Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 135
Filtrar
1.
Cell Metab ; 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38569557

RESUMO

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.

2.
Commun Chem ; 7(1): 68, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38555377

RESUMO

Bulk cobalt does not react with water at room temperature, but cobalt nanometals could yield corrosion at ambient conditions. Insights into the cobalt cluster reactions with water and oxygen enable us to better understand the interface reactivity of such nanometals. Here we report a comprehensive study on the gas-phase reactions of Con±/0 clusters with water and oxygen. All these Con±/0 clusters were found to react with oxygen, but only anionic cobalt clusters give rise to water dissociation whereas the cationic and neutral ones are limited to water adsorption. We elucidate the influences of charge states, bonding modes and dehydrogenation mechanism of water on typical cobalt clusters. It is unveiled that the additional electron of anionic Con- clusters is not beneficial to H2O adsorption, but allows for thermodynamics- and kinetics-favourable H atom transfer and dehydrogenation reactions. Apart from the charge effect, size effect and spin effect play a subtle role in the reaction process. The synergy of multiple metal sites in Con- clusters reduces the energy barrier of the rate-limiting step enabling hydrogen release. This finding of water dissociation on cobalt clusters put forward new connotations on the activity series of metals, providing new insights into the corrosion mechanism of cobalt nanometals.

3.
Cancer Sci ; 115(4): 1129-1140, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38351514

RESUMO

Oncolytic viruses (OVs) possess the unique ability to selectively replicate within tumor cells, leading to their destruction, while also reversing the immunosuppression within the tumor microenvironment and triggering an antitumor immune response. As a result, OVs have emerged as one of the most promising approaches in cancer therapy. However, the effective delivery of intravenously administered OVs faces significant challenges imposed by various immune cells within the peripheral blood, hindering their access to tumor sites. Notably, neutrophils, the predominant white blood cell population comprising approximately 50%-70% of circulating white cells in humans, show phagocytic properties. Our investigation revealed that the majority of oncolytic vaccinia viruses (VV) are engulfed and degraded by neutrophils in the bloodstream. The depletion of neutrophils using the anti-LY6G Ab (1-A8) resulted in an increased accumulation of circulating oncolytic VV in the peripheral blood and enhanced deposition at the tumor site, consequently amplifying the antitumor effect. Neutrophils heavily rely on PI3K signaling to sustain their phagocytic process. Additionally, our study determined that the inhibition of the PI3Kinase delta isoform by idelalisib (CAL-101) suppressed the uptake of oncolytic VV by neutrophils. This inhibition led to a greater presence of oncolytic VV in both the peripheral blood and at the tumor site, resulting in improved efficacy against the tumor. In conclusion, our study showed that inhibiting neutrophil functions can significantly enhance the antitumor efficacy of intravenous oncolytic VV.

4.
Anim Nutr ; 16: 251-266, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38362519

RESUMO

T-2 toxin is one of the most widespread and toxic fungal toxins in food and feed. It can cause gastrointestinal toxicity, hepatotoxicity, immunotoxicity, reproductive toxicity, neurotoxicity, and nephrotoxicity in humans and animals. T-2 toxin is physicochemically stable and does not readily degrade during food and feed processing. Therefore, suppressing T-2 toxin-induced organ toxicity through antidotes is an urgent issue. Protective agents against the organ toxicity of T-2 toxin have been recorded widely in the literature, but these protective agents and their molecular mechanisms of detoxification have not been comprehensively summarized. In this review, we provide an overview of the various protective agents to T-2 toxin and the molecular mechanisms underlying the detoxification effects. Targeting appropriate targets to antagonize T-2 toxin toxicity is also an important option. This review will provide essential guidance and strategies for the better application and development of T-2 toxin antidotes specific for organ toxicity in the future.

5.
Cell Death Dis ; 15(2): 111, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316760

RESUMO

Osteoclasts consume an amount of adenosine triphosphate (ATP) to perform their bone resorption function in the development of osteoporosis. However, the mechanism underlying osteoclast energy metabolism has not been fully elucidated. In addition to glucose, glutamine (Glu) is another major energy carrier to produce ATP. However, the role of Glu metabolism in osteoclasts and the related molecular mechanisms has been poorly elucidated. Here we show that Glu is required for osteoclast differentiation and function, and that Glu deprivation or pharmacological inhibition of Glu transporter ASCT2 by V9302 suppresses osteoclast differentiation and their bone resorptive function. In vivo treatment with V9302 improved OVX-induced bone loss. Mechanistically, RNA-seq combined with in vitro and in vivo experiments suggested that Glu mediates the role of IL-17 in promoting osteoclast differentiation and in regulating energy metabolism. In vivo IL-17 treatment exacerbated OVX-induced bone loss, and this effect requires the participation of Glu or its downstream metabolite α-KG. Taken together, this study revealed a previously unappreciated regulation of IL-17 on energy metabolism, and this regulation is Glu-dependent. Targeting the IL-17-Glu-energy metabolism axis may be a potential therapeutic strategy for the treatment of osteoporosis and other IL-17 related diseases.


Assuntos
Reabsorção Óssea , Glutamina , Interleucina-17 , Osteoclastos , Osteoporose , Humanos , Trifosfato de Adenosina/metabolismo , Reabsorção Óssea/metabolismo , Diferenciação Celular , Metabolismo Energético , Glutamina/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Osteoclastos/metabolismo , Osteogênese , Osteoporose/metabolismo , Ligante RANK/metabolismo
6.
J Phys Chem Lett ; 15(4): 1161-1171, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38270087

RESUMO

Carbon-based quantum dots (QDs) exhibit unique photoluminescence due to size-dependent quantum confinement, giving rise to fascinating full-color emission properties. Accurate emission calculations using time-dependent density functional theory are a time-costing and expensive process. Herein, we employed an artificial neural network (ANN) combined with statistical learning to establish the relationship between geometrical/electronic structures of ground states and emission wavelength for C3N QDs. The emission energy of these QDs can be doubly modulated by size and edge effects, which are governed by the number of C4N2 rings and the CH group, respectively. Moreover, these two structural characteristics also determine the phonon vibration mode of C3N QDs to harmonize the emission intensity and lifetime of hot electrons in the electron-hole recombination process, as indicated by nonadiabatic molecular dynamics simulation. These computational results provide a general approach to atomically precise design the full-color fluorescent carbon-based QDs with targeted functions and high performance.

7.
Cell Mol Immunol ; 21(3): 213-226, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38177245

RESUMO

Despite the tremendous progress of chimeric antigen receptor T (CAR-T) cell therapy in hematological malignancies, their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment (TME) and systemic toxicity caused by excessive cytokine release. As a key regulator of the immunosuppressive TME, TGF-ß promotes cytokine synthesis via the NF-κB pathway. Here, we coexpressed SMAD7, a suppressor of TGF-ß signaling, with a HER2-targeted CAR in engineered T cells. These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-ß-triggered exhaustion, which enabled sustained tumoricidal capacity after continuous antigen exposure. Moreover, SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells. Mechanistically, SMAD7 downregulated TGF-ß receptor I and abrogated the interplay between the TGF-ß and NF-κB pathways in CAR-T cells. As a result, these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-ß. SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids. Therefore, our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Animais , Humanos , Camundongos , Citocinas/metabolismo , Imunoterapia Adotiva , Neoplasias/terapia , NF-kappa B/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Proteína Smad7/genética , Proteína Smad7/metabolismo , Linfócitos T , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral
8.
Adv Sci (Weinh) ; 11(7): e2306203, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38063781

RESUMO

Endogenous essential metal ions play an important role in many life processes, especially in tumor development and immune response. The approval of various metallodrugs for tumor therapy brings more attention to the antitumor effect of metal ions. With the deepening understanding of the regulation mechanisms of metal ion homeostasis in vivo, breaking intracellular metal ion homeostasis becomes a new means to inhibit the proliferation of tumor cells and activate antitumor immune response. Diverse nanomedicines with the loading of small molecular ion regulators or metal ions have been developed to disrupt metal ion homeostasis in tumor cells, with higher safety and efficiency than free small molecular ion regulators or metal compounds. This comprehensive review focuses on the latest progress of various intracellular metal ion homeostasis regulation-based nanomedicines in tumor therapy including calcium ion (Ca2+ ), ferrous ion (Fe2+ ), cuprous ion (Cu+ ), managanese ion (Mn2+ ), and zinc ion (Zn2+ ). The physiological functions and homeostasis regulation processes of ions are summarized to guide the design of metal ion regulation-based nanomedicines. Then the antitumor mechanisms of various ions-based nanomedicines and some efficient synergistic therapies are highlighted. Finally, the challenges and future developments of ion regulation-based antitumor therapy are also discussed, hoping to provide a reference for finding more effective metal ions and synergistic therapies.


Assuntos
Metais , Zinco , Ferro , Íons , Homeostase/fisiologia
9.
Life Sci ; 336: 122254, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37977355

RESUMO

AIMS: Gliomas are the most common central nervous system malignancies, with limited therapeutic options and poor prognosis, which are primarily attributed to the "immune desert" microenvironment. Previously, we constructed a three-gene-deleted oncolytic adenovirus (Ad-TD) loaded with non-secreting interleukin-12 (nsIL-12), which could be amplified in tumor cells and induce immunity to suppress tumors. However, the effects of this oncolytic virus on gliomas and their immune microenvironment remain unclear. There is an urgent need for further research. MATERIALS AND METHODS: We constructed a Syrian hamster brain tumor model and demonstrated the efficacy and mechanism of the novel oncolytic virus in treating brain tumors through a series of in vitro and in vivo experiments. We investigated the efficacy and safety (the number of hamsters in each group is either 5 or 10) of the oncolytic virus treatment in Syrian hamsters using a virus-treated group, a control virus-treated group, and a blank control group. KEY FINDINGS: In vitro assays showed that Ad-TD-nsIL-12 could specifically proliferate in brain tumor cells which induce tumor cell apoptosis and intracellular expression of interleukin (IL)-12. Moreover, in vivo experiments demonstrated that Ad-TD-nsIL-12 could effectively inhibit the progression of brain tumors and prolong survival. Ad-TD-nsIL-12 significantly enhanced T-cell infiltration in the brain tumor microenvironment. SIGNIFICANCE: Ad-TD-nsIL-12 can inhibit glioma progression and increase T-cell infiltration in the tumor tissue, particularly infiltration by cytotoxic T cells (CD8+). Ad-TD-nsIL-12 can amplify and produce IL-12, inducing anti-glioma immune responses to inhibit tumor progression.


Assuntos
Neoplasias Encefálicas , Glioma , Terapia Viral Oncolítica , Vírus Oncolíticos , Cricetinae , Animais , Humanos , Vírus Oncolíticos/genética , Interleucina-12/genética , Microambiente Tumoral , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Glioma/terapia , Neoplasias Encefálicas/terapia , Mesocricetus
10.
Front Immunol ; 14: 1285801, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38077392

RESUMO

γδ T cells, a specialized subset of T lymphocytes, have garnered significant attention within the realm of cancer immunotherapy. Operating at the nexus between adaptive and innate immunological paradigms, these cells showcase a profound tumor discernment repertoire, hinting at novel immunotherapeutic strategies. Significantly, these cells possess the capability to directly identify and eliminate tumor cells without reliance on HLA-antigen presentation. Furthermore, γδ T cells have the faculty to present tumor antigens to αß T cells, amplifying their anti-tumoral efficacy.Within the diverse and heterogeneous subpopulations of γδ T cells, distinct immune functionalities emerge, manifesting either anti-tumor or pro-tumor roles within the tumor microenvironment. Grasping and strategically harnessing these heterogeneous γδ T cell cohorts is pivotal to their integration in tumor-specific immunotherapeutic modalities. The aim of this review is to describe the heterogeneity of the γδ T cell lineage and the functional plasticity it generates in the treatment of malignant tumors. This review endeavors to elucidate the intricate heterogeneity inherent to the γδ T cell lineage, the consequential functional dynamics in combating malignancies, the latest advancements from clinical trials, and the evolving landscape of γδ T cell-based oncological interventions, while addressing the challenges impeding the field.


Assuntos
Neoplasias , Receptores de Antígenos de Linfócitos T gama-delta , Humanos , Imunoterapia , Antígenos de Neoplasias , Apresentação de Antígeno , Microambiente Tumoral
11.
Biochem Pharmacol ; 218: 115920, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37989416

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with significant heterogeneity in incidence and outcomes. The role of Neuregulin 1 (NRG1) in ESCC and its contribution to aggressiveness remain unknown. This study aims to investigate the functions and molecular mechanisms of NRG1 in ESCC as well as the treatment strategy for ESCC with overexpression of NRG1. We firstly demonstrated the upregulation of NRG1 and a negative correlation trend between patients' overall survival (OS) and the expression level of NRG1 in esophageal cancer. And then we found NRG1 promoted cell proliferation, migration, inhibited apoptosis, and accelerated tumorigenesis and metastasis in ESCC using cell lines and xenograft models. Furthermore, we discovered that NRG1 activated the NF-κB/MMP9 signaling pathway, contributing to the metastatic phenotype in ESCC. Finally, we show that afatinib (FDA approved cancer growth blocker) could inhibit ESCC with overexpressed NRG1 and down-regulation of NRG1 along with afatinib treatment provides higher efficient strategy. This study uncovers the critical role and molecular mechanism of NRG1 in ESCC tumorigenesis and metastasis, suggesting its potential as a novel biomarker for ESCC treatment.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Afatinib , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Neuregulina-1/genética , Neuregulina-1/metabolismo , Carcinogênese/genética , Transformação Celular Neoplásica , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Movimento Celular
12.
Front Immunol ; 14: 1258156, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38022548

RESUMO

Introduction: Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors, and each component plays an important role in the function and anti-tumor efficacy. It has been reported that using human sequences or a low affinity of CAR single-chain variable fragments (scFvs) in the CAR binding domains is a potential way to enhance the function of CAR-T cells. However, it remains largely unknown how a lower affinity of CARs using humanized scFvs affects the function of CAR-T cells until recently. Methods: We used different humanized anti-HER2 antibodies as the extracellular domain of CARs and further constructed a series of the CAR-T cells with different affinity. Results: We have observed that moderately reducing the affinity of CARs (light chain variable domain (VL)-based CAR-T) could maintain the anti-tumor efficacy, and improved the safety of CAR therapy both in vitro and in vivo compared with high-affinity CAR-T cells. Moreover, T cells expressing the VL domain only antibody exhibited long-lasting tumor elimination capability after multiple challenges in vitro, longer persistence and lower cytokine levels in vivo. Discussion: Our findings provide an alternative option for CAR-T optimization with the potential to widen the use of CAR T cells.


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Anticorpos de Cadeia Única , Anticorpos de Domínio Único , Humanos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Anticorpos de Domínio Único/genética , Anticorpos de Domínio Único/metabolismo , Linfócitos T
13.
PLoS One ; 18(10): e0290973, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37812609

RESUMO

BACKGROUND: Restricted motion during touch screen device use may contribute to wrist overuse injuries. Wrist radioulnar deviation and extension while using touch screen devices and digital or manual counterparts in male and female medical professional dominant and non-dominant hands were quantified to test the hypothesis that mobile touch screen device use reduces wrist motion. METHODS: An active motion detection system was used to record wrist motion of 12 participants while: tablet swiping and turning book pages; raising a cell and traditional phone to the ear; texting and typing; and entering numbers on a cell phone and manual calculator. Medial and lateral wrist surface range of motion (ROM) and minimum and maximum wrist radial-ulnar deviation and flexion-extension were quantified. RESULTS: Device, sex and handedness effects were determined (P<0.05). Maximum medial radial deviation and ROM were greater using a cell versus traditional phone. Maximum medial radial deviation was higher in the nondominant wrist during backward tablet swiping and while backward page turning versus tablet swiping. Maximum and minimum medial extension angles and ROM were greater while typing versus texting. Female nondominant hand maximum lateral extension and ROM were greater for typing versus texting and maximum medial extension and lateral extension ROM greater during manual versus cell phone calculator use with handedness combined. Maximum lateral extension and ROM were greater in females versus males using manual calculators. CONCLUSIONS: Sex and handedness should instruct touch screen, digital and manual device design and use for optimal performance and injury prevention.


Assuntos
Traumatismos do Punho , Punho , Humanos , Masculino , Feminino , Articulação do Punho , Amplitude de Movimento Articular , Rádio (Anatomia) , Comprimidos , Fenômenos Biomecânicos
14.
Food Chem Toxicol ; 182: 114121, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37890761

RESUMO

Deoxynivalenol (DON) is one of the most prevalent mycotoxins in feed, which causes organ toxicity in animals. Therefore, reducing DON-induced organ toxicity can now be accomplished effectively using protective agents. This review provides an overview of multiple studies on a wide range of protective agents and their molecular mechanisms against DON organ toxicity. Protective agents include plant extracts, yeast products, bacteria, peptides, enzymes, H2, oligosaccharides, amino acids, adsorbents, vitamins and selenium. Among these, biological detoxification of DON using microorganisms to reduce the toxicity of DON without affecting the growth performance of pigs may be the most promising detoxification strategy. This paper also evaluates future developments related to DON detoxification and discusses the detoxification role and application potential of protective agents. This paper provides new perspectives for future research and development of safe and effective feed additives.


Assuntos
Micotoxinas , Tricotecenos , Suínos , Animais , Tricotecenos/metabolismo , Micotoxinas/análise , Bactérias/metabolismo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/metabolismo , Ração Animal/análise , Contaminação de Alimentos/análise
15.
Mol Ther Oncolytics ; 30: 216-226, 2023 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-37663131

RESUMO

CD19-targeted chimeric antigen receptor-modified T (CD19 CAR-T) cell therapy has been demonstrated as one of the most promising therapeutic strategies for treating B cell malignancies. However, it has shown limited treatment efficacy for diffuse large B cell lymphoma (DLBCL). This is, in part, due to the tumor heterogeneity and the hostile tumor microenvironment. Human interleukin-12 (IL-12), as a potent antitumor cytokine, has delivered encouraging outcomes in preclinical studies of DLBCL. However, potentially lethal toxicity associated with systemic administration precludes its clinical application. Here, an armed CD19 CAR expressing hypoxia-regulated IL-12 was developed (CAR19/hIL12ODD). In this vector, IL-12 secretion was restricted to hypoxic microenvironments within the tumor site by fusion of IL-12 with the oxygen degradation domain (ODD) of HIF1α. In vitro, CAR19/hIL12ODD-T cells could only secrete bioactive IL-12 under hypoxic conditions, accompanied by enhanced proliferation, robust IFN-γ secretion, increased abundance of CD4+, and central memory T cell phenotype. In vivo, adoptive transfer of CAR19/hIL12ODD-T cells significantly enhanced regression of large, established DLBCL xenografts in a novel immunodeficient Syrian hamster model. Notably, this targeted and controlled IL-12 treatment was without toxicity in this model. Taken together, our results suggest that armed CD19 CARs with hypoxia-controlled IL-12 (CAR19/hIL12ODD) might be a promising and safer approach for treating DLBCL.

16.
World J Gastroenterol ; 29(23): 3658-3667, 2023 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-37398883

RESUMO

BACKGROUND: The expression status of serum and glucocorticoid-induced protein kinase 3 (SGK3) in superficial esophageal squamous cell neoplasia (ESCN) remains unknown. AIM: To evaluate the SGK3 overexpression rate in ESCN and its influence on the prognosis and outcomes of patients with endoscopic resection. METHODS: A total of 92 patients who had undergone endoscopic resection for ESCN with more than 8 years of follow-up were enrolled. Immunohistochemistry was used to evaluate SGK3 expression. RESULTS: SGK3 was overexpressed in 55 (59.8%) patients with ESCN. SGK3 overexpression showed a significant correlation with death (P = 0.031). Overall survival and disease-free survival rates were higher in the normal SGK3 expression group than in the SGK3 overexpression group (P = 0.013 and P = 0.004, respectively). Cox regression analysis models demonstrated that SGK3 overexpression was an independent predictor of poor prognosis in ESCN patients (hazard ratio 4.729; 95% confidence interval: 1.042-21.458). CONCLUSION: SGK3 overexpression was detected in the majority of patients with endoscopically resected ESCN and was significantly associated with shortened survival. Thus, it might be a new prognostic factor for ESCN.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Humanos , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/cirurgia , Prognóstico , Células Epiteliais , Estudos Retrospectivos , Proteínas Serina-Treonina Quinases
17.
BMC Med Inform Decis Mak ; 23(1): 115, 2023 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-37415186

RESUMO

Deep learning models have been widely used in electroencephalogram (EEG) analysis and obtained excellent performance. But the adversarial attack and defense for them should be thoroughly studied before putting them into safety-sensitive use. This work exposes an important safety issue in deep-learning-based brain disease diagnostic systems by examining the vulnerability of deep learning models for diagnosing epilepsy with brain electrical activity mappings (BEAMs) to white-box attacks. It proposes two methods, Gradient Perturbations of BEAMs (GPBEAM), and Gradient Perturbations of BEAMs with Differential Evolution (GPBEAM-DE), which generate EEG adversarial samples, for the first time by perturbing BEAMs densely and sparsely respectively, and find that these BEAMs-based adversarial samples can easily mislead deep learning models. The experiments use the EEG data from CHB-MIT dataset and two types of victim models each of which has four different deep neural network (DNN) architectures. It is shown that: (1) these BEAM-based adversarial samples produced by the proposed methods in this paper are aggressive to BEAM-related victim models which use BEAMs as the input to internal DNN architectures, but unaggressive to EEG-related victim models which have raw EEG as the input to internal DNN architectures, with the top success rate of attacking BEAM-related models up to 0.8 while the top success rate of attacking EEG-related models only 0.01; (2) GPBEAM-DE outperforms GPBEAM when they are attacking the same victim model under a same distortion constraint, with the top attack success rate 0.8 for the former and 0.59 for the latter; (3) a simple modification to the GPBEAM/GPBEAM-DE will make it have aggressiveness to both BEAMs-related and EEG-related models (with top attack success rate 0.8 and 0.64), and this capacity enhancement is done without any cost of distortion increment. The goal of this study is not to attack any of EEG medical diagnostic systems, but to raise concerns about the safety of deep learning models and hope to lead to a safer design.


Assuntos
Aprendizado Profundo , Epilepsia , Humanos , Mapeamento Encefálico , Epilepsia/diagnóstico , Encéfalo , Eletroencefalografia
18.
Toxicology ; 494: 153589, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37419272

RESUMO

Deoxynivalenol (DON) is one of the most serious mycotoxins that contaminate food and feed, causing hepatocyte death. However, there is still a lack of understanding regarding the new cell death modalities that explain DON-induced hepatocyte toxicity. Ferroptosis is an iron-dependent type of cell death. The aim of this study was to explore the role of ferroptosis in DON-exposed HepG2 cytotoxicity and the antagonistic effect of resveratrol (Res) on its toxicity, and the underlying molecular mechanisms. HepG2 cells were treated with Res (8 µM) or/and DON (0.4 µM) for 12 h. We examined cell viability, cell proliferation, expression of ferroptosis-related genes, levels of lipid peroxidation and Fe(II). The results revealed that DON reduced the expression levels of GPX4, SLC7A11, GCLC, NQO1, and Nrf2 while promoting the expression of TFR1, GSH depletion, accumulation of MDA and total ROS. DON enhanced production of 4-HNE, lipid ROS and Fe(II) overload, resulting in ferroptosis. However, pretreatment with Res reversed these changes, attenuating DON-induced ferroptosis, improving cell viability and cell proliferation. Importantly, Res prevented Erastin and RSL3-induced ferroptosis, suggesting that Res exerted an anti-ferroptosis effect by activating SLC7A11-GSH-GPX4 signaling pathways. In summary, Res ameliorated DON-induced ferroptosis in HepG2 cells. This study provides a new perspective on the mechanism of DON-induced hepatotoxicity formation, and Res may be an effective drug to alleviate DON-induced hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Humanos , Células Hep G2 , Resveratrol/farmacologia , Espécies Reativas de Oxigênio , Compostos Ferrosos
19.
J Chem Phys ; 159(4)2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37489651

RESUMO

A comprehensive genetic algorithm is used to perform a global search for Cl-(H2O)1-9 and NaCl(H2O)1-9. The structural optimization, energy calculations, vibrational characteristics, and charge distribution were performed at an ab initio high-level theory. Combined with the calculation results of Na+(H2O)1-6 by Wang et al. [Front. Chem. 7, 624 (2019)] in our group, we systematically investigate these three systems at the same theoretical level. A comparison of bond lengths reveals that in Cl-(H2O)n, the inclusion of Na+ to form NaCl(H2O)n reduces the average distance between Cl- and H2O, indicating that Na+ has a stabilizing effect on ionic hydrogen bonds. Conversely, in Na+(H2O)n, the introduction of Cl- weakens the interactions between Na+ and H2O. In the NaCl(H2O)1-9 structures searched by the genetic algorithm, the ground-state configurations correspond to contact ion pairs, and the solvent-separated ion pair structures appear when n = 7. Furthermore, the anharmonic corrected infrared spectra of Cl-(H2O)1-5 and NaCl(H2O)1-4 exhibit good agreement with the experimental results. According to charge analysis of NaCl(H2O)n, it is observed that charge transfer primarily occurs from Cl- to H2O, resulting in the presence of negative charges on the water molecules. These findings are helpful to understand the effects of Na+ and Cl- on hydrated clusters at the molecular level.

20.
Turk J Gastroenterol ; 34(7): 720-727, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37326152

RESUMO

BACKGROUND/AIMS: Duodenal lipomas are rarely found in the gastrointestinal tract. Most published literature referring to the tumors is limited to case series. There remained issues about the understanding and management of duodenal lipomas to be clarified. We aimed to investigate the clinical and endoscopic features of duodenal lipomas. Additionally, outcomes of endoscopic resection for duodenal lipomas were evaluated. MATERIALS AND METHODS: A total of 29 duodenal lipomas resected endoscopically from December 2011 to October 2021 were included. Clinical characteristics, endoscopic features, and endoscopic ultrasound findings were analyzed retrospectively. The endoscopic resection was performed in 3 ways: hot snare polypectomy, endoscopic mucosa resection, and endoscopic submucosal dissection. RESULTS: Of the 29 duodenal lipomas, 21 were located at the second portion with a mean size of 25.8 mm (range, 7-60 mm). Yamada type IV was the most common macroscopic type in 14 lesions, exhibiting a tendency of forming large peduncles. Seven patients had digestive symptoms. The occurrence of symptoms is associated with the tumor size. Endoscopic ultrasound was performed on 23 duodenal lipomas, of which 20 demonstrated homogenous echogenicity and 3 presented heterogeneous with tubular anechoic region. The endoscopic resection operation was successfully conducted on 29 patients without severe adverse events. The rate of en bloc and endoscopic complete resection was 93.1% and 86.2%, respectively. Recurrence was noted in 1 patient. CONCLUSIONS: Clinical characteristics with typical endoscopic ultrasound features are helpful in duodenal lipomas diagnosis. The endoscopic resection is a safe and effective treatment for duodenal lipomas with considerable long-term outcomes.


Assuntos
Neoplasias Duodenais , Ressecção Endoscópica de Mucosa , Lipoma , Humanos , Endossonografia , Lipoma/cirurgia , Lipoma/patologia , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias Duodenais/patologia , Neoplasias Duodenais/cirurgia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...