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Cranial radiotherapy is a major treatment for leukemia and brain tumors. Our previous study found abscopal effects of cranial irradiation could cause spermatogenesis disorder in mice. However, the exact mechanisms are not yet fully understood. In the study, adult male C57BL/6 mice were administrated with 20â¯Gy X-ray cranial irradiation (5â¯Gy per day for 4 days consecutively) and sacrificed at 1, 2 and 4 weeks. Tandem Mass Tag (TMT) quantitative proteomics of testis was combined with bioinformatics analysis to identify key molecules and signal pathways related to spermatogenesis at 4 weeks after cranial irradiation. GO analysis showed that spermatogenesis was closely related to oxidative stress and inflammation. Severe oxidative stress occurred in testis, serum and brain, while serious inflammation also occurred in testis and serum. Additionally, the sex hormones related to hypothalamic-pituitary-gonadal (HPG) axis were disrupted. PI3K/Akt pathway was activated in testis, which upstream molecule SCF/C-Kit was significantly elevated. Furthermore, the proliferation and differentiation ability of spermatogonial stem cells (SSCs) were altered. These findings suggest that cranial irradiation can cause spermatogenesis disorder through brain-blood-testicular cascade oxidative stress, inflammation and the secretory dysfunction of HPG axis, and SCF/C-kit drive this process through activating PI3K/Akt pathway.
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Irradiação Craniana , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-kit , Espermatogênese , Animais , Masculino , Espermatogênese/efeitos da radiação , Camundongos , Proteínas Proto-Oncogênicas c-kit/metabolismo , Estresse Oxidativo/efeitos da radiação , Irradiação Craniana/efeitos adversos , Testículo/efeitos da radiação , Testículo/patologia , Transdução de Sinais/efeitos da radiação , Fator de Células-Tronco/metabolismo , InflamaçãoRESUMO
Synthetic di- or multimetallic complexes bearing NxHy nitrogenous ligands in a sulfur-rich coordination environment have attracted considerable attention due to their importance in evaluating the complex mechanism of biological nitrogen fixation. Herein, we report a series of thiolate-bridged dicobalt NxHy species obtained by treatment of CoIIICoIII precursor with hydrazine and its substituted derivatives at ambient temperature. Remarkably, when the substituent is the cyclohexyl group, the resulting species can interconvert through different pathways. This Co2S2 skeleton provides a new model system for obtaining valuable information about the early N2Hx-bound intermediate species during the catalytic cycle of nitrogenase.
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Acrolein is a highly toxic unsaturated aldehyde which is abundant in many circumstances. People exposed to acrolein may have significant clinical relevance in human cardiotoxicity situations. Paeoniflorin (PEF) is a bioactive glucoside isolated from the roots of Paeonia lactiflora Pall. It is reported that PEF performs a beneficial role in cardiovascular system. The aim of the current research was to evaluate the potential protective effect of PEF against acrolein-induced apoptotic damage in H9c2 cardiomyocytes. This study revealed that PEF exerted a protective effect on acrolein-induced cardiomyocyte apoptosis. Furthermore, treatment with acrolein could markedly increase the levels of reactive oxygen species (ROS) and expression of cleavage of caspase-9 and caspase-3 in H9c2 cardiomyocytes, which were significantly reversed by co-treatment with PEF (100uM). These results demonstrated that PEF protects H9c2 cardiomyocytes against acrolein-induced cardiomyocyte injury via decreasing ROS production and down regulating caspases cascade reaction, indicating that PEF is a potential therapeutic agent for cardiac toxic environmental pollutant injury.
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Acroleína/farmacologia , Apoptose/efeitos dos fármacos , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
A base-controlled regiodivergent azidation of trifluoromethyl alkenyl triflates providing either (E)-3-azido-1-aryl-4,4,4-trifluorobut-1-ene (CF3-containing allyl azides) or (Z)-1-azido-1-aryl-4,4,4-trifluorobut-1-ene (CF3-containing alkenyl azides) is described. Catalyzed by Et3N, the azidation of trifluoromethyl alkenyl triflates with TMSN3 gave CF3-containing allyl azides. On the other hand, using stoichiometric DBU, the regioisomeric azidation products, CF3-containing alkenyl azides, were obtained in good yield. A further transformation for CF3-containing amines, triazoles, and azirines highlights the practical applicability of this transition-metal-free protocol.
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OBJECTIVE: To observe clinical effects of three-dimensional conformal radiotherapy combined with Tegafur Gimeracil Oteracil Potassium chemotherapy in the treatment of patients with recurrent esophagus cancer. METHODS: One hundred and twelve senile patients who suffered from esophagus cancer were selected and randomly divided into two groups, namely, observation group (56 cases) and control group (56 cases). The observation group adopted three-dimensional conformal radiotherapy combined with Tegafur Gimeracil Oteracil Potassium chemotherapy and the control group adopted three-dimensional conformal radiotherapy only. RESULTS: All patients completed the treatment, with good compliance. Effective rate of the observation group was 82.1%, which was significantly higher than the control group (67.9%), and the difference was statistically significant (P<0.05). Main toxic and side effects of patients of two groups were radiation esophagitis, gastrointestinal reaction, hematologic toxicities and radiative skin reaction. Differences of incidence rates of all types of toxic and side effects were not statistically significant (P>0.05). The one-year and two-year survival rates of patients of the observation group were 80.4% and 53.6%, respectively, while the control group was 55.4% and 30.4%; differences between two groups were statistically significant (P<0.05). CONCLUSION: Three-dimensional conformal radiotherapy combined with Tegafur Gimeracil Oteracil Potassium chemotherapy has definite curative effect in treating patients with recurrent esophagus cancer and can improve survival rate of patients, without increasing adverse reaction.
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MicroRNAs (miRs) are endogenous ≈22-nt non-coding RNAs that participate in the regulation of gene expression at post-transcriptional level. MiR-1 is one of the muscle-specific miRs, aberrant expression of miR-1 plays important roles in many physiological and pathological processes. In this review, we focus on the recent studies about miR-1 in cardiac diseases and cancers. The findings indicate that miR-1 may be a novel, important biomarker, and a potential therapeutic target in cardiac diseases and cancers.
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Hepatocellular carcinoma (HCC), a highly lethal solid tumor, has shown responsiveness to ferroptosis inducers, presenting new avenues in cancer treatment. Our study focuses on the roles of STAT3 and Nf-κB in regulating ferroptosis, particularly their interaction in this process. Using HepG2 cells, we employed specific inhibitors (Stattic for STAT3 and Bay11-7082 for Nf-κB) and a ferroptosis inducer, SSPH I, to dissect their collective impact on ferroptosis. Our findings reveal that inhibiting STAT3 and Nf-κB enhances ferroptosis and cytotoxicity induced by SSPH I. This is mechanistically linked to alterations in iron metabolism-related proteins and GPX4 resulting from SSPH I action, which consequently triggers a STAT3-dependent activation of Nf-κB. The inhibition of STAT3 and Nf-κB led to increased intracellular ROS, MDA, and Fe2+, along with significant GSH depletion, thereby intensifying lipid peroxidation and iron overload in HepG2 cells. This study offers a deeper understanding of the ferroptosis mechanisms in HCC. It highlights the therapeutic potential of targeting STAT3 and Nf-κB pathways to enhance the efficacy of ferroptosis-based treatments.
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Ferroptose , Neoplasias Hepáticas , NF-kappa B , Fator de Transcrição STAT3 , Transdução de Sinais , Humanos , Ferroptose/efeitos dos fármacos , Células Hep G2 , Fator de Transcrição STAT3/metabolismo , NF-kappa B/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Sulfonas/farmacologia , Nitrilas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Óxidos S-Cíclicos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Viscum coloratum (Kom.) Nakai has been traditionally used in China for nearly a thousand years to treat rheumatic diseases. However, its efficacy and mechanisms in treating rheumatoid arthritis (RA) have not been demonstrated. AIM OF THE STUDY: To investigate the anti-arthritic effects and molecular mechanisms of Viscum coloratum (Kom.) Nakai on collagen-induced arthritic mice through network pharmacology technology and experimental validation. MATERIALS AND METHODS: First, the main ingredients of the extract of Viscum coloratum (Kom.) Nakai (EVC) were identified through chemical composition characterization using Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS). Then, the collagen-induced arthritis (CIA) model was established in DBA/1 J mice and the ameliorative effects of EVC on the progression of CIA mice were evaluated by oral treatment with different doses of the EVC for 28 days. After that, cytokine antibody microarray assay was used to detect the levels of multiple inflammation-related cytokines and chemokines in each group, and performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) enrichment analysis. Subsequently, the potential target for the effective chemical components of EVC in treating RA was identified using various databases. Additionally, a drug-disease target protein-protein interaction network (PPI) was conducted using Cytoscape for visualization and clustering, while GO and KEGG enrichment analyses were performed with the Metascape database. Finally, identified phenotypes and targets by network pharmacology analysis were experimentally validated in vivo. RESULTS: Treatment with EVC significantly suppressed the severity of CIA with a dramatic reduction of paw swelling, arthritis index, levels of IgGs (IgG, IgG1, IgG2a, and IgG2b), multi-inflammation-related cytokines and chemokines on the progression of CIA. Histopathological examinations showed EVC could markedly inhibit inflammatory cell infiltration, tartrate-resistant acid phosphatase (TRAP) activity of osteoclast, and bone destruction. Furthermore, GO and KEGG enrichment analyses revealed that EVC could ameliorate RA by inhibiting osteoclast differentiation and regulating multiple signaling pathways including Osteoclast differentiation, IL-17, and TNF. PPI network analysis demonstrated that AKT1, MMP9, MAPK3, and other genes were highly related to EVC in treating RA. Finally, we proved that EVC could inhibit the expression of NFTAc1, MMP9, Cathepsin K, and AKT which were closely related to osteoclast activity. CONCLUSIONS: EVC could treat RA through multiple components, multiple targets, and multiple pathways. The present study demonstrated the therapeutic efficacy of EVC and its molecular mechanisms in treating RA, indicating that it would be a potent candidate as a novel botanical drug for further investigation.
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Artrite Experimental , Artrite Reumatoide , Medicamentos de Ervas Chinesas , Viscum , Camundongos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Metaloproteinase 9 da Matriz , Cromatografia Líquida , Viscum/química , Espectrometria de Massas em Tandem , Camundongos Endogâmicos DBA , Citocinas/genética , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Quimiocinas , Colágeno , Medicamentos de Ervas Chinesas/efeitos adversosRESUMO
OBJECTIVE: To explore the inhibitory effect of calcitonin gene-related peptide (CGRP) on cardiac fibroblast proliferation and collagen synthesis induced by isoprenaline and the underlying mechanism. METHODS: The primary cultured cardiac fibroblasts were incubated with isoprenaline (10(-5) mol/L) for 48 h after pretreatment with CGRP (10(-8) or 10(-7) mol/L) for 1 h. Cell activity was detected by MTT. The mRNA expression of collagen (types I and III) and connective tissue growth factor (CTGF) was determined by RT-PCR, and the levels of intracellular ROS were determined by DCFH-DA fluorescent probe. RESULTS: Isoprenaline significantly promoted fibroblast proliferation and up-regulated collagen (types I and III) and CTGF mRNA expression concomitantly with an increase in ROS production, which were attenuated by CGRP. The effect of CGRP on cardiac fibroblasts was inhibited by CGRP8-37, a selective antagonist of CGRP receptor. CONCLUSION: CGRP is able to protect cardiac fibroblasts against isoprenaline-induced proliferation and collagen expression, which might be related to the down-regulation of CTGF expression through inhibition of ROS production.
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Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Proliferação de Células/efeitos dos fármacos , Fibroblastos/citologia , Isoproterenol/antagonistas & inibidores , Miócitos Cardíacos/citologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Isoproterenol/farmacologia , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is a common type of solid liver carcinoma. Regulating ferroptosis is important for the treatment of HCC. SSPH I is an anti-HCC steroidal saponin isolated from Schizocapsa plantaginea Hance. In this study, we found that SSPH I exerted significant anti-proliferation and anti-migration effects on HepG2 cell, ferroptosis inhibitor ferrostatin-1 or iron chelator ciclopirox partly attenuated the effect of SSPH I. SSPH I also induced apoptosis and G2/M phase cell cycle arrest. ROS accumulation, glutathione depletion and malondialdehyde accumulation were detected after SSPH I treatment, which leads to lipid peroxidation. Ferrostatin-1 or ciclopirox showed a significant antagonist effect towards SSPH I induced lipid peroxidation. Furthermore, typical morphologic changes of ferroptosis, such as increasing density of mitochondrial membrane and reduction of mitochondrial cristae were observed in HepG2 cells after SSPH I treatment. SSPH I does not regulate the xCT protein. Interestingly, SSPH I elevated the expression levels of SLC7A5, which is the negative regulator of ferroptosis. In contrast, SSPH I upregulated the expression of TFR and Fpn proteins, leading to the accumulation of Fe2+. Ferrostatin-1 and ciclopirox presented a similar antagonist effect on SSPH I. In conclusion, our research first reveals that SSPH I induced ferroptosis in HepG2 cells. In addition, our results suggest that SSPH I induces ferroptosis by causing iron overload in HepG2 cells.
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Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Saponinas , Humanos , Ferroptose/fisiologia , Células Hep G2 , Saponinas/farmacologia , Ciclopirox , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/patologia , Ferro/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Recently, some studies suggested that inhibition of Rho-kinase (ROCK) prevented cerebral ischemia injury through inhibiting inflammatory reaction, increasing cerebral blood flow, modulating the neuronal actin cytoskeleton polymerization, and preventing tau hyperphosphorylation and p25/CDK5 increase. However, there is little information regarding the effects of ROCK inhibitor on the neuronal apoptosis in ischemic brain injury. In this study, we determined whether ROCK inhibitor, fasudil, inhibited ischemic neuronal apoptosis through phosphatase and tensin homolog deleted on chromosome10 (PTEN)/Akt/signal pathway in vivo. Adult male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion. Rats received ROCK inhibitor, fasudil (10 mg/kg), at 30 min before middle cerebral artery occlusion. The infarct area, neuronal apoptosis and caspase-3 activity was significantly decreased by fasudil with improvement of neurological deterioration. However, the beneficial effects of fasudil were attenuated by the co-application of LY294002 (PI3K inhibitor). Fasudil maintained postischemic Akt activity at relatively proper level and decreased the augmentation of PTEN and ROCK activity in the penumbra area. Furthermore, fasudil inhibited attenuation of GSK-ß and Bad phosphorylation in the penumbra area. In conclusion, the findings provide another consideration that fasudil protects the brain against ischemia injury through decreasing neuronal apoptosis and reveals the link between the ROCK inhibition and the PTEN/Akt pathway.
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1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Encéfalo/enzimologia , Isquemia Encefálica/enzimologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , PTEN Fosfo-Hidrolase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Ratos Sprague-Dawley , Quinases Associadas a rho/metabolismoRESUMO
Increased intracellular reactive oxygen species (ROS) are involved in doxorubicin (DOX)-induced myocardial cell apoptosis, and paeoniflorin (PEF) has been shown to exert an antioxidant effect. The aim of the present study was to explore the protective effect of PEF on DOX-induced myocardial cell apoptosis and the underlying mechanisms. In cultured H9c2 cells, different concentrations (1, 10, or 100 µmol/L) of PEF was added for 2 h prior to exposure to DOX (5 µmol/L) for 24 h. Cell apoptosis was evaluated by hoechst 33342 staining, and caspase-3 expression and activity. The mRNA and protein expression of NADPH oxidase (NOX) 2 and NOX4 was determined by real-time polymerase chain reaction and Western blot, respectively. Intracellular ROS and NOX activity were measured by assay kit. The results showed that DOX significantly increased myocardial cell apoptosis, increased caspase-3 expression and activity concomitantly with enhanced ROS production, and increased NOX2, NOX4 mRNA and protein expression, and NOX activity. These effects were remarkably inhibited by pretreatment of PEF. Our results suggested that PEF has a protective effect against DOX-induced myocardial cell apoptosis through a mechanism involving a decrease in ROS production by inhibition of NOX2, NOX4 expression, and NOX activity.
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Antibióticos Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Benzoatos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Doxorrubicina/toxicidade , Glucosídeos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , NADPH Oxidases/antagonistas & inibidores , Animais , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Células Cultivadas , Interações Medicamentosas , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Monoterpenos , Miócitos Cardíacos/metabolismo , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , RNA Mensageiro/genética , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Metal-organic frameworks (MOFs) possess excellent advantages, such as high porosity, large specific surface area, and an adjustable structure, showing good potential for applications in gas adsorption and separation, catalysis, conductivity, sensing, magnetism, etc. However, they still suffer from significant limitations in terms of the scale-up synthesis and shaping, hindering the realization of large-scale commercial applications. Despite some attempts having been devoted to addressing this, challenges remain. In this paper, we outline the advantages and drawbacks of existing synthetic routes such as electrochemistry, microwave, ultrasonic radiation, green solvent reflux, room temperature stirring, steam-assisted transformation, mechanochemistry, and fluid chemistry in terms of scale-up production. Then, the shaping methods of MOFs such as extrusion, mechanical compaction, rolling granulation, spray drying, gel technology, embedded granulation, phase inversion, 3D printing and other shaping methods for the preparation of membranes, coatings and nanoparticles are discussed. Finally, perspectives on the large-scale synthesis and shaping of MOFs are also proposed. This work helps provide in-depth insight into the scale-up production and shaping process of MOFs and boost commercial applications of MOFs.
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PURPOSE: This study investigated the effects of oral administration of Clostridium butyricum (C. butyricum) on inflammation, oxidative stress, and gut flora in rats with hepatic ischemia reperfusion injury (HIRI). METHODS: The rats from C. butyricum group were given C. butyricum for 5 days. Then, hepatic ischemia for 30 min and reperfusion for 6 h were performed in all the rats. After the animals were sacrificed, alanine transaminase (ALT), aspartate aminotransferase (AST), lipopolysaccharide (LPS) in serum, short-chain fatty acids (SCFAs), and gut microbiota composition in feces, and malondialdehyde (MDA), glutathione (GSH), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), Toll-like receptor 4 (TLR4), nuclear factor-kappa Bp65 (NF-κBp65) and histological analysis in the liver were performed. RESULTS: The rats given C. butyricum showed decreased ALT, AST, LPS, and MDA; improved GSH and histological damage; changes in SCFAs; declined TNF-α, IL-6, TLR4, and pNF-κBp65/NF-κBp65; and changes in the gut microbial composition, which decreased the Firmicutes/Bacteroidetes ratio and increased the relative abundance (RA) of probiotics. CONCLUSIONS: C. butyricum supplementation protected against HIRI by regulating gut microbial composition, which contributed to the decreased LPS and attenuation of inflammation and oxidative stress. These indicate C. butyricum may be a potent clinical preoperative dietary supplement for HIRI.
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Clostridium butyricum , Probióticos , Traumatismo por Reperfusão , Ratos , Animais , Clostridium butyricum/fisiologia , Receptor 4 Toll-Like , Lipopolissacarídeos , Fator de Necrose Tumoral alfa , Interleucina-6 , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/patologia , Fígado/patologia , Aspartato Aminotransferases , Alanina Transaminase , Glutationa , Probióticos/farmacologia , Inflamação/patologiaRESUMO
OBJECTIVE: To explore the inhibitory effect of calcitonin gene-related peptide (CGRP) on cardiomyocyte apoptosis and the underlying mechanism. METHODS: In cultured rat cardiomyocytes, apoptosis was induced by the incubation of isoprenaline (10(-5) mol/L) for 48 h. CGRP (10(-8) or 10(-7) mol/L) was administrated for 1 h before incubating isoprenaline to evaluate its effect on cardiomyocyte apoptosis. At the end of the drug treatment, the rate of apoptotic cells and intracellular reactive oxygen species (ROS) were determined, and RNA was extracted to examine the expression of microRNA-1 and microRNA-133a. RESULTS: Isoprenaline significantly increased the rate of apoptotic cells and intracellular ROS production concomitantly with the increased microRNA-1 expression and the decreased microRNA-133a expression, which were inhibited by pretreatment with CGRP. The effects of CGRP were reversed by CGRP receptor antagonist. CONCLUSION: CGRP can inhibit the isoprenaline-induced cardiomyocyte apoptosis. The beneficial effect of CGRP is related to regulating microRNA-1 and microRNA-133a expression through the prevention of isoprenaline-induced ROS production.
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Apoptose/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Isoproterenol/antagonistas & inibidores , MicroRNAs/metabolismo , Miócitos Cardíacos/citologia , Animais , Células Cultivadas , Isoproterenol/farmacologia , MicroRNAs/genética , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung carcinoma (NSCLC), which characterized by insensitive to conventional radiotherapy and chemotherapy and poor prognosis. Except MET exon 14 alterations and other oncogene mutations, PSC commonly harbor high tumor mutational burden (TMB) and high level of PD-L1, which provide new therapeutic opportunities. Toripalimab (JS001) is IgG4 monoclonal antibody targeting PD-1, which has been approved for treatment of patients with metastatic melanoma after previous systemic therapy. PD-1 combined with radiotherapy has been tried in several cancer types. CASE PRESENTATION: We reported a case of a PSC patient with PD-L1 overexpression responding to toripalimab and after progression the patients also benefits from toripalimab combined with local radiotherapy, which provides a promising option for PSC patients. CONCLUSION: This case provides the evidence of the effective role of toripalimab and PD-1 combined with local radiotherapy in PSC patients, which was the first application as far as we know.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Doenças Raras/tratamento farmacológico , Idoso , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Indóis/uso terapêutico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Taxa de Mutação , Quinolinas/uso terapêutico , Doenças Raras/genética , Doenças Raras/metabolismo , Resultado do TratamentoRESUMO
Dysfunction of capsaicin-sensitive sensory nerves is involved in cardiac remodeling, and rutaecarpine has been shown to exert a beneficial effect on cardiac function through activating the sensory nerves. This study was conducted to explore the potential inhibitory effect of rutaecarpine on cardiac remodeling and the underlying mechanisms. A rat cardiac remodeling model was established by injection of isoprenaline (5 mg/kg per day, s.c.) for 10 days. Rutaecarpine (10 or 40 mg/kg, i.g.) was coadministrated with isoprenaline to evaluate the effect of rutaecarpine on cardiac remodeling. After echocardiographic analysis was performed, blood samples were collected to quantify calcitonin gene-related peptide (CGRP), dorsal root ganglia were isolated for examining CGRP mRNA expression, and the hearts were weighed and saved for evaluating the parameters related to apoptosis and hypertrophy. Isoprenaline significantly increased the ratio of left ventricle weight to body weight, the cross-sectional area of cardiomyocytes, cardiac apoptosis, and collagen deposition concomitantly with decreased CGRP production, which were reversed by rutaecarpine treatment. The beneficial effects of rutaecarpine were attenuated by pretreatment with capsaicin, which selectively depleted CGRP. These results suggest that rutaecarpine was able to reverse isoprenaline-induced cardiac remodeling through stimulating CGRP production.
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Peptídeo Relacionado com Gene de Calcitonina/biossíntese , Ventrículos do Coração/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Isoproterenol/farmacologia , Quinazolinas/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/sangue , Ecocardiografia , Gânglios Espinais/metabolismo , Ventrículos do Coração/inervação , Marcação In Situ das Extremidades Cortadas , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: To determine the effect of losartan on vascular remodeling and the underlying mechanism in spontaneously hypertensive rats(SHR). METHODS: SHR of 12 weeks old were given losartan orally [0, 15, 30 mg/(kg.d), n=12]. The tail arterial pressure was measured every week. Eight weeks later, the pathological changes and p22(phox) expression in the thoracic aorta, the activity of catalase (CAT), the contents of H(2)O(2) and Ang II in the plasma were evaluated. RESULTS: Blood pressure was increased in the SHR accompanied by the thickened wall and increased p22(phox) expression in the thoracic aorta. The plasma levels of H(2)O(2) and Ang II were elevated while the CAT level was decreased in the SHR. Administration of losartan reversed the thickened wall and increased the CAT activity concomitantly with the decreased plasma levels of H(2)O(2) and p22(phox) expression in the SHR. The plasma level of Ang II increased after the losartan treatment. CONCLUSION: Oxidative stress induces the vascular remodeling of the aorta in the SHR. Losartan can reverse the vascular remodeling through down-regulating p22(phox) expression and inhibiting the oxidative stress.
Assuntos
Anti-Hipertensivos/uso terapêutico , Aorta/patologia , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Losartan/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Angiotensina II/sangue , Animais , Anti-Hipertensivos/farmacologia , Aorta/fisiopatologia , Catalase/metabolismo , Peróxido de Hidrogênio/sangue , Hipertensão/fisiopatologia , Losartan/farmacologia , Masculino , NADPH Oxidases/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
At low temperature, interaction of the thiolate-bridged dicobalt carbonyl complex [Cp*Co(i)(µ-SEt)2(CO)CoCp*][I] (Cp* = η5-C5Me5) (1) with NH3 resulted in the C-N coupling of the coordinated CO and amido group that originate from ammonia activation to afford a dicobalt formylamino complex [Cp*Co(µ-SEt)2(µ-η1:η1-O[double bond, length as m-dash]CNH2)CoCp*][I] (2). Interestingly, at relatively high temperatures, the labile CO ligand was replaced by NH3 to give a thiolate-bridged dicobalt ammonia complex [Cp*Co(i)(µ-SEt)2(NH3)CoCp*][I] (3). Subsequently, in the presence of the dehalogenation reagent AgPF6, the Co2S2 scaffold can simultaneously activate NH3 and MeCN to produce the complex [Cp*Co(MeCN)(µ-SEt)2(NH3)CoCp*][PF6]2 (4). Furthermore, in the presence of NaOEt, the facile occurrence of the intramolecular cyclization led to the formation of acetamidino-bridged dicobalt complex [Cp*Co(µ-SEt)2(µ-η1:η1-NH(CCH3)NH)CoCp*][PF6] (5), which may proceed through the nucleophilic attack of amido from NH3 to coordinated MeCN followed by the hydrogen atom transfer process. In the presence of MeCN, treatment of 5 with HBF4 released the corresponding [MeC(NH2)NH2]BF4; meanwhile, the [Co2S2] core structural scaffold remained. In this Co2S2 reaction system, the cooperative activation effect between the two cobalt centers plays an important role for NH3 activation and functionalization.
RESUMO
The Aquilaria sinensis (Lour.) Gilg (CX)-Aucklandia costus Falc. (MX) herbal pair is frequently used in traditional Chinese medicine prescriptions for treating depression. The volatile oil from CX and MX has been shown to have good pharmacological activities on the central nervous system, but its curative effect and mechanism in the treatment of depression are unclear. Therefore, the antidepressant effect of the volatile oil from CX-MX (CMVO) was studied in chronic unpredictable mild stress (CUMS) rats. The suppressive effects of CMVO (25, 50, 100 µL/kg) against CUMS-induced depression-like behavior were evaluated using the forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT). The results showed that CMVO exhibited an antidepressant effect, reversed the decreased sugar preference in the SPT and prolongation of immobility time in the FST induced by CUMS, increased the average speed, time to enter the central area, total moving distance, and enhanced the willingness of rats to explore the environment in the OFT. Inhalational administration of CMVO decreased levels of adrenocorticotropic hormone and corticosterone in serum and the expression of corticotropin-releasing hormone mRNA in the hypothalamus, which indicated regulation of over-activation of the hypothalamic-pituitary-adrenal (HPA) axis. In addition, CMVO restored levels of 5-hydroxytryptamine (5-HT), dopamine, norepinephrine and acetylcholine in the hippocampus. The RT-PCR and immunohistochemistry results showed that CMVO up-regulated the expression of 5-HT1A mRNA. This study demonstrated the antidepressant effect of CMVO in CUMS rats, which was possibly mediated via modulation of monoamine and cholinergic neurotransmitters and regulation of the HPA axis.