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1.
Toxicol Res (Camb) ; 10(4): 911-927, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34484683

RESUMO

Cholestasis is a severe clinical complication that severely damages the liver. Kidneys are also the most affected extrahepatic organs in cholestasis. The pivotal role of oxidative stress has been mentioned in the pathogenesis of cholestasis-induced organ injury. The activation of the nuclear factor-E2-related factor 2 (Nrf2) pathway is involved in response to oxidative stress. The current study was designed to evaluate the potential role of Nrf2 signaling activation in preventing bile acids-induced toxicity in the liver and kidney. Dimethyl fumarate was used as a robust activator of Nrf2 signaling. Rats underwent bile duct ligation surgery and were treated with dimethyl fumarate (10 and 40 mg/kg). Severe oxidative stress was evident in the liver and kidney of cholestatic animals (P < 0.05). On the other hand, the expression and activity of Nrf2 and downstream genes were time-dependently decreased (P < 0.05). Moreover, significant mitochondrial depolarization, decreased ATP levels, and mitochondrial permeabilization were detected in bile duct-ligated rats (P < 0.05). Histopathological alterations included liver necrosis, fibrosis, inflammation and kidney interstitial inflammation, and cast formation. It was found that dimethyl fumarate significantly decreased hepatic and renal injury in cholestatic animals (P < 0.05). Based on these data, the activation of the cellular antioxidant response could serve as an efficient therapeutic option for managing cholestasis-induced organ injury.

2.
Biomolecules ; 11(9)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34572513

RESUMO

As a vertebrate model, zebrafish (Danio rerio) plays a vital role in the field of life sciences. Recently, gene-editing technology has become increasingly innovative, significantly promoting scientific research on zebrafish. However, the implementation of these methods in a reasonable and accurate manner to achieve efficient gene-editing remains challenging. In this review, we systematically summarize the development and latest progress in zebrafish gene-editing technology. Specifically, we outline trends in double-strand break-free genome modification and the prospective applications of fixed-point orientation transformation of any base at any location through a multi-method approach.

3.
J Biochem Mol Toxicol ; 35(9): e22846, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34250697

RESUMO

The liver is the primary organ affected by cholestasis. However, the brain, skeletal muscle, heart, and kidney are also severely influenced by cholestasis/cirrhosis. However, little is known about the molecular mechanisms of organ injury in cholestasis. The current study was designed to evaluate the mitochondrial glutathione redox state as a significant index in cell death. Moreover, tissue energy charge (EC) was calculated. Rats underwent bile duct ligation (BDL) and the brain, heart, liver, kidney, and skeletal muscle mitochondria were assessed at scheduled time intervals (3, 7, 14, and 28 days after BDL). A significant decrease in mitochondrial glutathione redox state and EC was detected in BDL animals. Moreover, disturbed mitochondrial indices were evident in different organs of BDL rats. These data could offer new insight into the mechanisms of organ injury and the source of oxidative stress during cholestasis and might provide novel therapeutic strategies against these complications.


Assuntos
Colestase/metabolismo , Metabolismo Energético , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Musculares/metabolismo , Animais , Colestase/patologia , Modelos Animais de Doenças , Masculino , Mitocôndrias Hepáticas/patologia , Mitocôndrias Musculares/patologia , Especificidade de Órgãos , Oxirredução , Ratos , Ratos Sprague-Dawley
4.
Front Vet Sci ; 8: 603262, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33842567

RESUMO

Lithium (Li+) is prescribed against a wide range of neurological disorders. Besides its excellent therapeutic properties, there are several adverse effects associated with Li+. The impact of Li+ on renal function and diabetes insipidus is the most common adverse effect of this drug. On the other hand, infertility and decreased libido is another complication associated with Li+. It has been found that sperm indices of functionality, as well as libido, is significantly reduced in Li+-treated men. These adverse effects might lead to drug incompliance and the cessation of drug therapy. Hence, the main aims of the current study were to illustrate the mechanisms of adverse effects of Li+ on the testis tissue, spermatogenesis process, and hormonal changes in two experimental models. In the in vitro experiments, Leydig cells (LCs) were isolated from healthy mice, cultured, and exposed to increasing concentrations of Li+ (0, 10, 50, and 100 ppm). In the in vivo section of the current study, mice were treated with Li+ (0, 10, 50, and 100 ppm, in drinking water) for five consecutive weeks. Testis and sperm samples were collected and assessed. A significant sign of cytotoxicity (LDH release and MTT assay), along with disrupted testosterone biosynthesis, impaired mitochondrial indices (ATP level and mitochondrial depolarization), and increased biomarkers of oxidative stress were detected in LCs exposed to Li+. On the other hand, a significant increase in serum and testis Li+ levels were detected in drug-treated mice. Moreover, ROS formation, LPO, protein carbonylation, and increased oxidized glutathione (GSSG) were detected in both testis tissue and sperm specimens of Li+-treated mice. Several sperm anomalies were also detected in Li+-treated animals. On the other hand, sperm mitochondrial indices (mitochondrial dehydrogenases activity and ATP levels) were significantly decreased in drug-treated groups where mitochondrial depolarization was increased dose-dependently. Altogether, these data mention oxidative stress and mitochondrial impairment as pivotal mechanisms involved in Li+-induced reproductive toxicity. Therefore, based on our previous publications in this area, therapeutic options, including compounds with high antioxidant properties that target these points might find a clinical value in ameliorating Li+-induced adverse effects on the male reproductive system.

5.
Front Vet Sci ; 8: 632218, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708811

RESUMO

Hepatitis-hydropericardium syndrome (HPS) causes severe economic losses in the global poultry industry. The present study aims to explore oral immunization of recombinant Lactococcus lactis and Enterococcus faecalis expressing Hexon protein of fowl adenovirus 4 (FAdV-4). The bacteria L. lactis NZ9000 and E. faecalis MDXEF-1 were, respectively, modified as host strain to deliver truncated Hexon protein (ΔHexon) or ΔHexon protein fusing with dendritic cell (DC) targeting peptide (DC-ΔHexon) on the surface of bacteria. The expression of target protein in L. lactis NZ9000 and E. faecalis MDXEF-1 were detected by western blot. To evaluate the immune responses and protective efficacies provided by the live recombinant bacteria, chickens were immunized with the constructed ΔHexon-expressing bacteria three times at 2-week intervals, then experimentally challenged with hypervirulent FAdV-4/GX01. The results showed that oral immunizations with the four ΔHexon-expressing bacteria (NZ9000/ΔHexon-CWA, NZ9000/DC-ΔHexon-CWA, MDXEF-1/ΔHexon-CWA, and MDXEF-1/DC-ΔHexon-CWA), especially the two bacteria carrying DC-targeting peptide, stimulated higher levels of ΔHexon-specific sera IgG and secretory IgA (sIgA) in jejunal lavage fluid, higher proliferation of peripheral blood lymphocytes (PBLs) and higher levels of Th1/Th2-type cytokines, along with significantly decreased virus loads in liver and more offered protective efficacies against FAdV infection compared with PBS and empty vector control groups (p < 0.01). For chickens in the group MDXEF-1/DC-ΔHexon-CWA, the levels of aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) in sera, and the virus loads in livers were significantly decreased vs. the other three ΔHexon-expressing bacteria (p < 0.01). The pathological changes in the hearts, livers, spleens and kidneys of chickens in MDXEF-1/DC-ΔHexon-CWA group were relatively slight compared to infection control group and other three ΔHexon-expressing bacteria groups. The rate of protection in MDXEF-1/DC-ΔHexon-CWA group was 90%. The present work demonstrated that cell surface-displayed target protein and immune enhancers in L. lactis and E. faecalis might be a promising approach to enhance immunity and immune efficacy against pathogen FAdV-4 infection.

6.
Vet Res ; 52(1): 24, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596990

RESUMO

Avian coccidiosis caused by Eimeria leads to huge economic losses on the global poultry industry. In this study, microneme adhesive repeat regions (MARR) bc1 of E. tenella microneme protein 3 (EtMIC3-bc1) was used as ligand, and peptides binding to EtMIC3 were screened from a phage display peptide library. The positive phage clones were checked by enzyme-linked immunosorbent assay (ELISA). Competitive ELISA was applied to further verify the binding capability between the positive phages and recombinant EtMIC3-bc1 protein or sporozoites protein. The inhibitory effects of target peptides on sporozoites invasion of MDBK cells were measured in vitro. Chickens were orally administrated with target positive phages and the protective effects against homologous challenge were evaluated. The model of three-dimensional (3D) structure for EtMIC3-bc1 was conducted, and molecular docking between target peptides and EtMIC3-bc1 model was analyzed. The results demonstrated that three selected positive phages specifically bind to EtMIC3-bc1 protein. The three peptides A, D and W effectively inhibited invasion of MDBK cells by sporozoites, showing inhibited ratio of 71.8%, 54.6% and 20.8%, respectively. Chickens in the group orally inoculated with phages A displayed more protective efficacies against homologous challenge than other groups. Molecular docking showed that amino acids in three peptides, especially in peptide A, insert into the hydrophobic groove of EtMIC3-bc1 protein, and bind to EtMIC3-bc1 through intermolecular hydrogen bonds. Taken together, the results suggest EtMIC3-binding peptides inhibit sporozoites entry into host cells. This study provides new idea for exploring novel strategies against coccidiosis.


Assuntos
Galinhas , Coccidiose/veterinária , Eimeria tenella/imunologia , Doenças das Aves Domésticas/prevenção & controle , Proteínas de Protozoários/imunologia , Esporozoítos/imunologia , Animais , Bacteriófagos , Ceco/patologia , Coccidiose/prevenção & controle , Simulação de Acoplamento Molecular , Doenças das Aves Domésticas/parasitologia , Ligação Proteica , Conformação Proteica
7.
Vet Res ; 52(1): 15, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514434

RESUMO

Avian coccidiosis caused by Eimeria leads to severe economic losses in the global poultry industry. Although chicken Toll-like receptor 15 (ChTLR15) was reported to be involved in Eimeria infection, the detailed mechanism underlying its role in the inflammatory response remains to be discovered. The present study demonstrated that the mRNA expression levels of ChTLR15, ChMyD88, ChNF-κB, ChNLRP3, ChCaspase-1, ChIL-18 and ChIL-1ß and the protein levels of ChTLR15 and ChNLRP3 in cecal tissues of Eimeria-infected chickens were significantly elevated at 4, 12, and 24 h compared with those in noninfected control chickens (p < 0.01). Moreover, the mRNA levels of molecules in the ChTLR15/ChNF-κB and ChNLRP3/ChIL-1ß pathways and the protein levels of ChTLR15 and ChNLRP3 in chicken embryo fibroblast cells (DF-1) stimulated by E. tenella sporozoites were consistent with those in Eimeria-infected chickens. Furthermore, overexpression of ChTLR15 in DF1 cells augmented activation of the ChTLR15/ChNF-κB and ChNLRP3/ChIL-1ß pathways when stimulated with E. tenella sporozoites, while knockdown of ChTLR15 in DF1 cells showed inverse effects. Taken together, the present study provides evidence that E. tenella sporozoites specifically activate ChTLR15 and then trigger activation of the ChNLRP3/ChIL-1ß pathway, which partially mediates inflammatory responses to Eimeria infection.


Assuntos
Proteínas Aviárias/genética , Galinhas , Coccidiose/veterinária , Eimeria tenella/fisiologia , Inflamação/veterinária , Doenças das Aves Domésticas/imunologia , Transdução de Sinais/imunologia , Animais , Proteínas Aviárias/metabolismo , Coccidiose/imunologia , Coccidiose/parasitologia , Inflamação/imunologia , Inflamação/parasitologia , Doenças das Aves Domésticas/parasitologia
8.
Vet Parasitol ; 289: 109320, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33248421

RESUMO

Avian coccidiosis leads to severe economic losses on the global poultry industry. Immune mapped protein-1 (IMP1) is a novel membrane protein, and was reported to be a candidate protective antigen. However, production and utilization modes of IMP1 using Lactococcus lactis as delivery vector were not reported untill now. In the present study, Eimeria tenella IMP1 (EtIMP1) protein was expressed in L. lactis under the nisin-inducible promoter, and EtIMP1 protein was produced in cytoplasmic, cell wall-anchored and secreted forms. Each chicken was orally immunized with one of the three live EtIMP1-expressing lactococci three times at 2 weeks intervals (immunized group), or with live bacteria harboring empty vector (immunized control group). Chickens in immunized and immunized control group were challenged with E. tenella sporulated oocysts to assess the immune responses. The results showed that proliferative responses of peripheral blood T lymphocytes, mRNA expression levels of IL-2, IL-4, IL-10 and IFN-γ in spleen tissues, levels of serum IgG and secretory IgA (sIgA) in cecal lavage fluids from chickens in immunized group were all significantly elevated compared to that in immunized control group. All three the live EtIMP1-expressing lactococci significantly decreased oocyst shedding, alleviated pathological damage in cecum and improved weight gain compared with bacteria harboring empty vector. These results suggested EtIMP1 protein delivered by L. lactis might be a promising candidate in developing novel vaccines against Eimeria infection.


Assuntos
Galinhas , Eimeria tenella/imunologia , Lactococcus lactis , Proteínas de Protozoários/imunologia , Vacinas Protozoárias/imunologia , Administração Oral , Animais , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Imunidade Humoral , Doenças das Aves Domésticas/parasitologia , Doenças das Aves Domésticas/prevenção & controle , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Organismos Livres de Patógenos Específicos
9.
Med Image Anal ; 54: 111-121, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30861443

RESUMO

Tumor proliferation is an important biomarker indicative of the prognosis of breast cancer patients. Assessment of tumor proliferation in a clinical setting is a highly subjective and labor-intensive task. Previous efforts to automate tumor proliferation assessment by image analysis only focused on mitosis detection in predefined tumor regions. However, in a real-world scenario, automatic mitosis detection should be performed in whole-slide images (WSIs) and an automatic method should be able to produce a tumor proliferation score given a WSI as input. To address this, we organized the TUmor Proliferation Assessment Challenge 2016 (TUPAC16) on prediction of tumor proliferation scores from WSIs. The challenge dataset consisted of 500 training and 321 testing breast cancer histopathology WSIs. In order to ensure fair and independent evaluation, only the ground truth for the training dataset was provided to the challenge participants. The first task of the challenge was to predict mitotic scores, i.e., to reproduce the manual method of assessing tumor proliferation by a pathologist. The second task was to predict the gene expression based PAM50 proliferation scores from the WSI. The best performing automatic method for the first task achieved a quadratic-weighted Cohen's kappa score of κ = 0.567, 95% CI [0.464, 0.671] between the predicted scores and the ground truth. For the second task, the predictions of the top method had a Spearman's correlation coefficient of r = 0.617, 95% CI [0.581 0.651] with the ground truth. This was the first comparison study that investigated tumor proliferation assessment from WSIs. The achieved results are promising given the difficulty of the tasks and weakly-labeled nature of the ground truth. However, further research is needed to improve the practical utility of image analysis methods for this task.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Proliferação de Células , Feminino , Expressão Gênica , Humanos , Mitose , Patologia/métodos , Valor Preditivo dos Testes , Prognóstico
10.
IEEE Trans Med Imaging ; 36(11): 2376-2388, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28692971

RESUMO

In this paper, we develop a new weakly supervised learning algorithm to learn to segment cancerous regions in histopathology images. This paper is under a multiple instance learning (MIL) framework with a new formulation, deep weak supervision (DWS); we also propose an effective way to introduce constraints to our neural networks to assist the learning process. The contributions of our algorithm are threefold: 1) we build an end-to-end learning system that segments cancerous regions with fully convolutional networks (FCNs) in which image-to-image weakly-supervised learning is performed; 2) we develop a DWS formulation to exploit multi-scale learning under weak supervision within FCNs; and 3) constraints about positive instances are introduced in our approach to effectively explore additional weakly supervised information that is easy to obtain and enjoy a significant boost to the learning process. The proposed algorithm, abbreviated as DWS-MIL, is easy to implement and can be trained efficiently. Our system demonstrates the state-of-the-art results on large-scale histopathology image data sets and can be applied to various applications in medical imaging beyond histopathology images, such as MRI, CT, and ultrasound images.


Assuntos
Histocitoquímica/métodos , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação , Aprendizado de Máquina Supervisionado , Algoritmos , Colo/diagnóstico por imagem , Neoplasias do Colo/diagnóstico por imagem , Bases de Dados Factuais , Humanos , Análise Serial de Tecidos
11.
BMC Bioinformatics ; 18(1): 281, 2017 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-28549410

RESUMO

BACKGROUND: Histopathology image analysis is a gold standard for cancer recognition and diagnosis. Automatic analysis of histopathology images can help pathologists diagnose tumor and cancer subtypes, alleviating the workload of pathologists. There are two basic types of tasks in digital histopathology image analysis: image classification and image segmentation. Typical problems with histopathology images that hamper automatic analysis include complex clinical representations, limited quantities of training images in a dataset, and the extremely large size of singular images (usually up to gigapixels). The property of extremely large size for a single image also makes a histopathology image dataset be considered large-scale, even if the number of images in the dataset is limited. RESULTS: In this paper, we propose leveraging deep convolutional neural network (CNN) activation features to perform classification, segmentation and visualization in large-scale tissue histopathology images. Our framework transfers features extracted from CNNs trained by a large natural image database, ImageNet, to histopathology images. We also explore the characteristics of CNN features by visualizing the response of individual neuron components in the last hidden layer. Some of these characteristics reveal biological insights that have been verified by pathologists. According to our experiments, the framework proposed has shown state-of-the-art performance on a brain tumor dataset from the MICCAI 2014 Brain Tumor Digital Pathology Challenge and a colon cancer histopathology image dataset. CONCLUSIONS: The framework proposed is a simple, efficient and effective system for histopathology image automatic analysis. We successfully transfer ImageNet knowledge as deep convolutional activation features to the classification and segmentation of histopathology images with little training data. CNN features are significantly more powerful than expert-designed features.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias do Colo/patologia , Processamento de Imagem Assistida por Computador/métodos , Algoritmos , Neoplasias Encefálicas/diagnóstico , Carcinoma/diagnóstico , Carcinoma/patologia , Neoplasias do Colo/diagnóstico , Humanos , Redes Neurais de Computação , Máquina de Vetores de Suporte
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