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The extensive application of Tetrabromobisphenol A (TBBPA) leads to the pollution of part of the water environment and brings great safety risks to aquatic animals. As a natural extract, tea polyphenols (TPs) have antioxidant and anti-inflammatory effects. Gills are one of the immune organs of fish and constitute the first line of defense of the immune system. However, it was unclear whether TPs could mitigate TBBPA-induced gills injury. Therefore, an animal model was established to investigate the effect of TPs on TBBPA-induced gills. The results indicated that TBBPA changed the coefficient and tissue morphology of carp gills. In addition, TBBPA induced oxidative stress and inflammation, leading to ferroptosis and apoptosis in carp gills. Dietary addition of TPs significantly improved the antioxidant capacity of carp, effectively inhibited the overexpression of TLR4/NF-κB and its mediated inflammatory response. Moreover, TPs restored iron metabolism, reduced the expression of pro-apoptotic factors thereby alleviating ferroptosis and apoptosis in carp gills. This study enriched the protective effect of TPs and provided a new way to improve the innate immunity of carp.
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Carpas , Ferroptose , Bifenil Polibromatos , Animais , NF-kappa B/genética , NF-kappa B/metabolismo , Antioxidantes/metabolismo , Receptor 4 Toll-Like/genética , Carpas/metabolismo , Brânquias , Polifenóis/farmacologia , Polifenóis/metabolismo , Transdução de Sinais , Proteínas de Peixes , Inflamação/induzido quimicamente , Inflamação/veterinária , Inflamação/metabolismo , Apoptose , Chá/metabolismoRESUMO
Nano-plastics (NPs) have emerged as a significant environmental pollutant, widely existing in water environment, and pose a serious threat to health and safety with the intake of animals. Skeletal muscle, a vital organ for complex life activities and functional demands, has received limited attention regarding the effects of NPs. In this study, the effects of polystyrene NPs (PS-NPs) on skeletal muscle development were studied by oral administration of different sizes (1 mg/kg) of PS-NPs in mice. The findings revealed that PS-NPs resulted in skeletal muscle damage and significantly hindered muscle differentiation, exhibiting an inverse correlation with PS-NPs particle size. Morphological analysis demonstrated PS-NPs caused partial disruption of muscle fibers, increased spacing between fibers, and lipid accumulation. RT-qPCR and western blots analyses indicated that PS-NPs exposure downregulated the expression of myogenic differentiation-related factors (Myod, Myog and Myh2), activated PPARγ/LXRß pathway, and upregulated the expressions of lipid differentiation-related factors (SREBP1C, SCD-1, FAS, ACC1, CD36/FAT, ADIPOQ, C/EBPα and UCP-1). In vitro experiments, C2C12 cells were used to confirm cellular penetration of PS-NPs (0, 100, 200, 400 µg/mL) through cell membranes along with activation of PPARγ expression. Furthermore, to verify LXRß as a key signaling molecule, silencing RNA transfection experiments were conducted, resulting in no increase in the expressions of PPARγ, LXRß, SREBP1C, FAS, CD36/FAT, ADIPOQ, C/EBPα and UCP-1 even after exposure to PS-NPs. However, the expressions of SCD-1and ACC1 remained unaffected. The present study evidenced that exposure to PS-NPs induced lipid accumulation via the PPARγ/LXRß pathway thereby influencing skeletal muscle development.
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PURPOSE: To investigate the impact of obstructive sleep apnea (OSA) on postoperative delirium (PD), and evaluate the effectiveness of positive airway pressure (PAP) therapy on PD among OSA patients. METHODS: We systematically searched Embase, Cochrane Library and PubMed databases from their establishment to November 27, 2022. A random-effects approach was employed to determine aggregated results. Subgroup and sensitivity analyses were carried out to investigate heterogeneity. RESULTS: Sixteen eligible studies were included in the analysis. Thirteen studies revealed that OSA significantly elevated the likelihood of developing PD (OR = 1.71; 95%CI = 1.17 to 2.49; p = 0.005). Subgroup analysis according to delirium assessment scales showed that OSA did not exhibit an association with the incidence of PD assessed by the Confusion Assessment Method-Intensive Care Unit (OR = 1.14; 95%CI = 0.77 to 1.67; p = 0.51) but enhanced the likelihood of developing PD evaluated with other measurement scales (OR = 2.15; 95%CI = 1.44 to 3.19; p = 0.0002). Three additional studies explored the impact of PAP treatment on PD among OSA individuals, indicating no significant reduction in PD incidence with PAP use (OR = 0.58; 95%CI = 0.13 to 2.47; p = 0.46). CONCLUSIONS: OSA may not be a risk factor for PD in critically ill patients in the intensive care unit, but may increase the likelihood of developing PD among individuals receiving regular care in the ward postoperatively. The efficacy of PAP therapy in decreasing PD incidence among OSA patients remains debatable.
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Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC's protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.
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Carcinoma de Células Renais , Aprendizado Profundo , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Células Endoteliais , Algoritmos , Análise de Célula Única , Antimetabólitos , Metilases de Modificação do DNA , Descoberta de Drogas , Neoplasias Renais/tratamento farmacológico , DNA , Microambiente TumoralRESUMO
A lack of the trace element zinc (Zn) in freshwater environments causes slow growth and malnutrition and affects the normal biological functions of organisms. In this study, a Zn deficiency model of grass carp hepatocytes was established with TPEN. Acetylcysteine (NAC) was used as an inhibitor. TPEN was added to L8824 cell culture medium, and LDH, AST, ALT, and AKP activities were enhanced in a Zn-deficient environment, leading to abnormal hepatopancreas function. Fluorescence microscopy showed an increase in ROS levels, and antioxidant enzyme activity assays revealed that SOD, CAT, GSH-PX, and T-AOC activities were decreased, indicating oxidative stress caused by Zn deficiency. The RTâPCR results showed that the mRNA expression of GRP78, PERK, EIF2α, ATF4, and Chop was increased due to the addition of TPEN. Calcium kits showed increased Ca2+ levels. The RTâPCR results showed that the mRNA expression levels of Caspase-12, Caspase-9, Caspase-3, and PARP apoptotic were increased due to the addition of TPEN. RTâPCR and ELISA showed that the expression levels of interleukin-1ß (IL-1ß), interleukin-8 (IL-8), tumour necrosis factor (TNF-α), and inducible nitric oxide synthase (iNOS) were increased. This led to the conclusion that Zn deficiency in the freshwater environment caused inflammation and apoptosis in hepatocytes in grass carp. For the first time, apoptosis caused by endoplasmic reticulum stress in grass carp hepatocytes due to Zn deficiency was studied in the context of Ca2+. The present study provided some insight into the adverse effects of Zn deficiency in freshwater environments on fish.
Assuntos
Carpas , Desnutrição , Animais , Dieta , Inflamação/induzido quimicamente , Inflamação/veterinária , Estresse Oxidativo , Apoptose , Hepatócitos , Zinco/farmacologia , Estresse do Retículo Endoplasmático , RNA MensageiroRESUMO
Microplastics (MPs) have attracted widespread attention as an emerging environmental pollutant. Especially in aquatic ecosystems, the harm of MPs to aquatic animals has increasingly become a severe environmental problem. In this study, we constructed a carp polystyrene microplastics (PS-MPs) exposure model to explore the damage and mechanism of PS-MPs exposure to carp myocardial tissue. The results of H&E, TUNEL, and AO/EB staining showed that PS-MPs exposure could induce inflammation, apoptosis, and necrosis in carp myocardial tissue and cardiomyocytes. In addition, our study explored the targeting relationship between PS-MPs and TLR4 and found that PS-MPs exposure could significantly increase the expression of TLR4 pathway-related factors. As the concentration of PS-MPs increased, the NF-κB pathway and inflammation-related factors increased dose-dependent. In addition, myocardial injury induced by exposure to PS-MPs was predominantly apoptotic, accompanied by necrosis. In short, our data suggest that PS-MPs cause damage to myocardial tissue via the TLR4\NF-κB pathway. The above findings enrich the theory of toxicological studies on PS-MPs and provide an essential reference for aquaculture.
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Carpas , Poluentes Químicos da Água , Animais , NF-kappa B , Microplásticos/toxicidade , Plásticos , Poliestirenos/toxicidade , Receptor 4 Toll-Like/genética , Ecossistema , Morte Celular , Necrose , Inflamação/induzido quimicamente , Inflamação/veterinária , Poluentes Químicos da Água/toxicidadeRESUMO
Selenium (Se), one of the essential trace elements of fish, regulates immune system function and maintains immune homeostasis. Muscle is the important tissue that generate movement and maintain posture. At present, there are few studies on the effects of Se deficiency on carp muscle. In this experiment, carps were fed with dietary with different Se content to successfully establish a Se deficiency model. Low-Se dietary led to the decrease of Se content in muscle. Histological analysis showed that Se deficiency resulted in muscle fiber fragmentation, dissolution, disarrangement and increased myocyte apoptosis. Transcriptome revealed a total of 367 differentially expressed genes (DEGs) were screened, including 213 up-regulated DEGs and 154 down-regulated DEGs. Bioinformatics analysis showed that DEGs were concentrated in oxidation-reduction process, inflammation and apoptosis, and were related to NF-κB and MAPKs pathways. Further exploration of the mechanism showed that Se deficiency led to excessive accumulation of ROS, decreased the activity of antioxidant enzymes, and also resulted in increased expression of the NF-κB and MAPKs pathways. In addition, Se deficiency significantly increased the expressions of TNF-α, IL-1ß and IL-6, and the pro-apoptotic factors BAX, p53, caspase-7 and caspase-3, while decreased the expressions of anti-apoptotic factors Bcl-2 and Bcl-xl. In conclusion, Se deficiency reduced the activities of antioxidant enzymes and led to excessive accumulation of ROS, which caused oxidative stress and affected the immune function of carp, leading to muscle inflammation and apoptosis.
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Carpas , Desnutrição , Selênio , Animais , Antioxidantes/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Suplementos Nutricionais , Selênio/metabolismo , Carpas/genética , Carpas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Imunidade Inata , Transdução de Sinais , Inflamação/veterinária , Apoptose , Músculos/metabolismoRESUMO
Microplastics cause varying degrees of damage to aquatic organisms. Exposure to microplastics contaminated water, the gills are among the first tissues, after the skin, to be affected by microplastics. As an essential immune organ, prolonged stimulation by microplastics disrupts immune function not only in the gills but throughout the body, yet the underlying mechanisms remain elusive. A model of gill injury from exposure to polyethylene (PE) microplastics was developed in this study. H&E staining revealed that polyethylene microplastics caused gill inflammation, vascular remodeling, and mucous cell proliferation. An increase in collagen indicates severe tissue damage. Additional analysis showed that polyethylene microplastics profoundly exacerbated oxidative stress in the gills. TUNEL assay demonstrated cell apoptosis induced by polyethylene microplastic. The mRNA levels were subsequently quantified using RT-PCR. The results showed that polyethylene microplastics increased the expression of the nuclear factor-κB (NF-κB) pathway (NF-κB p65, IKKα, IKKß) and apoptosis biomarkers (p53, caspase-3, caspase-9, and Bax). Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasomes, which is an influential component of innate immunity, were overactive. What's more, the pro-inflammatory factors (TNF-α, IFN-γ, IL-2, IL-6, IL-8, IL-1ß) that induce immune disorder also increased significantly, while the anti-inflammatory factors (IL-4, IL-10) decreased significantly. These results suggested that oxidative stress acted as an activation signal of apoptosis triggered by the NF-κB pathway and activating the NLRP3 inflammasome to promote inflammatory immune responses. The present study provided a different target for the prevention of toxin-induced gill injury under polyethylene microplastics.
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Carpas , Inflamassomos , Animais , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Microplásticos/toxicidade , Plásticos , Brânquias/metabolismo , Polietileno , Transdução de Sinais , Carpas/metabolismo , Inflamação/induzido quimicamente , Inflamação/veterinária , Inflamação/metabolismo , Apoptose , Estresse OxidativoRESUMO
Polystyrene microplastics (PS-MPs) affect the immune defense function on carp (Cyprinus carpio). The PS-MPs model of carp was established by feeding with PS-MPs particle size of 8 µm and concentration of 1000 ng/L water. Hepatopancreas function test revealed the activities of AKP, ALT, AST and LDH abnormal increase. PS-MPs induced tissue damage and lead to abnormal hepatopancreas function. The PS-MPs also induced a oxidative stress with the antioxidant enzymes SOD, CAT, GSH-PX, and T-AOC activities decreasing and reactive oxygen species (ROS) excessive accumulation. PS-MPs activated the Toll like receptor-2 (TLR2) signaling pathway. The mRNA and protein expressions of TLR2, Myeloid differentiation primary response 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6), NF-κB p65, Tumor necrosis factor (TNF-α), Interleukin-1ß (IL-1ß), Inducible Nitric Oxide Synthase (iNOS), and cycooxygenase 2(COX2) was revealed increased in both hepatopancreas and hepatocytes with the qPCR and Western blotting analysis mode. ELISA showed the expressions of TNF-α, IL-1ß, iNOS, and COX2 inflammatory molecule were increased in both hepatopancreas and hepatocytes. The results showed that PS-MPs caused a serious injure in the hepatopancreas and brought serious effects on the inflammatory response of carp. The present study displayed the harm caused by PS-MPs in freshwater fish, and provided some suggestions and references for toxicological studies of microplastics in freshwater environment.
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Carpas , Microplásticos , Animais , Microplásticos/toxicidade , Poliestirenos/toxicidade , Espécies Reativas de Oxigênio , Plásticos , Fator de Necrose Tumoral alfa , Receptor 2 Toll-Like , Ciclo-Oxigenase 2 , Hepatopâncreas , Inflamação/veterináriaRESUMO
Trimethyltin (TMT) is widely used as a major component of plastic stabilizers in agriculture and industry, and can accumulate in large quantities in the liver. To investigate the relationship between liver tissue damage induced by TMT exposure and YAP phosphorylation in mice, we gave the mice drinking water containing 0.01 mg/mL TMT for 14 days to establish an in vivo experimental model, and continuously treated AML12 cells with 20 µM TMT for 24 h to establish an in vitro experimental model. Transcriptomics revealed that TMT exposure altered 62,466 apparently diversely expressed genes, including 1197 upregulated and 899 downregulated genes, and that enrichment of the Hippo pathway occurred. Moreover, western blotting (WB) and quantitative real-time PCR (qRTPCR) results showed that TMT exposure triggered an increase in the expression of P-YAP, apoptosis and necroptosis-interrelated genes, and a decrease in Bcl-2 expression in mouse livers tissues and AML12 cells. The expression of P-YAP was significantly suppressed in the TRULI-treated TMT-exposed AML12 cells, while oxidative stress levels and damage were also significantly attenuated. In conclusion, TMT triggers YAP phosphorylation to induce oxidative stress inducing apoptosis and necroptosis in mouse livers tissues. Our results confirm the liver toxic effect and specific mechanism of TMT.
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Necroptose , Estresse Oxidativo , Animais , Camundongos , Fosforilação , Apoptose , FígadoRESUMO
Trimethyltin chloride (TMT) is an organotin heat stabilizer that is widely used in the production of plastics, and has strong toxicity. Here, the effect of trimethyltin chloride on mouse kidneys and its related mechanism were studied by taking TMT mouse with drinking water as a model. Histological examination and TUNEL results showed that the trimethyltin chloride group had typical apoptosis and necroptosis characteristics. Therefore, the level of oxidative stress was detected,and the expression of related genes was verified by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot methods. The results showed that oxidative stress was activated (MDA,SOD,CAT,T-AOC), released ROS, activated NF-κB pathway,activated inflammasome (NLRP3,Caspase-1,ASC), and inflammasome-secreted inflammatory factors (IL-1ß). The expression of apoptosis (BCL-2, BAX, Caspase-3, Caspase-9) and necroptosis (RIPK1, RIPK33, MLKL, Caspase-8) increased.In addition, HEK293T human embryonic kidney cells were treated with trimethyltin chloride, and the results were similar to the tissue. In conclusion, TMT can induce oxidative stress, activate NF-κB pathway, and induce apoptosis and necroptosis through inflammasomes.
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The flexoelectric effect, which manifests itself as a strain-gradient-induced electrical polarization, has triggered great interest due to its ubiquitous existence in crystalline materials without the limitation of lattice symmetry. Here, we propose a flexoelectric photodetector based on a thin-film heterostructure. This prototypical device is demonstrated by epitaxial LaFeO3 thin films grown on LaAlO3 substrates. A giant strain gradient of the order of 106/m is achieved in LaFeO3 thin films, giving rise to an obvious flexoelectric polarization and generating a significant photovoltaic effect in the LaFeO3-based heterostructures with nanosecond response under light illumination. This work not only demonstrates a novel self-powered photodetector different from the traditional interface-type structures, such as the p-n and Schottky junctions but also opens an avenue to design practical flexoelectric devices for nanoelectronics applications.
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Staphylococcus aureus (S. aureus)-induced mastitis is the most frequent, pathogenic, and prevalent infection of the mammary gland. The ligand growth arrest-specific 6 (Gas6) is a secretory protein that binds to and activates Tyro3, Axl, and MerTK receptors. This study explored the role of Gas6 in S. aureus-induced mastitis. Our results revealed that TLR receptors initiate the innate immune response in mammary gland tissues and epithelial cells and that introducing S. aureus activates TLR2 and TLR6 to drive multiple intracellular mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) pathways. Moreover, S. aureus also induces Gas6, which then activates the TAM receptor kinase pathway, which is related to the inhibition of TLR2- and TLR6-mediated inflammatory pathways through SOCS1 and SOCS3 induction. Gas6 absence alone was found to be involved in the downregulation of TAM receptor-mediated anti-inflammatory effects by inducing significantly prominent expression of TRAF6 and low protein and messenger RNA expression of SOCS1 and SOCS3. S. aureus-induced MAPK and NF-ĸB p65 phosphorylation were also dependent on Gas6, which negatively regulated the production of Pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) in S. aureus-treated mammary tissues and mammary epithelial cells. Our in vivo and in vitro study uncovered the Gas6-mediated negative feedback mechanism, which inhibits TLR2- and TLR6-mediated MAPK and NF-ĸB signaling by activating TAM receptor kinase (MerTK, Axl, and Tyro3) through the induction of SOCS1/SOCS3 proteins.
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Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Glândulas Mamárias Animais/metabolismo , Transdução de Sinais/fisiologia , Infecções Estafilocócicas/metabolismo , Receptores Toll-Like/metabolismo , Animais , Células Cultivadas , Citocinas/metabolismo , Regulação para Baixo/fisiologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Inflamação/microbiologia , Glândulas Mamárias Animais/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/patogenicidadeRESUMO
Acute lung inflammation is one among the top of infectious diseases. It is a pulmonary dysfunctional disease. It breaks the physiological coordination in the structures and functions of respiratory system. There are a few effective treatments to minimize the mortality of acute lung inflammation. It was induced by Staphylococcus aureus (S. aureus) via nasal instillation of mice. The common ivy (Hedera helix) is the most significant medicinal plant and considered as a traditional medicinal plant. The most active ingredient in the extract of ivy plant was Hederacoside-C (HDC). The purpose of this study was to investigate its anti-inflammatory effects on induced acute lung inflammation in vivo and (RAW 264.7â¯cells) in vitro and to elucidate its anti-inflammatory mechanisms. HDC was administered intraperitoneally 1â¯h after infection until 24â¯h. The dose was repeated every 8â¯h for three successful doses. Mice treated with HDC significantly reduced the pulmonary edema, white blood cells, wet-dry ratio (W/D) and myeloperoxidase (MPO) activity. HDC attenuated protein expression levels of MAPKs including p38, ERK, JNK and NF-κB including p65 and IκB-α pathways analyzed by ELISA. HDC also suppressed the protein expressions of TLR2 & TLR4 detected by Western blot. HDC also downregulated the gene expression of pro-inflammatory cytokines including IL-6, IL-1ß and TNF-α, but upregulated the gene expression of an anti-inflammatory cytokine IL-10 analyzed by qRT-PCR. In conclusion, our results stated that HDC could inhibit the S. aureus induced acute lung inflammation and it may be a potential therapeutic drug against acute lung inflammation.
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Anti-Inflamatórios/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Hedera/química , Ácido Oleanólico/análogos & derivados , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Feminino , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Ácido Oleanólico/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Infecções Estafilocócicas/genética , Staphylococcus aureus/genética , Staphylococcus aureus/fisiologia , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Due to its special aromatic structure, isorenieratene is thought to be an active natural antioxidant and photo/UV damage inhibitor. In this work, isorenieratene that was extracted from Rhodococcus sp. B7740 isolated from the Arctic Ocean, showed excellent scavenging ability of both singlet oxygen and hydroxyl radical in the UVB-induced auto-oxidation process using the EPR method. Within an ARPE-19 cell model damaged by UVB radiation, isorenieratene showed fine protective effects (1.13 ± 0.03 fold) compared with macular xanthophylls (MXs) through upregulating of tspo. The molecular docking was firstly performed to investigate the interaction of isorenieratene with TSPO as a special ligand. Results showed isorenieratene might form a better binding conformation (S-score -8.5438) than MXs and indicate that isorenieratene not only can function as a direct antioxidant but also activate tspo in ARPE-19 cells. Thus, isorenieratene might ease the UV-related damages including age-related macular degeneration (AMD).
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Carotenoides/farmacologia , Células/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Receptores de GABA/metabolismo , Rhodococcus/química , Animais , Regiões Árticas , Carotenoides/isolamento & purificação , Linhagem Celular , Células/efeitos da radiação , Citoproteção/efeitos dos fármacos , Humanos , Ligantes , Camundongos , Modelos Moleculares , Oceanos e Mares , Estresse Oxidativo/efeitos da radiação , Fenóis/isolamento & purificação , Extratos Vegetais/farmacologia , Estrutura Terciária de Proteína , Protetores contra Radiação/química , Protetores contra Radiação/farmacologia , Raios Ultravioleta/efeitos adversosRESUMO
There is a continued need to develop new selective human monoamine oxidase (hMAO) inhibitors that could be beneficial for the treatment of neurological diseases. However, hMAOs are closely related with high sequence identity and structural similarity, which hinders the development of selective MAO inhibitors. "Three-Dimensional Biologically Relevant Spectrum (BRS-3D)" method developed by our group has demonstrated its effectiveness in subtype selectivity studies of receptor and enzyme ligands. Here, we report a series of novel C7-substituted coumarins, either synthesized or commercially purchased, which were identified as selective hMAO inhibitors. Most of the compounds demonstrated strong activities with IC50 values (half-inhibitory concentration) ranging from sub-micromolar to nanomolar. Compounds, FR1 and SP1, were identified as the most selective hMAO-A inhibitors, with IC50 values of 1.5 nM (selectivity index (SI) < -2.82) and 19 nM (SI < -2.42), respectively. FR4 and FR5 showed the most potent hMAO-B inhibitory activity, with IC50 of 18 nM and 15 nM (SI > 2.74 and SI > 2.82). Docking calculations and molecular dynamic simulations were performed to elucidate the selectivity preference and SAR profiles.
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Cumarínicos/química , Cumarínicos/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Leptospira interrogans (L. interrogans), a worldwide zoonosis, infect humans and animals. In dogs, four syndromes caused by leptospirosis have been identified: icteric, hemorrhagic, uremic (Stuttgart disease) and reproductive (abortion and premature or weak pups), and also it caused inflammation. Extracellular matrix (ECM) is a complex mixture of matrix molecules that is crucial to the reproduction. Both inflammatory response and ECM are closed relative to reproductive. The aim of this study was to clarify how L. interrogans affected the uterus of dogs, by focusing on the inflammatory responses, and ECM expression in dogs uterine tissue infected by L. interrogans. In the present study, 27 dogs were divided into 3 groups, intrauterine infusion with L. interrogans, to make uterine infection, sterile EMJH, and normal saline as a control, respectively. The uteruses were removed by surgical operation in 10, 20, and 30 days, respectively. The methods of histopathological analysis, ELISA, Western blot and qPCR were used. The results showed that L. interrogans induced significantly inflammatory responses, which were characterized by inflammatory cellular infiltration and high expression levels of tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in uterine tissue of these dogs. Furthermore, L. interrogans strongly down-regulated the expression of ECM (collagens (CL) IV, fibronectins (FN) and laminins (LN)) in mRNA and protein levels. These data indicated that strongly inflammatory responses, and abnormal regulation of ECM might contribute to the proliferation of dogs infected by L. interrogans.
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Proteínas da Matriz Extracelular/biossíntese , Inflamação/patologia , Leptospira interrogans/fisiologia , Leptospirose/patologia , Útero/patologia , Animais , Western Blotting , Citocinas/biossíntese , Modelos Animais de Doenças , Cães , Ensaio de Imunoadsorção Enzimática , Feminino , Histocitoquímica , Leptospira interrogans/imunologia , Leptospira interrogans/patogenicidade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Tea brewed from the leaves of persimmon or Rosa agrestis have several medical functions including treating allergy, antiatopic dermatitis, and anti-inflammatory effects. The objective of this study was to investigate the molecular mechanisms of astragalin, a main flavonoid component isolated from these herbs, in modifying lipopolysaccharide (LPS)-induced signaling pathways in primary cultured mouse mammary epithelial cells (mMECs). MATERIALS AND METHODS: The mMECs were treated with LPS in the absence or presence of different concentrations of astragalin. The expression of proinflammatory cytokines tumor necrosis factor α, and interleukin 6, as well as nitric oxide production were determined by enzyme-linked immunosorbent assay and Griess reaction, respectively. Cyclooxygenase-2, inducible nitric oxide synthase, toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), inhibitor protein of NF-κB (IκBα), P38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase were measured by Western blot. RESULTS: The results showed that astragalin suppressed the expression of tumor necrosis factor α, interleukin 6, and nitric oxide in a dose-dependent manner in mMECs. Western blot results showed that the expression of inducible nitric oxide synthase and cyclooxygenase-2 was inhibited by astragalin. Besides, astragalin efficiently decreased LPS-induced TLR4 expression, NF-κB activation, IκBα degradation, and the phosphorylation of p38, extracellular signal-regulated kinase in BMECs. CONCLUSIONS: Our results indicated that astragalin exerts anti-inflammatory properties possibly via the inactivation of TLR4-mediated NF-κB and mitogen-activated protein kinases signaling pathways in LPS-stimulated mMECs. Thus, astragalin may be a potential therapeutic agent for bovine mastitis.
Assuntos
Anti-Inflamatórios/farmacologia , Quempferóis/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Mastite/tratamento farmacológico , Preparações de Plantas/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Diospyros/química , Interações Medicamentosas , Feminino , Interleucina-6/metabolismo , Quempferóis/química , Lipopolissacarídeos/farmacologia , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/imunologia , Mastite/induzido quimicamente , Mastite/imunologia , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Preparações de Plantas/química , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Soil microbial communities are major drivers of cycling of soil nutrients that sustain plant growth and productivity. Yet, a holistic understanding of the impact of abandoned agricultural land reclamation on the soil microbe is still poorly understood, especially for the microbial community assembly mechanisms. Here, we investigated the influence of reclamation on the relative importance of stochastic and deterministic processes in shaping microbial community assembly. After reclaiming abandoned cropland for corn and soybean cultivation, the fungal community assembly was shifted to stochastic processes, while bacterial communities remained predominantly influenced by stochastic processes. Our study revealed that reclamation did not significantly affect bacterial diversity, community niche breadth, and community similarity. In contrast, fungal communities exhibited lower alpha diversity, narrower niche breadths, greater niche overlap and higher community similarity in corn and soybean cultivation treatment in response to reclamation. Moreover, soil pH and soil available phosphorus were the most important environmental factors influencing fungal richness, niche breadths, community assembly processes, and community similarity. Together, the reclamation of abandoned cropland promoted the transformation of the fungal community assembly from deterministic process to a stochastic process, leading to decreased fungal diversity and broader ecological niche width, ultimately resulting in greater similarity among fungal communities. This finding provides insight into the varied responses of microbial diversity and ecological process to abandoned cropland reclamation, offering valuable guidance for the conservation and sustainable management of abandoned cropland in future land-use practices.
RESUMO
This study utilizes panel data from 30 provinces in mainland China from 2011 to 2020 to investigate the impact of carbon-neutral development on economic high-quality development by constructing an economic high-quality development index and a carbon-neutral development index. Firstly, the study examines the effects of carbon-neutral development on economic high-quality development using baseline regression and spatial Durbin regression. The results indicate that carbon-neutral development has a positive direct effect on economic high-quality growth, but there are negative spatial spillover effects. Secondly, this study employs total factor productivity (TFP) as an intermediate variable in the mediation model regression. The findings demonstrate that carbon-neutral development significantly improves TFP, and the significant improvement in TFP promotes high-quality economic growth. Lastly, the study conducts regional heterogeneity analysis and finds a significant promoting effect of carbon-neutral development on economic high-quality development in the eastern and central regions of China, while it is not significant in the western region. Therefore, it is recommended that China, in the process of achieving carbon-neutral growth, consider the geographical connections between different regions to prevent negative spillover effects. Additionally, regional heterogeneity should be taken into account when formulating relevant policies to promote economic high-quality development.