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Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease worldwide, without any Food and Drug Administration-approved pharmacological intervention in clinic. Trim38, as an important member of the TRIM (tripartite motif-containing) family, was largely reported to be involved in the regulation of innate immune and inflammatory responses. However, the functional roles of TRIM38 in NAFLD remain largely unknown. Here, the expression of TRIM38 was first detected in liver samples of both NAFLD mice model and patients diagnosed with NAFLD. We found that TRIM38 expression was downregulated in NAFLD liver tissues compared with normal liver tissues. Genetic Trim38-KO in vivo showed that TRIM38 depletion deteriorated the high-fat diet and high fat and high cholesterol diet-induced hepatic steatosis and high fat and high cholesterol diet-induced liver inflammation and fibrosis. In particular, we found that the effects of hepatocellular lipid accumulation and inflammation induced by palmitic acid and oleic acid were aggravated by TRIM38 depletion but mitigated by TRIM38 overexpression in vitro. Mechanically, RNA-Seq analysis demonstrated that TRIM38 ameliorated nonalcoholic steatohepatitis progression by attenuating the activation of MAPK signaling pathway. We further found that TRIM38 interacted with transforming growth factor-ß-activated kinase 1 binding protein 2 and promoted its protein degradation, thus inhibiting the transforming growth factor-ß-activated kinase 1-MAPK signal cascades. In summary, our study revealed that TRIM38 could suppress hepatic steatosis, inflammatory, and fibrosis in NAFLD via promoting transforming growth factor-ß-activated kinase 1 binding protein 2 degradation. TRIM38 could be a potential target for NAFLD treatment.
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Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Proteínas de Transporte/metabolismo , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Chemotherapy related cognitive impairment (CRCI) has seriously affected the quality of life (QOL) of patients with breast cancer (BCs), thus the neurobiological mechanism of CRCI attracted widespread attention. Previous studies have found that chemotherapy causes CRCI through affecting brain structure, function, metabolism, and blood perfusion. FINDINGS: A variety of neuroimaging techniques such as functional magnetic resonance imaging (fMRI), event-related potential (ERP), near-infrared spectroscopy (NIRS) have been widely applied to explore the neurobiological mechanism of CRCI. CONCLUSION: This review summarized the progress of neuroimaging research in BCs with CRCI, which provides a theoretical basis for further exploration of CRCI mechanism, disease diagnosis and symptom intervention in the future. Multiple neuroimaging techniques for CRCI research.
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Neoplasias da Mama , Comprometimento Cognitivo Relacionado à Quimioterapia , Disfunção Cognitiva , Humanos , Feminino , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Comprometimento Cognitivo Relacionado à Quimioterapia/complicações , Qualidade de Vida , NeuroimagemRESUMO
BACKGROUND AND AIMS: Milk fat globule-epidermal growth factor-factor 8 (MFGE8) has been shown to be a critical extracellular molecule that mediates apoptotic signaling in the pathological process of nonalcoholic fatty liver disease (NAFLD). MFGE8 is abundantly expressed in hepatocytes, but its function in the pathogenesis of NAFLD has not been characterized. APPROACH AND RESULTS: In our current study, hepatic MFGE8 showed a protective role in the pathogenesis of NAFLD. Hepatic MFGE8 deletion largely exacerbated lipid accumulation and inflammatory responses in the liver in response to overnutrition. Mechanistically, intercellular MFGE8 was shown to directly bind to apoptosis signal-regulating kinase 1 (ASK1) and to inhibit its dimerization and phosphorylation under a normal diet. However, under metabolic challenges, decreased cytoplasmic MFGE8 facilitated the dimerization and phosphorylation of ASK1 and subsequent mitogen-activated protein kinase signaling in hepatocytes. CONCLUSIONS: Hepatic MFGE8 is an endogenous inhibitor that halts the progression of hepatic steatosis and inflammation. Metabolic challenge-induced loss of intracellular MFGE8 facilitates ASK1 dimerization and phosphorylation. Therefore, maintaining hepatic MFGE8 levels may serve as an alternative strategy for the treatment of NAFLD.
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Antígenos de Superfície/metabolismo , Fígado/patologia , Proteínas do Leite/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Animais , Antígenos de Superfície/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Hepatócitos , Humanos , Metabolismo dos Lipídeos/imunologia , Fígado/imunologia , MAP Quinase Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Masculino , Camundongos , Camundongos Knockout , Proteínas do Leite/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Fosforilação/imunologia , Multimerização Proteica/imunologiaRESUMO
Inadequate fetomaternal interactions could directly lead to pregnancy failure in dairy cows. Exosomes are widely involved in endometrial matrix remodeling, immune function changes, placental development, and other processes of embryo implantation and pregnancy in dairy cows. However, the role of exosomes derived from placental trophoblast cells in regulating the receptivity of endometrial cells and facilitating fetomaternal interaction remains unclear. In this study, bovine trophoblast cells (BTCs) were obtained from bovine placenta and immortalized by transfection with telomerase reverse transcriptase (TERT). Immortalized BTCs still possess the basic and key properties of primary BTCs without exhibiting any neoplastic transformation signs. Subsequently, the effect of trophoblast-derived exosomes (TDEs) on endometrial receptivity in endometrial epithelial cells (EECs) was determined, and the mechanism whereby TDEs and their proteins participate in the fetomaternal interaction during bovine pregnancy were explored. EECs were co-cultured with the exosomes derived from BTCs treated with progesterone (P4). Such treatment enhanced the expression of the endometrial receptivity factors, integrin αv, ß3, Wnt7a, and MUC1 by changing the extracellular environment, metabolism, and redox balance in EECs via proteome alignment, compared with no treatment according to the DIA quantitation analysis. Our study demonstrated that trophoblast-derived exosome proteins are one of the most critical elements in fetomaternal interaction, and their changes may act as a key signal in altering endometrial receptivity and provide a potential target for improving fertility.
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Exossomos , Trofoblastos , Animais , Bovinos , Implantação do Embrião/fisiologia , Endométrio/metabolismo , Células Epiteliais/metabolismo , Exossomos/metabolismo , Feminino , Placenta , Gravidez , Trofoblastos/metabolismoRESUMO
BACKGROUND: Cooking oil is an indispensable component of the human diet. However, oils usually undergo thermal oxidation. Oxidized soybean oil (OSO) has been shown to have detrimental effects on humans and has emerged as a root cause of many chronic diseases. The objective of this work was to evaluate the effects of puerpera exposure to OSO on kidney damage in the mother and offspring using lactating rats as an experimental model. RESULTS: Pathological sections and ultrastructure showed that OSO exposure resulted in various levels of damage to lactating rats and their offspring. OSO induced oxidative stress in the kidneys of lactating rats, as evidenced by increased levels of hydrogen peroxide, interleukin (IL)-1ß, and IL-8. OSO increased the activities of glutathione peroxidase and superoxide dismutase. OSO upregulated the expression of apoptosis-related genes, nuclear factor-erythroid 2-related factor 2 (Nrf2), and nuclear factor κB-related inflammatory factor genes. In the offspring of the OSO-exposed mothers, hydrogen peroxide, malondialdehyde, IL-6, and tumor necrosis factor-alpha contents were increased. Furthermore, OSO enhanced the levels of Nrf2, NAD(P)H quinone oxidoreductase 1, heme oxygenase 1, and p65 and decreased B-cell lymphoma 2. CONCLUSION: These findings indicated that the kidneys of two generations of rats were compromised by oxidative damage when fed OSO during lactation. This study provides evidence for increasing the genes expression of the Nrf2/heme oxygenase 1 pathway to alleviate the kidney damage caused by OSO in the mother and offspring. © 2021 Society of Chemical Industry.
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Fator 2 Relacionado a NF-E2 , NF-kappa B , Animais , Feminino , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Peróxido de Hidrogênio/metabolismo , Rim/metabolismo , Lactação , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Transdução de Sinais , Óleo de Soja/químicaRESUMO
PURPOSE: To better understand the longitudinal risks and benefits of telephone disclosure of genetic test results in the era of multigene panel testing. METHODS: Adults who were proceeding with germline cancer genetic testing were randomized to telephone disclosure (TD) with a genetic counselor or in-person disclosure (IPD) (i.e., usual care) of test results. All participants who received TD were recommended to return to meet with a physician to discuss medical management recommendations. RESULTS: Four hundred seventy-three participants were randomized to TD and 497 to IPD. There were no differences between arms for any cognitive, affective, or behavioral outcomes at 6 and 12 months. Only 50% of participants in the TD arm returned for the medical follow-up appointment. Returning was associated with site (p < 0.0001), being female (p = 0.047), and not having a true negative result (p < 0.002). Mammography was lower at 12 months among those who had TD and did not return for medical follow-up (70%) compared with those who had TD and returned (86%) and those who had IPD (87%, adjusted p < 0.01). CONCLUSION: Telephone disclosure of genetic test results is a reasonable alternative to in-person disclosure, but attention to medical follow-up may remain important for optimizing appropriate use of genetic results.
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Revelação , Aconselhamento Genético , Adulto , Feminino , Seguimentos , Predisposição Genética para Doença , Testes Genéticos , Humanos , TelefoneRESUMO
Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone to in-person disclosure of genetic test results. We evaluated preferences for in-person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in-person disclosure. These patients were more likely to be older (P = 0.007) and to have had multigene panel testing (P < 0.001). General anxiety (P = 0.007), state anxiety (P = 0.008), depression (P = 0.011), cancer-specific distress (P = 0.021) and uncertainty (P = 0.03) were higher after pretest counseling. After disclosure of results, they also had higher general anxiety (P = 0.003), depression (P = 0.002) and cancer-specific distress (P = 0.043). While telephone disclosure is a reasonable alternative to in-person disclosure in most patients, some patients have a strong preference for in-person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in-person disclosure should be honored when possible.
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Comunicação , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Preferência do Paciente , Revelação da Verdade , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Aconselhamento Genético/ética , Aconselhamento Genético/métodos , Predisposição Genética para Doença , Testes Genéticos/ética , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Avaliação de Resultados em Cuidados de Saúde , Cooperação do Paciente , TelefoneRESUMO
We conduct first-principles calculations to study oxygen diffusion on the graphene surface as a function of temperature up to 3000 K. The minimum energy migration path and the corresponding activation energy are determined by the nudged elastic band method with explicit inclusion of thermal electronic excitations. Below 1000 K the activation energy for epoxy oxygen to migrate remains close to its room temperature value (0.72 eV). Above 1000 K the activation energy decreases near linearly with temperature, from 0.70 eV at 1000 K to 0.47 eV at 3000 K. We show that this reduction originates from thermal electronic excitations. In particular, the effect is determined by the large contrasts in the electronic structures of the initial and transition states: the transition state exhibits much larger electronic density of states near the Fermi level and is more susceptible to thermal electronic excitations. The reduction in activation energy leads to appreciable enhancement in the diffusivity of oxygen adatoms. A moderate decrease in the vibrational prefactor, also caused by thermal electronic excitations, does not alter this trend. These findings may facilitate future works to accurately describe the dynamics of O adatoms on graphene at high T, which are critical for determining surface thermodynamic properties such as equilibrium coverage.
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BACKGROUND: Despite regional brain structural changes having been reported in patients with chronic low back pain (CLBP), the topological properties of structural covariance networks (SCNs), which refer to the organization of the SCNs, remain unclear. This study applied graph theoretical analysis to explore the alterations of the topological properties of SCNs, aiming to comprehend the integration and separation of SCNs in patients with CLBP. METHODS: A total of 38 patients with CLBP and 38 healthy controls (HCs), balanced for age and sex, were scanned using three-dimensional T1-weighted magnetic resonance imaging. The cortical thickness was extracted from 68 brain regions, according to the Desikan-Killiany atlas, and used to reconstruct the SCNs. Subsequently, graph theoretical analysis was employed to evaluate the alterations of the topological properties in the SCNs of patients with CLBP. RESULTS: In comparison to HCs, patients with CLBP had less cortical thickness in the left superior frontal cortex. Additionally, the cortical thickness of the left superior frontal cortex was negatively correlated with the Visual Analogue Scale scores of patients with CLBP. Furthermore, patients with CLBP, relative to HCs, exhibited lower global efficiency and small-worldness, as well as a longer characteristic path length. This indicates a decline in the brain's capacity to transmit and process information, potentially impacting the processing of pain signals in patients with CLBP and contributing to the development of CLBP. In contrast, there were no significant differences in the clustering coefficient, local efficiency, nodal efficiency, nodal betweenness centrality, or nodal degree between the two groups. CONCLUSIONS: From the regional cortical thickness to the complex brain network level, our study demonstrated changes in the cortical thickness and topological properties of the SCNs in patients with CLBP, thus aiding in a better understanding of the pathophysiological mechanisms of CLBP.
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Córtex Cerebral , Dor Crônica , Dor Lombar , Imageamento por Ressonância Magnética , Humanos , Feminino , Masculino , Dor Lombar/diagnóstico por imagem , Dor Lombar/patologia , Adulto , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Dor Crônica/diagnóstico por imagem , Dor Crônica/patologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologiaRESUMO
Background: Neuroimaging studies have suggested a pivotal role for the amygdala involvement in chronic low back pain (CLBP). However, the relationship between the amygdala subregions and CLBP has not yet been delineated. This study aimed to analyze whether the amygdala subregions were linked to the development of CLBP. Methods: A total of 45 patients with CLBP and 45 healthy controls (HCs) were included in this study. All subjects were asked to complete a three-dimensional T1-weighted magnetic resonance imaging (3D-T1 MRI) scan. FreeSurfer 7.3.2 was applied to preprocess the structural MRI images and segment the amygdala into nine subregions. Afterwards, comparisons were made between the two groups in terms of the volumes of the amygdala subregions. Correlation analysis is utilized to examine the relationship between the amygdala subregion and the scale scores, as well as the pain duration in patients with CLBP. Additionally, logistic regression was used to explore the risk of the amygdala and its subregions for CLBP. Results: In comparison to HCs, patients with CLBP exhibited a significant enlargement of the left central nucleus (Ce) and left cortical nucleus (Co). Furthermore, the increased volume of the left Ce was associated with a higher risk of CLBP. Conclusion: Our study suggests that the left Ce and left Co may be involved in the pathophysiological processes of CLBP. Moreover, the volume of the left Ce may be a biomarker for detecting the risk of CLBP.
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The expression profile in the mouse hepatitis B virus X (HBx)-transfected model was investigated in order to lay a foundation for further study on the implication of cytokines expression in hepatitis B virus (HBV) infection. Hydrodynamic injection method via the tail vein was used to establish the animal HBx-transfected model. By using microassay, the differential expression of gene in each group was analyzed, which was further confirmed by using real-time PCR and semi-quantitative PCR. Most of chemokine genes such as Ccl2, Ccl5, Ccl9, MIG and IP-10 were up-regulated in the HBx-transfected mouse model versus the control mice, which was coincided with the microarray results. Western blotting and immunohistochemistry were applied to detect the expression of MIG and IP-10 in the liver tissues. Simultaneously, ELISA was adopted to measure the content of IFN-γ in the liver tissues. DNA microassay revealed that the expression of 611 genes changed in HBx-transfected mice as compared with that in pCMV-tag2B-transfected mice, and most of the screened chemokines were up-regulated (including MIG and IP-10). Additionally, IFN-γ protein levels were increased by 20.7% (P<0.05) in pCMV-tag2B-HBx-transfected mice as compared with the untreated mice. IFN-γ protein levels were reduced by 53.9% (P<0.05) in pCMV-tag2B-transfected mice as compared with the untreated mice, which was consistent with the up-regulation of MIG and IP-10. It was suggested HBx transfection could induce the expression of MIG and IP-10 in the liver tissues, which might play the roles in HBV-related liver immunity and cytokines-mediated antiviral effect.
Assuntos
Quimiocina CXCL10/imunologia , Quimiocina CXCL9/imunologia , Citocinas/imunologia , Vírus da Hepatite B/imunologia , Hepatite B/genética , Hepatite B/imunologia , Transativadores/genética , Animais , DNA Viral/genética , Hepatite B/virologia , Vírus da Hepatite B/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transfecção/métodos , Proteínas Virais Reguladoras e AcessóriasRESUMO
In response to an increasing desire for modern industries to be both green and sustainable, there has been increasing research focus on the reutilization of natural waste materials to effectively remove and degrade toxic wastewater effluents. One interesting food industry waste product is clam shell. Here a new photocatalytic nanomaterial derived from marine clam shells was successfully prepared and characterized. Thereafter the material was applied for the removal of two target dyes from aqueous solution, where the effect of both catalyst dose and initial dye concentration on adsorption and photocatalysis was investigated. The maximum adsorption capacities of methylene blue (100 mg/L) and Congo red (500 mg/L) were 123.45 mg/g and 679.91 mg/g, respectively, where adsorption followed pseudo second order kinetics predominantly via a chemical adsorption process. The photodegradation removal efficiencies of the two dye solutions under visible light irradiation were 99.6% and 83.3% for MB and CR, respectively. The excellent degradation performance in a mixed dye solution, with strong degradation capability and low cost, demonstrated that the clam shell catalyst material was a good candidate for practical field remediation of dye contaminated wastewater.
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Interferon-gamma inducible protein 10 (IP-10) involves inflammatory cell recruitment and cellular immune damage during virus infection. Although an increase of the peripheral IP-10 level is known in HBV-infected patients, the molecular basis of HBV infection inducing IP-10 expression has remained elusive. In the present study, we demonstrate that hepatitis B virus protein X (HBx) increases IP-10 expression in a dose-dependent manner. Transfection of the HBx-expressing vector into HepG2 cells results in nuclear translocation of NF-kappaB, which directly binds the promoter of IP-10 at positions from -122 to -113, thus facilitating transcription. The addition of the NF-kappaB inhibitor blocks the effect of HBx on IP-10 induction. In parallel, increase of NF-kappaB subunits p65 and p50 in HepG2 cells also augments IP-10 expression. Furthermore, we show that HBx induces activation of NF-kappaB through the TRAF2/TAK1 signaling pathway, leading to up-regulation of IP-10 expression. As a consequence, up-regulation of IP-10 may mediate the migration of peripheral blood leukocytes in a NF-kappaB-dependent manner. In conclusion, we report a novel molecular mechanism of HBV infection inducing IP-10 expression, which involves viral protein HBx affecting NF-kappaB pathway, leading to transactivation of the IP-10 promoter. Our study provides insight into the migration of leukocytes in response to HBV infection, thus causing immune pathological injury of liver.
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Quimiocina CXCL10/biossíntese , Quimiocina CXCL10/genética , Vírus da Hepatite B/patogenicidade , NF-kappa B/metabolismo , Transativadores/fisiologia , Regiões 5' não Traduzidas , Transporte Ativo do Núcleo Celular , Adulto , Idoso , Sequência de Bases , Sítios de Ligação/genética , Linhagem Celular , Movimento Celular , Primers do DNA/genética , Feminino , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/genética , Hepatite B Crônica/fisiopatologia , Hepatite B Crônica/virologia , Interações Hospedeiro-Patógeno , Humanos , Leucócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Regiões Promotoras Genéticas , Interferência de RNA , Transdução de Sinais , Transativadores/genética , Ativação Transcricional , Transfecção , Proteínas Virais Reguladoras e AcessóriasRESUMO
First-principles calculations of undoped HfO(2) and cobalt-doped HfO(2) have been carried out to study the magnetic properties of the dielectric material. In contrast to previous reports, it was found that the native defects in HfO(2) could not induce strong ferromagnetism. However, the cobalt substituting hafnium is the most stable defect under oxidation condition, and the ferromagnetic (FM) coupling between the cobalt substitutions is favorable in various configurations. We found that the FM coupling is mediated by the threefold-coordinated oxygen atoms in monoclinic HfO(2) and could be further enhanced in electron-rich condition.
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Cobalto/química , Háfnio/química , Magnetismo , Óxidos/química , Teoria Quântica , TermodinâmicaRESUMO
Similar to other food contaminants, dietary oxidized soybean oil (OSO) is also a toxic xenobiotic for animal and human nutrition. This research evaluated the effects of maternal OSO exposure during lactation on mammary mitochondrial injury and intestinal barrier of sucking progeny. Twenty-four female adult SD rats were fed a fresh soybean oil (FSO) homozygous diet (7%) or an OSO homozygous diet (7%) during lactation. On day 21 of lactation, upregulated mRNA expression of Sirt3 and PRDX3 and downregulated mRNA expression of Mfn2 were observed in mammary tissues in the OSO group compared to the control group (P < 0.05). Maternal OSO consumption increased the FasL transcriptional level in the mammary glands of rat dams (P < 0.05), while the mRNA expression of Bax, Bcl-2, Caspase3, and Fas was not different from that in the control group (P > 0.05). OSO enhanced the Nrf2 transcriptional level and decreased the expression of Keap1 and PPARα in mammary tissues (P < 0.05). In addition, the contents of CAT, MDA, SOD were not affected by dietary OSO (P > 0.05), while the concentration of H2O2 was significantly decreased in the OSO-treated mammary glands of rat dams (P < 0.05). Maternal OSO exposure during lactation did not affect the organ coefficients of pups (P > 0.05). However, maternal OSO consumption influenced the intestinal tight junction protein expression of progeny (P < 0.05). In summary, the present study demonstrated that dietary OSO may aggravate mammary injury and mitochondria dysfunction, but the OSO-induced damage was self-alleviating via the promotion of Sirt3 and PRDX3 expression and further scavenging of oxidative products.
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Intestinos/efeitos dos fármacos , Glândulas Mamárias Animais/ultraestrutura , Mitocôndrias/efeitos dos fármacos , Óleo de Soja/química , Óleo de Soja/toxicidade , Animais , Apoptose/genética , Dieta , Feminino , GTP Fosfo-Hidrolases/genética , Expressão Gênica/efeitos dos fármacos , Lactação , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/genética , Fator 2 Relacionado a NF-E2/genética , Oxirredução , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small moleculebased therapies for NASH.
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Hepatopatia Gordurosa não Alcoólica , Acetil-CoA Carboxilase , Animais , Fígado/metabolismo , Macaca/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
As an inflammation of the endometrium, endometritis can affect fertility and lead to serious economic losses in the dairy industry. Widely found in various tissues and body fluids, exosomes and exosome micro (mi)RNAs have been shown to play an important regulatory role in the immune responses. As one of differentially expressed exosome miRNAs, miR-218 is involved in the pathogenesis of bovine endometritis. The mechanisms of miR-218 in regulating the release of cytokines and chemokines in endometritis, however, are poorly understood. Exosomes were isolated from bovine uterine cavity fluid and verified by transmission electron microscopy. An in vitro lipopolysaccharide-treated cell model for bovine endometritis was then established to evaluate the correlation between exosome-derived miR-218 and the immune responses. We demonstrated that exosomes could be used to deliver miR-218 from endometrial epithelial cells (EECs) into the uterine microenvironment and adjacent recipient cells to modulate local immune responses. miR-218 packaged in the exosomes secreted from EECs acts as an inhibitor by blocking immune factors such as interleukin (IL)-6, IL-1ß, tumour necrosis factor-α, the chemokines macrophage inflammatory genes (MIP)-1α and MIP-1ß to maintain the immune balance in the uterus. However, uterine inflammation altered the immunoregulatory mechanism of exosome miR-218. MiR-218 is a potential biomarker for the detection of endometritis. Our findings also revealed a new mechanism for the development of endometritis in cows.
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Doenças dos Bovinos , Endometrite , Exossomos , MicroRNAs , Animais , Bovinos , Quimiocinas , Citocinas , Endometrite/veterinária , Feminino , MicroRNAs/genéticaRESUMO
BACKGROUND: This study will explore the association between tumor necrosis factor α (TNF-α) and uterine fibroids (UFs). METHODS: We will retrieve electronic databases in Cochrane Library, PUBMED, EMBASE, Web of Science, WANGFANG, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from inception to the present. All potential case-controlled studies investigating the association between TNF-α and UFs will be included in this study. Two researchers will independently select literature, appraise study quality, and extract outcome data. We will utilize a fixed-effects model or a random-effects model to synthesize outcome data. All data analysis will be performed by RevMan 5.3 software. RESULTS: The present study will supply high-quality synthesis and/or descriptive analysis of the recent evidence to explore the association between TNF-α and UFs. CONCLUSION: This study will exert evidence to determine whether or not TNF-α is associated with UFs. STUDY REGISTRATION NUMBER: INPLASY202070010.
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Leiomioma/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Neoplasias Uterinas/metabolismo , Biomarcadores Tumorais , Estudos de Casos e Controles , Feminino , Humanos , Revisões Sistemáticas como AssuntoRESUMO
Glyphosate (GLP), the most widely used and productive pesticide worldwide, which safety and reliability gradually become a social concern. It is important to explore the toxic of GLP on the limitation level by governments on piglets and the potential role of hepatic CAR/PXR and Keap1-Nrf2 pathways in low levels of glyphosate detoxification. Compared with the control group, the production performance and organ index of GLP group showed no significant change. However, the liver GLP residue of 40 mg/kg group was significantly higher than the control group. We also found that the activity of ALP increased linearly and DBIL content increased quadratically. Furthermore, GLP could significantly increase SOD and GSH-Px and decrease T-AOC and CAT activities and significantly increase MDA and H2O2 contents (P < 0.05); however, the genes expression of Keap1/Nrf2 pathway was not affected. Gene expression of CAR/PXR pathway showed that GLP could significantly stimulate the expression of CAR, but it could not affect the expression of phase â (CYP1A1, CYP1A2, CYP2E1, CYP2A19, CYP3A29), phase â ¡ (UGT1A6, GSTA1, GSTA2) detoxification enzymes and transporters (MDR1, MRP2, P-gp). Our study showed that although 10-40 mg/kg GLP would inevitably cause some liver damage and dysfunction, it can self-alleviating the toxic effect of GLP.
Assuntos
Glicina/análogos & derivados , Herbicidas/toxicidade , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ração Animal , Animais , Receptor Constitutivo de Androstano , Feminino , Contaminação de Alimentos , Expressão Gênica/efeitos dos fármacos , Glicina/toxicidade , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Suínos , GlifosatoRESUMO
In this study, an activated wakame biochar material (AWBM) was prepared by a one-step calcination and activation method, whose adsorption performances for methylene blue (MB), Rhodamine B (RB) and malachite green (MG) were also analyzed. The results showed AWBM was a mesoporous fluffy structure material with a higher specific surface (1156.25 m2/g), exhibiting superior adsorption capacities for MB (841.64 mg/g), RB (533.77 mg/g) and MG (4066.96 mg/g), respectively. In addition, FT-IR analysis showed that AWBM possessed abundant active groups (such as -OH, -CO and -CH), further enhancing the adsorption efficiencies. The Langmuir model could better fit the three dyes adsorption isotherms process using AWBM, and the Pseudo-second-order model could better describe the adsorption kinetic experimental data. The thermodynamic analysis showed that the three dyes adsorption using AWBM was spontaneous endothermic reaction. This study suggests AWBM has enormous potential in the application of removing organic dyes from wastewater.