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The extensive utilization of pesticides results in their frequent detection in aquatic environments, often as complex mixtures, posing risks to aquatic organisms. The hook snout carp (Opsariichthys bidens) serves as a valuable bioindicator for evaluating the impacts of environmental pollutants in aquatic ecosystems. However, few studies examined the toxic effects of pesticides on O.bidens, let alone the characterization of the combined effects resulting from their mixtures. This study aims to elucidate the toxic effects of beta-cypermethrin and pyraclostrobin on O.bidens, individually and in combination, focusing on biochemical, transcriptional, and molecular responses. By organizing and analyzing the toxicogenomic databases, both pesticides were identified as a contributor to processes such as apoptosis, oxidative stress, and inflammatory responses. The acute toxicity test revealed comparable acute toxicity of beta-cypermethrin and pyraclostrobin on O.bidens, with LC50 being 0.019 and 0.027 mg/L, respectively, whereas the LC50 decreased to 0.0057 and 0.0079 mg/L under the combined exposure, indicating potential synergistic effects. The activities of enzymes involved in oxidative stress and detoxification were significantly altered after exposure, with superoxide dismutase (SOD) and catalase (CAT) increasing, while malondialdehyde (MDA) levels decreased. The activity of CYP450s was significantly changed. Likewise, the expression levels of genes (mn-sod, p53, esr, il-8) associated with oxidative stress, apoptosis, endocrine and immune systems were significantly increased. Combined exposure to the pesticides significantly exacerbated the aforementioned biological processes in O.bidens. Furthermore, both pesticides can modify protein activity by binding to the surface of SOD molecules and altering protein conformation, contributing to the elevated enzyme activity. Through the investigation of the synergistic toxic effects of pesticides and molecular mechanisms in O.bidens, our findings highlight the importance of assessing the combined effects of pesticide mixtures in aquatic environments.
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Corynebacterium pseudotuberculosis (C. p), a facultative intracellular bacterium, is an important zoonotic pathogen that causes abscesses and pyogenic granulomas. The relationship between gut microbiota and host health or diseases has received increasing attention. However, the role of gut microbiota in the process of C. p infection is still unclear. In this study, we established a C. p infection model in C57BL/6 mice and examined the impact of preemptive oral administration Lactobacillus acidophilus (L. acidophilus) on infection. Our findings revealed that C. p infection led to pronounced pathological alterations in the liver and kidneys, characterized by abscess formation, intense inflammatory responses, and bacterial overload. Remarkably, these deleterious effects were greatly relieved by oral administration of L. acidophilus before infection with C. p. Additionally, we further found that during C. p infection, peritoneal macrophages (PMs) of mice orally administered with L. acidophilus accumulated more rapidly at sites of infection. Furthermore, our results showed that PMs from mice with oral L. acidophilus administration showed a stronger C. p clearance effect, and this was mediated by high expression of LC3-II protein. Meanwhile, oral administration of L. acidophilus protected the gut microbiota disorder in C57BL/6 mice caused by C. p infection. In summary, our study demonstrates that oral administration of L. acidophilus confers effective protection against C. p infection in C57BL/6 mice by modulating macrophage autophagy, thereby augmenting bacterial clearance and preserving gut microbiota and function stability. These findings position L. acidophilus as a viable probiotic candidate for the clinical prevention of C. p infection. IMPORTANCE: Corynebacterium pseudotuberculosis (C. p) is known to induce a range of chronic diseases in both animals and humans. Currently, clinical treatment for C. p infection mainly relies on antibiotic therapy or surgical intervention. However, excessive use of antibiotics may increase the risk of drug-resistant strains, and the effectiveness of treatment remains unsatisfactory. Furthermore, surgical procedures do not completely eradicate pathogens and can easily cause environmental pollution. Probiotic interventions are receiving increasing attention for improving the body's immune system and maintaining health. In this study, we established a C. p infection model in C57BL/6 mice to explore the impact of Lactobacillus acidophilus during C. p infection. Our results showed that L. acidophilus effectively protected against C. p infection by regulating the autophagy of macrophages and maintaining intestinal microbiota homeostasis. This study may provide a new strategy for the prevention of C. p infection.
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Autofagia , Infecciones por Corynebacterium , Corynebacterium pseudotuberculosis , Microbioma Gastrointestinal , Lactobacillus acidophilus , Ratones Endogámicos C57BL , Animales , Autofagia/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Lactobacillus acidophilus/fisiología , Ratones , Infecciones por Corynebacterium/prevención & control , Infecciones por Corynebacterium/microbiología , Homeostasis/efectos de los fármacos , Probióticos/administración & dosificación , Probióticos/farmacología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/microbiología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Modelos Animales de EnfermedadRESUMEN
We examined the occurrence and levels of 19 legacy and emerging per- and polyfluoroalkyl substances (PFASs) in 7 species of marine bivalve molluscs collected from four coastal cities of Shandong Province, China. Perfluorooctanoic acid (PFOA) was the most prevalent component, accounting for 68.1 % of total PFASs. The total PFASs in bivalve molluscs ranged from 0.86 to 6.55 ng/g wet weight, with the highest concentration found in Meretrix meretrix L. The concentration of total PFASs in bivalve molluscs showed the following trend: clams > scallops > oysters > mussels. Estimation on the human intake of PFASs from consumption of bivalve molluscs resulted in hazard ratios (HR) ranging from 0.12 to 6.40. Five of the seven species had HR >1, indicating high exposure risks associated with PFASs. Therefore, the occurrence of PFASs in marine biota is particularly concerning and further investigations on the sources of PFASs in Shandong are warranted.
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Bivalvos , Monitoreo del Ambiente , Fluorocarburos , Contaminantes Químicos del Agua , Animales , China , Fluorocarburos/análisis , Contaminantes Químicos del Agua/análisis , Humanos , Caprilatos/análisisRESUMEN
Prenatal environmental exposure could be an essential health risk factor associated with neurodevelopmental disorders in offspring. However, the exact mechanisms underlying the impact of prenatal PM2.5 exposure on offspring cognition remain unclear. In our recent study using a PM2.5 exposed pregnant mouse model, we observed significant synaptic dysfunction in the hippocampi of the offspring. Concurrently, the epigenetic regulator of KDM5A and the Shh signaling pathway exhibited decreased activities. Significantly, changes in hippocampal KDM5A and Shh levels directly correlated with PM2.5 exposure intensity. Subsequent experiments revealed a marked reduction in the expression of Shh signaling and related synaptic proteins when KDM5A was silenced in cells. Notably, the effects of KDM5A deficiency were reversed significantly with the supplementation of a Shh activator. Furthermore, our findings indicate that Shh activation significantly attenuates PM2.5-induced synaptic impairments in hippocampal neurons. We further demonstrated that EGR1, a transcriptional inhibitor, plays a direct role in KDM5A's regulation of the Shh pathway under conditions of PM2.5 exposure. Our results suggest that the KDM5A's inhibitory regulation on the Shh pathway through the EGR1 gene is a crucial epigenetic mechanism underlying the synaptic dysfunction in hippocampal neurons caused by maternal PM2.5 exposure. This emphasizes the role of epigenetic regulations in neurodevelopmental disorders caused by environmental factors.
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Epigénesis Genética , Proteínas Hedgehog , Hipocampo , Material Particulado , Efectos Tardíos de la Exposición Prenatal , Transducción de Señal , Hipocampo/efectos de los fármacos , Animales , Femenino , Embarazo , Transducción de Señal/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Ratones , Material Particulado/toxicidad , Proteína 2 de Unión a Retinoblastoma/genética , Exposición Materna/efectos adversos , Sinapsis/efectos de los fármacos , Contaminantes Atmosféricos/toxicidadRESUMEN
Aflatoxin B1 (AFB1) is a major mycotoxin contaminant showing in the environment and foods. In this study, the molecular initiating events (MIEs) of AFB1-induced steatohepatitis were explored in mice and human cell model. We observed dose-dependent steatohepatitis in the AFB1-treated mice, including triglyceride accumulation, fibrotic collagen secretion, enrichment of CD11b + and F4/80+ macrophages/Kupffer cells, cell death, lymphocytes clusters and remarkable atrophy areas. The gut barrier and gut-microbiota were also severely damaged after the AFB1 treatment and pre-conditioned colitis in the experimental mice aggravated the steatohepatitis phenotypes. We found that macrophages cells can be pro-inflammatorily activated to M1-like phenotype by AFB1 through an AHR/TLR4/p-STAT3 (Ser727)-mediated mitochondrial oxidative stress. The phenotypes can be rescued by AHR inhibitors in the mice model and human cell model. We further showed that this signaling axis is based on the cross-talk interaction between AHR and TLR4. Gene knock-up experiment found that the signaling is dependent on AFB1 ligand-binding with AHR, but not protein expressions of TLR4. The signaling elevated NLRP3 and two immune metabolic enzymes ICAM-1 and IDO that are associated with macrophage polarization. Results from intervention experiments with natural anti-oxidant and AHR inhibitor CH223191 suggest that the macrophage polarization may rely on AHR and ROS. Our study provides novel and critical references to the food safety and public health regulation of AFB1.
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Aflatoxina B1 , Hígado Graso , Animales , Humanos , Ratones , Molécula 1 de Adhesión Intercelular/metabolismo , Macrófagos/metabolismo , Estrés Oxidativo , Factor de Transcripción STAT3/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Pesticide residue was one of the stress factors affecting quality and safety of Chinese herbal medicines (CHMs). The present study was designed to investigate the occurrence and dietary exposure of 70 pesticide residues in 307 samples of CHMs, including 104 American ginseng, 100 Ganoderma lucidum (G. lucidum), and 103 Dendrobium officinale (D. officinale) in Shandong Province, China. The study revealed that a total of 29 pesticides were detected in the majority (92.5%) of samples, and the pesticide residues of 85 (27.7%) samples exceeded the maximum residue levels (MRLs). Particularly, the maximum concentration of chlorpyrifos was 23.8 mg kg-1, almost 50 times of the MRLs in food in GB 2763-2021, while there's no standard restrictions specified in CHMs in China. The chronic, acute, and cumulative risk assessment results indicated that risk exposure of the three types of CHMs were unlikely to pose a health risk to consumers. However, more attention should be paid to the multiple residues with the presence of four or more pesticides in one sample and high over-standard rate of pesticides. The pesticide users and the government should pay more attention to the pesticides used in CHMs and regularly monitor the presence of these compounds. The study recommended the MRLs of these pesticides in CHMs should be established and perfected by the relevant departments in China.
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Residuos de Plaguicidas , Plaguicidas , Residuos de Plaguicidas/análisis , Plaguicidas/análisis , Alimentos , China , Contaminación de Alimentos/análisis , Extractos Vegetales , Medición de RiesgoRESUMEN
Sesamin, a special compound present in sesame and sesame oil, has been reported a role in regulating lipid metabolism, while the underlying mechanisms remain unclear. Autophagy has been reported associated with lipid metabolism and regarded as a key modulator in liver steatosis. The present work aimed to investigate whether sesamin could exert its protective effects against lipid accumulation via modulating autophagy in HepG2 cells stimulated with oleic acid (OA). Cell viability was evaluated using the CCK-8 method, and triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein, cholesterol (LDL-C), alanine aminotransferase (ALT), along with aspartate aminotransferase (AST) were assessed by oil red O staining, transmission electron microscopy (TEM), and biochemical kits to investigate the lipid-lowering effects of sesamin. Differentially expressed genes were screened by RNA sequencing and validated using real-time quantitative PCR and Western blot. Autophagy and mitophagy related molecules were analyzed employing TEM, Western blot, and immunofluorescence. The data shows that in HepG2 cells stimulated by OA, sesamin reduces levels of TG, TC, LDL-C, ALT, and AST while elevating HDL-C, alleviates the lipid accumulation and improves fatty acid metabolism through modulating the levels of fat metabolism related genes including PCSK9, FABP1, CD36, and SOX4. Sesamin restores the suppressed autophagy in HepG2 cells caused by OA, which could be blocked by autophagy inhibitors. This indicates that sesamin improves fatty acid metabolism by enhancing autophagy levels, thereby mitigating the intracellular lipid accumulation. Furthermore, sesamin significantly enhances the mitophagy and improves mitochondrial homeostasis via activating the PINK/Parkin pathway. These data suggest that sesamin alleviates the excessive lipid accumulation in HepG2 caused by OA by restoring the impaired mitophagy via the PINK1/Parkin pathway, probably playing a preventive or therapeutic role in hepatic steatosis.
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Dioxoles , Hígado Graso , Lignanos , Proproteína Convertasa 9 , Factores de Transcripción SOXC , Humanos , Células Hep G2 , Proproteína Convertasa 9/metabolismo , Mitofagia , Ácido Oléico/metabolismo , LDL-Colesterol/metabolismo , LDL-Colesterol/farmacología , Hígado Graso/metabolismo , Metabolismo de los Lípidos , Colesterol/metabolismo , Triglicéridos/metabolismo , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Hígado/metabolismoRESUMEN
Cardiovascular disease (CVD) has been the leading cause of death worldwide. As a chronic inflammatory disease, atherosclerosis (AS) acts as the initiating factor for CVD and reactive oxygen species (ROS) play a vital role in its development. Superoxide dismutases (SOD) can alleviate the detrimental effects of ROS and serve as the first line of defense through detoxifying the products derived from oxidative stress in vivo. Considering the potential preventive effects of high-density lipoprotein (HDL) on AS and the close relationship between CuZn superoxide dismutase (CuZnSOD) and HDL, the present work investigated whether CuZnSOD overexpression in swine could improve the function of HDL. Seven CuZnSOD transgenic swine, constructed by sperm and magnetic nanoparticles, demonstrated overexpressed CuZnSOD in the liver (P < 0.01) but comparable level to control in plasma (P > 0.05). CuZnSOD overexpression significantly down-regulated the levels of triglyceride (TG), apolipoprotein A-I (apoA-I) (P < 0.05), and high-density lipoprotein cholesterol (HDL-C) (P < 0.01) in plasma. In the presence of CuZnSOD overexpression, HDL3 significantly inhibited levels of IL-6 and TNF-α induced by oxidized low-density lipoprotein (oxLDL) (P < 0.05), indicating enhanced anti-inflammatory activity of HDL. At the same time, HDL-mediated cholesterol efflux did not decrease (P > 0.05). CuZnSOD overexpression improves the anti-inflammatory function of HDL despite decreased levels of HDL-C. In Conclusion, CuZnSOD overexpression improves HDL function in swine.
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Lipoproteínas HDL , Superóxido Dismutasa , Animales , Porcinos , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/genética , Lipoproteínas HDL/metabolismo , Animales Modificados Genéticamente , Interleucina-6/metabolismo , Interleucina-6/genética , Apolipoproteína A-I/metabolismo , Apolipoproteína A-I/genética , Masculino , Hígado/metabolismo , Triglicéridos/metabolismo , Triglicéridos/sangreRESUMEN
In this study 13 heavy metals were analysed in representative livestock meat, poultry meat, livestock offal and poultry offal samples (20 per category) from marketplaces and retail stores in 16 cities in Shandong province, China. The investigated heavy metals were Cu, Cr, V, Ni, As, Se, Sn, Cd, Pb, Sb, Mn, Ba and Hg. Results revealed mean levels of total heavy metals in meat and offal of 1.56 mg/kg and 39.8 mg/kg, respectively. Cu, Cr, Mn, Ni, Se, Ba and Pb were found in all samples (100%), followed by Hg (95.0%), V (91.3%), Sn (73.8%), Cd (51.3%), As (21.3%) and Sb (11.3%). Hazard Quotient (HQ) and Hazard Index (HI) values showed that high meat intake can cause potential health risks. Thus, continuous monitoring of health risks and trends of heavy metals in meat products is needed, both for food safety and consumer's health.
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Productos de la Carne , Mercurio , Metales Pesados , Contaminantes del Suelo , Monitoreo del Ambiente/métodos , Productos de la Carne/análisis , Cadmio/análisis , Plomo/análisis , Contaminación de Alimentos/análisis , Contaminantes del Suelo/análisis , Metales Pesados/análisis , Mercurio/análisis , Medición de Riesgo , ChinaRESUMEN
In this article, the issue of event-triggered multiasynchronous H∞ control for Markov jump systems with transmission delay is concerned. In order to reduce sampling frequency, multiple event-triggered schemes (ETSs) are introduced. Then hidden Markov model (HMM) is employed to describe multiasynchronous jumps among subsystems, ETSs, and controller. Based on the HMM, the time-delay closed-loop model is constructed. In particular, when triggered data are transmitted over networks, a large transmission delay may cause disorder of transmission data such that the time-delay closed-loop model cannot be developed directly. To overcome this difficulty, a packet loss schedule is presented and the unified time-delay closed-loop system is obtained. By the use of the Lyapunov-Krasovskii functional method, sufficient conditions with the controller design are formulated for guaranteeing the H∞ performance of the time-delay closed-loop system. Finally, the effectiveness of the proposed control strategy is demonstrated by two numerical examples.
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Biomass-derived carbon materials have broad application prospects in energy storage, but still face problems such as complex synthesis paths and the massive use of corrosive activators. In this study, we proposed a mild and efficient pathway to prepare nitrogen-doped porous carbon material (N-YAC) using one-step pyrolysis with solid K2CO3, tobacco straw, and melamine. The optimized material (N-YAC0.5) was not only enriched with nitrogen, but also exhibited a high specific surface area (2367 m2/g) and a reasonable pore size distribution (46.49% mesopores). When utilized in electrodes, N-YAC0.5 exhibited an excellent capacitance performance (338 F/g at 1 A/g) in the three-electrode system, and benefitted from a high mesopore distribution that maintained a capacitance of 85.2% (288 F/g) at high current densities (20 A/g). Furthermore, the composed symmetric capacitor achieved an energy density of 14.78 Wh/kg at a power density of 400 W/kg. In summary, our work provides a novel and eco-friendly approach for converting biomass into high-performance energy-storage materials.
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Background: Human gut microbiota play a crucial role in the immune response of the host to respiratory viral infection. However, evidence regarding the association between the gut microbiome, host immune responses, and disease severity in coronavirus disease 2019 (COVID-19) remains insufficient. Methods: To better comprehend the interactions between the host and gut microbiota in COVID-19, we conducted 16S rRNA sequencing and characterized the gut microbiome compositions in stool samples from 40 COVID-19 patients and 33 non-pneumonia controls. We assessed several hematological parameters to determine the immune status. Results: We found that the gut microbial composition was significantly changed in COVID-19 patients, which was characterized by increased opportunistic pathogens and decreased commensal bacteria. The frequency of prevalent opportunistic pathogens Enterococcus and Lactobacillus increased, especially in severe patients; yet the abundance of butyrate-producing bacteria, Faecalibacterium, Roseburia, and Anaerostipes, decreased significantly, and Faecalibacterium prausnitzii might help discriminate severe patients from moderate patients and non-pneumonia people. Furthermore, we then obtained a correlation map between the clinical characteristics of COVID-19 and severity-related gut microbiota. We observed a notable correlation between the abundance of Enterococcus faecium and abnormal neutrophil or lymphocyte percentage in all COVID-19 patients. Faecalibacterium was positively correlated with lymphocyte counts, while negatively correlated with neutrophil percentage. Conclusion: These results suggested that the gut microbiome could have a potential function in regulating host immune responses and impacting the severity or consequences of diseases.
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COVID-19 , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiología , ARN Ribosómico 16S/genética , Clostridiales/genética , Gravedad del Paciente , InmunidadRESUMEN
Recent extensive evidence suggests that ambient fine particulate matter (PM2.5, with an aerodynamic diameter ≤2.5 µm) may be neurotoxic to the brain and cause central nervous system damage, contributing to neurodevelopmental disorders, such as autism spectrum disorders, neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and mental disorders, such as schizophrenia, depression, and bipolar disorder. PM2.5 can enter the brain via various pathways, including the blood-brain barrier, olfactory system, and gut-brain axis, leading to adverse effects on the CNS. Studies in humans and animals have revealed that PM2.5-mediated mechanisms, including neuroinflammation, oxidative stress, systemic inflammation, and gut flora dysbiosis, play a crucial role in CNS damage. Additionally, PM2.5 exposure can induce epigenetic alterations, such as hypomethylation of DNA, which may contribute to the pathogenesis of some CNS damage. Through literature analysis, we suggest that promising therapeutic targets for alleviating PM2.5-induced neurological damage include inhibiting microglia overactivation, regulating gut microbiota with antibiotics, and targeting signaling pathways, such as PKA/CREB/BDNF and WNT/ß-catenin. Additionally, several studies have observed an association between PM2.5 exposure and epigenetic changes in neuropsychiatric disorders. This review summarizes and discusses the association between PM2.5 exposure and CNS damage, including the possible mechanisms by which PM2.5 causes neurotoxicity.
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Enfermedad de Alzheimer , Síndromes de Neurotoxicidad , Animales , Humanos , Material Particulado/toxicidad , Encéfalo , Barrera Hematoencefálica , Síndromes de Neurotoxicidad/etiologíaRESUMEN
Neurofibromatosis type 1 is a rare autosomal dominant genetic disorder, with up to 50% of patients clinically displaying skeletal defects. Currently, the pathogenesis of bone disorders in NF1 patients is unclear, and there are no effective preventive and treatment measures. In this study, we found that knockout of the NF1 gene reduced cAMP levels and osteogenic differentiation in an osteoblast model, and icariin activated the cAMP/PKA/CREB pathway to promote osteoblast differentiation of the NF1 gene knockout cell model by increasing intracellular cAMP levels. The PKA selective inhibitor H89 significantly impaired the stimulatory effect of icariin on osteogenesis in the NF1 cell model. In this study, an osteoblast model of NF1 was successfully constructed, and icariin was applied to the cell model for the first time. The results will help to elucidate the molecular mechanism of NF1 bone disease and provide new ideas for the clinical prevention and treatment of NF1 bone disease and drug development in the future.
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Enfermedades Óseas , Neurofibromatosis 1 , Humanos , Osteogénesis/genética , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Genes de Neurofibromatosis 1 , Técnicas de Inactivación de Genes , Diferenciación Celular/genética , Enfermedades Óseas/metabolismo , OsteoblastosRESUMEN
This article addresses the practically predefined-time adaptive fuzzy tracking control problem of strict-feedback nonlinear stochastic systems, where the system under consideration includes stochastic disturbances and uncertain parameters. First, in this study, practically predefined-time stochastic stabilization (PPSS) in the p th moment sense is introduced, and a Lyapunov-type criterion for PPSS is proposed to assure the stabilization of the system considered. With these ideas, based on the backstepping design method, a semiglobally practically predefined-time adaptive fuzzy tracking control algorithm is proposed with a fuzzy system used to approximate the unknown part of the system. Moreover, the settling time of the system response can be arbitrarily adjusted in a mean-value sense, and such freedom can be used to improve the stochastic finite-/fixed-time control results. Finally, a practical example and a numerical example of a comparison are provided to validate the effectiveness of the proposed control strategy.
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The tumor suppressor TP53 is the most frequently mutated gene in human cancers. Mutant p53 (mutp53) proteins often accumulate to very high levels in human cancers to promote cancer progression through the gain-of-function (GOF) mechanism. Currently, the mechanism underlying mutp53 accumulation and GOF is incompletely understood. Here, we identified TRIM21 as a critical E3 ubiquitin ligase of mutp53 by screening for specific mutp53-interacting proteins. TRIM21 directly interacted with mutp53 but not WT p53, resulting in ubiquitination and degradation of mutp53 to suppress mutp53 GOF in tumorigenesis. TRIM21 deficiency in cancer cells promoted mutp53 accumulation and GOF in tumorigenesis. Compared with p53R172H knockin mice, which displayed mutp53 accumulation specifically in tumors but not normal tissues, TRIM21 deletion in p53R172H knockin mice resulted in mutp53 accumulation in normal tissues, an earlier tumor onset, and a shortened life span of mice. Furthermore, TRIM21 was frequently downregulated in some human cancers, including colorectal and breast cancers, and low TRIM21 expression was associated with poor prognosis in patients with cancers carrying mutp53. Our results revealed a critical mechanism underlying mutp53 accumulation in cancers and also uncovered an important tumor-suppressive function of TRIM21 and its mechanism in cancers carrying mutp53.
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Mutación con Ganancia de Función , Proteína p53 Supresora de Tumor , Animales , Humanos , Ratones , Carcinogénesis/genética , Línea Celular Tumoral , Mutación , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The imbalance of mitochondrial fission and fusion dynamics causes ischemic cardiomyocyte apoptosis and heart injury by affecting mitophagy. Regulation of mitochondrial dynamics is an important therapeutic strategy for ischemic heart diseases. Considering the important roles of MORN motifs in heart diseases and chloroplast fission, we aimed to investigate the possible role of MORN repeat-containing protein 4 (MORN4) in the progression of myocardial infarction (MI), ischemic cardiomyocyte apoptosis, mitochondrial dynamics, and mitophagy. We found that in the MI mouse, MORN4 knockdown remarkably accelerated cardiac injury and fibrosis with deteriorating cardiac dysfunction. Sphingosylphosphorylcholine (SPC) alleviated ischemic cardiomyocyte apoptosis and heart injury through increased level of MORN4, indicating a vital function of MORN4 in heart with SPC used to clarify the molecular mechanisms underlying the functions of MORN4. Mechanistically, we found that MORN4 directly binds to MFN2 and promotes the phosphorylation of MFN2 S442 through Rho-associated protein kinase 2 (ROCK2), which mediates beneficial mitophagy induced by mitochondrial dynamics, while SPC promoted the binding of MORN4 and MFN2 and the process. Taken together, our data reveal a new perspective role of MORN4 in ischemic heart injury, and report that SPC could regulate myocardial mitochondrial homeostasis by activating the MORN4-MFN2 axis during the ischemic situation, this finding provides novel targets for improving myocardial ischemia tolerance and rescue of acute myocardial infarction.
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Lesiones Cardíacas , Infarto del Miocardio , Isquemia Miocárdica , Ratones , Animales , Miocitos Cardíacos/metabolismo , Dinámicas Mitocondriales , Mitofagia/genética , Miocardio/metabolismo , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismoRESUMEN
Human exposure to aflatoxins (AFs) and zearalenone (ZEA) has not been sufficiently investigated. Here, we analyzed the exposure level and health risks posed by AFs (B1, B2, G1, G2) and ZEA through cooking oil consumption in Shandong, China. The individual daily consumption of cooking oil was calculated through 2745 questionnaires during 2017-2019. The average contamination levels of mycotoxins were estimated by examining 60 cooking oil samples. For the peanut oil, AFs ranged from <0.2 to 274 µg/kg, with a positive rate of 66.6% (20/30). Average levels of 36.62 µg/kg AFB1 and 44.43 µg/kg total AFs were found. Over-the-limit level (20 µg/kg) of AFB1 was detected in 8/30 samples. Estimated daily intake (EDI) and margin of exposure (MOE) for age-stratified population groups showed that children are facing highest adverse health risk with AFB1 (MOE 5.88-6.39). The liver cancer incidences attributable to AFB1 exposure are non-negligible as 0.896, 0.825, and 0.767 cases per 100,000 for 6-14 age group, 15-17 age group, and adult labor-intensive workers. Over-the-limit level (60 µg/kg) ZEA contamination was detected in 25/30 corn oil samples with a 50th percentile value of 97.95 µg/kg. Our health risk assessment suggested significant health risks of enterohepatic (inflammation and cancer), reproductive, and endocrine systems posed by AFs and ZEA. However, the health risk of immunotoxicity is unclear because currently animal study data are not available for the immunotoxicity induced after long-term exposure. In general, the health risks posed by mycotoxins are non-negligible and long-term mycotoxin surveillance is necessary.
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Aflatoxinas , Micotoxinas , Zearalenona , Animales , Adulto , Niño , Humanos , Micotoxinas/análisis , Aflatoxinas/análisis , Aceites de Plantas/análisis , Verduras , Contaminación de Alimentos/análisisRESUMEN
Rare earth elements (REEs) can cause neoplasms, reduce bone density, affect children's intelligence, etc., and diet is an important way for the human body to absorb REEs. With the increasing use of REEs, the impact on human health is becoming more and more important. So, we used a probabilistic assessment method with Monte Carlo simulation to evaluate the dietary intake of REEs by residents of a large light rare earth mining area in Shandong Province. 16 REEs in 447 samples (including wheat, maize, dry beans, vegetables, fruits and eggs) were detected. The mean value of total REEs for all samples was 286.96 µg/kg, and of light rare earth elements (LREEs) was 270.18 µg/kg. Among of LREEs, Ce, La, Nd and Pr were dominant. The REEs content of different food categories showed that wheat, leafy vegetables and allium vegetables had higher content of REEs, melons vegetables, root vegetables, fruits and eggs had the lowest content. The mean dietary intake of rare earth oxides for the whole population was 4.20 µg/kg bw/d, wheat and vegetables (leafy vegetables, allium vegetables and root vegetables) were the main sources of REEs. Dietary intake estimates of REEs by age and gender did not exceed the acceptable daily intake which means implying no impact on human health.