1 expression, corroborating the role of SIRT1 in the anti-senescence function of PPARδ. The effects of PPARδ on HG-induced premature senescence and the expression of the senescence-associated genes p53, p21, and SMP-30 were mimicked by the SIRT1 activator resveratrol, but blocked by the SIRT1 inhibitor sirtinol. Collectively, these results indicate that GW501516-activated PPARδ inhibits HG-triggered premature senescence of RPE cells by modulating SIRT1 signaling.
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Intracellular iron accumulation in dopaminergic neurons contributes to neuronal cell death in progressive neurodegenerative disorders such as Parkinson's disease. However, the mechanisms of iron homeostasis in this context remain incompletely understood. In the present study, we assessed the role of the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) in cellular iron homeostasis. We identified that PPARδ inhibited 6-hydroxydopamine (6-OHDA)-triggered neurotoxicity in SH-SY5Y neuroblastoma cells. PPARδ activation with GW501516, a specific PPARδ agonist, mitigated 6-OHDA-induced neuronal damage. Further, PPARδ activation also suppressed iron accumulation, which contributes to 6-OHDA-induced neuronal damage. PPARδ activation attenuated 6-OHDA-induced neuronal damage in a similar manner to that of the iron chelator deferoxamine. We further elucidated that PPARδ modulated cellular iron homeostasis by regulating expression of divalent metal transporter 1, ferroportin 1, and ferritin, but not transferrin receptor 1, through iron regulatory protein 1 in 6-OHDA-treated cells. Interestingly, PPARδ activation suppressed 6-OHDA-triggered generation of reactive oxygen species and lipid peroxides. The effects of GW501516 were abrogated by shRNA knockdown of PPARδ, indicating that the effects of GW501516 were PPARδ-dependent. Taken together, these findings suggest that PPARδ attenuates 6-OHDA-induced neurotoxicity by preventing intracellular iron accumulation, thereby suppressing iron overload-associated generation of reactive oxygen species and lipid peroxides, key mediators of ferroptotic cell death.