RESUMO
Increasing levels of plasma urotensin II (UII) are positively associated with atherosclerosis. In this study we investigated the role of macrophage-secreted UII in atherosclerosis progression, and evaluated the therapeutic value of urantide, a potent competitive UII receptor antagonist, in atherosclerosis treatment. Macrophage-specific human UII-transgenic rabbits and their nontransgenic littermates were fed a high cholesterol diet for 16 weeks to induce atherosclerosis. Immunohistochemical staining of the cellular components (macrophages and smooth muscle cells) of aortic atherosclerotic lesions revealed a significant increase (52%) in the macrophage-positive area in only male transgenic rabbits compared with that in the nontransgenic littermates. However, both male and female transgenic rabbits showed a significant decrease (45% in males and 31% in females) in the smooth muscle cell-positive area compared with that of their control littermates. The effects of macrophage-secreted UII on the plaque cellular components were independent of plasma lipid level. Meanwhile the wild-type rabbits were continuously subcutaneously infused with urantide (5.4 µg· kg-1· h-1) using osmotic mini-pumps. Infusion of urantide exerted effects opposite to those caused by UII, as it significantly decreased the macrophage-positive area in male wild-type rabbits compared with that of control rabbits. In cultured human umbilical vein endothelial cells, treatment with UII dose-dependently increased the expression of the adhesion molecules VCAM-1 and ICAM-1, and this effect was partially reversed by urantide. The current study provides direct evidence that macrophage-secreted UII plays a key role in atherogenesis. Targeting UII with urantide may promote plaque stability by decreasing macrophage-derived foam cell formation, which is an indicator of unstable plaque.
Assuntos
Aterosclerose/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Urotensinas/farmacologia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Infusões Subcutâneas , Macrófagos/metabolismo , Masculino , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/sangue , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Coelhos , Urotensinas/administração & dosagem , Urotensinas/sangueRESUMO
BACKGROUND/AIMS: The proliferation and migration of vascular smooth muscle cells (VSMCs) are key steps in the progression of atherosclerosis. The aim of the present study was to investigate the potential roles of salusin-α in the functions of VSMCs during the development of atherosclerosis. METHODS: In vivo, the effects of salusin-α on atherogenesis were examined in rabbits fed a cholesterol diet. The aortas were en face stained with Sudan IV to evaluate the gross atherosclerotic lesion size. The cellular components of atherosclerotic plaques were analyzed by immunohistochemical methods. In vitro, Cell Counting Kit-8 and wound-healing assays were used to assess the effects of salusin-α on VSMC proliferation and migration. In addition, western blotting was used to evaluate the total and phosphorylated levels of Akt (also known as protein kinase B) and mammalian target of rapamycin (mTOR) in VSMCs. RESULTS: Salusin-α infusion significantly reduced the aortic lesion areas of atherosclerosis, with a 39% reduction in the aortic arch, a 71% reduction in the thoracic aorta, and a 71% reduction in the abdominal aorta; plasma lipid levels were unaffected. Immunohistochemical staining showed that salusin-α decreased both macrophage- and VSMC-positively stained areas in atherosclerotic lesions by 54% and 69%, cell proliferative activity in the intima and media of arteriosclerotic lesions, and matrix metalloproteinase 2 (MMP-2) and MMP-9 expression in plaques. Studies using cultured VSMCs showed that salusin-α decreased VSMC migration and proliferation via reduced phosphorylation of Akt and mTOR. CONCLUSION: Our data indicate that salusin-α suppresses the development of atherosclerosis by inhibiting VSMC proliferation and migration through the Akt/mTOR pathway.
Assuntos
Proliferação de Células/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Becaplermina , Movimento Celular/efeitos dos fármacos , Dieta Hiperlipídica , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-sis/farmacologia , Coelhos , Ratos , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/metabolismoRESUMO
[This corrects the article DOI: 10.1155/2017/3824276.].
RESUMO
Intimal hyperplasia (IH) is a common pathological feature of vascular proliferative diseases, such as atherosclerosis and restenosis after angioplasty. Urotensin II (UII) and its receptor (UTR) are widely expressed in cardiovascular tissues. However, it remains unclear whether the UII/UTR system is involved in IH. Right unilateral common carotid artery ligation was performed and maintained for 21 days to induce IH in UTR knockout (UTR-/-) and wild-type (WT) mice. Histological analysis revealed that compared with WT mice, UTR-deficient mice exhibited a decreased neointimal area, angiostenosis and intima-media ratio. Immunostaining revealed fewer smooth muscle cells (SMCs), endothelial cells and macrophages in the lesions of UTR-/- mice than in those of WT mice. Protein interaction analysis suggested that the UTR may affect cell proliferation by regulating YAP and its downstream target genes. In vitro experiments revealed that UII can promote the proliferation and migration of SMCs, and western blotting also revealed that UII increased the protein expression of RhoA, CTGF, Cyclin D1 and PCNA and downregulated p-YAP protein expression, while these effects could be partly reversed by urantide. To evaluate the translational value of UTRs in IH management, WT mice were also treated with two doses of urantide, a UTR antagonist, to confirm the benefit of UTR blockade in IH progression. A high dose of urantide (600 µg/kg/day), rather than a low dose (60 µg/kg/day), successfully improved ligation-induced IH compared with that in mice receiving vehicle. The results of the present study suggested that the UII/UTR system may regulate IH partly through the RhoA-YAP signaling pathway.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proliferação de Células , Hiperplasia , Camundongos Knockout , Receptores Acoplados a Proteínas G , Transdução de Sinais , Proteínas de Sinalização YAP , Proteína rhoA de Ligação ao GTP , Animais , Masculino , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Movimento Celular , Hiperplasia/metabolismo , Hiperplasia/patologia , Ligadura , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neointima/metabolismo , Neointima/patologia , Neointima/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteína rhoA de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Túnica Íntima/patologia , Túnica Íntima/metabolismo , Urotensinas/metabolismo , Urotensinas/genética , Urotensinas/farmacologia , Proteínas de Sinalização YAP/metabolismoRESUMO
Stress is an important environmental factor affecting mental health that cannot be ignored. Moreover, due to the great physiological differences between males and females, the effects of stress may vary by sex. Previous studies have shown that terrified-sound stress, meaning exposed mice to the recorded vocalizations in response to the electric shock by their kind to induce psychological stress, can cause cognitive impairment in male. In the study, we investigated the effects of the terrified-sound stress on adult female mice. METHODS: 32 adults female C57BL/6 mice were randomly divided into control (n = 16) and stress group (n = 16). Sucrose preference test (SPT)was carried out to evaluate the depressive-like behavior. Using Open field test (OFT) to evaluate locomotor and exploratory alterations in mice. Spatial learning and memory ability were measured in Morris Water maze test (MWM), Golgi staining and western blotting showed dendritic remodeling after stress. In addition, serum hormone quantifications were performed by ELISA. RESULTS: we found the sucrose preference of stress group was significantly decreased (p < 0.05) compared with control group; the escape latency of the stress group was significantly prolonged (p < 0.05), the total swimming distance and the number of target crossings(p < 0.05) were significantly increased (p < 0.05) in MWM; Endocrine hormone, Testosterone (T) (p < 0.05), GnRH (p < 0.05), FSH and LH levels was decreased; Golgi staining and western blotting showed a significant decrease in dendritic arborization, spine density and synaptic plasticity related proteins PSD95 and BDNF in the stress group. CONCLUSION: Terrified-sound stress induced depressive-like behaviors, locomotor and exploratory alterations. And impaired cognitive by altering dendritic remodeling and the expression of synaptic plasticity-related proteins. However, females are resilient to terrified-sound stress from a hormonal point of view.
Assuntos
Disfunção Cognitiva , Plasticidade Neuronal , Animais , Feminino , Masculino , Camundongos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Depressão/etiologia , Hipocampo/metabolismo , Hormônios/metabolismo , Camundongos Endogâmicos C57BL , Estresse Psicológico/metabolismo , Sacarose/metabolismoRESUMO
Porcine reproductive and respiratory syndrome virus (PRRSV) induces secretion of high mobility group box 1 (HMGB1) to mediate inflammatory response that is involved in the pulmonary injury of infected pigs. Our previous study indicates that protein kinase C-delta (PKC-delta) is essential for HMGB1 secretion in PRRSV-infected cells. However, the underlying mechanism in HMGB1 secretion induced by PRRSV infection is still unclear. Here, we discovered that the phosphorylation level of HMGB1 in threonine residues increased in PRRSV-infected cells. A site-directed mutagenesis study showed that HMGB1 phosphorylation at threonine-51 was associated with HMGB1 secretion induced by PRRSV infection. Co-immunoprecipitation (co-IP) of HMGB1 failed to precipitate PKC-delta, but interestingly, mass spectrometry analysis of the HMGB1 co-IP product showed that PRRSV infection enhanced HMGB1 binding to ribosomal protein S3 (RPS3), which has various extra-ribosomal functions. The silencing of RPS3 by siRNA blocked HMGB1 secretion induced by PRRSV infection. Moreover, the phosphorylation of HMGB1 at threonine-51 was correlated with the interaction between HMGB1 and RPS3. In vivo, PRRSV infection also increased RPS3 levels and nuclear accumulation in pulmonary alveolar macrophages. These results demonstrate that PRRSV may induce HMGB1 phosphorylation at threonine-51 and increase its interaction with RPS3 to enhance HMGB1 secretion. This finding provides insights into the pathogenesis of PRRSV infection.
Assuntos
Proteína HMGB1 , Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Animais , Proteína HMGB1/metabolismo , Fosforilação , Vírus da Síndrome Respiratória e Reprodutiva Suína/metabolismo , Suínos , Treonina/metabolismoRESUMO
BACKGROUND: Dapagliflozin, a sodium glucose transporter protein-2 (SGLT-2) inhibitor, reduces the risk for cardiovascular diseases. However, the influence of dapagliflozin on nondissecting abdominal aortic aneurysms (AAAs) remains unclear. METHODS: AAAs were created in male C57BL/6 mice via intra-aortic porcine pancreatic elastase (PPE) infusion. Mice were daily treated with dapagliflozin (1 or 5 mg/kg body weight) or an equal volume of vehicle through oral gavage beginning one day prior to PPE infusion for 14 days. To investigate its translational value, dapagliflozin or vehicle was also administered to mice with existing AAAs in another cohort. Aortic diameters were measured prior to (day 0 for baseline) and 14 days after PPE infusion. After sacrifice, mice aortae were collected, and following histological analyses were performed. RESULTS: Dapagliflozin treatment significantly reduced aneurysmal aortic expansion following PPE infusion as compared to vehicle treatment especially at 5 mg/kg body weight (approximately 21% and 33% decreases in 1 and 5 mg/kg treatment groups, respectively). The dose-dependent attenuation of AAAs by dapagliflozin was also confirmed on histological analyses. Dapagliflozin remarkably reduced aortic accumulation of macrophages, CD4+ T cells, and B cells particularly following dapagliflozin treatment at 5 mg/kg. Dapagliflozin treatment also markedly attenuated medial SMC loss. Though the difference was not significant, dapagliflozin treatment tended to attenuate CD8+ T cells and elastin degradation. Dapagliflozin treatment at 5 mg/kg caused a 53% reduction in neovessel density. Furthermore, dapagliflozin treatment mitigated further progress of existing AAAs. CONCLUSION: Dapagliflozin treatment ameliorated PPE-induced AAAs by inhibiting aortic leukocytes infiltration and angiogenesis.
Assuntos
Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aortite/complicações , Aortite/tratamento farmacológico , Compostos Benzidrílicos/administração & dosagem , Progressão da Doença , Glucosídeos/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Animais , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/imunologia , Aortite/imunologia , Aortite/patologia , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/tratamento farmacológico , Elastase Pancreática/efeitos adversos , Suínos , Resultado do TratamentoRESUMO
OBJECTIVE: Elastase-induced abdominal aortic aneurysm (AAA) model is widely used for aneurysmal pathogenesis and translational research. However, temporal alternations in aneurysmal histologies remain unknown. This study is aimed at analyzing temporal immunopathologies of aneurysmal aorta following experimental AAA induction. METHODS: Male C57BL/6J mice at the age of 10-14 weeks received intra-aortic infusion of elastase to induce AAAs. Aortic diameters at the baseline and indicated days after AAA induction were measured, and aortae were collected for histopathological analysis. RESULTS: Aorta diameters increased from 0.52 mm at the baseline levels to 0.99 mm, 1.34 mm, and 1.41 mm at days 7, 14, and 28, respectively, corresponding 90%, 158%, and 171% increases over the baseline level. Average aortic diameters did not differ between days 14 and 28. Severe elastin degradation and smooth muscle cell depletion were found at days 14 and 28 as compared to the baseline and day 7. No difference in the scores of medial elastin and SMC destruction was noted between days 14 and 28. Consistent results were found for leukocyte accumulation, neoangiogenesis, and matrix metalloproteinase expression. Twenty-eight days after AAA induction, all aneurysmal pathologies showed an attenuated trend, although most histopathological parameters did no differ between days 14 and 28. CONCLUSION: Our data suggest that almost aneurysmal immunohistopathologies reach maximal 14 days following AAA induction. Analysis of day 14 histologies is sufficient for AAA pathogenesis and translational studies in elastase-induced mouse experimental AAAs.
Assuntos
Aorta/patologia , Aneurisma da Aorta Abdominal/imunologia , Miócitos de Músculo Liso/patologia , Animais , Aorta/metabolismo , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Elastina/metabolismo , Humanos , Infusões Intra-Arteriais , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica , Elastase Pancreática/metabolismoRESUMO
Mitochondrion, the primary source of reactive oxygen species (ROS), is also the target of ROS. 8-Hydroxy-2'-deoxyguanosine (8-OH-dG) is the major end-product of damaged DNA caused by ROS. In our previous studies, we showed that prenatal stress (PNS) preferentially caused cognitive dysfunction and increased ROS in the hippocampus of female offspring rats. The present study aimed to determine 8-OH-dG level of mitochondria in order to elucidate the mechanism of hippocampal pyramidal neuronal damage and cognitive dysfunction induced by PNS. Pregnant rats were divided into two groups: control group (undisturbed) and PNS group (exposed to a restraint stress for 7 days at the late stage of gestation). Offspring rats were divided into four groups: female-control group, male-control group, female-stress group, male-stress group and used at 30-day-old after their birth. The content of 8-OH-dG was determined by high performance liquid chromatography-electrochemical detection (HPLC-ECD). The results showed that the contents of 8-OH-dG in female and male prenatal stressed offspring were significantly higher than that in their respective controls (P < 0.001). 8-OH-dG level was significantly higher in the female-stress group than in the male-stress group (P < 0.05), whereas there was no any gender-dependent difference in the control groups. These results suggest that accumulation of oxidative mitochondrial DNA damage may play an important role in PNS-induced cognitive dysfunction in female offspring rats.
Assuntos
Dano ao DNA , DNA Mitocondrial/metabolismo , Hipocampo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Estresse Psicológico/complicações , 8-Hidroxi-2'-Desoxiguanosina , Animais , Cromatografia Líquida de Alta Pressão , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Feminino , Masculino , Estresse Oxidativo , Gravidez , Ratos , Ratos Sprague-Dawley , Restrição FísicaRESUMO
OBJECTIVE: To perform a Meta-analysis on peginterferon with interferon in treatment of HIV patients coinfected with refractory genotype HCV. METHODS: A literature search of Medline was conducted to identify eligible randomized controlled trials. Meta analysis was conducted to evaluate peginterferon and interferon in treatment of coinfected HCV genotype 1 or 4 in HIV patients. RESULT: Six trials of 88 matched the selection criteria. Total 1,131 patients with coinfection of HCV genotype 1 or 4 and HIV were included. Sustain viral response was higher in patients treated with peginterferon plus ribavirin compared with that of interferon plus ribavirin (26 % compared with 8 %) or peginterferon alone (26 % compared with 13 %). Severe adverse effects and withdrawal rates were similar for patients treated with peginterferon and patients treated with interferon. CONCLUSION: Peginterferon plus ribavirin in treatment of patients with coinfection of genotype 1 or 4 HCV and HIV can achieve higher sustain viral response and the likelihoods of serious adverse effects and withdrawal rates are similar to other therapies.
Assuntos
Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Adulto , Antivirais/administração & dosagem , Quimioterapia Combinada , Feminino , Genótipo , Infecções por HIV/complicações , Infecções por HIV/imunologia , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas RecombinantesRESUMO
Neurogranin, a neuron-specific postsynaptic protein, has been considered to play an important role in synaptic plasticity and learning and memory. The present study aimed to investigate the effects of prenatal restraint stress on neurogranin expression in rat offspring hippocampus. Pregnant rats were given a restraint stress (3 times a day for 7 d, 45 min each time) at the late stage of gestation except that in the control group. The offspring rats were divided into four groups: female control group, male control group, female stress group and male stress group. Expression of neurogranin was determined by immunohistochemistry and Western blot. The results showed that neurogranin-positive immunostaining was detected in all areas of the hippocampus. The staining density was stronger in the CA1 and CA3 regions than that in the dentate gyrus (DG) region. Western blot assay showed that neurogranin protein level in female and male prenatal stressed offspring was significantly lower than that in the controls (P<0.01). Neurogranin level was significantly lower in the female stress group than that in the male stress group, whereas there was no significant gender difference in the control group. Immunohistochemical data further confirmed these results. The present study provides evidence that prenatal restraint stress induces gender-dependent decrease in neurogranin expression in the offspring hippocampus. The prenatal restraint stress-induced decrease in neurogranin expression in the hippocampus might be associated with the deficit in spatial learning and memory reported previously.
Assuntos
Hipocampo/química , Neurogranina/análise , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico/metabolismo , Animais , Western Blotting , Feminino , Imuno-Histoquímica , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Restrição FísicaRESUMO
INTRODUCTION: Traditional Chinese herbs are widely used for the treatment of chronic hepatitis B (CHB) in China. The aim of this study was to perform a meta-analysis of randomized controlled trials (RCTs) comparing peginterferon therapies with peginterferon plus Chinese herbal therapies in hepatitis B e antigen (HBeAg)-positive CHB patients. METHODOLOGY: The main biomedical databases were searched to identify RCTs that compared the efficiency of peginterferon with peginterferon plus Chinese herbs in CHB patients. RESULTS: The literature search yielded 616 studies, and 8 RCTs (624 patients) matched the selection criteria. Combined therapies of peginterferon plus Chinese herbal therapies were superior to peginterferon therapies alone in achieving the serum HBV DNA clearance rate (64.5% vs. 45.0%), serum HBeAg clearance rate (47.4% vs. 33.5%), and HBeAg seroconversion rates (39.2% vs. 23.1%) at the end of treatment. Combined therapies were more effective than peginterferon alone therapies in the improvement of liver fibrosis related biomarkers, including hyaluronic acid, procollagen type III, type IV collagen, and lamina. Combined therapies also resulted in fewer relapses, fewer adverse events, and more rapid alanine transaminase normalization. CONCLUSIONS: The current evidence suggests that peginterferon plus Chinese herbal therapies were associated with higher virological response than peginterferon alone in HBeAg-positive CHB patients.
Assuntos
Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Extratos Vegetais/administração & dosagem , Plantas Medicinais , Adulto , Povo Asiático , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
To evaluate the beneficial and adverse effects of breviscapine injection in combination with Western medicine on the treatment of patients with angina pectoris. The Cochrane Central Register of Controlled Trials, Medline, Science Citation Index, EMBASE, the China National Knowledge Infrastructure, the Wanfang Database, the Chongqing VIP Information Database and the China Biomedical Database were searched to identify randomized clinical trials (RCTs) that evaluated the effects of Western medicine compared to breviscapine injection plus Western medicine on angina pectoris patients. The included studies were analyzed using RevMan 5.1.0 software. The literature search yielded 460 studies, wherein 16 studies matched the selection criteria. The results showed that combined therapy using Breviscapine plus Western medicine was superior to Western medicine alone for improving angina pectoris symptoms (OR=3.77, 95% Cl: 2.76~5.15) and also resulted in increased electrocardiogram (ECG) improvement (OR=2.77, 95% Cl: 2.16~3.53). The current evidence suggests that Breviscapine plus Western medicine achieved a superior therapeutic effect compared to Western medicine alone.
Assuntos
Angina Pectoris/tratamento farmacológico , Flavonoides/uso terapêutico , Angina Pectoris/diagnóstico por imagem , Flavonoides/efeitos adversos , Humanos , Injeções , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto , UltrassonografiaRESUMO
The administration of statin might increase the risk of new-onset diabetes in hypercholesterolemic patients based on the recent clinical evidence. However, the causal relationship must be clarified and confirmed in animal experiments. Therefore, we mimicked hypercholesterolemia by feeding rabbits a high-cholesterol diet (HCD) and performed 16 weeks of atorvastatin administration to investigate the effect of statin on glucose metabolism. The intravenous glucose tolerance test showed that plasma glucose levels in the statin-treated rabbits were consistently higher and that there was a slower rate of glucose clearance from the blood than in HCD rabbits. The incremental area under the curve for glucose in the statin-treated rabbits was also significantly larger than in the HCD rabbits. However, there was no significant difference between the two groups in the intravenous insulin tolerance test. The glucose-lowering ability of exogenous insulin was not impaired by statin treatment in hypercholesterolemic rabbits. The administration of a single dose of statin did not affect glucose metabolism in normal rabbits. The statin also significantly increased the levels of high-density lipoprotein cholesterol, alanine aminotransferase and aspartate transaminase and decreased plasma levels of total cholesterol, triglycerides and low-density lipoprotein cholesterol in the hypercholesterolemic rabbits, whereas it did not affect plasma levels of glucose and insulin. The current results showed that atorvastatin treatment resulted in a significant delay of glucose clearance in hypercholesterolemic rabbits, and this rabbit model could be suitable for studying the effects of statin on glucose metabolism.
Assuntos
Atorvastatina/uso terapêutico , Glucose/metabolismo , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Atorvastatina/administração & dosagem , Atorvastatina/farmacologia , Glicemia/metabolismo , Dieta , Comportamento Alimentar/efeitos dos fármacos , Teste de Tolerância a Glucose , Hipercolesterolemia/sangue , Insulina/sangue , Lipídeos/sangue , Masculino , Tamanho do Órgão/efeitos dos fármacos , CoelhosRESUMO
Stressor acting upon the organism during pregnancy can produce distinct and long lasting effects on the offspring. However, the essential mechanism remains unclear. Neurogranin (Ng) is a postsynaptic brain-specific protein involved in the regulation of calcium signaling and neuronal plasticity. Our purpose was to investigate whether Ng plays a regulating role in the effects of prenatal restraint stress (PS) and prenatal pulsed magnetic fields (PMFs) on the hippocampus of rat offspring. Sprague Dawley female rats at gestational days 14-20 were given restraint stress or pulsed magnetic fields. The male and female offspring rats were sacrificed at the age of 1 month. The expression of Ng in the offspring hippocampus was determined using immunohistochemistry and western blotting. The results showed that PS induces a significantly inhibitory effect on the expression of Ng, especially in female offspring. The 0.11 T of prenatal PMFs could increase the expression of Ng in offspring hippocampus. There was no significant difference between female and male offspring in PMFs group. The prenatal restraint stress-induced decrease in Ng expression in offspring hippocampus might be associated with the deficit in spatial learning and memory reported previously. The 0.11 T of prenatal PMFs induced a significant stimulatory effect on protein expression of Ng. It was believed that PMFs stress might enhance the synaptic growth and remodeling.
Assuntos
Hipocampo/crescimento & desenvolvimento , Campos Magnéticos , Neurogranina/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Restrição Física/efeitos adversos , Estresse Psicológico/fisiopatologia , Animais , Western Blotting , Doença Crônica , Modelos Animais de Doenças , Feminino , Hipocampo/fisiopatologia , Imuno-Histoquímica , Masculino , Periodicidade , Gravidez , Distribuição Aleatória , Ratos Sprague-Dawley , Caracteres SexuaisRESUMO
The results of several new clinical trials that compared the effectiveness of entecavir (ETV) treatment with that of adefovir (ADV) treatment in patients with chronic hepatitis B (CHB) were published in recent years. However, the numbers of patients included in these clinical trials were too small to draw a clear conclusion as to whether ETV is more effective than ADV. Therefore, a new meta-analysis was needed to compare ETV with ADV for the treatment of CHB. A search of the Cochrane Central Register of Controlled Trials (CCTR), MEDLINE, the Science Citation Index, Embase, the China National Knowledge Infrastructure (CNKI), and the Wanfang Database for relevant studies published between 1966 and 2010 was performed. Trials comparing the use of ETV and ADV for the treatment of CHB were assessed. Of the 2,358 studies screened, 13 randomized controlled clinical trials comprising 1,230 patients (ETV therapy, 621; ADV therapy, 609) were analyzed. The serum hepatitis B virus (HBV) DNA clearance rate obtained in patients treated with ETV was significantly higher than that in patients treated with ADV at the 24th and 48th weeks of treatment (24 weeks: 59.6% vs. 31.8%, relative risk [RR], 1.82, 95% CI: 1.49-2.23; 48 weeks: 78.3% vs. 50.4%, RR, 1.61, 95% CI: 1.32-1.96). The serum HBeAg clearance rate, the HBeAg seroconversion rate, and the ALT normalization rate obtained for patients treated with ETV were also higher than the corresponding values for patients treated with ADV at the 48th week of treatment. The safety profiles were similar between patients treated with ETV and those treated with ADV. The evidence reviewed in this meta-analysis suggests that patients with hepatitis B have a greater likelihood of achieving a viral response and a biomedical response when treated with ETV than when treated with ADV.
Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/uso terapêutico , Adenina/uso terapêutico , Guanina/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
A substantial number of human epidemiological data, as well as experimental studies, suggest that adverse maternal stress during gestation is involved in abnormal behavior, mental, and cognition disorder in offspring. To explore the effect of prenatal stress (PS) on hippocampal neurons, in this study, we observed the dendritic field of pyramidal neurons in hippocampal CA3, examined the concentration of glutamate (Glu), and detected the expression of synaptotagmin-1 (Syt-1) and N-methyl-D-aspartate receptor 1 (NR1) in hippocampus of juvenile female offspring rats. Pregnant rats were divided into two groups: control group (CON) and PS group. Female offspring rats used were 30-day old. The total length of the apical dendrites of pyramidal neurons in hippocampal CA3 of offspring was significantly shorter in PS than that in CON (p < 0.01). The number of branch points of the apical dendrites of pyramidal neurons in hippocampal CA3 of offspring was significantly less in PS (p < 0.01). PS offspring had a higher concentration of hippocampal Glu compared with CON (p < 0.05). PS offspring displayed increased expression of Syt-1 and decreased NR1 in hippocampus compared with CON (p < 0.001 and p < 0.01, respectively). The expression of NR1 in different hippocampus subfields of offspring was significantly decreased in PS than that in CON (p < 0.05-0.01). This study shows that PS increases the Glu in hippocampus and causes apical dendritic atrophy of pyramidal neurons of hippocampal CA3 in offspring rats. The decline of NR1 in hippocampus may be an adaptive response to the increased Glu.
Assuntos
Região CA3 Hipocampal/fisiopatologia , Dendritos/fisiologia , Ácido Glutâmico/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Células Piramidais/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Região CA3 Hipocampal/patologia , Dendritos/patologia , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Gravidez , Células Piramidais/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Restrição Física , Estresse Psicológico/patologia , Sinaptotagmina I/metabolismoRESUMO
BACKGROUND: The standard treatments for chronic infection with the hepatitis C virus (HCV) are peginterferon α-2a or α-2b plus ribavirin, but it remains unclear if one has a better efficacy and safety profile. OBJECTIVE: The aim of this study was to perform a meta-analysis of randomized controlled trials (RCTs) comparing peginterferon α-2a and α-2b (in combination with ribavirin) treatments for chronic HCV. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, Science Citation Index, and EMBASE were searched (1966-April 2010) to identify RCTs that evaluated the sustained virologic response (SVR) to peginterferon α-2a and peginterferon α-2b in patients with chronic HCV. The inclusion criteria were: RCT studies designed to compare the therapeutic effects of peginterferon α-2a (180 µg/wk) and peginterferon α-2b (1.5 µg/kg/wk) for treatment-naive patients with chronic HCV; patients treated for ≥24 weeks if infected with HCV genotypes 2 or 3 and for ≥48 weeks if infected with genotypes 1 or 4, with 24-week follow-ups; and publications written in any language. Reports of duplicated studies were excluded by examining the author list, parent institution, sample size, and results. The primary outcome was the SVR, and the other measures included the liver-related morbidity, all-cause mortality, and adverse events leading to treatment discontinuation. RESULTS: The literature search yielded 5580 studies, and 7 RCTs comprising 3212 patients matched the inclusion/exclusion criteria. Overall, the SVR rate was significantly higher in patients treated with peginterferon α-2a than in patients treated with peginterferon α-2b (50% vs 46%, respectively; relative risk [RR] = 1.11; 95% CI, 1.02-1.20; P < 0.05) and varying levels of ribavirin treatment. The subgroup analysis found that, in patients with genotypes 1 or 4, the difference between SVR rate in patients treated with peginterferon α-2a and patients treated with peginterferon α-2b was not statistically significant (43% vs 39%; RR = 1.25; 95% CI, 0.99-1.57). A significantly higher SVR rate was achieved in the HCV patients with genotypes 2 or 3 treated with peginterferon α-2a compared with the patients treated with peginterferon α-2b (86% vs 77%; RR = 1.11; 95% CI, 1.02-1.22; P = 0.02). The meta-analysis of adverse events leading to treatment discontinuation revealed no significant differences between the 2 treatments. CONCLUSIONS: The evidence reviewed in this meta-analysis suggests that peginterferon α-2a treatment was associated with a higher SVR rate than peginterferon α-2b treatment in patients with chronic HCV also treated with ribavirin. However, the available evidence on adverse events was insufficient to make recommendations.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Quimioterapia Combinada , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Resultado do TratamentoRESUMO
The results of several new clinical trials that compared the effectiveness of entecavir (ETV) treatment with that of adefovir (ADV) treatment in patients with chronic hepatitis B (CHB) were published in recent years. However, the numbers of patients included in these clinical trials were too small to draw a clear conclusion as to whether ETV is more effective than ADV. Therefore, a new meta-analysis was needed to compare ETV with ADV for the treatment of CHB. A search of the Cochrane Central Register of Controlled Trials (CCTR), MEDLINE, the Science Citation Index, Embase, the China National Knowledge Infrastructure (CNKI), and the Wanfang Database for relevant studies published between 1966 and 2010 was performed. Trials comparing the use of ETV and ADV for the treatment of CHB were assessed. Of the 2,358 studies screened, 13 randomized controlled clinical trials comprising 1,230 patients (ETV therapy, 621; ADV therapy, 609) were analyzed. The serum hepatitis B virus (HBV) DNA clearance rate obtained in patients treated with ETV was significantly higher than that in patients treated with ADV at the 24th and 48th weeks of treatment (24 weeks: 59.6% vs. 31.8%, relative risk [RR], 1.82, 95% CI: 1.49-2.23; 48 weeks: 78.3% vs. 50.4%, RR, 1.61, 95% CI: 1.32-1.96). The serum HBeAg clearance rate, the HBeAg seroconversion rate, and the ALT normalization rate obtained for patients treated with ETV were also higher than the corresponding values for patients treated with ADV at the 48th week of treatment. The safety profiles were similar between patients treated with ETV and those treated with ADV. The evidence reviewed in this meta-analysis suggests that patients with hepatitis B have a greater likelihood of achieving a viral response and a biomedical response when treated with ETV than when treated with ADV.