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1.
Acta cir. bras ; 34(11): e201901104, Nov. 2019. graf
Artigo em Inglês | LILACS | ID: biblio-1054677

RESUMO

Abstract Purpose: Myocardial ischemia/reperfusion (Ml/R) injury is a leading cause of damage in cardiac tissues, with high rates of mortality and disability. Biochanin A (BCA) is a main constituent of Trifolium pratense L. This study was intended to explore the effect of BCA on Ml/R injury and explore the potential mechanism. Methods: In vivo MI/R injury was established by transient coronary ligation in Sprague-Dawley rats. Triphenyltetrazolium chloride staining (TTC) was used to measure myocardial infarct size. ELISA assay was employed to evaluate the levels of myocardial enzyme and inflammatory cytokines. Western blot assay was conducted to detect related protein levels in myocardial tissues. Results: BCA significantly ameliorated myocardial infarction area, reduced the release of myocardial enzyme levels including aspartate transaminase (AST), creatine kinase (CK-MB) and lactic dehydrogenase (LDH). It also decreased the production of inflammatory cytokines (IL-1β, IL-18, IL-6 and TNF-α) in serum of Ml/R rats. Further mechanism studies demonstrated that BCA inhibited inflammatory reaction through blocking TLR4/NF-kB/NLRP3 signaling pathway. Conclusion: The present study is the first evidence demonstrating that BCA attenuated Ml/R injury through suppressing TLR4/NF-kB/NLRP3 signaling pathway-mediated anti-inflammation pathway.


Assuntos
Animais , Masculino , Cardiotônicos/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , NF-kappa B/efeitos dos fármacos , Genisteína/farmacologia , Receptor 4 Toll-Like/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Valores de Referência , Traumatismo por Reperfusão Miocárdica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Western Blotting , Reprodutibilidade dos Testes , Citocinas/sangue , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Creatina Quinase/sangue , Lactato Desidrogenases/sangue , Receptor 4 Toll-Like/metabolismo , Anti-Inflamatórios/farmacologia
2.
Rev. Soc. Cardiol. Estado de Säo Paulo ; 29(4 (Supl)): 400-407, out.-dez. 2019.
Artigo em Português | LILACS | ID: biblio-1047333

RESUMO

O coração é um órgão que se adapta frente aos diferentes estímulos ou desafios a que é exposto. No entanto, o tipo de adaptação e a magnitude da mesma dependem do tipo, da magnitude e do tempo de duração do estímulo. Logo, a adaptação cardíaca observada após um período de treinamento físico é diferente da adaptação cardíaca observada nas doenças cardiovasculares. Além disso, as variáveis inerentes ao exercício físico como tipo, intensidade, volume e frequência semanal também apresentam uma relação direta quanto ao tipo de adaptação cardíaca. No presente artigo revisaremos os efeitos dos diferentes tipos treinamento físico na estrutura e função cardíaca, abordando os diferentes tipos de hipertrofia cardíaca (excêntrica e concêntrica), bem como as principais vias de sinalização intracelular responsáveis por essa hipertrofia. Além disso, abordaremos como alguns dos principais fatores (massa corporal, sexo, etnia e fatores genéticos) influenciam na magnitude da hipertrofia cardíaca e discutiremos se o treinamento físico praticado em grandes volumes pode ser prejudicial à saúde cardíaca


The heart is an organ that adapts to the different stimuli or challenges to which it is exposed. However, the type of adaptation and its magnitude depend on the stimulus type, magnitude and duration. Therefore, the cardiac adaptation observed after a period of exercise training is different from the cardiac adaptation observed in cardiovascular diseases. In addition, the variables inherent in exercise training such as type, intensity, volume and weekly frequency also have a direct relation to the type of cardiac adaptation. In this article we will review the effects of different types of exercise training on cardiac structure and function, addressing the different types of cardiac hypertrophy (eccentric and concentric), as well as the main intracellular signaling pathways responsible for this hypertrophy. In addition, we will discuss how some of the major factors (body mass, gender, ethnicity, and genetic factors) influence the magnitude of cardiac hypertrophy and will discuss whether high-volume of exercise training can be detrimental to heart health


Assuntos
Exercício Físico , Coração , Doenças Cardiovasculares , Sistema Cardiovascular , Transdução de Sinais , Fatores Sexuais , Fatores de Risco , Fatores Etários , MicroRNAs , Hipertensão , Hipertrofia
3.
Acta cir. bras ; 34(1): e20190010000005, 2019. graf
Artigo em Inglês | LILACS | ID: biblio-983682

RESUMO

Abstract Purpose: To investigate the role of PI3k/Akt signal pathway in the protective effects of propofol on intestinal and lung injury induced by intestinal ischemia/reperfusion(I/R). Methods: Male Sprague-Dawley rats were subjected to 45 min of ischemia by occluding the superior mesenteric artery and to 2h of reperfusion to establish the model of I/R. Twenty four rats were randomly divided into four groups: Sham, intestinal I/R (II/R), propofol (P), wortmannin (W). In groups P, W, propofol was injected intravenously and continuously at the onset of reperfusion via infusion pump. PI3K inhibitor (wortmannin) was administered intravenously in group W 25 min before ischemia. Intestinal tissues and lung tissues were obtained for determination of histologic injury, wet/dry weight ratio, malondialdehyde (MDA) levels, superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. Meanwhile, the expressions of caspase-3 and phosphorylated Akt (p-Akt) in intestines and lungs were detected by western blot. Results: Propofol treatment alleviated intestinal and lung morphological changes which were observed in II/R group,Moreover, wet/dry weight ratio, the MDA level, MPO activity and expression of caspase-3 were significantly decreased whereas the SOD activity and p-Akt expression were significantly increased. Notably, the protections were significantly reversed by pretreatment of wortmannin. Conclusion: PI3K/Akt pathway activation play a critical role in the protective effects of propofol on intestinal and lung injury induced by ischemia/reperfusion.


Assuntos
Animais , Masculino , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Propofol/farmacologia , Anestésicos Intravenosos/farmacologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Lesão Pulmonar/prevenção & controle , Isquemia Mesentérica/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/fisiologia , Ratos Sprague-Dawley , Modelos Animais de Doenças , Isquemia Mesentérica/metabolismo
4.
Acta cir. bras ; 34(1): e20190010000003, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-983683

RESUMO

Abstract Purpose: To investigate the influence of lycium barbarum polysaccharides (LBP), a functional derivative from lycium barbarum, on septic kidney injury. Methods: The SD male rats were randomly divided into 8 groups. The concentration of IL-1β, IL-6, IL-8, TNF-α, NF-κB and ROS, in kidney cortex homogenates after 12 h treatments were determined by enzyme-linked immunosorbent assay and ROS test kit, respectively. Morphology observation of kidney tissue was conducted with HE staining. The mRNA and protein expression levels of Nrf2, HO-1, NQO1, NF-κB, and Keap1 in kidney tissues were determined by qRT-PCR and Western blot, respectively. Results: LPS treatment significantly increased the oxidative stress. After LBP treatment, the ROS content reduced significantly in a dose-depend manner. However, the levels of HO-1, NQO1 and Nrf2 as molecular elements that respond to oxidative stress were further increased. Also, administration of LBP increased the levels of NF-κB and Keap1, and decreased the levels of Nrf2 in the Keap 1-Nrf2∕ARE signaling pathway. By administrating the brusatol, the inhibition of Nrf2 enhanced the expression of NF-κB, inhibits the antioxidant responses, and further reverse the protective effect of LBP on the LPS induced septic kidney injury. Conclusion: Lycium barbarum polysaccharides can reduce inflammation and activate the antioxidant responses via regulating the level of pro-inflammatory cytokines and the Keap1-Nrf2/ARE signaling pathway.


Assuntos
Animais , Masculino , Ratos , Medicamentos de Ervas Chinesas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Lesão Renal Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças
5.
Acta cir. bras ; 34(1): e20190010000006, 2019. graf
Artigo em Inglês | LILACS | ID: biblio-983690

RESUMO

Abstract Purpose: To investigate whether hirudin exerts its antithrombin action to decrease the ratio of Human Microvascular Endothelial Cells (HMVECs) apoptosis. Methods: Human microvascular endothelial cells (HMVECs) cultured in the third and fifth generations were used. HMVECs were divided into normal group, thrombin group (T group), natrual hirudin group (H group), thrombin + natrual hirudin group (T + H group), AG490 group, thrombin + AG490 group (T + AG490 group), natrual hirudin + AG490 group (H + AG490 group), thrombin + natural hirudin + AG490 (T + H + AG490 group).Apart from the normal group, the other groups were exposed to the relevant drugs for 24 hours.HMVEC apoptosis was assessed by flow cytometric and double Immunofluorescence of phosphorylation of JAK (P-JAK2) and TUNEL assay. Results: Compared with the normal group, in thrombin group the HMVECs apoptosis rate were significantly increased (P<0.05).The results indicated that the index of apoptosis and the apoptosis rate were improved in cultures treated by natural hirudin (T + H group), relative to cultures with thrombin only (T group). We found that the index of apoptosis and the apoptosis rate in the AG490 + thrombin group were higher than that in the hirudin + thrombin group (P<0.05). Double Immunofluorescence of p-JAK2 and TUNEL assays showed that cells were double positive for P-JAK2 uptake and TUNEL detection liquid binding. Conclusion: The natural hirudin and JAK2/STATs signal inhibitor AG490 could block the effects of thrombin. Natural hirudin could attenuate HMVECs apoptosis via antagonizing thrombin and it is suggested that this effect may occur by blocking the JAK2/STATs signaling pathway and this signaling pathways appears to be not the only pathway.


Assuntos
Humanos , Trombina/efeitos dos fármacos , Antitrombinas/farmacologia , Hirudinas/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Microvasos/metabolismo
6.
Acta cir. bras ; 34(2): e201900209, 2019. graf
Artigo em Inglês | LILACS | ID: biblio-989056

RESUMO

Abstract Purpose: To explore the effect of milk fat globule-epidermal growth factor 8 (MFG-E8) on sepsis-induced acute kidney injury (SAKI). Methods: Male C57BL/6 mice were randomized to control, sham, CLP, CLP+PBS, and CLP+rmMFG-E8 groups. SAKI was induced by cecal ligation and puncture (CLP). Recombinant mouse MFG-E8 (rmMFG-E8) (20 μg/kg) or PBS (vehicle) was administered intraperitoneally. Blood, urine and renal tissue were collected at 24 h after CLP. Blood samples were tested for serum kidney injury biomarker and cytokines. Urine samples were collected to detect KIM-1, and NGAL. Real-time PCR was tested for Bax and Bcl-2. TUNEL staining was used to determine renal apoptosis. Western blot was used to detect the expression of Bax, Bcl-2, and proteins in the NF-κB pathway. Results: MFG-E8 alleviated SAKI by decreasing serum Cre, BUN, urine KIM-1 and NGAL and by mitigating renal pathological changes significant (p < 0.05). IL-1β, IL-6, TNF-α were significantly inhibited by MFG-E8 (p < 0.05). Apoptosis induced by SAKI was markedly suppressed by MFG-E8. Finally, MFG-E8 attenuated the activation of the NF-��B signaling pathway in SAKI. Conclusion: MFG-E8 has beneficial effects on SAKI, which may be achieved by inhibiting the NF-κB pathway.


Assuntos
Animais , Masculino , Ratos , NF-kappa B/antagonistas & inibidores , Sepse/complicações , Substâncias Protetoras/uso terapêutico , Lesão Renal Aguda/prevenção & controle , Proteínas do Leite/uso terapêutico , Antígenos de Superfície/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Lesão Renal Aguda/etiologia , Camundongos Endogâmicos C57BL
7.
Acta cir. bras ; 34(6): e201900609, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1019266

RESUMO

Abstract Purpose The research is intended for clarification of the efficacy as well as the underlying mechanism of GSK-3β inhibitors on the advancement of acute lung injuries in acute necrotizing pancreatitis (ANP) in rats. Methods Seventy-two rats were randomly divided into 6 groups: (1)ANP-vehicle; (2)ANP-TDZD-8;(3)ANP-SB216763;(4)Sham-vehicle;(5)Sham-TDZD-8;(6)Sham-SB216763; Blood biochemical test, histopathological examination and immunohistochemical analysis of rats pancreas and lung tissues were performed. The protein expression of GSK-3β, phospho-GSK-3β (Ser9), iNOS, ICAM-1, TNF-α, and IL-10 were detected in lung tissues by Western-blot. Results The outcomes revealed that the intervention of GSK-3β inhibitors alleviated the pathological damage of pancreas and lung (P<0.01), reduced serum amylase, lipase, hydrothorax and lung Wet-to-Dry Ratio, attenuated serum concentrations of IL-1β and IL-6 (P<0.01), inhibited the activation of NF-κB, and abated expression of iNOS, ICAM-1 and TNF-α protein, but up-regulated IL-10 expression in lung of ANP rats (P<0.01). The inflammatory response and various indicators in ANP-TDZD-8 groups were lower than those in ANP-SB216763 groups. Conclusions Inhibition of GSK-3β weakens acute lung injury related to ANP via the inhibitory function of NF-κB signaling pathway. Different kinds of GSK-3β inhibitors have different effects to ANP acute lung injury.


Assuntos
Animais , Masculino , Ratos , Pancreatite Necrosante Aguda/complicações , Lesão Pulmonar Aguda/prevenção & controle , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Fosforilação , Imuno-Histoquímica , Transdução de Sinais , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ratos Wistar , Pancreatite Necrosante Aguda/patologia , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia
8.
Acta cir. bras ; 34(7): e201900708, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1038121

RESUMO

Abstract Purpose: To investigate the effect of astragaloside IV (As-IV) on myocardial ischemia-reperfusion (I/R) injury in rats and reltaed mechanisms. Methods: Sixty rats were randomly divided into sham-operated, control I/R and 2.5, 5 and 10 mg/kg As-IV groups, 12 rats in each group. The later three groups were intragastrically administered with As-IV for 7 days, with a dose of 2.5, 5 and 10 mg/kg, respectively. The myocardial I/R injury model was constructed in later four groups. At the end of reperfusion, the cardiac function indexes, serum lactate dehydrogenase (LDH) and creatine kinase (CK) levels, heart weight (HW)/body weight (BW) ratio and infarct size, and expressions of phosphatidylinositol-3 kinase/serine-threonine protein kinase (PI3K/AKT) and glycogen synthase kinase-3β (GSK-3β) proteins and the phosphorylated forms (p-AKT, p-GSK-3β) were determined. Results: Compared with control I/R group, in 5 and 10 mg/kg As-IV groups the left ventricular systolic pressure, fractional shortening and ejection fraction were increased, the left ventricular end-diastolic pressure was decreased, the serum LDH and CK levels were decreased, the HW/BW ratio and myocardial infarct size were decreased, and the p-Akt/Akt ratio and p-GSK-3β/GSK-3β ratio were increased (all P < 0.05). Conclusion: As-IV can alleviate the myocardial I/R injury in rats through regulating PI3K/AKT/GSK-3β signaling pathways.


Assuntos
Animais , Masculino , Ratos , Saponinas/farmacologia , Triterpenos/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Fosforilação , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Ratos Sprague-Dawley
9.
Acta cir. bras ; 34(8): e201900802, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1038128

RESUMO

Abstract Purpose To reveal the function of miR-134 in myocardial ischemia. Methods Real-time PCR and western blotting were performed to measure the expression of miR-134, nitric oxide synthase 3 (NOS3) and apoptotic-associated proteins. Lactic dehydrogenase (LDH) assay, cell counting kit-8 (CCK-8), Hoechst 33342/PI double staining and flow cytometry assay were implemented in H9c2 cells, respectively. MiR-134 mimic/inhibitor was used to regulate miR-134 expression. Bioinformatic analysis and luciferase reporter assay were utilized to identify the interrelation between miR-134 and NOS3. Rescue experiments exhibited the role of NOS3. The involvement of PI3K/AKT was assessed by western blot analysis. Results MiR-134 was high regulated in the myocardial ischemia model, and miR-134 mimic/inhibitor transfection accelerated/impaired the speed of cell apoptosis and attenuated/exerted the cell proliferative prosperity induced by H/R regulating active status of PI3K/AKT signaling. LDH activity was also changed due to the different treatments. Moreover, miR-134 could target NOS3 directly and simultaneously attenuated the expression of NOS3. Co-transfection miR-134 inhibitor and pcDNA3.1-NOS3 highlighted the inhibitory effects of miR-134 on myocardial H/R injury. Conclusion This present work puts insights into the crucial effects of the miR-134/NOS3 axis in myocardial H/R injury, delivering a potential therapeutic technology in future.


Assuntos
Animais , Ratos , Traumatismo por Reperfusão Miocárdica/metabolismo , MicroRNAs/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Hipóxia/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , MicroRNAs/genética , MicroRNAs/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo
10.
Acta cir. bras ; 34(12): e201901202, 2019. graf
Artigo em Inglês | LILACS | ID: biblio-1054685

RESUMO

Abstract Purpose To explore the potential role and unclear molecular mechanisms of vaccarin in wound healing. Methods Rats' skin excision model to study the effects of vaccarin on wound healing in vivo . Hematoxylin and eosin staining was performed to evaluate Histopathologic characteristics. Immunohistochemistry was employed to assess the effects of vaccarin in accelerating angiogenesis. Western blot was used to evaluate relative protein expressed levels. Results Vaccarin could significantly promote wound healing and endothelial cells and fibroblasts proliferation in the wound site. Immunohistochemistry and Western blot studies showed that the nodal proteins and receptor (bFGFR) related to angiogenesis signaling pathway were activated, and the microvascular density in the wound site was markedly higher than that in the control group. Conclusions The present study was the first to demonstrate that vaccarin is able to induce angiogenesis and accelerate wound healing in vivo by increasing expressions of p-Akt, p-Erk and p-bFGFR. This process is mediated by MAPK/ERK and PI3K/AKT signaling pathways.


Assuntos
Animais , Masculino , Cicatrização/efeitos dos fármacos , Extratos Vegetais/farmacologia , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/efeitos dos fármacos , Caryophyllaceae/química , Indutores da Angiogênese/farmacologia , Fatores de Tempo , Imuno-Histoquímica , Extratos Vegetais/química , Transdução de Sinais , Western Blotting , Reprodutibilidade dos Testes , Ratos Sprague-Dawley , Fosfatidilinositol 3-Quinases/análise , Quinases de Proteína Quinase Ativadas por Mitógeno/análise , Células Endoteliais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos
11.
Rev. Hosp. Niños B.Aires ; 60(270): 264-268, sept. 2018.
Artigo em Espanhol | LILACS | ID: biblio-1099780

RESUMO

Como homenaje a la actuación del Dr. Juan Jorge Heinrich en su carácter de docente, pediatra clínico e investigador, los autores del presente artículo consideran adecuada una revisión de su participación en el descubrimiento de dos nuevas patologías dentro del campo de la resistencia a la acción de la hormona de crecimiento. La primera es causada por una mutación en el gen que codifica para la STAT5b (transductor de señal y activador de transcripción 5b), proteína que participa en la transmisión intracelular de la señal de GH. La segunda es causada por una mutación en el gen que codifica para la subunidad ácido lábil (ALS), una proteína esencial para la formación de complejos ternarios con IGF-I e IGFBP-3, los que incrementan marcadamente la vida media del IGF-I en la circulación


In homage to Dr. Juan Jotge Heinrich actions as teacher, pediatrician, and researcher, we feel pertinent to remark his contributions to the discovery of two new pathologies within the field of resistance to the action of growth hormone. One is due to a mutation in the gene coding for a protein, STAT5b (signal transducer and activator of transcription 5b), involved in the intracellular chain of transmission of the growth hormone signal; the other due to a mutation in the gene coding for ALS (acid labile subunit) a protein essential for the ternary complex formation among IGF-I, IGFBP-3, and ALS, which markedly increases the half life of IGF-I in the circulation


Assuntos
Humanos , Síndrome de Laron , Pediatria , Transdução de Sinais , Endocrinologia
12.
Braz. j. med. biol. res ; 51(5): e6714, 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-889083

RESUMO

This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms. Thirty Sprague-Dawley rats received forebrain ischemia for 10 min. The dilation responses of the cerebral pial artery to hypercapnia and hypotension were assessed in rats before and 1 h after ischemia. The ischemia reperfusion (IR) control group received DMSO (1 µL/kg) immediately after ischemia. Two different doses of salvinorin A (10 and 20 µg/kg) were administered following the onset of reperfusion. The 5th, 6th, and 7th groups received salvinorin A (20 µg/kg) and LY294002 (10 µM), L-NAME (10 μM), or norbinaltorphimine (norBIN, 1 μM) after ischemia. The levels of cGMP in the cerebrospinal fluid (CSF) were also measured. The phosphorylation of AKT (p-AKT) was measured in the cerebral cortex by western blot at 24 h post-ischemia. Cell necrosis and apoptosis were examined by hematoxylin-eosin staining (HE) and TUNEL staining, respectively. The motor function of the rats was evaluated at 1, 2, and 5 days post-ischemia. The dilation responses of the cerebral pial artery were significantly impaired after ischemia and were preserved by salvinorin A treatment. In addition, salvinorin A significantly increased the levels of cGMP and p-AKT, suppressed cell necrosis and apoptosis of the cerebral cortex and improved the motor function of the rats. These effects were abolished by LY294002, L-NAME, and norBIN. Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.


Assuntos
Animais , Masculino , Ratos , Artérias Cerebrais/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Diterpenos Clerodânicos/farmacologia , Transdução de Sinais , Artérias Cerebrais/fisiopatologia , Isquemia Encefálica/tratamento farmacológico , Morfolinas/administração & dosagem , Cromonas/administração & dosagem , Ratos Sprague-Dawley , GMP Cíclico/líquido cefalorraquidiano , GMP Cíclico/metabolismo , NG-Nitroarginina Metil Éster , Diterpenos Clerodânicos/antagonistas & inibidores , Modelos Animais de Doenças , Naltrexona/administração & dosagem , Naltrexona/análogos & derivados
13.
Mem. Inst. Oswaldo Cruz ; 113(6): e140421, 2018. graf
Artigo em Inglês | LILACS | ID: biblio-894933

RESUMO

BACKGROUND Streptococcus agalactiae can causes sepsis, pneumonia, and meningitis in neonates, the elderly, and immunocompromised patients. Although the virulence properties of S. agalactiae have been partially elucidated, the molecular mechanisms related to reactive oxygen species (ROS) generation in infected human endothelial cells need further investigation. OBJECTIVES This study aimed to evaluate the influence of oxidative stress in human umbilical vein endothelial cells (HUVECs) during S. agalactiae infection. METHODS ROS production during S. agalactiae-HUVEC infection was detected using the probe CM-H2DCFDA. Microfilaments labelled with phalloidin-FITC and p47phox-Alexa 546 conjugated were analysed by immunofluorescence. mRNA levels of p47phox (NADPH oxidase subunit) were assessed using Real Time qRT-PCR. The adherence and intracellular viability of S. agalactiae in HUVECs with or without pre-treatment of DPI, apocynin (NADPH oxidase inhibitors), and LY294002 (PI3K inhibitor) were evaluated by penicillin/gentamicin exclusion. Phosphorylation of p47phox and Akt activation by S. agalactiae were evaluated by immunoblotting analysis. FINDINGS Data showed increased ROS production 15 min after HUVEC infection. Real-Time qRT-PCR and western blotting performed in HUVEC infected with S. agalactiae detected alterations in mRNA levels and activation of p47phox. Pre-treatment of endothelial cells with NADPH oxidase (DPI and apocynin) and PI3K/Akt pathway (LY294002) inhibitors reduced ROS production, bacterial intracellular viability, and generation of actin stress fibres in HUVECs infected with S. agalactiae. CONCLUSIONS ROS generation via the NADPH oxidase pathway contributes to invasion of S. agalactiae in human endothelial cells accompanied by cytoskeletal reorganisation through the PI3K/Akt pathway, which provides novel evidence for the involvement of oxidative stress in S. agalactiae pathogenesis.


Assuntos
Humanos , Espécies Reativas de Oxigênio/análise , NADPH Oxidases/análise , NADPH Oxidases/metabolismo , Células Endoteliais da Veia Umbilical Humana/microbiologia , Transdução de Sinais/fisiologia , Reação em Cadeia da Polimerase em Tempo Real
14.
Braz. j. med. biol. res ; 51(4): e7139, 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-889060

RESUMO

Obesity and its consequent type 2 diabetes are significant threats to global health. Emerging evidence indicates that ginsenosides from ginseng (Panax ginseng) have anti-diabetic activity. We hypothesized that ginsenosides Rg1 could suppress dietary-induced obesity and improve obesity-related glucose metabolic disorders. Our results showed that ginsenoside Rg1 attenuated dietary-induced body weight gain and fat accumulation in white adipocyte tissue of mice fed a high-fat diet. Furthermore, we found that ginsenosides Rg1 not only decreased fasting glucose concentration and the 2-h postprandial glucose concentration, but also improved insulin resistance and glucose intolerance in those mice. Ginsenoside Rg1 also activated the AMPK pathway in vitro and in vivo and increased plasma membrane translocation of GLUT4 in C2C12 skeletal muscle cells. In conclusion, our observations suggested that ginsenoside Rg1 inhibited dietary-induced obesity and improved obesity-related insulin resistance and glucose intolerance by activation of the AMPK pathway.


Assuntos
Animais , Masculino , Camundongos , Dieta Hiperlipídica , Ginsenosídeos/farmacologia , Transtornos do Metabolismo de Glucose/prevenção & controle , Obesidade/complicações , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Transtornos do Metabolismo de Glucose/etiologia , Transtornos do Metabolismo de Glucose/metabolismo , Resistência à Insulina , Obesidade/metabolismo , Transdução de Sinais , Fatores de Tempo
15.
Braz. j. med. biol. res ; 51(5): e6889, 2018. graf
Artigo em Inglês | LILACS | ID: biblio-889078

RESUMO

2-Methyl-2-butanol (MBT) is a chemical compound from the group of alcohols more specifically pentanols, which has shown an excellent anti-cancer activity in our previous study. However, its mechanism of action remains unclear. The present study was designed to investigate the anti-cancer effect of MBT on human retinoblastoma cells. The results showed that the use of MBT leads to HXO-RB44 cell death but is cytotoxic to normal cells at higher concentrations. It showed a dose- as well as a time-dependent inhibition of HXO-RB44 cells. P27 is a cell cycle inhibitory protein, which plays an important role in cell cycle regulation whereas cyclin-B1 is a regulatory protein involved in mitosis. MBT increased the cell cycle arrest in a dose-dependent manner by augmenting p27 and reducing cyclin B1 expression. Moreover, it also accelerated apoptosis, increased light chain-3 (LC-3) conversion in a dose-dependent manner, and helped to debulk cancerous cells. LC3 is a soluble protein, which helps to engulf cytoplasmic components, including cytosolic proteins and organelles during autophagy from autophagosomes. In order to verify the effect of MBT, bafilomycin A1, an autophagy inhibitor, was used to block the MTB-induced apoptosis and necrosis. Additionally, a specific Akt agonist, SC-79, reversed the MBT-induced cell cycle arrest and autophagy. Thus, from the present study, it was concluded that MBT induced cell cycle arrest, apoptosis and autophagy through the PI3K/Akt pathway in HXO-RB44 cells.


Assuntos
Humanos , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pentanóis/farmacologia , Retinoblastoma/patologia , Western Blotting , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
16.
Braz. j. med. biol. res ; 51(6): e7065, 2018. graf
Artigo em Inglês | LILACS | ID: biblio-889100

RESUMO

Ulcerative colitis is a chronic inflammatory disease of the colon where intestinal motility is disturbed. Interstitial cells of Cajal (ICC) are required to maintain normal intestinal motility. In the present study, we assessed the effect of tumor necrosis factor-alpha (TNF-α) on viability and apoptosis of ICC, as well as on the expression of stem cell factor (SCF), ghrelin, and substance P. ICC were derived from the small intestines of Swiss albino mice. Cell viability and apoptosis were measured using CCK-8 assay and flow cytometry, respectively. ELISA was used to measure the concentrations of IL-1β, IL-6, ghrelin, substance P, and endothelin-1. Quantitative RT-PCR was used to measure the expression of SCF. Western blotting was used to measure the expression of apoptosis-related proteins, interleukins, SCF, and NF-κB signaling pathway proteins. TNF-α induced inflammatory injury in ICC by decreasing cell viability and increasing apoptosis and levels of IL-1β and IL-6. TNF-α decreased the levels of SCF, ghrelin, and substance P, but had no effect on endothelin-1. TNF-α down-regulated expressions of SCF, ghrelin, and substance P by activating the NF-κB pathway in ICC. In conclusion, TNF-α down-regulated the expressions of SCF, ghrelin, and substance P via the activation of the NF-κB pathway in ICC.


Assuntos
Animais , Masculino , Camundongos , Grelina/metabolismo , Células Intersticiais de Cajal/efeitos dos fármacos , NF-kappa B/metabolismo , Fator de Células-Tronco/metabolismo , Substância P/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Ensaio de Imunoadsorção Enzimática , Motilidade Gastrointestinal/efeitos dos fármacos , Grelina/antagonistas & inibidores , Células Intersticiais de Cajal/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos
17.
Braz. j. med. biol. res ; 51(6): e6452, 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-889104

RESUMO

Several microRNAs (miRNAs) have been reported as oncogenes or tumor suppressors in many cancers, including gastric cancer (GC). However, the role and molecular mechanism of miR-3129 in GC is largely unknown. We aimed to explore the function and the underlying molecular mechanism of miR-3129 in GC. Cancer tissues and corresponding adjacent tissues were collected from 50 patients with GC, and the expression of miR-3129 was detected by RT-qPCR. The expression of miR-3129 and pRb in human GC cell line SCG7091 was altered by transient transfection. Thereafter, MTT and flow cytometry assays were used to analyze cell viability and cell cycle. The expression of cyclin E, CDK2, CDK2 inhibitors (p16 and 21), and pRb were detected by RT-qPCR and western blot. A significant up-regulation of miR-3129 was observed in GC tissues compared to adjacent tissues. Overexpression of miR-3129 significantly improved cell viability after 4 days of post-transfection. Flow cytometry assay results showed that the miR-3129 overexpression arrested more SGC7901 cells at S phase. Moreover, overexpression of miR-3129 down-regulated the expression of CDK2 inhibitors while it up-regulated the expression levels of cyclin E, CDK2, and pRb. Interestingly, we found that pRb inhibition reversed the effect of miR-3129 inhibitor on cell proliferation in SGC7901 cells, increased cell viability, reduced cells at G0/1 phase, and modulated the expression of proliferation-related factors. Our results revealed that miR-3129 functioned as an oncogene through positive regulation of pRb and may prove to be a promising option for molecular therapy of GC.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Proliferação de Células/genética , Proteína do Retinoblastoma/genética , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação para Baixo , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase em Tempo Real , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Transfecção , Regulação para Cima
18.
Braz. j. med. biol. res ; 51(6): e6555, 2018. graf
Artigo em Inglês | LILACS | ID: biblio-889109

RESUMO

Long non-coding RNAs (lncRNAs) play an important role in the pathogenesis of cardiovascular diseases, especially in myocardial infarction and ischemia/reperfusion (I/R). However, the underlying molecular mechanism remains unclear. In this study, we determined the role and the possible underlying molecular mechanism of lncRNA-ROR in myocardial I/R injury. H9c2 cells and human cardiomyocytes (HCM) were subjected to either hypoxia/reoxygenation (H/R), I/R or normal conditions (normoxia). The expression levels of lncRNA-ROR were detected in serum of myocardial I/R injury patients, H9c2 cells, and HCM by qRT-PCR. Then, levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) were measured by kits. Cell viability, apoptosis, apoptosis-associated factors, and p38/MAPK pathway were examined by MTT, flow cytometry, and western blot assays. Furthermore, reactive oxygen species (ROS) production was determined by H2DCF-DA and MitoSOX Red probes with flow cytometry. NADPH oxidase activity and NOX2 protein levels were measured by lucigenin chemiluminescence and western blot. Results showed that lncRNA-ROR expression was increased in I/R patients and in H/R treatment of H9c2 cells and HCM. Moreover, lncRNA-ROR significantly promoted H/R-induced myocardial injury via stimulating release of LDH, MDA, SOD, and GSH-PX. Furthermore, lncRNA-ROR decreased cell viability, increased apoptosis, and regulated expression of apoptosis-associated factors. Additionally, lncRNA-ROR increased phosphorylation of p38 and ERK1/2 expression and inhibition of p38/MAPK, and rescued lncRNA-ROR-induced cell injury in H9c2 cells and HCM. ROS production, NADPH oxidase activity, and NOX2 protein levels were promoted by lncRNA-ROR. These data suggested that lncRNA-ROR acted as a therapeutic agent for the treatment of myocardial I/R injury.


Assuntos
Humanos , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , RNA Longo não Codificante/metabolismo , Apoptose , Western Blotting , Sobrevivência Celular , Glutationa Peroxidase/metabolismo , Hidroliases/metabolismo , Malondialdeído/metabolismo , Isquemia Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos , Reação em Cadeia da Polimerase em Tempo Real , RNA Longo não Codificante/genética , Transdução de Sinais , Superóxido Dismutase/metabolismo , Transfecção
19.
Acta cir. bras ; 32(10): 862-872, Oct. 2017. graf
Artigo em Inglês | LILACS | ID: biblio-886174

RESUMO

Abstract Purpose: To investigate whether the neuroprotective effect of TSA on cerebral ischemia reperfusion injury is mediated by the activation of Akt/GSK-3β signaling pathway. Methods: Mice were randomly divided into four groups (n=15): sham group (S); ischemia reperfusion group (IR); ischemia reperfusion and pretreated with TSA group (IR+T); ischemia reperfusion and pretreated with TSA and LY294002 group (IR+T+L). The model of cerebral ischemia reperfusion was established by 1h of MCAO following 24h of reperfusion. TSA (5mg/kg) was intraperitoneally given for 3 days before MCAO, Akt inhibitor, LY294002 (15 nmol/kg) was injected by tail vein 30 min before the MCAO. Results: TSA significantly increased the expression of p-Akt, p-GSK-3β proteins and the levels of SOD, Bcl-2, reduced the infarct volume and the levels of MDA, ROS, TNF-α, IL-1β, Bax, Caspase-3, TUNEL and attenuated neurological deficit in mice with transient MCAO, LY294002 weakened such effect of TSA dramatically. Conclusions: TSA could significantly decrease the neurological deficit and reduce the cerebral infarct volume, oxidative stress, inflammation, as well as apoptosis during cerebral ischemia reperfusion injury, which was achieved by activation of the Akt/GSK-3β signaling pathway.


Assuntos
Animais , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacos , Ataque Isquêmico Transitório/metabolismo , Fármacos Neuroprotetores/farmacologia , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Transdução de Sinais/fisiologia , Ataque Isquêmico Transitório/fisiopatologia , Quinase 3 da Glicogênio Sintase/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C
20.
Acta cir. bras ; 32(6): 429-439, June 2017. graf
Artigo em Inglês | LILACS | ID: biblio-886202

RESUMO

Abstract Purpose: To determine whether dexmedetomidine (DEX) could attenuate acute kidney injury (AKI) induced by ischemia/reperfusion (I/R) in streptozotocin (STZ)-induced diabetic rats. Methods: Four groups each containing six rats were created (sham control(S), diabetes-sham (DS), diabetes I/R (DI/R), and diabetes-I/R-dexmedetomidine (DI/R-DEX). In diabetes groups, single-dose (65 mg/kg) STZ was administered intraperitoneally (i.p.). In Group DI/R, ischemia reperfusion was produced via 25 min of bilateral renal pedicle clamping followed by 48 h of reperfusion. In Group DI/R-DEX, 50 μg/kg dexmedetomidine was administered intraperitoneally 30 minutes before ischemia. Renal function, histology, apoptosis, the levels of TNF-α, IL-1β, and oxidative stress in diabetic kidney were determined. Moreover, expression of P38 mitogen-activated protein kinase (P38-MAPK), phosphorylated-P38-MAPK(p-P38-MAPK) and thioredoxin-interacting protein (TXNIP) were assessed. Results: The degree of renal I/R injury was significantly increased in DI/R group compared with S group and DS group. The levels of TNF-α, IL-1β, oxidative stress and apoptosis were found significantly higher in DI/R Group when compared with S Group and DS Group. The protein expression of p-P38-MAPK and TXNIP were significantly increased after I/R. All these changes were reversed by DEX treatment. Conclusion: The renoprotective effects of DEX-pretreatment which attenuates I/R-induced AKI were partly through inhibition of P38-MAPK activation and expression of TXINP in diabetic kidney.


Assuntos
Animais , Masculino , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Dexmedetomidina/uso terapêutico , Diabetes Mellitus Experimental/complicações , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Ratos Sprague-Dawley , Estreptozocina , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Rim/lesões , Rim/patologia
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