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1.
Life Sci ; 297: 120228, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34921864

RESUMO

AIMS: Alcoholic liver disease (ALD) comprises an important component in chronic liver diseases, and its clinical significance has increased due to the high consumption of alcohol worldwide. Vitamin C is a potent antioxidant, and several previous studies have suggested that its therapeutic role in ALD is derived from its antioxidant role. However, its anti-inflammatory role in ALD remains to be elucidated. Especially, the relationship between vitamin C and infiltration of neutrophils in ALD has not been discussed to date. For the reason, the present study investigated the precise role of vitamin C in neutrophil infiltration in ALD. MAIN METHODS: In the present study, wild-type C57BL/6 and vitamin C-deficient senescence marker protein 30-knockout mice were pair-fed with a Lieber-DeCarli control or ethanol diet. Ethanol-fed groups were fed with increasing concentrations of EtOH (Lieber-DeCarli control diet for 5 days, 3% EtOH diet for a week, and 5% diet for 2 weeks) with or without vitamin C supplementation. KEY FINDINGS: Vitamin C dramatically attenuated the ethanol-mediated liver disease in the vitamin C-deficient ethanol-fed mice group by suppressing the infiltration of neutrophils accompanied by less CD68-positive cell infiltration. This attenuating role of vitamin C in neutrophil infiltration in the liver is associated with its protective effect for the ethanol-mediated intestinal damage in vitamin C-deficient ethanol-fed mice. SIGNIFICANCE: This study provides a novel possibility of vitamin C to be used as an anti-inflammatory therapeutic agent associated with neutrophil infiltration in ALD, thereby helping to establish strategies for attenuating ALD.


Assuntos
Antioxidantes , Hepatopatias Alcoólicas , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Fígado/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos
2.
Am J Pathol ; 191(9): 1550-1563, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34126083

RESUMO

Despite the increasing clinical importance of nonalcoholic fatty liver disease (NAFLD), little is known about its underlying pathogenesis or specific treatment. The senescence marker protein 30 (SMP30), which regulates the biosynthesis of vitamin C (VC) in many mammals, except primates and humans, was recently recognized as a gluconolactonase. However, the precise relation between VC and lipid metabolism in NAFLD is not completely understood. Therefore, this study aimed to clearly reveal the role of VC in NAFLD progression. SMP30 knockout (KO) mice were used as a VC-deficient mouse model. To investigate the precise role of VC on lipid metabolism, 13- to 15-week-old SMP30 KO mice and wild-type mice fed a 60% high-fat diet were exposed to tap water or VC-containing water (1.5 g/L) ad libitum for 11 weeks. Primary mouse hepatocytes isolated from the SMP30 KO and wild-type mice were used to demonstrate the relation between VC and lipid metabolism in hepatocytes. Long-term VC deficiency significantly suppressed the progression of simple steatosis. The high-fat diet-fed VC-deficient SMP30 KO mice exhibited impaired sterol regulatory element-binding protein-1c activation because of excessive cholesterol accumulation in hepatocytes. Long-term VC deficiency inhibits de novo lipogenesis through impaired sterol regulatory element-binding protein-1c activation.


Assuntos
Deficiência de Ácido Ascórbico/metabolismo , Hepatócitos/metabolismo , Lipogênese/fisiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Progressão da Doença , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Knockout
3.
Life Sci ; 278: 119578, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33965379

RESUMO

Hepatic fibrosis is a common liver disease caused by excessive collagen deposition in the liver. Since liver transplantation is the only current treatment for cirrhosis with worsened fibrosis, a new strategy to develop anti-fibrosis drugs with no adverse effects is necessary. In recent studies, amino acids have been applied as a type of therapy in various fields. l-serine plays a major role in antioxidant production via the maintenance of nicotinamide adenine dinucleotide phosphate hydride production in the mitochondria. l-serine may reduce fibrotic lesions in a mouse model of chronic liver injury. This study used 27 six-week-old C57BL/6 mice and injected them three times a week for eight weeks with carbon tetrachloride (CCl4) (1.5 mg/kg, 10% v/v CCl4 in olive oil) to create a hepatic fibrosis mouse model. The mice, which weighed approximately 20-30 g, were randomly classified into four groups: 1) the olive oil group, which received intraperitoneal injection of olive oil (1.5 mg/kg, 3 times per week for 8 weeks); 2) the CCl4-only group; 3) the CCl4 + losartan (10 mg/kg, PO, 5 days on, weekend off for 8 weeks) group; and 4) the CCl4 + l-serine (100 g/L, free access for 8 weeks) group. Hematoxylin and eosin staining and Masson's trichrome staining showed reduced inflammatory cell deposition and collagen deposition in the liver tissue in the l-serine supplemented group. l-serine was found to reduce the spread of hepatic fibrosis and has potential use in clinical settings. Based on these histopathological observations, l-serine is a potential anti-fibrosis drug.


Assuntos
Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Losartan/farmacologia , Serina/farmacologia , Animais , Peso Corporal , Tetracloreto de Carbono/química , Colágeno/química , Modelos Animais de Doenças , Inflamação , Cirrose Hepática/patologia , Cirrose Hepática Experimental/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio
4.
In Vivo ; 35(3): 1473-1483, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33910825

RESUMO

BACKGROUND/AIM: The pathological role of vascular endothelial growth factor receptor 2 (VEGFR-2) in chronic liver injury and liver regeneration is not fully understood. This study analysed the role of VEGFR-2 in liver fibrosis and its regeneration process. MATERIALS AND METHODS: We administered intraperitoneally 50 mg/kg to 300 mg/kg thioacetamide (TAA) to 9-week-old male mice for 17 weeks. We measured levels of VEGFR-2 protein and identified the location of cells that specifically express VEGFR-2. RESULTS: VEGFR-2 is rarely expressed in normal hepatocytes. However, high VEGFR-2 expression in liver sinusoidal endothelial cells was noted in the TAA group. Conversely, the group that experienced regeneration from liver fibrosis showed significantly higher VEGFR-2 expression in the nucleus of hepatocytes compared to the other groups. CONCLUSION: VEGFR-2 plays a pivotal role in the nucleus of hepatocytes during liver regeneration and VEGFR-2 may be closely related to cell division. Therefore, VEGFR-2 may be a new therapeutic target for liver regeneration.


Assuntos
Regeneração Hepática , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Animais , Proliferação de Células , Hepatócitos , Fígado , Masculino , Camundongos , Fator A de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
5.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652881

RESUMO

Senescence marker protein 30 (SMP30) is a cell survival factor playing an important role in vitamin C synthesis and antiapoptosis. Moreover, its cytoprotective role suggests a possibility to be related to cancer cell survival. Mammary carcinoma is a common cancer in both humans and animals. Because of its histopathological diversity, especially in the early stage, histopathological diagnosis may be complicated; therefore, a diagnostic marker is helpful for confirmation. The present study analyzed the expression pattern of SMP30 in mammary carcinoma in humans, dogs, and cats. Immunohistochemistry, immunofluorescence, and western blot analysis were used to investigate SMP30 expression patterns. The expression was specifically observed in neoplastic glandular epithelial cells. The expression increased with the malignancy of glandular epithelial cells with a highly proliferative status. However, SMP30 expression was low in normal mammary gland tissues or well-differentiated adenoma tissues. The patterns were consistently reproduced in canine primary mammary carcinoma cells and MCF-7 and MDA-MB-231 human carcinoma cell lines. This study provides useful information to understand SMP30 expression in various stages of mammary carcinoma and to suggest its utility as a pan-species diagnostic marker, thereby helping to establish strategies for diagnosing mammary carcinoma in several species.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Ligação ao Cálcio/análise , Doenças do Gato/patologia , Doenças do Cão/patologia , Peptídeos e Proteínas de Sinalização Intracelular/análise , Neoplasias Mamárias Animais/patologia , Animais , Biomarcadores Tumorais/análise , Mama/patologia , Neoplasias da Mama/diagnóstico , Doenças do Gato/diagnóstico , Gatos , Linhagem Celular Tumoral , Doenças do Cão/diagnóstico , Cães , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Animais/diagnóstico , Prognóstico
6.
J Comp Pathol ; 180: 1-4, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33222865

RESUMO

Myofibromas are mesenchymal tumours of myofibroblastic origin that occur in solitary or multicentric forms. Solitary benign myofibromas mainly occur on the head and neck, especially in the subcutaneous region. They rarely occur in visceral organs in humans, but visceral myofibroma has not been reported in animals. We now report a case of testicular myofibroma in a 6-year-old rabbit in which orchiectomy revealed an enlarged testis with a multinodular surface. The cut surface of the testis showed a thick, homogeneous white-yellow mass surrounding the testicular parenchyma. Histopathologically, the mass was composed of collagen and eosinophilic fascicles of spindle cells that were immunopositive for α-smooth muscle actin but not desmin, S-100 or von Willebrand factor. These features distinguished the myofibroma from other spindle cell tumours. To the best of our knowledge, this is the first report of solitary testicular myofibroma in any animal species.


Assuntos
Miofibroma , Testículo/patologia , Animais , Masculino , Miofibroma/diagnóstico , Miofibroma/veterinária , Coelhos
7.
Arch Biochem Biophys ; 688: 108407, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32407712

RESUMO

Prostate cancer has the highest incidence among men in advanced countries, as well as a high mortality rate. Despite the efforts of numerous researchers to identify a gene-based therapeutic target as an effective treatment of prostate cancer, there is still a need for further research. The cathepsin gene family is known to have a close correlation with various cancer types and is highly expressed across these cancer types. This study aimed at investigating the correlation between the cathepsin A (CTSA) gene and prostate cancer. Our findings indicated a significantly elevated level of CTSA gene expression in the tissues of patients with prostate cancer when compared with normal prostate tissues. Furthermore, the knockdown of the CTSA gene in the representative prostate cancer cell lines PC3 and DU145 led to reduced proliferation and a marked reduction in anchorage-independent colony formation, which was shown to be caused by cell cycle arrest in the S phase. In addition, CTSA gene-knockdown prostate cancer cell lines showed a substantial decrease in migration and invasion, as well as a decrease in the marker genes that promote epithelial mesenchymal transition (EMT). Such phenotypic changes in prostate cancer cell lines through CTSA gene suppression were found to be mainly caused by reduced p38 MAPK protein phosphorylation; i.e. the inactivation of the p38 MAPK cell signaling pathway. Tumorigenesis was also found to be inhibited in CTSA gene-knockdown prostate cancer cell lines when a xenograft assay was carried out using Balb/c nude mice, and the p38 MAPK phosphorylation was inhibited in tumor tissues. Thus, the CTSA gene is presumed to play a key role in human prostate cancer tissues through high-level expression, and the suppression of the CTSA gene leads to the inhibition of prostate cancer cell proliferation, colony formation, and metastasis. The mechanism, by which these effects occur, was demonstrated to be the inactivation of the p38 MAPK signaling pathway.


Assuntos
Catepsina A/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Neoplasias da Próstata/metabolismo , Transdução de Sinais/fisiologia , Animais , Sequência de Bases , Catepsina A/genética , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos Endogâmicos BALB C , Metástase Neoplásica/genética , Metástase Neoplásica/fisiopatologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Vet Sci ; 6(4)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561583

RESUMO

A black bear of 29-year-old (Ursus americanus) died unexpectedly in captivity without any gross lesions or clinical signs. We identified a firm, lobulated, yellowish tan, and well-circumscribed mass embedded inside the testicular tissue at the time of necropsy. The tumor sections exhibited soft necrotic and hemorrhagic areas beneath its capsule. Histologically, the tumor comprised Sertoli cells arranged in tubules and solid sheets supported by prominent fibrous connective tissues. The Sertoli cells were positive for vimentin and ER-ß expression, whereas it showed negative staining for inhibin-α, cytokeratin 19, and S-100. To the best of our knowledge, this is the rare case report of testicular Sertoli cell tumor in black bear.

9.
Int J Mol Sci ; 20(15)2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31387201

RESUMO

The cellular distribution of silica nanoparticles (NPs) in the liver is not well understood. Targeting specific cells is one of the most important issues in NP-based drug delivery to improve delivery efficacy. In this context, the present study analyzed the relative cellular distribution pattern of silica NPs in the liver, and the effect of surface energy modification on NPs. Hydrophobic NP surface modification enhanced NP delivery to the liver and liver sinusoid fFendothelial cells (LSECs). Conversely, hydrophilic NP surface modification was commensurate with targeting hepatic stellate cells (HSCs) rather than other cell types. There was no notable difference in NP delivery to Kupffer cells or hepatocytes, regardless of hydrophilic or hydrophobic NP surface modification, suggesting that both the targeting of hepatocytes and evasion of phagocytosis by Kupffer cells are not associated with surface energy modification of silica NPs. This study provides useful information to target specific cell types using silica NPs, as well as to understand the relationship between NP surface energy and the NP distribution pattern in the liver, thereby helping to establish strategies for cell targeting using various NPs.


Assuntos
Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Fígado/metabolismo , Nanopartículas , Dióxido de Silício , Portadores de Fármacos/química , Células Endoteliais/metabolismo , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Macrófagos do Fígado/metabolismo , Nanopartículas/química , Dióxido de Silício/química , Propriedades de Superfície , Distribuição Tecidual
10.
J Vet Med Sci ; 81(2): 269-273, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30606914

RESUMO

A 2-year-old castrated male mongrel dog presented with a well-demarcated fluctuant dermal mass, located on the back of the neck. Grossly along with cystic structures filled with a black greasy fluid, when cut open. Microscopically, the mass was multi-lobulated. The lobules consisted of neoplastic basaloid cells and showed central degeneration, forming multiple central cystic structures filled with dark melanin-pigmented materials. Immunohistochemically, the neoplastic cells were strongly positive for CK14 and partially positive for CK19, but negative for CK7, CK8/18, CD34, S-100, Melan-A and α-SMA. Based on the findings, the present case was diagnosed as a feline-type basal cell tumor characterized by cystic structures filled with abundant black fluid.


Assuntos
Doenças do Cão/patologia , Melaninas/análise , Neoplasia de Células Basais/veterinária , Neoplasias Cutâneas/veterinária , Animais , Doenças do Cão/diagnóstico , Cães , Masculino , Pescoço , Neoplasia de Células Basais/química , Neoplasia de Células Basais/diagnóstico , Neoplasia de Células Basais/patologia , Pele/patologia , Neoplasias Cutâneas/química , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia
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