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1.
Cells ; 9(3)2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32138352

RESUMO

Bacterial translocation (BT) and splenomegaly contribute to cirrhosis-associated immune dysfunction (CAID) including T cell depletion, infection, and chronic inflammation. ß-blockers have been reported to decrease BT and improve splenomegaly. This study explores the modulation of ß1 and ß2 adrenergic receptors (ADRB1/ADRB2) by propranolol treatment on the peripheral and splenic immune dysfunction of cirrhotic mice. In vivo experiments were performed in bile duct ligation (BDL)- and thioacetamide (TAA)-cirrhotic mice receiving two weeks of propranolol treatment. Acute effects of propranolol were evaluated in T-helper (Th) cells isolated from spleen of cirrhotic mice. Over-expression of ß1 and ß2 adrenergic receptors (ADRB1/ADRB2) in spleen and T lymphocytes was associated with high peripheral/splenic lipopolysaccharide binding protein levels. Moreover, a decrease in Th cells percentage, increase in Treg subset, and cytokines were accompanied by increased apoptosis, proliferation, and reduced white pulp hyperplasia in cirrhotic mice, which were counteracted by propranolol treatment. The Th-cell depletion, systemic inflammation, BT, and infection were improved by chronic propranolol treatment. Acute propranolol treatment inhibited apoptosis, Treg-conditioned differentiation, and promoted Th2-conditioned differentiation through ADRB-cyclic adenosine monophosphate (cAMP) signals in cirrhotic mice. In conclusion, suppression of ADRB1 and ADRB2 expressions in spleen and splenic T lymphocytes by acute and chronic propranolol treatment ameliorate systemic and splenic immune dysfunction in cirrhosis.

2.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31455001

RESUMO

The purpose of this study was to investigate whether Ger-Gen-Chyn-Lian-Tang (GGCLT) suppresses oxidative stress, inflammation, and angiogenesis during experimental liver fibrosis through the hypoxia-inducible factor-1α (HIF-1α)-mediated pathway. Male C57BL/6 mice were randomly assigned to a sham-control or bile duct ligation (BDL) group with or without treatment with GGCLT at 30, 100, and 300 mg/kg. Plasma alanine aminotransferase (ALT) levels were analyzed using a diagnostic kit. Liver histopathology and hepatic status parameters were measured. Compared to control mice, the BDL mice exhibited an enlargement in liver HIF-1α levels, which was suppressed by 100 and 300 mg/kg GGCLT treatments (control: BDL: BDL + GGCLT-100: BDL + GGCLT-300 = 0.95 ± 0.07: 1.95 ± 0.12: 1.43 ± 0.05: 1.12 ± 0.10 fold; p < 0.05). GGCLT restrained the induction of hepatic hydroxyproline and malondialdehyde levels in the mice challenged with BDL, further increasing the hepatic glutathione levels. Furthermore, in response to increased hepatic inflammation and fibrogenesis, significant levels of ALT, nuclear factor kappa B, transforming growth factor-ß, α-smooth muscle actin, matrix metalloproteinase-2 (MMP-2), MMP-9, and procollagen-III were found in BDL mice, which were attenuated with GGCLT. In addition, GGCLT reduced the induction of angiogenesis in the liver after BDL by inhibiting vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2. In conclusion, the anti-liver fibrosis effect of GGCLT, which suppresses hepatic oxidative stress and angiogenesis, may be dependent on an HIF-1α-mediated pathway.


Assuntos
Colestase/complicações , Medicamentos de Ervas Chinesas/farmacologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Animais , Biomarcadores , Biópsia , Colestase/patologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Masculino , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Resultado do Tratamento
3.
Biomed Res Int ; 2019: 6740616, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31321239

RESUMO

Identification of new pharmacological approaches to inhibit the excessive fat intake-induced steatohepatitis and chronic kidney disease (CKD) is important. High-fat diet (HFD)-induced steatohepatitis and CKD share common pathogenesis involving peroxisome proliferator-activated receptor (PPAR)-α and -δ. Elafibranor, a dual PPARα/δ agonist, can ameliorate the HFD-induced steatohepatitis. Nonetheless, the effects of HFD-induced CKD had not yet explored. This study investigated the effects of elafibranor (elaf) on the progression of HFD-induced CKD in mice. In vivo and in vitro renal effects were evaluated in HFD-elaf mice receiving 12 weeks of elafibranor (from 13th to 24th week of HFD feeding) treatment. In elafibranor-treated HFD mice, increased insulin sensitivity, reduced obesity and body fat mass, decreased severity of steatohepatitis, increased renal expression of PPARα, PPARδ, SIRT1, and autophagy (Beclin-1 and LC3-II) as well as glomerular/renal tubular barrier markers [synaptopodin (podocyte marker), zona occludin-1, and cubulin], reduced renal oxidative stress and caspase-3, and less urinary 8-isoprostanes excretion were observed. Aforementioned benefits of elafibranor were associated with low renal tubular injury and tubulointerstitial fibrosis scores, less albuminuria, low urinary albumin-to-creatinine ratio, and preserved glomerular filtration rate. Acute incubation of podocytes and HK-2 cells with elafibranor or recombinant SIRT1 reversed the HFD-sera-induced oxidative stress, autophagy dysfunction, cell apoptosis, barrier marker loss, albumin endocytosis, and reuptake reduction. Besides hepatoprotective and metabolic beneficial effects, current study showed that elafibranor inhibited the progression of HFD-induced CKD through activation of renal PPARα, PPARδ, SIRT1, autophagy, reduction of oxidative stress, and apoptosis in mice with steatohepatitis.


Assuntos
Chalconas/farmacologia , PPAR alfa/genética , PPAR delta/genética , Propionatos/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Sirtuína 1/genética , Animais , Apoptose/efeitos dos fármacos , Proteína Beclina-1/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Estresse Oxidativo/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia
4.
Cells ; 8(3)2019 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884843

RESUMO

Obesity has been shown to play a role in the pathogenesis of several forms of metabolic syndrome, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. Ursodeoxycholic acid (UDCA) has been shown to possess antioxidant and anti-inflammatory properties and prevents mitochondrial dysfunction in the progression of obesity-associated diseases. The aim of the study was to evaluate the mechanisms of UDCA during obesity-linked hepatic mitochondrial dysfunction and obesity-associated adipose tissue macrophage-induced inflammation in obese mice. UDCA significantly decreased lipid droplets, reduced free fatty acids (FFA) and triglycerides (TG), improved mitochondrial function, and enhanced white adipose tissue browning in ob/ob mice. This is associated with increased hepatic energy expenditure, mitochondria biogenesis, and incorporation of bile acid metabolism (Abca1, Abcg1 mRNA and BSEP, FGFR4, and TGR5 protein). In addition, UDCA downregulated NF-κB and STAT3 phosphorylation by negative regulation of the expression of SOCS1 and SOCS3 signaling. These changes were accompanied by decreased angiogenesis, as shown by the downregulation of VEGF, VCAM, and TGF-ßRII expression. Importantly, UDCA is equally effective in reducing whole body adiposity. This is associated with decreased adipose tissue expression of macrophage infiltration (CD11b, CD163, and CD206) and lipogenic capacity markers (lipofuscin, SREBP-1, and CD36). Furthermore, UDCA significantly upregulated adipose browning in association with upregulation of SIRT-1-PGC1-α signaling in epididymis adipose tissue (EWAT). These results suggest that multi-targeted therapies modulate glucose and lipid biosynthesis fluxes, inflammatory response, angiogenesis, and macrophage differentiation. Therefore, it may be suggested that UDCA treatment may be a novel therapeutic agent for obesity.


Assuntos
Tecido Adiposo Branco/patologia , Polaridade Celular , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Leptina/deficiência , Fígado/metabolismo , Macrófagos/metabolismo , Ácido Ursodesoxicólico/farmacologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Polaridade Celular/efeitos dos fármacos , Ácidos Graxos/metabolismo , Glucose/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Leptina/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Oxirredução , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Int J Nanomedicine ; 14: 421-429, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30666104

RESUMO

Background: In this study, we developed biodegradable andrographolide (AG)-eluting nanofibrous mats and evaluated their efficacy in treating cervical cancer. Materials and methods: Membranes of two different poly[(d,l)-lactide-co-glycolide] (PLGA)-to-AG ratios (6:1 and 3:1) were prepared via electrospinning technology. The liberation behavior of AG was evaluated. A cervical cancer model with C57BL/6J mice was created and employed for an in vivo efficacy assessment of the drug-eluting nanofibers. Twelve mice with cervical cancer were stochastically divided into three different groups (four animals per group): group A received no treatment as the control, group B was treated with pure PLGA mats, and group C was treated with AG-loaded nanofibrous membranes. The changes in tumor sizes were recorded. Results: All membranes eluted high concentrations of AG at the target area for three weeks, while the systemic drug concentration in the blood remained low. Histological analysis showed no obvious tissue inflammation. Compared with the mice in groups A and B, the tumor size of the mice in group C decreased with time until day 25, when the daily drug concentration reduced to 3 µg/mL. Conclusion: Biodegradable nanofibers with a sustainable release of AG exhibit adequate efficacy and durability for the treatment of mice with cervical cancer.


Assuntos
Materiais Biocompatíveis/química , Diterpenos/uso terapêutico , Nanofibras/química , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/farmacologia , Portadores de Fármacos , Liberação Controlada de Fármacos , Feminino , Membranas Artificiais , Camundongos Endogâmicos C57BL , Nanofibras/ultraestrutura , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Resistência à Tração , Carga Tumoral/efeitos dos fármacos , Neoplasias do Colo do Útero/patologia , Água/química
6.
Clin Sci (Lond) ; 133(3): 531-544, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30602573

RESUMO

Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.


Assuntos
Chalconas/administração & dosagem , Fígado Gorduroso Alcoólico/tratamento farmacológico , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Propionatos/administração & dosagem , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Autofagia/efeitos dos fármacos , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/metabolismo , Humanos , Intestinos/citologia , Intestinos/lesões , Fígado/lesões , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR delta/genética , PPAR delta/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-30174710

RESUMO

Background: The Auto Manipulation Device for Acupuncture (AMDA) is designed for providing stable, quantified effects and higher frequency when doing lifting and thrusting manipulation. The purpose of this study is to investigate the safety of manipulation by AMDA in different frequency and duration in healthy rats. Methods: The study was divided into two parts: single intervention and once a day for a week. 12 rats and 15 rats were randomly allocated to different groups: Control (needle insertion only), AMDA (2Hz/10Mins), AMDA (2Hz/20Mins), AMDA (20Hz/10Mins), and AMDA (20Hz/20Mins) for single and repeated interventions. Real-time physiological functions, laboratory data, and the bilateral muscle tissue of acupoint (ST 36) were obtained after the intervention. Results: We found neither real-time physiological functions nor laboratory data differences between control group and AMDA groups in both parts. In the muscle tissue samples, the slight damage had been observed in the AMDA group with a frequency of 2 Hz for 20 minutes after once intervention, and the repeated session groups noted more obvious tissue damage with fibrotic change. Although the period was shorter, higher frequency manipulation caused more damage that fibroblast nuclei became more slender and obvious. However, no significant adverse effect was noted such as crippled and molting in the whole process. Conclusion: Our study suggested that the safety issue of AMDA operation in rats is feasible because there was no difference between control group and AMDA groups among real-time physiological functions and laboratory data. However, manipulation with higher frequency should be more preserved.

8.
Int J Mol Med ; 41(3): 1455-1462, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29328388

RESUMO

Liver injury is associated with devastating consequences caused by inflammation and apoptosis. The farnesoid X receptor (FXR) is a nuclear receptor that has an essential role in hepatoprotection by maintaining the homeostasis of liver metabolism. The present study investigated the capacity of the FXR agonist GW4064 to protect the livers of mice from lipopolysaccharide (LPS)­induced inflammation and apoptosis. Male C57BL/6J [wild­type (WT)] and FXR knockout (KO) mice were intraperitoneally injected with LPS or saline. LPS­treated mice were intraperitoneally injected with vehicle or GW4064 (20 mg/kg) twice and then sacrificed. Activation of FXR by GW4064 alleviated hepatic inflammation in the LPS­induced murine liver injury model as reflected by reduced serum levels of aspartate aminotransferase and pro­inflammatory cytokine mRNA expression, including tumor necrosis factor­α, as well as interleukin­6 and ­1ß in WT mice. In addition, Toll­like receptor 4 (TLR4), p38 mitogen­activated protein kinase (MAPK), B­cell lymphoma­2­associated X protein and cytochrome c protein levels were decreased in WT mice receiving LPS with simultaneous GW4064 administration compared with those receiving LPS alone, while this was not observed in FXR KO mice. These results indicated that in WT mice, administration of GW4064 ameliorated LPS­mediated liver injury by upregulation of FXR expression, which was in part mediated by the TLR4/p38 MAPK pathway.


Assuntos
Apoptose/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/patologia , Isoxazóis/farmacologia , Fígado/metabolismo , Fígado/patologia , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Alanina Transaminase/sangue , Animais , Inflamação/sangue , Isoxazóis/administração & dosagem , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo
9.
Food Chem Toxicol ; 112: 435-440, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28947358

RESUMO

Prolamin is a heat-stable storage protein of rice (Oryza sativa). This study aimed to examine the effect of prolamin on anti-tumor immune response in vitro and leukemia growth in vivo. The prolamin-enriched rice fractions were prepared to stimulate peripheral blood mononuclear cells (MNC) from mice spleen. The MNC-conditioned medium (MNC-CM) was collected to treat leukemia L1210 cells. Human MNC-CM was prepared to treat Jurkat acute T cell leukemia cells. Purified prolamin was orally administered to syngeneic L1210-bearing DBA/2 mice to assess weights of tumor, liver and spleen, liver histopathology, peripheral blood neutrophil count and cytokine levels. Prolamin-prepared MNC-CM inhibited the viability of murine leukemia L1210 cells and human leukemia Jurkat cells, indicating an immunomodulatory effect. In syngeneic L1210-bearing DBA/2 mice, oral administration of purified prolamin dose-dependently decreased the tumor weight and attenuated the leukemia-induced reduction of liver and spleen weights. Prolamin inhibited the increase of peripheral blood leukocyte count. The levels of tumor necrosis factor-α and interferon-γ in MNC-CM and mice serum were significantly increased by prolamin treatment. No significant change in body weight, serum alanine aminotransferase and creatinine levels was noted by prolamin treatment. Rice prolamin could effectively promote anti-tumor immunity and inhibit leukemia growth without significant toxicity.


Assuntos
Proliferação de Células/efeitos dos fármacos , Leucemia L1210/imunologia , Oryza/química , Proteínas de Plantas/farmacologia , Prolaminas/farmacologia , Alanina Transaminase/sangue , Animais , Creatinina/sangue , Meios de Cultivo Condicionados , Humanos , Interferon gama/sangue , Células Jurkat , Leucemia L1210/patologia , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos DBA , Neutrófilos/citologia , Tamanho do Órgão/efeitos dos fármacos , Reprodutibilidade dos Testes , Baço/efeitos dos fármacos , Baço/patologia , Fator de Necrose Tumoral alfa/sangue
10.
Oncotarget ; 8(51): 88563-88574, 2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-29179457

RESUMO

Purpose: The induction of autophagic cell death is an important process in the development of anticancer therapeutics. We aimed to evaluate the activity of the ancient Chinese decoction Danggui Buxue Tang (DBT) against colorectal cancer (CRC) and the associated autophagy-related mechanism. Materials and methods: CT26 CRC cells were implanted into syngeneic BALB/c mice for the tumor growth assay. DBT extracts and DBT-PD (polysaccharide-depleted) fractions were orally administered. The toxicity profiles of the extracts were analyzed using measurements of body weight, hemogram, and biochemical parameters. The morphology of tissue sections was observed using light and transmission electron microscopy. Western blotting and small interference RNA assays were used to determine the mechanism. Results: DBT-PD and DBT, which contained an equal amount of DBT-PD, inhibited CT26 syngeneic tumor growth. In the tumor specimen, the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3B) was upregulated by DBT-PD and DBT. The development of autophagosomes was observed via transmission electron microscopy in tumors treated with DBT-PD and DBT. In vitro experiments for mechanism clarification demonstrated that DBT-PD could induce autophagic death in CT26 cells accompanied by LC3B lipidation, downregulation of phospho-p70s6k, and upregulation of Atg7. RNA interference of Atg7, but not Atg5, partially reversed the effect of DBT-PD on LC3B lipidation and expression of phospho-p70s6k and Atg7. The changes in ultrastructural morphology and LC3B expression induced by DBT-PD were also partially blocked by the knockdown of Atg7 mRNA. Conclusion: DBT induced autophagic death of colorectal cancer cells through the upregulation of Atg7 and modulation of the mTOR/p70s6k signaling pathway.

11.
Oncotarget ; 8(49): 86206-86216, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29156788

RESUMO

Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The aim of the study was to evaluate the mechanisms of HIF-1α inhibitor, YC-1, during bile duct ligation (BDL)-induced liver fibrosis in mice. Liver fibrosis was induced in mice, and YC-1 was then given intraperitoneally (50 mg/kg) once daily following 5 days. Liver injuries mice that were treated with YC-1 showed improved inflammatory response and diminished angiogenesis and hepatic fibrosis. YC-1 treatment inhibited liver neutrophil infiltration, while a decreased in TNF-α signaling as well as macrophage aggregation. In addition, YC-1 downregulates iNOS and COX-2 levels by inhibiting the activation of NF-κB and STAT3 phosphorylation by negative regulation the expression of SOCS1 and SOCS3 signaling. On the other hand, YC-1 decreased angiogenesis, as shown by the downregulation of hypoxia-inducible cascade genes, i.e. VEGF. YC-1 treatment resulted in a significant decrease in hepatic fibrogenesis, α-SMA abundance, and TGF-ßR1 expression as well as hypoxia were assessed using VEGFR1, vWF and HIF-1α immunostaining. These results suggest that multi-targeted therapies directed against angiogenesis, hypoxia, and fibrosis. Therefore, it may be suggested that YC-1 treatment may be a novel therapeutic agent for the treatment of liver disease.

12.
Int Immunopharmacol ; 51: 25-30, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28772243

RESUMO

Daphnoretin, an active constituent of Wikstroemia indica C.A. Meys, has been shown possessing anti-cancer activity. In this study, we examined the effect of daphnoretin on differentiation and maturation of human myeloid dendritic cells (DCs). After treatment with daphnoretin (0, 1.1, 3.3, 10 and 30µM) to initiate monocytes, the recovery rate of DCs was reduced in a dose-dependent manner. The mature DCs differentiated in the presence of daphnoretin had fewer and shorter dendrites. Daphnoretin modulated DCs differentiation and maturation in terms of lower expression of CD1a, CD40, CD83, DC-SIGN, and HLA-DR. Daphnoretin inhibited the allostimulatory activity of DCs on proliferation of naive CD4+CD45+RA+ T cell. On the mitogen-activated protein kinase, daphnoretin down-regulated the lipopolysaccharide-augmented expression of phosphorylated c-Jun N-terminal kinase (pJNK), but not p38 and extracellular signal-regulated kinase 1/2 (ERK1/2). Activation of JNK by anisomycin reversed the effect of daphnoretin on daphnoretin-inhibited pJNK expression and dendrite formation of DCs. In disease model related to maturation of DCs, daphnoretin suppressed the acute rejection of skin allografts in mice. Our results suggest that daphnoretin modulated differentiation and maturation of DCs toward a state of atypical maturation with impaired allostimulatory function and this effect may go through down-regulation of phosphorylated JNK.


Assuntos
Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Cumarínicos/farmacologia , Células Dendríticas/fisiologia , Rejeição de Enxerto/prevenção & controle , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transplante de Pele , Doença Aguda , Animais , Anisomicina/farmacologia , Diferenciação Celular , Células Cultivadas , Dendritos/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Modelos Animais de Doenças , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante Homólogo , Wikstroemia/imunologia
13.
Sci Rep ; 7(1): 2705, 2017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28578410

RESUMO

Loss of regenerative capacity plays a critical role in age-related autoimmune hepatitis. Evidence implicates SIRT1 and p66shc in cell senescence, apoptosis, oxidative stress, and proliferation. This study investigated the effect of resveratrol on concanavalin A (Con A)-induced hepatitis in aged mice and the roles of SIRT1 and p66shc. Aged mice were administrated resveratrol (30 mg/kg orally) seven times at an interval of 12 h before a single intravenous injection of Con A (20 mg/kg). Results showed that the cytokines, TNF-α, IL-6, IFN-γ, and MCP-1, as well as infiltration of macrophages, neutrophils, and T lymphocytes in liver were dramatically enhanced in the mice given only Con A. The aged mouse livers showed markedly raised oxidative stress and cell apoptosis. This oxidative stress further aggravated regenerative dysfunction as indicated by the decreased levels of Ki67, PCNA, Cyclin D1, and Cdk2. Conversely, these phenomena were attenuated by pretreatment with resveratrol. Moreover, resveratrol suppressed the elevation of p66shc in the liver by reversing Con-A-mediated downregulation of SIRT1. The findings suggest that resveratrol protected against Con A-induced hepatitis in aged mice by attenuating an aberration of immune response and liver regeneration, partially via the mechanism of SIRT1-mediated repression of p66shc expression.


Assuntos
Concanavalina A/efeitos adversos , Hepatite/etiologia , Hepatite/metabolismo , Regeneração Hepática/efeitos dos fármacos , Resveratrol/farmacologia , Fatores Etários , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatite/patologia , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Camundongos , Estresse Oxidativo/efeitos dos fármacos
14.
Biochem Biophys Res Commun ; 490(3): 841-848, 2017 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-28647362

RESUMO

Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory condition of the gastro intestinal tract characterized by diarrhoea and abdominal pain. Farnesoid X receptor (FXR) plays an important role in enteroprotection and mucosal injury by regulating inflammatory responses and barrier function in the intestinal tract. Here we show the mechanisms of FXR agonist, GW4064, inhibits mucosal injury in ileum caused by lipopolysaccharides (LPS). Ileum injury was induced by intraperitoneal injection of LPS in Wild-type (WT) and FXR knockout (KO) mice. GW4064 alleviates LPS-mediated tight junction dysfunction as well as macrophage infiltration in WT mice, but not in FXR KO mice. Interesting, GW4064 suppresses NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome mediates tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-1ß, as well as mitochondrial respiratory complexes mRNA expression in WT and FXR KO mice treated with LPS. This results demonstrated that central roles of FXR in coordinating regulation of both inflammation and mitochondrial dysfunction. We propose that GW4064 is promising therapeutic agent for treatment of ileocolitis.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Isoxazóis/uso terapêutico , Fator 88 de Diferenciação Mieloide/imunologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptor 4 Toll-Like/imunologia , Animais , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Íleo/efeitos dos fármacos , Íleo/imunologia , Íleo/patologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Mitocôndrias/patologia , Fator 88 de Diferenciação Mieloide/análise , Receptores Citoplasmáticos e Nucleares/análise , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/imunologia , Receptor 4 Toll-Like/análise
16.
Proteomics ; 17(1-2)2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27928909

RESUMO

Over activity of cannabinoid receptor type 1 (CB1R) plays a key role in increasing the incidence of obesity-induced non-alcoholic fatty liver disease. Tissue proteome analysis has been applied to investigate the bioinformatics regarding the mode of action and therapeutic mechanism. The aim of this study was to explore the potential pathways altered with CB1R in obesity-induced fatty liver. Male C57BL/6 mice were fed either a standard chow diet (STD) or a high-fat diet (HFD) with or without 1-week treatment of CB1R inverse agonist AM251 at 5 mg/kg. Then, liver tissues were harvested for 2DE analysis and protein profiles were identified by using MALDI-MS. Results showed that eight of significantly altered protein spots at the level of changes > twofold were overlapped among the three groups, naming major urinary protein 1, ATP synthase subunit ß, glucosamine-fructose-6-phosphate aminotransferase 1, zine finger protein 2, s-adenosylmethionine synthase isoform type-1, isocitrate dehydrogenase subunit α, epoxide hydrolase 2 and 60S acidic ribosomal protein P0. These identified proteins were involved in glucose/lipid metabolic process, xenobiotic metabolic system, and ATP synthesized process in mitochondria. Based on the findings, we speculated that CB1R blockade might exert its anti-metabolic disorder effect via improvement of mitochondrial function in hepatic steatosis in HFD condition.


Assuntos
Biomarcadores/sangue , Antagonistas de Receptores de Canabinoides/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/sangue , Piperidinas/uso terapêutico , Proteômica/métodos , Pirazóis/uso terapêutico , Receptores de Canabinoides/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo
17.
Molecules ; 21(12)2016 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-27929437

RESUMO

Chemotherapy is an important treatment modality for colon cancer, and concurrent chemoradiation therapy (CCRT) is the preferred treatment route for patients with stage II and III rectal cancer. We examined whether DangguiBuxue Tang (DBT), a traditional Chinese herbal extract, sensitizes colorectal cancer cells to anticancer treatments. The polysaccharide-depleted fraction of DBT (DBT-PD) contains greater amounts of astragaloside IV (312.626 µg/g) and ferulic acid (1.404 µg/g) than does the original formula. Treatment of the murine colon carcinoma cell line (CT26) with DBT-PD inhibits growth, whereas treatment with comparable amounts of purified astragaloside IV and ferulic acid showed no significant effect. Concurrent treatment with DBT-PD increases the growth inhibitory effect of 5-fluorouracil up to 4.39-fold. DBT-PD enhances the effect of radiation therapy (RT) with a sensitizer enhancement ratio (SER) of up to 1.3. It also increases the therapeutic effect of CCRT on CT26 cells. Cells treated with DBP-PD showed ultrastructural changes characteristic of autophagy, including multiple cytoplasmic vacuoles with double-layered membranes, vacuoles containing remnants of degraded organelles, marked swelling and vacuolization of mitochondria, and autolysosome-like vacuoles. We conclude that DBT-PD induces autophagy-associated cell death in CT26 cells, and may have potential as a chemotherapy or radiotherapy sensitizer in colorectal cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fluoruracila/farmacologia , Quimiorradioterapia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Células HT29 , Humanos , Concentração Inibidora 50 , Tolerância a Radiação/efeitos dos fármacos
18.
Int J Mol Med ; 37(3): 743-54, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26847930

RESUMO

Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance. The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function. The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity. For this purpose, male C57BL/6 mice were randomly assigned to groups and either fed a standard diet (STD), a HFD, or a HFD with 1-week treatment of the CB1R inverse agonist, AM251, at 1 or 5 mg/kg. For in vitro experiments, AML12 hepatocytes were incubated with FoxO1 siRNA prior to challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of free fatty acids (HFFA). Plasma parameters were analyzed using colorimetric methods. Liver histopathology and hepatic status markers were examined. The HFD-fed mice exhibited an increase in CB1R levels in the liver. Moreover, in response to increased hepatic oxidative stress, the HFD-fed mice also displayed hepatic mitochondrial dysfunction, as indicated by the decreased mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and citrate synthase. On the contrary, these effects in the HFD-fed mice were reversed by treatment with 5 mg/kg AM251. The administration of AM251 suppressed the induction of FoxO1, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) expression in the livers of the mice fed a HFD by enhancing the phosphorylation of insulin signaling cascades thus, further lowering the high level of the homeostatic model assessment of insulin resistance (HOMA­IR) index. In our in vitro experiments, transfection with FoxO1 siRNA prevented the HFFA- and ACEA-induced decrease in the gene expression of mitochondrial biogenesis-related factors, and abrogated the HFFA- and ACEA-induced increase in PEPCK and G6Pase expression. Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Proteína Forkhead Box O1/metabolismo , Resistência à Insulina/fisiologia , Obesidade/metabolismo , Receptores de Canabinoides/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Citrato (si)-Sintase/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 Relacionado a NF-E2/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia
19.
Sci Rep ; 6: 19622, 2016 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-26847148

RESUMO

LC is an herbal remedy effectively reduced therapeutic dosage of glucocorticoid for systemic lupus erythematosus (SLE) patients in clinical trial (ISRCTN81818883). This translational research examined the impact of LC on biomarkers of endothelial injury in the enrolled subjects. Fifty seven patients with SLE were randomized to receive standard treatment without or with LC supplements. Blood samples were taken serially for quantification of endothelial progenitor cells (EPCs), circulating endothelial cells (CECs) and serological factors. The proportion of EPCs in the placebo group continued to increase during trial and was further elevated after withdrawal of standard treatment. The EPC ratio of LC group remained stationary during the entire observation period. The CEC ratio in placebo group exhibited an increasing trend whereas that in LC group declined. The ratio of apoptotic CECs had an increasing trend in both groups, to a lesser extent in LC group. After treatment, the levels of VEGF and IL-18 have a trend declined to a level lower in the LC group than the placebo group. No significant alteration was noted in serum levels of IFN-α, IL-1ß and IL-6. The reduction of the steroid dosage by adding LC might be correlated with less extensive endothelial injury in SLE patients.


Assuntos
Biomarcadores/sangue , Medicamentos de Ervas Chinesas/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Medicina Tradicional Chinesa , Citocinas/sangue , Suplementos Nutricionais , Medicamentos de Ervas Chinesas/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Interleucina-18/sangue , Lúpus Eritematoso Sistêmico/metabolismo , Efeito Placebo , Fator A de Crescimento do Endotélio Vascular/sangue
20.
BMC Complement Altern Med ; 15: 452, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26714835

RESUMO

BACKGROUND: Electroacupuncture (EA) shows anti-inflammation and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that EA prevents inflammatory response and weight gain in obese mice through modulation of hypoxia-inducible factors-1α (HIF1-α)-dependent pathways in white adipose tissues. METHODS: Mice were divided in 4 groups: Non-obese, ob/ob, ob/ob submitted to 3 treatments, ob/ob submitted to 7 treatments. Low-frequency EA (2 Hz) was applied at the Zusanli (ST36) acupoint 10 min three times weekly for one or two consecutive weeks in male ob/ob mice. At 22 weeks of age, plasma lipid, glucose, other metabolites and relevant markers were measured by standard assays. Adipose tissue was assessed with immunohistochemical staining. Adipose tissue extracts were also analyzed with quantitative real-time polymerase chain reaction (Q-PCR) and Western blotting. RESULTS: EA treatment is associated with decreased adipose tissue inflammation, and markedly decreased fat mass and adipocyte size in ob/ob mice. In obese mice, The protein levels of HIF-α were increased, EA shown a marked trend in inhibiting the hypoxic response in adipose tissue. The expression level of hypoxia-related genes (vascular endothelial growth factor A, VEGFA; glucose transporter type 1, Slc2al; glutathione peroxidase 1, GPX1) and inflammation-related genes (TNF-α, IL-6, MCP-1) expression were also reduced in adipose tissue after EA treatment. EA treatment decreased the macrophage recruitment and infiltration (F4/80), and in addition we found that decrease in NF-κB and increase in IkBα were both correlated to reduction in inflammatory processes in adipose tissue. This phenomenon was paralleled by the decrease in the levels of inflammatory cytokines, such as TNF-α, IL-6 and IL-1ß in obese mice. CONCLUSIONS: We conclude that EA prevents weight gain through modulation of HIF-1α-dependent pathways and inflammatory response in obese adipose tissues.


Assuntos
Tecido Adiposo Branco/metabolismo , Eletroacupuntura , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/prevenção & controle , Obesidade/metabolismo , Animais , Modelos Animais de Doenças , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Obesos , Transdução de Sinais , Ganho de Peso
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