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1.
Int J Med Sci ; 17(6): 815-823, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218703

RESUMO

Importin-11 (Ipo11) is a novel member of the human importin family of transport receptors (karyopherins), which are known to mediate the nucleocytoplasmic transport of protein and RNA cargos. Despite its role in the transport of protein, we found that knockout of Ipo11 nuclear import factor affects normal embryonic development and govern embryo-lethal phenotypes in mice. In this study, we for the first time produced a mouse line containing null mutation in Ipo11 gene utilized by gene trapping. The Ipo11-/- embryos showed an embryonic lethal phenotype. The Ipo11-/- embryos showed a reduced size at embryonic day 10.5 (E10.5) when compared with Ipo11+/+ or Ipo11+/- embryos and died by E11.5. Whereas Ipo11+/- mice were healthy and fertile, and there was no detectable changes in embryonic lethality and phenotype when reviewed. In the X-gal staining with the Ipo11-/- or Ipo11+/- embryos, strong X-gal staining positivity was detected systematically in the whole mount embryos at E10.5, although almost no X-gal positivity was detected at E9.5, indicating that the embryos die soon after the process of Ipo11 expression started. These results indicate that Ipo11 is essential for the normal embryonic development in mice.

2.
Int J Med Sci ; 16(12): 1557-1563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839743

RESUMO

E2F3, a member of the E2F family, plays a critical role in cell cycle and proliferation by targeting downstream, retinoblastoma (RB) a tumor suppressor family protein. The purpose of this study, was to investigate the role and function of E2F3 in vivo. We examined phenotypic abnormalities, by deletion of the E2f3 gene in mice. Complete ablation of the E2F3 was fully penetrant, in the pure C57BL/6N background. The E2f3+/ - mouse embryo developed normally without fatal disorder. However, they exhibited reduced body weight, growth retardation, skeletal imperfection, and poor grip strength ability. Findings suggest that E2F3 has a pivotal role in muscle and bone development, and affect normal mouse growth.


Assuntos
Desenvolvimento Ósseo/genética , Fator de Transcrição E2F3/genética , Desenvolvimento Embrionário/genética , Músculo Esquelético/crescimento & desenvolvimento , Animais , Apoptose/genética , Peso Corporal/genética , Ciclo Celular/genética , Proliferação de Células/genética , Embrião de Mamíferos , Humanos , Camundongos , Camundongos Knockout , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Fenótipo
3.
Biomol Ther (Seoul) ; 27(5): 457-465, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30739427

RESUMO

Patients with diabetes mellitus (DM) often suffer from diverse skin disorders, which might be attributable to skin barrier dysfunction. To explore the role of lipid alterations in the epidermis in DM skin disorders, we quantitated 49 lipids (34 ceramides, 14 free fatty acids (FFAs), and cholesterol) in the skin epidermis, liver, and kidneys of db/db mice, a Type 2 DM model, using UPLC-MS/MS. The expression of genes involved in lipid synthesis was also evaluated. With the full establishment of hyperglycemia at the age of 20 weeks, remarkable lipid enrichment was noted in the skin of the db/db mice, especially at the epidermis and subcutaneous fat bed. Prominent increases in the ceramides and FFAs (>3 fold) with short or medium chains (<C26) occurred in the skin epidermis (16NS, 18NS, 24NS, 16NDS, 18NDS, 20NDS, 22NDS, 24NDS, C16:1FA, C18:2FA, and C18:1FA) and the liver (16NS, 18NS, 20NS, 24:1NS, 18NDS, 20NDS, 22NDS, C16:1FA, C18:2FA, C18:1FA), whereas those with very long chains were not affected. In the kidney, only slight increases (<3 fold) were observed for 16NS, 18NS, 20NS, 26NDS, C26FA, and C22:1FA. Consistently, LXRα/ß and PPARγ, nuclear receptors promoting lipid synthesis, lipid synthesis enzymes such as elongases 1, 4, and 6, and fatty acid synthase and stearoyl-CoA desaturase were highly expressed in the skin and livers of the db/db mice. Collectively, our study demonstrates an extensive alteration in the skin and systemic lipid profiles of db/db mice, which could contribute to the development of skin disorders in DM.

4.
Biomed Chromatogr ; 33(2): e4388, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30238481

RESUMO

In this study, we developed a method for the determination of Penicillium griseofulvum-oriented pyripyropene A (PPPA), a selective inhibitor of acyl-coenzyme A:cholesterol acyltransferase 2, in mouse and human plasma and validated it using liquid chromatography-tandem mass spectrometry. Pyripyropene A (PPPA) and an internal standard, carbamazepine, were separated using a Xterra MS C18 column with a mixture of acetonitrile and 0.1% formic acid as the mobile phase. The ion transitions monitored in positive-ion mode [M + H]+ of multiple-reaction monitoring (MRM) were m/z 148.0 from m/z 584.0 for PPPA and m/z 194.0 from m/z 237.0 for the internal standard. The detector response was specific and linear for PPPA at concentrations within the range from 1 to 5,000 ng/mL. The intra-/inter-day precision and accuracy of the method was acceptable by the criteria for assay validation. The matrix effects of PPPA ranged from 97.6 to 104.2% and from 93.3 to 105.3% in post-preparative mouse and human plasma samples, respectively. PPPA was also stable under various processing and/or handling conditions. Finally, PPPA concentrations in the mouse plasma samples could be measured after intravenous, intraperitoneal, or oral administration of PPPA, suggesting that the assay is useful for pharmacokinetic studies on mice and applicable to human studies.


Assuntos
Cromatografia Líquida/métodos , Penicillium/química , Piridinas/sangue , Piridinas/farmacocinética , Sesquiterpenos/sangue , Sesquiterpenos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Piridinas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sesquiterpenos/química , Esterol O-Aciltransferase/antagonistas & inibidores
5.
Circ Res ; 123(10): 1127-1142, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30359200

RESUMO

RATIONALE: Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during atherosclerosis. OBJECTIVE: We sought to examine the transcriptomic profiles of foamy and nonfoamy macrophages isolated from atherosclerotic intima. METHODS AND RESULTS: Single-cell RNA sequencing analysis of CD45+ leukocytes from murine atherosclerotic aorta revealed that there are macrophage subpopulations with distinct differentially expressed genes involved in various functional pathways. To specifically characterize the intimal foamy macrophages of plaque, we developed a lipid staining-based flow cytometric method for analyzing the lipid-laden foam cells of atherosclerotic aortas. We used the fluorescent lipid probe BODIPY493/503 and assessed side-scattered light as an indication of cellular granularity. BODIPYhiSSChi foamy macrophages were found residing in intima and expressing CD11c. Foamy macrophage accumulation determined by flow cytometry was positively correlated with the severity of atherosclerosis. Bulk RNA sequencing analysis showed that compared with nonfoamy macrophages, foamy macrophages expressed few inflammatory genes but many lipid-processing genes. Intimal nonfoamy macrophages formed the major population expressing IL (interleukin)-1ß and many other inflammatory transcripts in atherosclerotic aorta. CONCLUSIONS: RNA sequencing analysis of intimal macrophages from atherosclerotic aorta revealed that lipid-loaded plaque macrophages are not likely the plaque macrophages that drive lesional inflammation.


Assuntos
Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Transcriptoma , Animais , Aorta/metabolismo , Aorta/patologia , Células Cultivadas , Humanos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/patologia
6.
Exp Biol Med (Maywood) ; 243(5): 408-417, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29409347

RESUMO

FRY like transcription coactivator ( Fryl) gene located on chromosome 5 is a paralog of FRY microtubule binding protein ( Fry) in vertebrates. It encodes a protein with unknown functions. Fryl gene is conserved in various species ranging from eukaryotes to human. Although there are several reports on functions of Fry gene, functions of Fryl gene remain unclear. A mouse line containing null mutation in Fryl gene by gene trapping was produced in this study for the first time. The survival and growth of Fryl-/- mice were observed. Fryl gene expression levels in mouse tissues were determined and histopathologic analyses were conducted. Most Fryl-/- mice died soon after birth. Rare Fryl-/- survivors showed growth retardation with significantly lower body weight compared to their littermate controls. Although they could breed, more than half of Fryl-/- survivors died of hydronephrosis before age 1. No abnormal histopathologic lesion was apparent in full-term embryo or adult tissues except the kidney. Abnormal lining cell layer detachments from walls of collecting and convoluted tubules in kidneys were apparent in Fryl-/- neonates and full-term embryos. Fryl gene was expressed in renal tubular tissues including the glomeruli and convoluted and collecting tubules. This indicates that defects in tubular systems are associated with Fryl functions and death of Fryl-/- neonates. Fryl protein is required for normal development and functional maintenance of kidney in mice. This is the first report of in vivo Fryl gene functions. Impact statement FRY like transcription coactivator ( Fryl) gene is conserved in various species ranging from eukaryotes to human. It expresses a protein with unknown function. We generated a Fryl gene mutant mouse line and found that most homozygous mice died soon after their birth. Rare Fryl-/- survivors showed growth retardation with significantly lower body weight compared to their littermate controls. Although they could breed, more than half of Fryl-/- survivors died of hydronephrosis before age 1. Full-term mutant embryos showed abnormal collecting and convoluted tubules in kidneys where Fryl gene was expressed. Collectively, these results indicate that Fryl protein is required for normal development and functional maintenance of kidney in mice. To the best of our knowledge, this is the first report on in vivo Fryl gene functions.


Assuntos
Hidronefrose/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Glomérulos Renais/embriologia , Túbulos Renais/embriologia , Proteínas de Membrana/genética , Animais , Linhagem Celular , Feminino , Hidronefrose/mortalidade , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Glomérulos Renais/patologia , Túbulos Renais/patologia , Masculino , Proteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
Lab Anim Res ; 34(4): 311-316, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30671120

RESUMO

Laboratory inbred mice are used widely and commonly in biomedical research, but inbred mice do not have a big enough gene pool for the research. In this study, genetic and morphometric analyses were performed to obtain data on the characteristics of a newly developing inbred strain (KWM/Hym) captured from Chuncheon, Korea. All of five Korean wild male mice have the zinc-finger Y (ZfY) gene. Also, all of 19 Korean wild mice used in this analysis have the AKV-type murine leukemia virus gene, indicating that Korean wild mice might be Mus musculus musculus. To identify the genetic polymorphism in KWM/Hym, SNP analysis was performed. In a comparison with 28 SNP markers, there was a considerable difference between KWM/Hym and several inbred strains. The homogeneity between KWM/Hym and the inbred strains was as follows: C57BL/6J (39.3%), BALB/c AJic (42.9%), and DBA/2J (50%). KWM/Hym is most similar to the PWK/PhJ inbred strain (96.4%) derived from wild mice (Czech Republic). To identify the morphometric characteristics of KWM/Hym, the external morphology was measured. The tail ratio of male and female was 79.60±3.09 and 73.55±6.14%, respectively. KWM/Hym has short and agouti-colored hairs and its belly is white with golden hair. Taking these results together, KWM/Hym, a newly developing inbred mouse originated from wild mouse, might be use as new genetic resources to overcome the limitations of the current laboratory mice.

9.
Cell Metab ; 23(5): 852-66, 2016 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-27166946

RESUMO

Plasmacytoid dendritic cells (pDCs) are unique bone-marrow-derived cells that produce large amounts of type I interferon in response to microbial stimulation. Furthermore, pDCs also promote T cell tolerance in sterile-inflammation conditions. However, the immunomodulatory role of aortic pDCs in atherosclerosis has been poorly understood. Here, we identified functional mouse and human pDCs in the aortic intima and showed that selective, inducible pDC depletion in mice exacerbates atherosclerosis. Aortic pDCs expressed CCR9 and indoleamine 2,3-dioxygenase 1 (IDO-1), an enzyme involved in driving the generation of regulatory T cells (Tregs). As a consequence, loss of pDCs resulted in decreased numbers of Tregs and reduced IL-10 levels in the aorta. Moreover, antigen presentation by pDCs expanded antigen-specific Tregs in the atherosclerotic aorta. Notably, Tregs ablation affected pDC homeostasis in diseased aorta. Accordingly, pDCs in human atherosclerotic aortas colocalized with Tregs. Collectively, we identified a mechanism of atheroprotection mediated by tolerogenic aortic pDCs.


Assuntos
Aorta/patologia , Aterosclerose/enzimologia , Aterosclerose/prevenção & controle , Células Dendríticas/enzimologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Anticorpos/farmacologia , Aterosclerose/imunologia , Aterosclerose/patologia , Medula Óssea/patologia , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Epitopos , Homeostase/efeitos dos fármacos , Humanos , Interferon Tipo I/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Receptores de LDL/metabolismo , Fatores de Tempo , Receptor Toll-Like 9/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo
10.
Environ Toxicol Pharmacol ; 40(1): 191-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26143167

RESUMO

This study investigated the time-course of 1,3-dichloro-2-propanol (1,3-DCP)-induced hepatotoxicity and the molecular mechanism of its oxidative stress and apoptotic changes in rats. Thirty-six male rats were randomly assigned to six groups of six rats each and were administered a single oral dose of 1,3-DCP (90 mg/kg) or its vehicle. 1,3-DCP caused acute hepatic damage, as evidenced by marked increases in serum aminotransferase, alkaline phosphatase, and histopathological alterations. These functional and histopathological changes in the liver peaked at 12h after administration and then decreased progressively. Oxidative stress indices were increased significantly at 6h, peaked at 12h, and then decreased progressively. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)- and caspase-3-positive cells increased after 6h, peaked at 12 and 24h, and then decreased. The protein levels of phosphorylated mitogen-activated protein kinases (MAPKs) including p-Erk1/2 and p-JNK showed a similar trend to the numbers of TUNEL- and caspase-3-positive cells. These results indicate that 1,3-DCP increases oxidative stress, nuclear translocation of Nrf2, and expression of Nrf2-targeted genes, followed by increased functional and histopathological alterations in the liver. The increase in hepatocellular apoptosis induced by 1,3-DCP may be related to oxidative stress-mediated MAPK activation.


Assuntos
Fígado/efeitos dos fármacos , alfa-Cloridrina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , alfa-Cloridrina/toxicidade
12.
Nat Commun ; 5: 4410, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25022542

RESUMO

Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-α-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.


Assuntos
Colesterol/metabolismo , Hiperlipidemias/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Tecido Adiposo/metabolismo , Animais , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Feminino , Homeostase/genética , Homeostase/fisiologia , Hiperlipidemias/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo
13.
J Vet Sci ; 14(3): 257-62, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23820201

RESUMO

Vitamin D3 up-regulated protein 1 (VDUP1) is a potent growth suppressor that inhibits tumor cell proliferation and cell cycle progression when overexpressed. In a previous study, we showed that VDUP1 knockout (KO) mice exhibited accelerated liver regeneration because such animals could effectively control the expression of cell cycle regulators that drive the G1-to-S phase progression. In the present study, we further investigated the role played by VDUP1 in initial priming of liver regeneration. To accomplish this, VDUP1 KO and wild-type (WT) mice were subjected to 70% partial hepatectomy (PH) and sacrificed at different times after surgery. The hepatic levels of TNF-α and IL-6 increased after PH, but there were no significant differences between VDUP1 KO and WT mice. Nuclear factor-κB (NF-κB), c-Jun-N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT-3) were activated much earlier and to a greater extent in VDUP1 KO mice after PH. A single injection of TNF-α or IL-6 caused rapid activation of JNK and STAT-3 expression in both mice, but the responses were stronger and more sustained in VDUP1 KO mice. In conclusion, our findings provide evidence that VDUP1 plays a role in initiation of liver regeneration.


Assuntos
Proteínas de Transporte/genética , Regulação da Expressão Gênica , Hepatócitos/citologia , Fígado/fisiologia , Regeneração , Tiorredoxinas/genética , Animais , Western Blotting , Proteínas de Transporte/metabolismo , Proliferação de Células , Hepatectomia , Hepatócitos/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Reação em Cadeia da Polimerase , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Tiorredoxinas/metabolismo
14.
Gut ; 61(1): 53-63, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21917648

RESUMO

OBJECTIVE: Vitamin D(3) upregulated protein 1 (VDUP1) is a potent tumour suppressor whose expression is dramatically reduced in various types of human cancers, including gastric cancer. However, the precise mechanisms underlying tumour development remain unclear. In the present study, the authors examined the effect of VDUP1 on Helicobacter pylori-induced gastric carcinogenesis in mice. DESIGN: Gastric cancer was generated in VDUP1 knockout (KO) and wild-type mice using a combination of N-methyl-N-nitrosourea treatment and H pylori infection. Fifty weeks after treatment, gastric tissues from both types of mice were examined by histopathology, immunohistochemistry and immunoblotting. In vitro tests on the human gastric cancer cell line, AGS, were also performed to identify the underlying mechanisms of cancer development. RESULTS: The overall incidence of gastric cancer was significantly higher in VDUP1 KO mice than in wild-type mice. Similarly, VDUP1 KO mice showed more severe chronic gastritis, glandular atrophy, foveolar hyperplasia, metaplasia and dysplasia. Although no differences in the apoptotic index were apparent, lack of VDUP1 increased the rate of gastric epithelial cell proliferation in non-cancerous stomachs, with corresponding increases in tumour necrosis factor alpha (TNFα) level, nuclear transcription factor kappa B (NF-κB) activation and cyclooxygenase-2 (COX-2) expression. An in vitro study showed that H pylori-associated cell proliferation and induction of TNFα, NF-κB and COX-2 were inhibited in cells transfected with VDUP1. In addition, overexpression of VDUP1 in AGS cells suppressed TNFα-induced NF-κB activation and COX-2 expression. CONCLUSION: Our data show that VDUP1 negatively regulates H pylori-associated gastric carcinogenesis, in part by disrupting cell growth and inhibiting the induction of TNFα, NF-κB and COX-2. These findings provide important insights into the role of VDUP1 in H pylori-associated tumourigenesis.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori , Neoplasias Gástricas/etiologia , Tiorredoxinas/metabolismo , Animais , Biomarcadores Tumorais/fisiologia , Proteínas de Transporte/fisiologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Humanos , Metilnitrosoureia/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Distribuição Aleatória , Neoplasias Gástricas/metabolismo , Tiorredoxinas/fisiologia , Análise Serial de Tecidos , Fator de Necrose Tumoral alfa/metabolismo
15.
Eur J Pharmacol ; 668(3): 459-66, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21827747

RESUMO

B cell-activating factor (BAFF) is a key regulator of B lymphocyte development. Signals from BAFF are transmitted through binding to a specific BAFF receptor (BAFF-R). Here, we established screening method to find a specific inhibitor for the interference of BAFF-BAFF-R interactions. We screened oxazole-4-carbonylguanidine derivatives and selected KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, as a candidate to interfere BAFF-BAFF-R interactions. KR33426 inhibited BAFF-mediated anti-apoptotic effect on splenocytes as judged by hypodiploid cell formation. KR33426 also increased the degradation of procaspase-3 that was inhibited by BAFF protein. In addition, we examined whether KR33426 was effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mouse. When 5 or 10mg/kg KR33426 was intraperitoneally administered to MRL(lpr/lpr) mice for 4 weeks, histopathological changes were ameliorated in the narrowed space between renal glomerulus and glomerulus capsule. KR33426 reduced B220(+) B cell population and B cell mitogen, lipopolysaccharide-stimulated lymphocyte proliferation in splenocytes. KR33426 attenuated an increase in CD43(-)IgM(+) immature pro-B and a decrease in CD21(+) IgM(+) T2-B and IgD(+) IgM(-)recirculating-B cells on B cell development. Data show that KR33426 inhibits BAFF-BAFF-R interactions and it is effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mice. Thus, it suggests that KR33426 is a novel candidate to develop anti-autoimmune therapeutics by the interference of BAFF-BAFF-R interactions, specifically.


Assuntos
Guanidinas/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Oxazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Guanidinas/uso terapêutico , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Baço/imunologia
16.
Food Chem Toxicol ; 49(9): 2453-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21745528

RESUMO

In the present study, we examined the effect of a mixture of dietary components, including red grape extract, soy isoflavone and L-carnitine (RISC), on obesity. RISC substantially inhibited high-fat diet (HFD)-induced increase in body weight in a dose-dependent manner in C57BL/6 mice. The amount of subcutaneous and mesenteric fat was also significantly decreased by RISC treatment in HFD-fed C57BL/6 mice, whereas epididymal fat was not affected. Moreover, HFD-induced plasma leptin levels were down-regulated by RISC treatment. In these mice, RISC treatment significantly increased the plasma level of high density lipoprotein cholesterol without affecting the level of low density lipoprotein cholesterol and triglycerides. In addition, HFD-induced increase in liver weight and lipid accumulation in liver was significantly suppressed by RISC treatment in C57BL/6mice. Plasma level of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase was also inhibited by RISC treatment. These results demonstrate that RISC suppresses HFD-induced obesity and suggest that RISC supplementation might be a promising adjuvant therapy for the treatment of obesity and its complications, such as cardiovascular and non-alcoholic fatty liver diseases.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Carnitina/farmacologia , Gorduras na Dieta/administração & dosagem , Fígado Gorduroso/prevenção & controle , Isoflavonas/farmacologia , Obesidade/prevenção & controle , Extratos Vegetais/farmacologia , Soja/química , Vitis/química , Animais , Lipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Tamanho do Órgão/efeitos dos fármacos
17.
Phytother Res ; 25(12): 1789-95, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21480410

RESUMO

To develop a therapeutic agent for obesity-related metabolic disorders, a mixture of dietary components was prepared, including grape extract, green tea extract and l-carnitine (RGTC), and its effects on obesity, hyperlipidemia and non-alcoholic fatty liver disease examined. The RGTC dramatically inhibited the high-fat diet (HFD)-induced increase in body weight and fat in C57BL/6 mice, whereas food consumption was not affected by RGTC treatment. The RGTC also concentration-dependently suppressed the HFD-induced increase in plasma lipids, such as low-density lipoprotein cholesterol and triglycerides. In addition, increases in liver weight and liver steatosis were returned to normal by RGTC treatment in HFD-fed C57BL/6 mice. The plasma levels of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase were also significantly down-regulated by RGTC treatment. These results suggest that RGTC suppressed HFD-induced obesity, hyperlipidemia and non-alcoholic fatty liver disease, suggesting that RGTC supplementation might be a promising adjuvant therapy for the treatment of these metabolic disorders.


Assuntos
Carnitina/farmacologia , Fígado Gorduroso/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Tecido Adiposo/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Leptina/sangue , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Chá/química , Vitis/química
18.
J Hepatol ; 54(6): 1168-76, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21145821

RESUMO

BACKGROUND & AIMS: Liver regeneration is a complicated process involving a variety of interacting factors. Vitamin D3 up-regulated protein 1 (VDUP1) is a potent growth suppressor that, upon over-expression, inhibits tumor cell proliferation and cell-cycle progression. Here, we investigated the function of VDUP1 in liver regeneration following hepatectomy in mice. METHODS: Liver regeneration after 70% partial hepatectomy (PH) was compared in VDUP1 knockout (KO) and wild-type (WT) mice, and the activities of proliferative- and cell-cycle-related signaling pathways were measured. RESULTS: Compared with WT mice, liver recovery was significantly accelerated in VDUP1 KO mice during the first day after PH, in association with increased DNA synthesis. Consistent with this observation, the expression levels of key cell-cycle regulatory proteins, including cyclin D, cyclin E, cyclin-dependent kinase 4 (CDK4), p21, and p27, were markedly altered in the livers of VDUP1 KO mice. Induction of growth factors and activation of proliferative signaling pathway components including extracellular signal-regulated kinase 1/2 (ERK1/2), Akt, glycogen synthase kinase 3ß (GSK3ß), mammalian target of rapamycin (mTOR), and p70S6 kinase (p70(S6K)), occurred much earlier and to a greater extent in VDUP1 KO mouse livers. In addition, primary hepatocytes isolated from VDUP1 KO mice displayed increased activation of ERK1/2 and Akt in response to HGF and TGF-α. CONCLUSIONS: Our results reveal an important role for VDUP1 in the regulation of proliferative signaling during liver regeneration. Altered activation of genes involved in ERK1/2 and Akt signaling pathways may explain the accelerated growth responses seen in VDUP1 KO mice.


Assuntos
Proteínas de Transporte/fisiologia , Regeneração Hepática/fisiologia , Tiorredoxinas/fisiologia , Animais , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Tamanho Celular , Ciclinas/metabolismo , Hepatectomia , Fator de Crescimento de Hepatócito/farmacologia , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Regeneração Hepática/genética , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genética , Fator de Crescimento Transformador alfa/farmacologia
19.
J Immunol ; 185(7): 3980-9, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20826751

RESUMO

Vitamin D(3) upregulated protein 1 (VDUP1) is a candidate tumor suppressor, the expression of which is dramatically reduced in various tumor tissues. In this study, we found that VDUP1 expression is suppressed during human hepatic carcinogenesis, and mice lacking VDUP1 are much more susceptible to diethylnitrosamine-induced hepatocarcinogenesis compared with wild type mice. VDUP1-deficient tumors proliferated significantly more than wild type tumors and had corresponding changes in the expression of key cell cycle regulatory proteins. In addition, the hepatomitogen-induced response was associated with a considerable increase in the release of TNF-α and subsequent enhancement of NF-κB activation in VDUP1-deficient mice. When cells were treated with TNF-α, the VDUP1 level was markedly reduced, concomitant with elevated NF-κB activation. Furthermore, the overexpression of VDUP1 resulted in the robust suppression of TNF-α-activated NF-κB activity via association with HDAC1 and HDAC3. These results indicate that VDUP1 negatively regulates hepatocarcinogenesis by suppressing TNF-α-induced NF-κB activation.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Hepáticas/metabolismo , NF-kappa B/metabolismo , Tiorredoxinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Ensaio de Desvio de Mobilidade Eletroforética , Ativação Enzimática/fisiologia , Humanos , Imuno-Histoquímica , Imunoprecipitação , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia
20.
Toxicol Appl Pharmacol ; 248(3): 277-84, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20713078

RESUMO

Thioacetamide (TA) is a commonly used drug that can trigger acute hepatic failure (AHF) through generation of oxidative stress. Vitamin D3 upregulated protein 1 (VDUP1) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. In this study, we investigated the role of VDUP1 in AHF using a TA-induced liver injury model. VDUP1 knockout (KO) and wild-type (WT) mice were subjected to a single intraperitoneal TA injection, and various parameters of hepatic injury were assessed. VDUP1 KO mice displayed a significantly higher survival rate, lower serum alanine aminotransferase and aspartate aminotransferase levels, and less hepatic damage, compared to WT mice. In addition, induction of apoptosis was decreased in VDUP1 KO mice, with the alteration of caspase-3 and -9 activities, Bax-to-Bcl-2 expression ratios, and mitogen activated protein kinase (MAPK) signaling pathway. Importantly, analysis of TA bioactivation revealed lower plasma clearance of TA and covalent binding of [¹4C]TA to liver macromolecules in VDUP1 KO mice. Furthermore, the level of oxidative stress was significantly less in VDUP1 KO mice than in their WT counterparts, as evident from lipid peroxidation assay. These results collectively indicate that VDUP1 deficiency protects against TA-induced acute liver injury via lower bioactivation of TA and antioxidant effects.


Assuntos
Proteínas de Transporte/fisiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Tioacetamida/toxicidade , Tiorredoxinas/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Transporte/genética , Doença Hepática Induzida por Substâncias e Drogas/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição Aleatória , Tiorredoxinas/genética
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