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1.
Mol Cells ; 42(10): 693-701, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31617339

RESUMO

Plants monitor changes in day length to coordinate their flowering time with appropriate seasons. In Arabidopsis , the diel and seasonal regulation of CONSTANS (CO) protein stability is crucial for the induction of FLOWERING LOCUS T (FT) gene in long days. FLAVIN-BINDING, KELCH REPEAT, F-BOX 1 (FKF1) and ZEITLUPE (ZTL) proteins control the shape of CO expression profile antagonistically, although regulation mechanisms remain unknown. In this study, we show that GIGANTEA (GI) protein modulates the stability and nuclear function of FKF1, which is closely related to the stabilization of CO in the afternoon of long days. The abundance of FKF1 protein is decreased by the gi mutation, but increased by GI overexpression throughout the day. Unlike the previous report, the translocation of FKF1 to the nucleus was not prevented by ZTL overexpression. In addition, the FKF1-ZTL complex formation is higher in the nucleus than in the cytosol. GI interacts with ZTL in the nucleus, implicating the attenuation of ZTL activity by the GI binding and, in turn, the sequestration of FKF1 from ZTL in the nucleus. We also found that the CO-ZTL complex presents in the nucleus, and CO protein abundance is largely reduced in the afternoon by ZTL overexpression, indicating that ZTL promotes CO degradation by capturing FKF1 in the nucleus under these conditions. Collectively, our findings suggest that GI plays a pivotal role in CO stability for the precise control of flowering by coordinating balanced functional properties of FKF1 and ZTL.

2.
Cell Commun Signal ; 17(1): 104, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438968

RESUMO

BACKGROUND: Alcohol abuse and alcoholism lead to alcohol liver disease such as alcoholic fatty liver. Parkin is a component of the multiprotein E3 ubiquitin ligase complex and is associated with hepatic lipid accumulation. However, the role of parkin in ethanol-induced liver disease has not been reported. Here, we tested the effect of parkin on ethanol-induced fatty liver in parkin knockout (KO) mice with chronic ethanol feeding. METHODS: Male wild type (WT) and parkin KO mice (10-12 weeks old, n = 10) were fed on a Lieber-DeCarli diet containing 6.6% ethanol for 10 days. Liver histological, biochemical, and gene-expression studies were performed. RESULTS: Parkin KO mice exhibited lower hepatosteatosis after ethanol consumption. Because several studies reported that ß-catenin is a critical factor in ethanol metabolism and protects against alcohol-induced hepatosteatosis, we investigated whether parkin changes ß-catenin accumulation in the liver of ethanol-fed mice. Our results show that ß-catenin was greatly accumulated in the livers of ethanol-fed parkin KO mice compared to ethanol-fed WT mice, and that parkin binds to ß-catenin and promotes its degradation it by ubiquitination. Moreover, the ß-catenin inhibitor IWR-1 abrogated the attenuation of ethanol-induced hepatic lipid accumulation by parkin deficiency in the livers of parkin KO mice and parkin siRNA-transfected human hepatic cell line. CONCLUSIONS: Parkin deficiency prevents ethanol-induced hepatic lipid accumulation through promotion of ß-catenin signaling by failure of ß-catenin degradation.

3.
Life Sci ; 225: 98-106, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959026

RESUMO

AIMS: Arterial insufficiency ulcers are frequent complications of peripheral artery disease and infection or long-term neglect of the ulcer can eventually lead to amputation of the affected body part. An ischemic environment, caused by interrupted blood flow, affects the supply of nutrients and elongates the inflammation period, inducing tissue degeneration. Thus, the modulation of neovascularization and inflammation could be an ideal therapeutic strategy for ischemic wound healing. This study aimed to elucidate whether systemically administered substance P (SP) could promote ischemic wound repair in mice by restoring blood perfusion and suppressing inflammation. MAIN METHODS: The effects of SP were assessed by analyzing wound size, blood flow, epidermal and dermal layer regeneration, vessel formation, and the inflammatory cytokine profiles in a hind-limb ischemia non-clinical mouse model. KEY FINDINGS: SP-treated mice exhibited dramatically rapid wound healing and restoration of blood flow within the ischemic zone, compared with saline-treated mice. Notably, SP-treated mice showed enhanced pericyte-covered vasculature compared to saline-treated mice. Moreover, anti-inflammatory effects were detected in mice in the SP-treated group, including suppression of inflammation-mediated spleen enlargement, reduction of tumor necrosis factor-alpha, and promotion of circulatory interleukin-10 levels. SIGNIFICANCE: These results suggest that SP could be a possible therapeutic candidate for patients with peripheral artery disease, including those with ischemic ulcers.


Assuntos
Modelos Animais de Doenças , Inflamação/prevenção & controle , Isquemia/complicações , Neovascularização Fisiológica/efeitos dos fármacos , Neurotransmissores/farmacologia , Substância P/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Inflamação/etiologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pele/efeitos dos fármacos , Pele/metabolismo
4.
J Exp Clin Cancer Res ; 37(1): 293, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30486830

RESUMO

BACKGROUND: Interleukin-32 (IL-32) has been associated with various diseases. Previous studies have shown that IL-32 inhibited the development of several tumors. However, the role of IL-32γ, an isotype of IL-32, in skin carcinogenesis remains unknown. METHODS: We compared 7,12-Dimethylbenz[a]anthracene/12-O-Tetradecanoylphorbol-13-acetate (DMBA/TPA)-induced skin carcinogenesis in wild type (WT) and IL-32γ-overexpressing mice to evaluate the role of IL-32γ. We also analyzed cancer stemness and NF-κB signaling in skin cancer cell lines with or without IL-32γ expression by western blotting, quantitative real-time PCR and immunohistochemistry analysis. RESULTS: Carcinogen-induced tumor incidence in IL-32γ mice was significantly reduced in comparison to that in WT mice. Infiltration of inflammatory cells and the expression levels of pro-inflammatory mediators were decreased in the skin tumor tissues of IL-32γ mice compared with WT mice. Using a genome-wide association study analysis, we found that IL-32 was associated with integrin αV (ITGAV) and tissue inhibitor of metalloproteinase-1 (TIMP-1), which are critical factor for skin carcinogenesis. Reduced expression of ITGAV and TIMP-1 were identified in DMBA/TPA-induced skin tissues of IL-32γ mice compared to that in WT mice. NF-κB activity was also reduced in DMBA/TPA-induced skin tissues of IL-32γ mice. IL-32γ decreased cancer cell sphere formation and expression of stem cell markers, and increased chemotherapy-induced cancer cell death. IL-32γ also downregulated expression of ITGAV and TIMP-1, accompanied with the inhibition of NF-κB activity. In addition, IL-32γ expression with NF-κB inhibitor treatment further reduced skin inflammation, epidermal hyperplasia, and cancer cell sphere formation and downregulated expression levels of ITGAV and TIMP-1. CONCLUSIONS: These findings indicated that IL-32γ suppressed skin carcinogenesis through the inhibition of both stemness and the inflammatory tumor microenvironment by the downregulation of TIMP-1 and ITGAV via inactivation of NF-κB signaling.

5.
Nat Plants ; 4(10): 824-835, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30250277

RESUMO

Plants sense light and temperature changes to regulate flowering time. Here, we show that expression of the Arabidopsis florigen gene, FLOWERING LOCUS T (FT), peaks in the morning during spring, a different pattern than we observe in the laboratory. Providing our laboratory growth conditions with a red/far-red light ratio similar to open-field conditions and daily temperature oscillation is sufficient to mimic the FT expression and flowering time in natural long days. Under the adjusted growth conditions, key light signalling components, such as phytochrome A and EARLY FLOWERING 3, play important roles in morning FT expression. These conditions stabilize CONSTANS protein, a major FT activator, in the morning, which is probably a critical mechanism for photoperiodic flowering in nature. Refining the parameters of our standard growth conditions to more precisely mimic plant responses in nature can provide a powerful method for improving our understanding of seasonal response.

6.
Cell Death Dis ; 9(3): 306, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29467412

RESUMO

The low expression of tissue inhibitor of metalloproteinase 3 (TIMP-3) is important in inflammatory responses. Therefore, inhibition of TIMP-3 may promote tumor development. Our study showed that expression of TIMP-3 was elevated in lL-32γ mice lung tissues. In this study, we investigated whether IL-32γ mice inhibited lung tumor development through overexpression of TIMP-3 and its methylation. To explore the possible underlying mechanism, lung cancer cells were transfected with IL-32γ cDNA plasmid. A marked increase in TIMP-3 expression was caused by promoter methylation. Mechanistic studies indicated that TIMP-3 overexpression reduced NF-κB activity, which led to cell growth inhibition in IL-32γ transfected lung cancer cells. We also showed that IL-32γ inhibits expression of DNA (cytosine-5-)-methyltransferase 1 (DNMT1). Moreover, IL-32γ inhibits the binding of DNMT1 to TIMP-3 promoter, but this effect was reversed by the treatment of DNA methyltransferase inhibitor (5-Aza-CdR) and NF-κB inhibitor (PS1145), suggesting that a marked increase in TIMP-3 expression was caused by inhibition of promoter hypermethylation via decreased DNMT1 expression through the NF-κB pathway. In an in vivo carcinogen induced lung tumor model, tumor growth was inhibited in IL-32γ overexpressed mice with elevated TIMP-3 expression and hypomethylation accompanied with reduced NF-κB activity. Moreover, in the lung cancer patient tissue, the expression of IL-32 and TIMP-3 was dramatically decreased at a grade-dependent manner compared to normal lung tissue. In summary, IL-32γ may increase TIMP-3 expression via hypomethylation through inactivation of NF-κB activity, and thereby reduce lung tumor growth.

8.
J Am Chem Soc ; 139(11): 4202-4210, 2017 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-28287258

RESUMO

The covalent functionalization of single and bilayer graphene on SiO2 (300 nm)/Si was effected through sequential treatment with the alkalide reductant [K(15-crown-5)2]Na and electrophilic aryl or alkyl halides, of which the iodides proved to be the most reactive. The condensation reactions proceeded at room temperature and afforded the corresponding aryl- or alkyl-appended graphenes. For each sample, Raman and X-ray photoelectron spectroscopies were used to evaluate the degrees and uniformities of functionalization. Statistical analyses of the Raman data revealed that the introduction of the organic moieties was accompanied by sp3-rehybridization of the basal plane atoms. When bilayers consisting of 13C and 12C layers were treated, both the top and bottom sheets were decorated with organic groups. The reaction was followed using Raman spectroscopy, and the mechanism was studied by theoretical calculations. Indicative of its structure and reactivity, 4-pyridyl-decorated single-layer graphene was readily benzylated and appears to be an ideal platform to develop functional materials.

9.
Cytokine ; 90: 21-30, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27750083

RESUMO

Intestinal inflammation alters immune responses in the mucosa and destroys colon architecture, leading to serious diseases such as inflammatory bowel disease (IBD). Thus, regulation of inflammation is regarded as the ultimate therapy for intestinal disease. Substance-P (SP) is known to mediate proliferation, migration, and cellular senescence in a variety of cells. SP was found to mobilize stem cells from bone marrow to the site of injury and to suppress inflammatory responses by inducing regulatory T cells (Tregs) and M2 macrophages. In this study, we explored the effects of SP in a dextran sodium sulfate (DSS)-induced intestine damage model. The effects of SP were evaluated by analyzing crypt structures, proliferating cells within the colon, cytokine secretion profiles, and immune cells population in the spleen/mesenteric lymph nodes in vivo. DSS treatment provoked an inflammatory response with loss of crypts in the intestines of experimental mice. This response was associated with high levels of inflammatory cytokines such as TNF-α and IL-17, and low levels of Tregs and M2 macrophages, leading to severely damaged tissue structure. However, SP treatment inhibited inflammatory responses by modulating cytokine production as well as the balance of Tregs/Th 17 cells and the M1/M2 transition in lymphoid organs, leading to accelerated tissue repair. Collectively, our data indicate that SP can promote the regeneration of tissue following damage by DSS treatment, possibly by modulating immune response. Our results propose SP as a candidate therapeutic for intestine-related inflammatory diseases.


Assuntos
Sulfato de Dextrana/toxicidade , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , Substância P/farmacologia , Animais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/patologia , Interleucina-17/metabolismo , Intestinos/patologia , Macrófagos/patologia , Masculino , Camundongos , Fator de Necrose Tumoral alfa/metabolismo
10.
Oncotarget ; 7(30): 46943-46958, 2016 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-27409674

RESUMO

Neuroinflammation is implicated for dopaminergic neurodegeneration. Sulfur compounds extracted from garlic have been shown to have anti-inflammatory properties. Previously, we have investigated that thiacremonone, a sulfur compound isolated from garlic has anti-inflammatory effects on several inflammatory disease models. To investigate the protective effect of thiacremonone against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment and dopaminergic neurodegeneration, 8 week old ICR mice were given thiacremonone (10 mg/kg) in drinking water for 1 month and received intraperitoneal injection of MPTP (15 mg/kg, four times with 2 h interval) during the last 7 days of treatment. Our data showed that thiacremonone decreased MPTP-induced behavioral impairments (Rotarod test, Pole test, and Gait test), dopamine depletion and microglia and astrocytes activations as well as neuroinflammation. Higher activation of p38 was found in the substantia nigra and striatum after MPTP injection, but p38 activation was reduced in thiacremonone treated group. In an in vitro study, thiacremonone (1, 2, and 5 µg/ml) effectively decreased MPP+ (0.5 mM)-induced glial activation, inflammatory mediators generation and dopaminergic neurodegeneration in cultured astrocytes and microglial BV-2 cells. Moreover, treatment of p38 MAPK inhibitor SB203580 (10 µM) further inhibited thiacremonone induced reduction of neurodegeneration and neuroinflammation. These results indicated that the anti-inflammatory compound, thiacremonone, inhibited neuroinflammation and dopaminergic neurodegeneration through inhibition of p38 activation.


Assuntos
Sintomas Comportamentais/tratamento farmacológico , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Inflamação/tratamento farmacológico , Tiofenos/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Anti-Inflamatórios/uso terapêutico , Astrócitos/efeitos dos fármacos , Sintomas Comportamentais/induzido quimicamente , Linhagem Celular , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Humanos , Imidazóis/farmacologia , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Substância Negra/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
11.
Oncotarget ; 7(17): 23425-38, 2016 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-26993600

RESUMO

To evaluate the significance of interleukin 4 (IL-4) in tumor development, we compared B16F10 melanoma growth in IL-4-overespressing transgenic mice (IL-4 mice) and non-transgenic mice. In IL-4 mice, reduced tumor volume and weight were observed when compared with those of non-transgenic mice. Significant activation of DNA binding activity of STAT6, phosphorylation of STAT6 as well as IL-4, IL-4Rα and p21 expression were found in the tumor tissues of IL-4 mice compared to non-transgenic mice. Higher expression of IL-4, STAT6 and p21 in human melanoma tissue compared to normal human skin tissue was also found. Higher expression of apoptotic protein such as cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax, p53 and p21, but lower expression levels of survival protein such as Bcl-2 were found in the tumor of IL-4 mice. In vitro study, we found that overexpression of IL-4 significantly inhibited SK-MEL-28 human melanoma cell and B16F10 murine melanoma cell growth via p21-mediated activation of STAT6 pathway as well as increased expression of apoptotic cell death proteins. Moreover, p21 knockdown with siRNA abolished IL-4 induced activation of STAT6 and expression of p53 and p21 accompanied with reduced IL-4 expression as well as melanoma cell growth inhibition. Therefore, these results showed that IL-4 overexpression suppressed tumor development through p21-mediated activation of STAT6 pathways in melanoma models.


Assuntos
Biomarcadores Tumorais/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Interleucina-4/metabolismo , Melanoma/patologia , Fator de Transcrição STAT6/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/genética , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-4/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Masculino , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Prognóstico , Fator de Transcrição STAT6/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Oncotarget ; 7(11): 11984-99, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26910914

RESUMO

Chemokine receptors are implicated in inflammation and immune responses. Neuro-inflammation is associated with activation of astrocyte and amyloid-beta (Aß) generations that lead to pathogenesis of Alzheimer disease (AD). Previous our study showed that deficiency of CC chemokine receptor 5 (CCR5) results in activation of astrocytes and Aß deposit, and thus memory dysfunction through increase of CC chemokine receptor 2 (CCR2) expression. CCR5 knockout mice were used as an animal model with memory dysfunction. For the purpose LPS was injected i.p. daily (0.25 mg/kg/day). The memory dysfunctions were much higher in LPS-injected CCR5 knockout mice compared to CCR5 wild type mice as well as non-injected CCR5 knockout mice. Associated with severe memory dysfuction in LPS injected CCR5 knockout mice, LPS injection significant increase expression of inflammatory proteins, astrocyte activation, expressions of ß-secretase as well as Aß deposition in the brain of CCR5 knockout mice as compared with that of CCR5 wild type mice. In CCR5 knockout mice, CCR2 expressions were high and co-localized with GFAP which was significantly elevated by LPS. Expression of monocyte chemoattractant protein-1 (MCP-1) which ligands of CCR2 also increased by LPS injection, and increment of MCP-1 expression is much higher in CCR5 knockout mice. BV-2 cells treated with CCR5 antagonist, D-ala-peptide T-amide (DAPTA) and cultured astrocytes isolated from CCR5 knockout mice treated with LPS (1 µg/ml) and CCR2 antagonist, decreased the NF-ĸB activation and Aß level. These findings suggest that the deficiency of CCR5 enhances response of LPS, which accelerates to neuro-inflammation and memory impairment.


Assuntos
Astrócitos/patologia , Gliose/etiologia , Inflamação/complicações , Lipopolissacarídeos/toxicidade , Transtornos da Memória/etiologia , Placa Amiloide/etiologia , Receptores CCR5/fisiologia , Animais , Apoptose , Astrócitos/efeitos dos fármacos , Comportamento Animal , Proliferação de Células , Células Cultivadas , Gliose/patologia , Inflamação/induzido quimicamente , Masculino , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Amiloide/patologia
13.
Nano Lett ; 16(2): 1179-85, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26784743

RESUMO

One-dimensional metallic/semiconducting materials have demonstrated as building blocks for various potential applications. Here, we report on a unique synthesis technique for redox-responsive assembled carbon-sheathed metal/semiconducting nanowire heterostructures that does not require a metal catalyst. In our approach, germanium nanowires are grown by the reduction of germanium oxide particles and subsequent self-catalytic growth during the thermal decomposition of natural gas, and simultaneously, carbon sheath layers are uniformly coated on the nanowire surface. This process is a simple, reproducible, size-controllable, and cost-effective process whereby most metal oxides can be transformed into metallic/semiconducting nanowires. Furthermore, the germanium nanowires exhibit stable chemical/thermal stability and outstanding electrochemical performance including a capacity retention of ∼96% after 1200 cycles at the 0.5-1C rate as lithium-ion battery anode.

14.
Brain Behav Immun ; 53: 113-122, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26593275

RESUMO

Nearly 7-10 million people are living with Alzheimer's disease (AD) worldwide. Senile plaques composed of ß-amyloid (Aß) are a pathological hallmark of Alzheimer's disease. Presenilin 2 (PS2) mutations increase Aß generation in the brains of AD patients. The Aß is generated through the sequential cleavage of amyloid precursor protein by ß- and γ-secretases. Additionally, increasing evidences suggest that estrogen can reduce the development of AD via regulation of ß-secretases activity and beta-site APP-cleaving enzyme (BACE1) expression. But the underlying correlation mechanism of Aß generation by PS2 mutations and estrogen remains to be clarified. To investigate the anti-amyloidogenesis effect of estrogen in a PS2 mutative condition, we examined memory impairment in ovariectomized PS2 mutation (N141I) mice in which cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, Western blot analysis, immunostaining, immunofluorescence staining, ELISA and enzyme activity assays were used to examine the degree of Aß deposition in the brains. In the present study, Aß accumulated more in the ovariectomized PS2 mutant mice brain, and greatly worsened memory impairment and glial activation as well as neurogenic inflammation. In parallel with increased memory impairment, activity of ß-secretase and expression of the BACE1 increased inovariectomized PS2 mutant mice. Much higher activity of NF-κB was observed by EMSA in ovariectomized PS2 mutant mice. In addition, the Aß level was decreased by treatment of ß-estradiol through inhibiting BACE1 expression in PS2 transfacted PC12 cells. These results suggest that mutation of PS2 can lead to NF-κB mediate amyloidogensis, and this effect can be amplified by the absence of estrogen.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Amiloide/biossíntese , Estrogênios/deficiência , Transtornos da Memória/metabolismo , NF-kappa B/metabolismo , Presenilina-2/metabolismo , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Cognição , Estrogênios/metabolismo , Feminino , Masculino , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Placa Amiloide/metabolismo , Presenilina-2/genética , Transdução de Sinais
15.
Int J Clin Pharmacol Ther ; 53(11): 980-6, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26396135

RESUMO

BACKGROUND: Acetyl-L-carnitine (ALC) has demonstrated neuroprotective effects in several experiments and is widely prescribed to reduce cognitive impairment in Alzheimer's disease patients or manage neuropathic symptoms in diabetic patients. OBJECTIVES: This study was designed to assess the pharmacokinetic (PK) bioequivalence between a new generic (test) formulation of ALC hydrochloride 590 mg and a branded (reference) formulation of ALC hydrochloride 590 mg in healthy Korean male volunteers. METHODS: This was a randomizedsequence, single-dose, two-way crossover study. All subjects randomly received one formulation of the test or reference tablet and the other formulation with a 7-day washout period. Blood samples (7 mL) were collected immediately before dosing, and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 12 hours postdose. The plasma concentrations of ALC were analyzed using liquid chromatography tandem mass spectrometry. Tolerability was assessed throughout the study. RESULTS: The PK profiles of both formulations showed similar rends. The mean (±SD) baseline (predose) concentration of ALC was 1.23±0.31 µg/mL and 1.09±0.30 µg/mL for the test and the reference formulations, respectively. The mean Cmax for the test and reference formulations were 1.74±0.43 µg/mL and 1.68±0.48 µg/mL, respectively. The mean AUClast of ALC was 12.96±1.89 µg×h/mL and 12.49±2.44 µg×h/mL for the test and reference formulations, respectively. The geometric mean ratios of test/reference (90% CI) were 1.050 (0.960-1.149) for Cmax and 1.048 (1.000-1.099) for AUClast. Both formulations were well tolerated in all treatment groups. CONCLUSION: The test and the reference formulations of ALC were bioequivalent with regard to the PK parameters.


Assuntos
Acetilcarnitina/farmacocinética , Grupo com Ancestrais do Continente Asiático , Medicamentos Genéricos/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Acetilcarnitina/administração & dosagem , Acetilcarnitina/efeitos adversos , Acetilcarnitina/sangue , Acetilcarnitina/química , Administração Oral , Adulto , Área Sob a Curva , Química Farmacêutica , Cromatografia Líquida , Estudos Cross-Over , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Medicamentos Genéricos/química , Voluntários Saudáveis , Humanos , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/química , República da Coreia , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto Jovem
16.
Lab Anim Res ; 27(4): 283-91, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22232636

RESUMO

This study was conducted to provide basic data on physiological and hematological characteristics, and organ weights of beagle dogs. A total of 237 beagle dogs were used to determine differences in physiological and hematological parameters, and organ weights depending on sex and age. The respiratory rate of both sexes tended to increase as they grew older and the female heart rate was slightly higher than that of males. Male and female body weights increased rapidly to 33 weeks old followed by a gradual increase to 41-weeks-old. The relative weight of the brain was negatively correlated with body weight, whereas the weight of reproductive organs was positively correlated with body weight. The platelet count of female dogs was slightly higher than that of males. The red blood cell, hemoglobin, and hematocrit of both sexes increased non-significantly with age. In the leukocyte differential count, the neutrophils, and eosinophils of both sexes tended to increase as they grew older, whereas basophils, lymphocytes, and monocytes decreased. In the serum biochemical profiles, alkaline phosphatase was slightly higher in males than females, while the total cholesterol of female dogs at 9-months-old was higher than that of males at the same age. Other biochemical components, including alanine aminotransferase, blood urea nitrogen, creatinine, triglyceride, and total protein increased non-significantly with age in both sexes. To conclude, we observe no significant physiological or hematological differences with sex or age, although decreasing and increasing trends were detected with some parameters. These data provide valuable reference indices of the normal physiological and hematological characteristics of beagle dogs, which should prove useful in toxicological and pharmacological studies.

17.
Free Radic Biol Med ; 50(1): 66-77, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20974250

RESUMO

Presenilin 2 (PS2) mutation increases Aß generation and neuronal cell death in the brains of Alzheimer disease (AD) patients. In a previous study, we showed that increased oxidative damage and activation of extracellular signal-regulated kinase (ERK) were associated with Aß generation and neuronal cell death in neuronal cells expressing mutant PS2. In this study, we show that oral treatment with 4-O-methylhonokiol, a novel compound isolated from Magnolia officinalis, for 3 months (1.0mg/kg) prevented PS2 mutation-induced memory impairment and neuronal cell death accompanied by a reduction in Aß(1-42) accumulation. We also found that 4-O-methylhonokiol inhibited PS2 mutation-induced activation of ERK and ß-secretase, and oxidative protein and lipid damage, but recovered glutathione levels in the cortex and hippocampus of PS2 mutant mice. Additionally, 4-O-methylhonokiol prevented PS2 mutation-induced activation of astrocytes as well as production of TNF-α, IL-1ß, reactive oxygen species (ROS), and nitric oxide (NO) in neurons. Generation of TNF-α, IL-1ß, ROS, and NO and ERK activation in cultured astrocytes treated with lipopolysaccharide (1µg/ml) were also prevented by 4-O-methylhonokiol in a dose-dependent manner. These results suggest that the improving effects of 4-O-methylhonokiol on memory function may be associated with a suppression of the activation of ERK and astrocytes as well as a reduction in oxidative damage. Thus, 4-O-methylhonokiol may be useful in the prevention and treatment of AD.


Assuntos
Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Lignanas/farmacologia , Transtornos da Memória/prevenção & controle , Presenilina-2/genética , Animais , Anti-Inflamatórios/farmacologia , Apoptose/genética , Astrócitos/metabolismo , Astrócitos/patologia , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Transtornos da Memória/genética , Transtornos da Memória/patologia , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética
18.
Exp Anim ; 52(2): 99-107, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12806884

RESUMO

The primary aim of the present study was to define central and peripheral physiological differences between dietary obesity-susceptible (DOS) and obesity-resistant (DOR) outbred Sprague Dawley (SD) rats when given a moderate high fat diet containing 32.34% of energy as a fat. After a 9-week feeding period, the DOS-SD rats consumed significantly more feed (11.1%) and had higher abdominal (39.9%) and epididymal (27.5%) fat pads than the DOR-SD rats. In addition, serum leptin and insulin levels were significantly increased in the DOS-SD rats compared with those in the DOR-SD rats. However, we did not observe significant differences in serum triglyceride, cholesterol and glucose. No differences in hypothalamic OB-Ra and Rb mRNA expressions were found between the two groups. In contrast, arcuate NPY immunohistochemical expression was much higher in the DOS-SD rats than in the DOR-SD rats, though NPY expression in the supraoptic and paraventricular nuclei was not different between the two phenotypes. In peripheral tissues, the DOS-SD rats showed noticeably increased acetyl CoA carboxylase (ACC) mRNA expression in the liver, not epididymal fat. However, Western blot of peroxisomal proliferator activated factor gamma (PPAR gamma) in the liver and epididymal fat was not different between the two phenotypes of SD rats. It was concluded that different body weight phenotypes within outbred SD population responded differently to the development of dietary induced obesity via altered anabolic features in the hypothalamus and liver.


Assuntos
Dieta , Predisposição Genética para Doença , Obesidade/etiologia , Acetil-CoA Hidrolase/genética , Animais , Sequência de Bases , Colesterol/sangue , Primers do DNA , Imuno-Histoquímica , Insulina/sangue , Leptina/sangue , Masculino , Obesidade/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/genética , Receptores para Leptina , Triglicerídeos/sangue
19.
Br J Nutr ; 89(3): 429-38, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12628037

RESUMO

The present study was designed to define how dietary fat type regulates body adiposity in dietary obesity-susceptible (DOS) Sprague-Dawley (SD) rats. Eighty-three SD rats received a purified diet containing 50 g maize oil (MO)/kg for 3 weeks and then thirty-nine of the rats, designated as the DOS rats, were allotted to diets containing 160 g MO (DOS-MO), beef tallow (DOS-BT) or fish oil (DOS-FO)/kg for 9 weeks. As a result of the experiment, the DOS-FO rats had significantly (P<0.05) reduced weight gain and abdominal and epididymal fat-pad mass than the DOS-MO and DOS-BT rats. Serum leptin level was also significantly (P<0.05) lower in the DOS-FO rats; however, hypothalamic leptin receptor (a and b) mRNA and neuropeptide Y expressions were not altered by dietary fat sources. A lower acetyl-CoA carboxylase mRNA expression in the liver was observed in the DOS-FO group, whereas hepatic peroxisome proliferator-activated receptor-gamma mRNA and protein expressions were markedly elevated in the DOS-FO group compared with those in the other groups. We did not observe differences in acetyl-CoA carboxylase and peroxisome proliferator-activated receptor-gamma expressions in epididymal fat of the DOS rats consuming MO, BT or FO. It is concluded from our present observations that dietary fat type, especially that rich in FO, plays a potential role in down-regulation of adiposity by altering hepatic lipogenic genes, rather than feeding behaviour, in the DOS-SD rats.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Gorduras na Dieta/farmacologia , Suscetibilidade a Doenças , Obesidade/etiologia , Acetil-CoA Carboxilase/metabolismo , Animais , Bovinos , Óleo de Milho/farmacologia , Ingestão de Alimentos , Óleos de Peixe/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Leptina/sangue , Fígado/metabolismo , Masculino , Neuropeptídeo Y/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores para Leptina , Fatores de Transcrição/metabolismo , Ganho de Peso/efeitos dos fármacos
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