RESUMO
Hypertrophy of adipocytes in obese adipose tissues causes metabolic abnormality by adipocytokine dysregulation, which promotes type 2 diabetes mellitus, hypertension, and dyslipidemia. We investigated the effects of wasabi (Wasabia japonica Matsum) leaf extracts on metabolic abnormalities in SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP/ZF), which are a model of metabolic syndrome. Male SHRSP/ZF rats aged 7 weeks were divided into two groups: control and wasabi leaf extract (WLE) groups, which received water or oral treatment with 4 g/kg/day WLE for 6 weeks. WLE improved the body weight gain and high blood pressure in SHRSP/ZF rats, and the plasma triglyceride levels were significantly lower in the WLE group. Adipocyte hypertrophy was markedly prevented in adipose tissue. The expression of PPARγ and subsequent downstream genes was suppressed in the WLE group adipose tissues. Our data suggest that WLE inhibits adipose hypertrophy by suppressing PPARγ expression in adipose tissue and stimulating the AMPK activity by increased adiponectin.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , PPAR gama/genética , Extratos Vegetais/farmacologia , Wasabia/química , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/metabolismo , Adipócitos/patologia , Adiponectina/agonistas , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Modelos Animais de Doenças , Esquema de Medicação , Regulação da Expressão Gênica , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Folhas de Planta/química , Ratos , Ratos Transgênicos , Transdução de Sinais , Triglicerídeos/sangue , Aumento de Peso/efeitos dos fármacosRESUMO
PURPOSE: To assess the efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive unresectable or recurrent/metastatic salivary gland carcinoma. PATIENTS AND METHODS: This trial was an open-label, single-arm, multicenter phase II study. Patients with histologically confirmed unresectable or recurrent/metastatic salivary gland carcinoma with AR expression were included. The primary endpoint was the overall response rate (ORR) according to RECIST v1.1 by an independent central radiology review in the first 24 response-evaluable (RE) patients who had been observed at least 24 weeks from study initiation (primary RE patients). The efficacy was to be declared when at least 8 of the 24 primary RE patients responded. RESULTS: A total of 31 patients were enrolled. In the first 24 primary RE patients with a median follow-up of 7.4 months, confirmed ORR by independent central radiology review was 25.0% [6/24 patients; 95% confidence interval, 9.8%-46.7%; P = 0.11 (one-sided)], which did not meet the predefined criteria of efficacy. Clinical benefit rate (ORR + rate of stable disease for at least 24 weeks) and median progression-free survival were 50.0% and 7.4 months, respectively. Both median duration of response and overall survival were not reached. Exploratory analyses showed a better ORR of 54.5% (6/11) in patients with AR positivity ≥70% and no history of prior systemic therapy. Grade 3 or higher treatment-emergent adverse events were reported in 35.5% (11/31), which included skin rash, anemia, leukopenia, and cancer pain. CONCLUSIONS: Although this study did not meet the predefined efficacy criteria, apalutamide plus goserelin showed clinically meaningful efficacy in a subset of patients with AR-positive salivary gland carcinoma and safety consistent with prior experience in prostate cancer.
Assuntos
Gosserrelina , Receptores Androgênicos , Neoplasias das Glândulas Salivares , Tioidantoínas , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/mortalidade , Receptores Androgênicos/metabolismo , Tioidantoínas/administração & dosagem , Tioidantoínas/uso terapêutico , Tioidantoínas/efeitos adversos , Adulto , Gosserrelina/administração & dosagem , Gosserrelina/uso terapêutico , Gosserrelina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso de 80 Anos ou mais , Resultado do Tratamento , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologiaRESUMO
The population pharmacokinetic (PK) and exposure-response (E-R) analyses for the safety of ibrutinib for the treatment of chronic graft-versus-host disease (cGVHD) is presented. This work aims to develop a population PK model for ibrutinib based on data from clinical studies in subjects with cGVHD, to evaluate the impact of intrinsic and extrinsic factors on PK parameters as well as systemic exposure levels, and to assess an E-R relationship for selected safety end points. Pooled data from 162 subjects with cGVHD enrolled in 4 clinical studies were included in the population PK analysis. In the studies, an ibrutinib dose of 420 mg once daily was administered orally. With the exception of 1 study, the study protocols instructed for a reduction of the ibrutinib dose to 140 or 280 mg once daily, depending on concomitant CYP3A inhibitor use. Concomitant CYP3A inhibitor use was found to be a primary covariate for relative bioavailability (F1): the F1 value increased 2.22-fold with concomitant moderate CYP3A inhibitors and 3.09-fold with concomitant strong CYP3A inhibitors, compared with the F1 value in the absence of CYP3A inhibitors. In addition, Japanese ethnicity led to an F1 value that was 1.70-fold higher than that in the non-Japanese population. Simulations using the final PK model suggest that ibrutinib exposure was appropriately controlled within the therapeutic range in the entire cGVHD population by applying dose reductions depending on the use of CYP3A inhibitors, and that additional dose modification for the Japanese population would not be required. The subsequent E-R analysis suggests no apparent association between the systemic exposure to ibrutinib and the selected safety end points.
Assuntos
Síndrome de Bronquiolite Obliterante , Inibidores do Citocromo P-450 CYP3A , Humanos , Adenina/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/farmacologia , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Piperidinas/uso terapêuticoRESUMO
BACKGROUND: JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947). METHODS: Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients). RESULTS: Thirty non-Japanese (n = 4/dose; placebo, n = 10) and 24 Japanese healthy participants (n = 6/dose; placebo, n = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4-9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate. CONCLUSION: JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.
Assuntos
Hepatite B Crônica , Adulto , Antivirais/efeitos adversos , Método Duplo-Cego , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Japão , Compostos Orgânicos , RNA Interferente Pequeno/uso terapêuticoRESUMO
Ceramic hydroxyapatite (CHT) high-performance liquid chromatography (HPLC) is used to purify a variety of classes of monoclonal antibodies (mAbs) from crude murine ascites fluids. We report here that this method is also applicable for simple and efficient purification of many mAb fragments that are generated by pepsin treatment of crude ascites. F(ab')(2) fragments were quantitatively generated from IgG(1) mAbs in ascitic fluids by incubation with pepsin for 6 h at pH 3.9-4.1. Under the same conditions, pepsin also cleaved unwanted ascites components, such as albumin and transferrin to very low molecular weight polypeptides. The F(ab')(2) fragments, but not the low molecular weight products, selectively bound to and were eluted from the CHT column using a linear gradient of phosphate ion concentration over 15 min. The recovery of the F(ab')(2) fragments by CHT-HPLC was >90%. This method also allowed single-step purification of mAb fragments from distinct IgG subclasses (IgG(2a) and IgG(2b)) and IgM directly from crude digested ascitic samples. This CHT-HPLC method combined with direct pepsinolysis of murine ascites is a useful strategy for rapid purification and characterization of many types of mAb fragments.
Assuntos
Anticorpos Monoclonais/isolamento & purificação , Líquido Ascítico/imunologia , Cromatografia Líquida de Alta Pressão/métodos , Durapatita/química , Fragmentos Fab das Imunoglobulinas/isolamento & purificação , Pepsina A/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Cerâmica/química , Fragmentos Fab das Imunoglobulinas/metabolismo , CamundongosRESUMO
A porous hydroxyapatite/collagen composite (HAp/Col) was developed that consists of hydroxyapatite nanocrystals and atelocollagen. In this study, cylindrical (diameter: 5 mm, height: 3 mm) porous HAp/Col implants with different pore sizes (diameter: 160 or 290 microm) were prepared, and the influences of pore size and implanted volume were evaluated using a rabbit bone defect model. In the implant groups, one or three (diameter: 5 mm, total height: 9 mm) implants were transplanted into bone holes created in the anteromedial site of the proximal tibiae, while a group without implantation was used as a control. Histological observation revealed that at two weeks after implantation, bone formation was initiated not only from the periosteum but in regions where the implants bordered on bone marrow. At four weeks, bone formation expanded from the marrow cavity side into the center of the implants, particularly in those implants with large pores. At twelve weeks, four implant groups showed repair of cortical defects and implant absorption, which was thought to be the result of natural bone remodeling mechanisms. The control group showed bone formation developed from the periosteum without bone induction in the marrow cavity, and at four weeks, the bone hole was almost healed. pQCT analysis revealed that the expansion rates of bone tissue were higher in the large-pore implant groups than in the small-pore groups. These data demonstrate the osteoconductivity of porous HAp/Col and the importance of its porous structure.
Assuntos
Implantes Absorvíveis , Regeneração Óssea/efeitos dos fármacos , Colágeno/farmacologia , Durapatita/farmacologia , Implantes Experimentais , Animais , Medula Óssea/fisiologia , Modelos Animais , Nanocompostos , Periósteo/fisiologia , Porosidade , Coelhos , Radiografia , Tíbia/diagnóstico por imagem , Tíbia/cirurgiaRESUMO
This Phase 1, randomized, double-blind, placebo-controlled study was conducted to evaluate the safety, tolerability and immunogenicity of different doses of ExPEC4V conjugate vaccine (4-16µg Polysaccharide [PS]/serotype) in healthy Japanese participants, stratified into younger (≥20 to <50 years) or older age groups (≥50 years). Within each age group, participants were randomized to a single vaccination with 1 of 3 dose levels of ExPEC4V (4, 8 and 16 µg PS/serotype) or placebo. Safety and tolerability were the primary objectives; immunogenicity was secondary. Of the 48 participants, 47 (98%) completed; one (2%) in the placebo group discontinued. A total of 48% participants had ≥1 AE (younger group: n = 13 [54%]; older group: n = 10 [41.7%]). Solicited and unsolicited AEs were reported in 44% and 8% participants, respectively in the combined ExPEC4V groups. Pain/tenderness (n = 11 [31%]) and redness (n = 9 [25%]) were the most frequently reported solicited local AEs, whereas fatigue (n = 4 [11%]), headache (n = 4 [11%]), muscle pain (n = 2 [6%]), and malaise (n = 5 [14%]) were the most common solicited systemic AEs in the combined ExPEC4V group. No serious AEs, deaths, or discontinuation due to AEs were reported. All doses were immunogenic with an increase in IgG (ELISA) geometric mean titers of at least 5-fold from baseline to Days 15 and 30 for all serotypes. Of participants vaccinated with ExPEC4V, 75% - 100% demonstrated an ELISA titer increase of ≥2-fold. Strong correlation observed between ELISA and OPK. ExPEC4V was well tolerated and elicited an immunogenic response at all dose levels (up to 16 µg PS/serotype) in healthy Japanese participants.
Assuntos
Bacteriemia/prevenção & controle , Infecções por Escherichia coli/prevenção & controle , Vacinas contra Escherichia coli/efeitos adversos , Vacinas contra Escherichia coli/imunologia , Escherichia coli Extraintestinal Patogênica/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/sangue , Povo Asiático , Bacteriemia/microbiologia , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Ensaio de Imunoadsorção Enzimática , Infecções por Escherichia coli/microbiologia , Vacinas contra Escherichia coli/administração & dosagem , Feminino , Voluntários Saudáveis , Humanos , Esquemas de Imunização , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologia , Adulto JovemRESUMO
Two new bioabsorbable inorganic/organic composite materials were developed for bone regeneration. One material used was beta-TCP/PLGC in which poly(L-lactide-co-glycolide-co-epsilon-caprolactone) and beta-tricalcium phosphate were used as the matrix and filler, respectively. The other material used was HAp/Col-a soft nanocomposite of hydroxyapatite and type I collagen. Using these composites, two bone implants were designed. The efficacy of these implants was investigated by applying them to the critical-sized bone defects that were created in the canine tibia. Although no tissue engineering techniques such as application of growth factors or stem cells was utilized, successful healing was observed. These results suggested that bone regeneration in the critical-sized defects is possible without the use of growth factors or stem cells if the materials and the bone implants are suitably designed.
Assuntos
Regeneração Óssea , Substitutos Ósseos , Absorção , Animais , Substitutos Ósseos/química , Substitutos Ósseos/farmacocinética , Cães , Masculino , Teste de Materiais , Nanotecnologia , Tíbia/anatomia & histologia , Tíbia/fisiologiaRESUMO
Dense hydroxyapatite (HA) ceramics are useful bone substitutes, but they degrade minimally. One solution is to incorporate degradable materials in the HA. In this study, we manufactured glass-containing HA and investigated whether the degradability and bone-bonding ability of the HA were improved. The glass-containing HA was manufactured from a mixture of HA powder and 1.0 wt% glass powder. The control HA was manufactured from pure HA powder. In vitro degradability was evaluated by soaking in physiological saline, and a rabbit model was used to evaluate in vivo degradability and bone-bonding ability. Detaching tests were performed for all removed samples to quantify bone-bonding ability of each type of HA. The glass-containing HA showed higher degradability than the control HA, both in vitro and in vivo. The detaching failure load of the glass-containing HA was rapidly elevated after implantation and was higher than that of the control HA. Our results suggest that the dissolution of the added glass made the glass-containing HA degradable and that the detaching failure load of the glass-containing HA was elevated by reinforcement of the mechanical locking at the roughened interface. Incorporation of glass additives into HA can be concluded to be a good candidate for producing a bone substitute that can partially degrade and bond to bone firmly and rapidly.
Assuntos
Implantes Absorvíveis , Substitutos Ósseos/química , Substitutos Ósseos/uso terapêutico , Durapatita/química , Durapatita/uso terapêutico , Fraturas da Tíbia/patologia , Fraturas da Tíbia/cirurgia , Absorção , Adesividade , Animais , Cerâmica/química , Cerâmica/uso terapêutico , Vidro/química , Masculino , Teste de Materiais , Coelhos , Resultado do TratamentoRESUMO
Five-aminolevulinic acid (ALA) is a prodrug to generate phototoxic protoporphyrin IX (PPIX) for photodynamic cancer therapy. It remains unclear how PPIX accumulates in cancer cells; therefore, we aimed to clarify determinant factors by assessing ALA uptake, PPIX biosynthesis, conversion of PPIX to heme (ferrochelatase activity), and PPIX efflux, independently, in 10 human cancer cell lines. ALA-induced PPIX accumulation was not correlated with ALA uptake clearance. ALA uptake rates were far greater than maximum conversion rates of ALA to PPIX in the five cell lines, where ALA uptake activity was detected. A negative correlation of PPIX accumulation with ferrochelatase activity was found, but not statistically significant among all cell lines. As PPIX accumulation was restored in MCF-7 and DU145 cells by adding an inhibitor of PPIX efflux transporter BCRP, a compartment model incorporating PPIX synthesis, ferrochelatase activity, and PPIX efflux, was established, and hybrid parameters (π index) calculated using the model were significantly correlated with ALA-induced PPIX accumulation (r = 0.90, p = 0.005). Accordingly, kinetic analyses indicate that ALA-induced PPIX levels are determined by the three processes of PPIX biosynthesis, conversion of PPIX to heme, and PPIX efflux, suggesting that π index is a useful to predict ALA-induced PPIX accumulation.
Assuntos
Ácido Aminolevulínico/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Heme/metabolismo , Humanos , Células K562 , Cinética , Células MCF-7 , Fotoquimioterapia/métodos , Células U937RESUMO
Japanese encephalitis virus-specific IgM is a reliable indicator for serodiagnosis of Japanese encephalitis. A particle agglutination (PA) assay system was developed to detect anti-Japanese encephalitis virus IgM in human serum samples. The newly developed PA assay consisted of hydroxyapatite-coated nylon beads and V-bottom 96-well microplates. Hydroxyapatite-coated nylon beads were coated with Japanese encephalitis virus antigens. Japanese encephalitis virus antigen-coated, hydroxyapatite-coated nylon beads agglutinated in the IgM-captured wells when anti-Japanese encephalitis virus IgM-positive serum samples were used. A button pattern was formed at the bottom of the wells when anti-Japanese encephalitis virus IgM-negative serum samples were used. Thirty anti-Japanese encephalitis virus IgM-positive serum samples from Japanese encephalitis-confirmed cases were tested by the PA assay. All these serum samples were determined to be Japanese encephalitis virus IgM-positive. IgM titers determined by the PA assay corresponded to those determined by enzyme-linked immunosorbent assay. The titers were consistent in two independent PA assays. These results indicate that the newly developed PA assay is a reliable method for detecting anti-Japanese encephalitis virus IgM in human serum samples and that this assay will be a suitable diagnostic system especially in rural areas of Asia.
Assuntos
Anticorpos Antivirais/sangue , Vírus da Encefalite Japonesa (Espécie)/imunologia , Encefalite Japonesa/diagnóstico , Imunoglobulina M/sangue , Testes de Aglutinação/métodos , Especificidade de Anticorpos , Durapatita , Vírus da Encefalite Japonesa (Espécie)/isolamento & purificação , Encefalite Japonesa/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Nylons , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND AND PURPOSE: Our newly developed biocompatible embolic materials, hydroxyapatite ceramic microparticles, have good visibility during injection control and were shown to be capable of producing effective occlusion of the distal arteriocapillary bed in an experimental animal study. The purpose of this present study was to evaluate hydroxyapatite ceramic microparticles for use in human meningioma embolization. METHODS: Thirteen patients with meningiomas underwent preoperative superselective embolization with the use of hydroxyapatite microparticles. Radiologic and histopathologic studies of the surgical specimens were performed. RESULTS: During embolization, no microcatheter clogging was observed and angiographic devascularization was consistently obtained without unexpected proximal occlusions. Histopathologic findings showed that there was mild inflammatory response in the thrombosed lumen. CONCLUSION: Hydroxyapatite microparticles are excellent embolic materials for the treatment of human meningioma. They have excellent biocompatibility and good injection control, which produces occlusion of the distal arteriocapillary bed.
Assuntos
Materiais Biocompatíveis/administração & dosagem , Cerâmica , Durapatita/administração & dosagem , Embolização Terapêutica/métodos , Neoplasias Meníngeas/irrigação sanguínea , Neoplasias Meníngeas/terapia , Meningioma/irrigação sanguínea , Meningioma/terapia , Terapia Neoadjuvante , Adulto , Idoso , Angiografia Cerebral , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Microcirculação/patologia , Microesferas , Pessoa de Meia-Idade , Tamanho da Partícula , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Hydroxyapatite ceramic microparticles are newly developed embolic materials. The purpose of this study was to evaluate the characteristics, embolic properties of hydroxyapatite ceramic microparticles, and effects of transcatheter embolization from an angiographic standpoint and to histopathologically evaluate the results of animal experimentation. METHODS: After physical evaluation of the characteristics and embolic properties of hydroxyapatite microparticles (100-250 micro m in diameter), microcatheter superselective renal artery embolization was performed in rabbits by using this material. Follow-up angiography and histopathologic study of 18 rabbits were performed at different intervals within 24 weeks after embolization. RESULTS: No microcatheter clogging was observed because of excellent visibility of this material in the suspension and because of its excellent navigability due to its nearly oval shape with no "spines." Angiographic renal arterial devascularization was consistently obtained without unexpected proximal occlusions; follow-up angiography showed persistent occlusion. Histopathologic evaluation confirmed satisfactory embolization of peripheral arteries. Chronic inflammatory cells were observed in several vessels containing hydroxyapatite microparticles. No evidence of angionecrosis, hemorrhage, or extraluminal migration was noted in any sections. CONCLUSION: Hydroxyapatite microparticles are excellent biocompatible embolic materials with good visibility during injection control, capable of producing effective occlusion of the distal arteriocapillary bed.
Assuntos
Cerâmica/química , Durapatita/química , Embolização Terapêutica/métodos , Teste de Materiais , Animais , Rim/irrigação sanguínea , Microscopia Eletrônica de Varredura , Microesferas , Tamanho da Partícula , Coelhos , Radiografia , Artéria Renal/diagnóstico por imagem , Artéria Renal/patologia , SuspensõesRESUMO
Galanin-like peptide (GALP) is a neuropeptide involved in energy metabolism. The interactive effect of GALP and exercise on energy metabolism has not been investigated. The aim of this study was to determine if energy metabolism in spontaneously exercising mice could be promoted by intracerebroventricular (ICV) GALP administration. Changes in respiratory exchange ratio in response to GALP ICV administration indicated that lipids were primarily consumed followed by a continuous consumption of glucose throughout the dark period in non-exercising mice. In mice permitted to spontaneously exercise on a running-wheel, GALP ICV administration increased the consumed oxygen volume and heat production level from 5 to 11h after administration. These effects occurred independently from the total running distance. The interaction between GALP ICV administration and spontaneous exercise decreased body weight within 24h (F(1,16)=5.772, p<0.05), with no significant interaction observed regarding food and water intake or total distance. Energy metabolism-related enzymes were assessed in liver and skeletal muscle samples, with a significant interaction on mRNA expression between GALP ICV administration and spontaneous exercise observed in phosphoenolpyruvate carboxykinase (F(1,16)=18.602, p<0.001) that regulates gluconeogenesis and glucose transporter-4 (F(1,16)=21.092, p<0.001). GALP significantly decreased the mRNA expression of sterol regulatory element-binding protein-1c (p<0.05) that regulates fatty acid synthesis regardless of spontaneous exercise with no changes to acetyl-CoA carboxylase a and fatty acid synthetase. These results indicate the GALP ICV administration can further promote energy metabolism when administered to spontaneously exercising mice.
Assuntos
Metabolismo Energético , Peptídeo Semelhante a Galanina/fisiologia , Condicionamento Físico Animal , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The anti-obesity effects of a hot water extract from wasabi (Wasabia japonica Matsum.) leaves (WLE), without its specific pungent constituents, such as allyl-isothiocyanate, were investigated in high fat-diet induced mice. C57J/BL mice were fed a high-fat diet (control group) or a high-fat diet supplemented with 5% WLE (WLE group). Physical parameters and blood profiles were determined. Gene expression associated with lipid metabolism in liver and white adipose tissue were analyzed. After 120 days of feeding, significantly lower body weight gain, liver weight and epididymal white adipose tissue weight was observed in the WLE group compared to the control group. In liver gene expression within the WLE group, PPARα was significantly enhanced and SREBP-1c was significantly suppressed. Subsequent downstream genes controlled by these regulators were significantly suppressed. In epididymal white adipose tissue of the WLE group, expression of leptin, PPARγ, and C/EBPα were significantly suppressed and adiponectin was significantly enhanced. Acox, related to fatty acid oxidization in adipocytes, was also enhanced. Our results demonstrate that the WLE dietary supplement induces mild suppression of obesity in a high-fat diet induced mice, possibly due to suppression of lipid accumulation in liver and white adipose tissue.
RESUMO
Tissue engineering is a promising approach, not only for cartilage, but also for osteochondral repair. Recent studies have demonstrated that scaffold-free cartilaginous tissue can be engineered using the alginate-recovered-chondrocyte (ARC) method. This method has also been applied to form osteochondral tissue using bovine articular chondrocytes and coralline hydroxyapatite (HA). The purpose of this study was to test whether osteochondral tissue, fabricated in vitro using the ARC method combined with a block of HA, would undergo maturation in vivo using a subcutaneous model in immunodeficient mice. Articular chondrocytes were isolated from the cartilage of New Zealand white rabbits and cultured in alginate beads. The cells with their associated matrix were recovered by dissolving the alginate beads with a sodium citrate buffer, resuspended in media and seeded onto a porous HA block. After 4 weeks of culture, some samples were analyzed, and others were implanted into subcutaneous pockets in nude mice. The analysis involved removing the cartilage portion of the de novo-formed ARC-HA graft and performing biochemical and histological examinations. Some samples were subjected to nondecalcified histology. Histological and immunohistochemical analyses of cartilaginous tissue were performed at 0, 2, 4, and 8 weeks after implantation. Biochemical characteristics were examined at 0, 4, and 8 weeks. The size and shape of the implanted ARC osteochondral tissue changed with time. The histological and immunohistochemical examination of the tissue revealed that it contained a cartilage-like matrix that stained strongly with Toluidine blue and for collagen type II. The proteoglycan (PG) content had increased significantly at 4 weeks from baseline. However, by 8 weeks, the PG content had decreased from 4 weeks. The results presented here represent a possible approach to form a tissue-engineered osteochondral implant. Further studies are needed to improve biomechanical properties of the osteochondral implant to be suitable for surgical transplantation.