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1.
Article in English | WPRIM | ID: wpr-878318

ABSTRACT

Objective@#Antimony (Sb) has recently been identified as a novel nerve poison, although the cellular and molecular mechanisms underlying its neurotoxicity remain unclear. This study aimed to assess the effects of the nuclear factor kappa B (NF-κB) signaling pathway on antimony-induced astrocyte activation.@*Methods@#Protein expression levels were detected by Western blotting. Immunofluorescence, cytoplasmic and nuclear fractions separation were used to assess the distribution of p65. The expression of protein in brain tissue sections was detected by immunohistochemistry. The levels of mRNAs were detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and reverse transcription-polymerase chain reaction (RT-PCR).@*Results@#Antimony exposure triggered astrocyte proliferation and increased the expression of two critical protein markers of reactive astrogliosis, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP), indicating that antimony induced astrocyte activation @*Conclusion@#Antimony activated astrocytes by activating the NF-κB signaling pathway.


Subject(s)
Animals , Antimony/toxicity , Astrocytes/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Glial Fibrillary Acidic Protein/metabolism , MAP Kinase Kinase Kinases , Male , Mice, Inbred ICR , NF-kappa B/metabolism , Nitric Oxide Synthase Type II/metabolism , Rats , Signal Transduction/drug effects
2.
Article in English | WPRIM | ID: wpr-881040

ABSTRACT

As a representative drug for the treatment of severe community-acquired pneumonia and sepsis, Xuebijing (XBJ) injection is also one of the recommended drugs for the prevention and treatment of coronavirus disease 2019 (COVID-19), but its treatment mechanism for COVID-19 is still unclear. Therefore, this study aims to explore the potential mechanism of XBJ injection in the treatment of COVID-19 employing network pharmacology and molecular docking methods. The corresponding target genes of 45 main active ingredients in XBJ injection and COVID-19 were obtained by using multiple database retrieval and literature mining. 102 overlapping targets of them were screened as the core targets for analysis. Then built the PPI network, TCM-compound-target-disease, and disease-target-pathway networks with the help of Cytoscape 3.6.1 software. After that, utilized DAVID to perform gene ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to predict the action mechanism of overlapping targets. Finally, by applying molecular docking technology, all compounds were docked with COVID-19 3 CL protease(3CLpro), spike protein (S protein), and angiotensin-converting enzyme II (ACE2). The results indicated that quercetin, luteolin, apigenin and other compounds in XBJ injection could affect TNF, MAPK1, IL6 and other overlapping targets. Meanwhile, anhydrosafflor yellow B (AHSYB), salvianolic acid B (SAB), and rutin could combine with COVID-19 crucial proteins, and then played the role of anti-inflammatory, antiviral and immune response to treat COVID-19. This study revealed the multiple active components, multiple targets, and multiple pathways of XBJ injection in the treatment of COVID-19, which provided a new perspective for the study of the mechanism of traditional Chinese medicine (TCM) in the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Biological Availability , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Drugs, Chinese Herbal/therapeutic use , Humans , Medicine, Chinese Traditional/methods , Molecular Docking Simulation/methods , Protein Interaction Mapping/methods , SARS-CoV-2/physiology , Signal Transduction/drug effects , Spike Glycoprotein, Coronavirus/metabolism
3.
Article in English | WPRIM | ID: wpr-881038

ABSTRACT

Due to the poor repair ability of cartilage tissue, regenerative medicine still faces great challenges in the repair of large articular cartilage defects. Quercetin is widely applied as a traditional Chinese medicine in tissue regeneration including liver, bone and skin tissues. However, the evidence for its effects and internal mechanisms for cartilage regeneration are limited. In the present study, the effects of quercetin on chondrocyte function were systematically evaluated by CCK8 assay, PCR assay, cartilaginous matrix staining assays, immunofluorescence assay, and western blotting. The results showed that quercetin significantly up-regulated the expression of chondrogenesis genes and stimulated the secretion of GAG (glycosaminoglycan) through activating the ERK, P38 and AKT signalling pathways in a dose-dependent manner. Furthermore, in vivo experiments revealed that quercetin-loaded silk protein scaffolds dramatically stimulated the formation of new cartilage-like tissue with higher histological scores in rat femoral cartilage defects. These data suggest that quercetin can effectively stimulate chondrogenesis in vitro and in vivo, demonstrating the potential application of quercetin in the regeneration of cartilage defects.


Subject(s)
Animals , Cartilage/cytology , Chondrocytes/drug effects , Chondrogenesis/drug effects , Extracellular Matrix/metabolism , Quercetin/pharmacology , Rats , Signal Transduction/drug effects , Tissue Scaffolds
4.
Article in English | WPRIM | ID: wpr-881035

ABSTRACT

Taurochenodeoxycholic acid (TCDCA) is one of the main effective components of bile acid, playing critical roles in apoptosis and immune responses through the TGR5 receptor. In this study, we reveal the interaction between TCDCA and TGR5 receptor in TGR5-knockdown H1299 cells and the regulation of inflammation via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding (CREB) signal pathway in NR8383 macrophages. In TGR5-knockdown H1299 cells, TCDCA significantly activated cAMP level via TGR5 receptor, indicating TCDCA can bind to TGR5; in NR8383 macrophages TCDCA increased cAMP content compared to treatment with the adenylate cyclase (AC) inhibitor SQ22536. Moreover, activated cAMP can significantly enhance gene expression and protein levels of its downstream proteins PKA and CREB compared with groups of inhibitors. Additionally, TCDCA decreased tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-12 through nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity. PKA and CREB are primary regulators of anti-inflammatory and immune response. Our results thus demonstrate TCDCA plays an essential anti-inflammatory role via the signaling pathway of cAMP-PKA-CREB induced by TGR5 receptor.


Subject(s)
Animals , Cell Line , Cyclic AMP/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Cytokines/metabolism , Humans , Inflammation , Macrophages , Rats , Receptors, G-Protein-Coupled/metabolism , Signal Transduction/drug effects , Taurochenodeoxycholic Acid/pharmacology
5.
Article in English | WPRIM | ID: wpr-880306

ABSTRACT

BACKGROUND@#Resveratrol has been shown to inhibit platelet aggregation. However, the mechanism for this action of resveratrol remains to be clarified. The purpose of this study was to elucidate the Ca@*METHODS@#Ca@*RESULTS@#Thapsigargin-induced Ca@*CONCLUSIONS@#The results suggest that resveratrol inhibits thrombin-induced platelet aggregation through decreasing Ca


Subject(s)
Antioxidants/administration & dosage , Calcium/physiology , Humans , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Resveratrol/pharmacology , Signal Transduction/drug effects
6.
Article in Chinese | WPRIM | ID: wpr-879933

ABSTRACT

OBJECTIVE@#To explore the mechanism of Flos Puerariae and Semen Hoveniae in treatment of alcoholic liver injury (ALI) based on network pharmacology and molecular docking.@*METHODS@#The information of chemical constituents and targets of Flos Puerariae and Semen Hoveniae was collected from TCMSP and Swiss databases, and the threshold values of oral bioavailability (OB) ≥ 30%, drug likeness (DL) ≥0.18 were used to screen the potential active compounds. The GeneCard and DrugBank databases were used to obtain the targets corresponding to ALI. The common targets were queried using Venn Diagram, and the network of PPI and Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed through DAVID and Reactome database. Autodock Vina software was used for molecular docking of potential ingredients and key targets.@*RESULTS@#A total of 21 potential active compounds and 431 therapeutic targets were gathered in Flos Puerariae and Semen Hoveniae, which involved 273 biological functions, 90 KEGG pathways and 362 Reactome pathways. The GO functions involved protein binding, ATP binding, etc.; the KEGG pathways mainly included PI3K-Akt signaling pathway and TNF signaling pathway; the Reactome pathways contained signal transduction and immune system, etc. The results of molecular docking showed that 21 potential active ingredients had good affinity with the core targets Akt1, TP53 and IL-6.@*CONCLUSIONS@#The network pharmacology and molecular docking analysis demonstrate the synergetic effect of Flos Puerariae and Semen Hoveniae with multi-compounds, multi-targets and multi-pathways in the treatment of ALI; and also predict the possible medicinal substance, key targets and pathways, which provides clues for the new drug development and mechanism research.


Subject(s)
Animals , Computer Simulation , Drugs, Chinese Herbal/therapeutic use , Lepidoptera/chemistry , Liver/drug effects , Liver Diseases, Alcoholic/therapy , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Plant Extracts/therapeutic use , Rhamnaceae/chemistry , Signal Transduction/drug effects
7.
Article in Chinese | WPRIM | ID: wpr-879924

ABSTRACT

Endothelial progenitor cells (EPCs) play an important role in diabetic vascular complications. A large number of studies have revealed that some clinical antihyperglycemics can improve the complications of diabetes by regulating the function of EPCs. Metformin can improve EPCs function in diabetic patients by regulating oxidative stress level or downstream signaling pathway of adenosine monophosphate activated protein kinase; Pioglitazone can delay the aging of EPCs by regulating telomerase activity; acarbose, sitagliptin and insulin can promote the proliferation, migration and adhesion of EPCs. In addition to lowering blood glucose, the effects of antihyperglycemics on EPCs may also be one of the mechanisms to improve the complications of diabetes. This article reviews the research progress on the regulation of EPC proliferation and function by antihyperglycemics.


Subject(s)
Cell Movement/drug effects , Cells, Cultured , Endothelial Progenitor Cells/drug effects , Humans , Hypoglycemic Agents/pharmacology , Signal Transduction/drug effects
8.
Biol. Res ; 53: 28, 2020. graf
Article in English | LILACS | ID: biblio-1124213

ABSTRACT

BACKGROUND: Kidney ischemia-reperfusion injury is a common pathophysiological phenomenon in the clinic. A large number of studies have found that the tyrosine protein kinase/signal transducer and activator of transcription (JAK/STAT) pathway is involved in the development of a variety of kidney diseases and renal protection associated with multiple drugs. Edaravone (EDA) is an effective free radical scavenger that has been used clinically for the treatment of postischemic neuronal injury. This study aimed to identify whether EDA improved kidney function in rats with ischemia-reperfusion injury by regulating the JAK/STAT pathway and clarify the underlying mechanism. METHODS: Histomorphological analysis was used to assess pathological kidney injury, and mitochondrial damage was observed by transmission electron microscopy. Terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL) staining was performed to detect tubular epithelial cell apoptosis. The expression of JAK2, P-JAK2, STAT3, P-STAT3, STAT1, P-STAT1, BAX and Bcl-2 was assessed by western blotting. Mitochondrial function in the kidney was assessed by mitochondrial membrane potential (ΔψM) measurement. RESULTS: The results showed that EDA inhibited the expression of p-JAK2, p-STAT3 and p-STAT1, accompanied by downregulation of the expression of Bax and caspase-3, and significantly ameliorated kidney damage caused by ischemia-reperfusion injury (IRI). Furthermore, the JC-1 dye assay showed that edaravone attenuated ischemia-reperfusion-induced loss of kidney (ΔψM). CONCLUSION: Our findings indicate that EDA protects against kidney damage caused by ischemia-reperfusion through JAK/STAT signaling, inhibiting apoptosis and improving mitochondrial injury.


Subject(s)
Animals , Male , Rats , Reperfusion Injury/drug therapy , Free Radical Scavengers/pharmacology , Edaravone/pharmacology , Signal Transduction/drug effects , Rats, Sprague-Dawley , Apoptosis , STAT Transcription Factors/drug effects , Janus Kinases/drug effects , Mitochondria
9.
Braz. j. med. biol. res ; 53(2): e8793, 2020. tab, graf
Article in English | LILACS | ID: biblio-1055493

ABSTRACT

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.


Subject(s)
Animals , Male , Rats , Apoptosis/drug effects , Cardiomegaly/prevention & control , TOR Serine-Threonine Kinases/metabolism , Fumarates/administration & dosage , Amides/administration & dosage , Fibrosis/chemically induced , Fibrosis/prevention & control , Angiotensin II/pharmacology , Signal Transduction/drug effects , Blotting, Western , Rats, Sprague-Dawley , Cardiomegaly/chemically induced , Cardiomegaly/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Disease Models, Animal , TOR Serine-Threonine Kinases/drug effects , Flow Cytometry , Isoproterenol/pharmacology
10.
Acta cir. bras ; 34(11): e201901104, Nov. 2019. graf
Article in English | LILACS | ID: biblio-1054677

ABSTRACT

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.


Subject(s)
Animals , Male , Cardiotonic Agents/pharmacology , Myocardial Reperfusion Injury/prevention & control , NF-kappa B/drug effects , Genistein/pharmacology , Toll-Like Receptor 4/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/drug effects , Aspartate Aminotransferases/blood , Reference Values , Myocardial Reperfusion Injury/metabolism , Signal Transduction/drug effects , Blotting, Western , Reproducibility of Results , Cytokines/blood , NF-kappa B/metabolism , Rats, Sprague-Dawley , Creatine Kinase/blood , Lactate Dehydrogenases/blood , Toll-Like Receptor 4/metabolism , Anti-Inflammatory Agents/pharmacology
11.
Electron. j. biotechnol ; 38: 27-31, Mar. 2019. graf, ilus
Article in English | LILACS | ID: biblio-1051305

ABSTRACT

BACKGROUND: Oral cancer is one of the common malignant tumors of the head and neck. However, current treatments have numerous side effects, and drugs from natural sources may have better therapeutic potential. This research investigated the induction of apoptosis by α-hederin (α-HN), a constituent of Pulsatilla chinensis (Bunge) Regel, in the oral cancer cell line SCC-25 and its underlying mechanism. RESULTS: SCC-25 cells were treated with 50, 100, and 200 µmol/L α-HN. Cell proliferation; extent of apoptosis; activities of caspases-3, 8, and 9; and the expression of Bcl-2, Bax, phosphorylated (p)-phosphoinositide 3-kinase (PI3K), p-Akt, and p-mammalian target of rapamycin (mTOR) proteins were determined using the 3-(4,5)-2-thiazole-(2,5)-diphenyl tetrazolium bromide, flow cytometry, caspase activity detection kits, and western blot assays, respectively. The results showed that the proliferation of SCC-25 cells in the α-HN-treated groups decreased significantly, and the inhibitory effect was time and concentration dependent. Compared with cells in the control group, the extent of apoptosis increased significantly, caspase-3 and -9 activities were significantly enhanced, and the Bcl-2 level was lowered and the Bax level was elevated significantly in SCC-25 cells treated with α-HN for 48 h (P b 0.05). The expression of p-PI3K, p-Akt, and p-mTOR was also significantly lower in SCC-25 cells treated with α-HN than that in the control group (P b 0.05). CONCLUSION: These results indicate that α-HN can inhibit proliferation and induce apoptosis of SCC-25 cells and may exert these effects by inhibiting the PI3K/Akt/mTOR signaling pathway.


Subject(s)
Oleanolic Acid/analogs & derivatives , Saponins/pharmacology , Mouth Neoplasms/metabolism , Apoptosis/drug effects , Oleanolic Acid/metabolism , Oleanolic Acid/pharmacology , Saponins/metabolism , Signal Transduction/drug effects , Cell Survival , Blotting, Western , Phosphatidylinositol 3-Kinases/metabolism , Caspases , Pulsatilla , Cell Proliferation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , Flow Cytometry , Head and Neck Neoplasms/metabolism
12.
Rev. bras. anestesiol ; 69(1): 48-57, Jan.-Feb. 2019. tab, graf
Article in English | LILACS | ID: biblio-977418

ABSTRACT

Abstract Background: Anesthetic pre-conditioning attenuates inflammatory response during ischemia-reperfusion lung injury. The molecular mechanisms to explain it are not fully understood. The aim of our investigation was to analyze the molecular mechanism that explain the anti-inflammatory effects of anesthetic pre-conditioning with sevoflurane focusing on its effects on MAPKs (mitogen-activated protein kinases), NF-κB (nuclear factor kappa beta) pathways, and apoptosis in an experimental lung autotransplant model. Methods: Twenty large white pigs undergoing pneumonectomy plus lung autotransplant were divided into two 10-member groups on the basis of the anesthetic received (propofol or sevoflurane). Anesthetic pre-conditioning group received sevoflurane 3% after anesthesia induction and it stopped when one-lung ventilation get started. Control group did not receive sevoflurane in any moment during the whole study period. Intracellular signal-transduction pathways (MAPK family), transcription factor (NF-κB), and apoptosis (caspases 3 and 9) were analyzed during experiment. Results: Pigs that received anesthetic pre-conditioning with sevoflurane have shown significant lower values of MAPK-p38, MAPK-P-p38, JNK (c-Jun N-terminal kinases), NF-κB p50 intranuclear, and caspases (p < 0.05) than pigs anesthetized with intravenous propofol. Conclusions: Lung protection of anesthetic pre-conditioning with sevoflurane during experimental lung autotransplant is, at least, partially associated with MAPKs and NF κB pathways attenuation, and antiapoptotic effects.


Resumo Justificativa: O pré-condicionamento anestésico atenua a resposta inflamatória durante a lesão de isquemia-reperfusão do pulmão. Os mecanismos moleculares para explicá-lo não são totalmente compreendidos. O objetivo de nossa investigação foi analisar o mecanismo molecular que explica os efeitos anti-inflamatórios do pré-condicionamento anestésico com sevoflurano, enfocar seus efeitos sobre as proteínas quinases ativadas por mitógenos (MAPKs), o fator nuclear kappa beta (NF-κB) e a apoptose em modelo experimental de autotransplante pulmonar. Métodos: Vinte porcos Large White submetidos à pneumonectomia e autoimplante de pulmão foram divididos em dois grupos de 10 membros com base no anestésico recebido (propofol ou sevoflurano). O grupo de pré-condicionamento anestésico recebeu sevoflurano a 3% após a indução da anestesia, que foi descontinuado quando a ventilação monopulmonar foi iniciada. O grupo controle não recebeu sevoflurano em qualquer momento durante todo o período do estudo. As vias de transdução de sinal intracelular (família MAPK), o fator de transcrição (NF-κB) e a apoptose (caspases 3 e 9) foram analisados durante o experimento. Resultados: Os suínos que receberam pré-condicionamento anestésico com sevoflurano apresentaram valores mais baixos de MAPK-p38, MAPK-P-p38, c-Jun N-terminal quinases (JNK), NF-κB p50 intranuclear e caspases (p < 0,05) do que os suínos anestesiados com propofol intravenoso. Conclusões: A proteção pulmonar do pré-condicionamento anestésico com sevoflurano durante o autotransplante pulmonar experimental está, pelo menos, parcialmente associada à atenuação das vias de MAPKs e NF κB e aos efeitos antiapoptóticos.


Subject(s)
Animals , Signal Transduction/drug effects , Lung Transplantation , Apoptosis/drug effects , Anesthetics, Inhalation/pharmacology , Sevoflurane/pharmacology , Anesthesia/methods , Swine , Transplantation, Autologous , Models, Theoretical
13.
Braz. j. med. biol. res ; 52(7): e8092, 2019. tab, graf
Article in English | LILACS | ID: biblio-1011595

ABSTRACT

Acute lung injury (ALI) is a serious clinical syndrome with a high rate of mortality. The activation of inflammation is well-recognized as a vital factor in the pathogenesis of lipopolysaccharide (LPS)-induced ALI. Therefore, suppression of the inflammatory response could be an ideal strategy to prevent ALI. Epigallocatechin-3-gallate (EGCG), mainly from green tea, has been shown to have an anti-inflammatory effect. The aim of the study was to explore whether EGCG alleviates inflammation in sepsis-related ALI. Male BALB/C mice were treated with EGCG (10 mg/kg) intraperitoneally (ip) 1 h before LPS injection (10 mg/kg, ip). The results showed that EGCG attenuated LPS-induced ALI as it decreased the changes in blood gases and reduced the histological lesions, wet-to-dry weight ratios, and myeloperoxidase (MPO) activity. In addition, EGCG significantly decreased the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the lung, serum, and bronchoalveolar lavage fluid, and alleviated the expression of TLR-4, MyD88, TRIF, and p-p65 in the lung tissue. In addition, it increased the expression of IκB-α and had no influence on the expression of p65. Collectively, these results demonstrated the protective effects of EGCG against LPS-induced ALI in mice through its anti-inflammatory effect that may be attributed to the suppression of the activation of TLR 4-dependent NF-κB signaling pathways.


Subject(s)
Animals , Male , Rabbits , Catechin/analogs & derivatives , NF-kappa B/drug effects , Toll-Like Receptor 4/drug effects , Acute Lung Injury/prevention & control , Signal Transduction/drug effects , Catechin/administration & dosage , Lipopolysaccharides , Disease Models, Animal , Acute Lung Injury/chemically induced , Mice, Inbred BALB C
14.
Clinics ; 74: e688, 2019. tab, graf
Article in English | LILACS | ID: biblio-989635

ABSTRACT

OBJECTIVES This study aims to compare the differential gene expression resulting from tocotrienol-rich fraction and α-tocopherol supplementation in healthy older adults. METHODS A total of 71 eligible subjects aged 50 to 55 years from Gombak and Kuala Lumpur, Malaysia, were divided into three groups and supplemented with placebo (n=23), α-tocopherol (n=24) or tocotrienol-rich fraction (n=24). Blood samples were collected at baseline and at 3 and 6 months of supplementation for microarray analysis. RESULTS The number of genes altered by α-tocopherol was higher after 6 months (1,410) than after 3 months (273) of supplementation. α-Tocopherol altered the expression of more genes in males (952) than in females (731). Similarly, tocotrienol-rich fraction modulated the expression of more genes after 6 months (1,084) than after 3 months (596) and affected more genes in males (899) than in females (781). α-Tocopherol supplementation modulated pathways involving the response to stress and stimuli, the immune response, the response to hypoxia and bacteria, the metabolism of toxins and xenobiotics, mitosis, and synaptic transmission as well as activated the mitogen-activated protein kinase and complement pathways after 6 months. However, tocotrienol-rich fraction supplementation affected pathways such as the signal transduction, apoptosis, nuclear factor kappa B kinase, cascade extracellular signal-regulated kinase-1 and extracellular signal-regulated kinase-2, immune response, response to drug, cell adhesion, multicellular organismal development and G protein signaling pathways. CONCLUSION Supplementation with either α-tocopherol or tocotrienol-rich fraction affected the immune and drug response and the cell adhesion and signal transduction pathways but modulated other pathways differently after 6 months of supplementation, with sex-specific responses.


Subject(s)
Humans , Male , Female , Middle Aged , Gene Expression/drug effects , Dietary Supplements , alpha-Tocopherol/pharmacology , Tocotrienols/pharmacology , Antioxidants/pharmacology , Protein Kinases/drug effects , Time Factors , Signal Transduction/drug effects , Cell Adhesion/drug effects , Single-Blind Method , Sex Factors , Gene Expression Regulation/drug effects , Oxidative Stress/drug effects , Immune System/drug effects
15.
Acta cir. bras ; 34(7): e201900708, 2019. tab, graf
Article in English | LILACS | ID: biblio-1038121

ABSTRACT

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.


Subject(s)
Animals , Male , Rats , Saponins/pharmacology , Triterpenes/pharmacology , Myocardial Reperfusion Injury/prevention & control , Signal Transduction/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Phosphorylation , Myocardial Reperfusion Injury/drug therapy , Rats, Sprague-Dawley
16.
Acta cir. bras ; 34(8): e201900802, 2019. tab, graf
Article in English | LILACS | ID: biblio-1038128

ABSTRACT

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.


Subject(s)
Animals , Rats , Myocardial Reperfusion Injury/metabolism , MicroRNAs/metabolism , Nitric Oxide Synthase Type III/metabolism , Hypoxia/metabolism , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/drug therapy , Signal Transduction/drug effects , Apoptosis/drug effects , Apoptosis/physiology , Phosphatidylinositol 3-Kinases/metabolism , MicroRNAs/genetics , MicroRNAs/therapeutic use , Cell Proliferation/drug effects , Nitric Oxide Synthase Type III/genetics , Nitric Oxide Synthase Type III/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism
17.
Acta cir. bras ; 34(1): e20190010000003, 2019. tab, graf
Article in English | LILACS | ID: biblio-983683

ABSTRACT

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.


Subject(s)
Animals , Male , Rats , Drugs, Chinese Herbal/therapeutic use , Oxidative Stress/drug effects , NF-E2-Related Factor 2/metabolism , Acute Kidney Injury/drug therapy , Anti-Inflammatory Agents/therapeutic use , Signal Transduction/drug effects , Cytokines/drug effects , Disease Models, Animal
18.
Acta cir. bras ; 34(1): e20190010000006, 2019. graf
Article in English | LILACS | ID: biblio-983690

ABSTRACT

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.


Subject(s)
Humans , Thrombin/drug effects , Antithrombins/pharmacology , Hirudins/pharmacology , Apoptosis/drug effects , Endothelial Cells/drug effects , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , Cell Proliferation/drug effects , Microvessels/drug effects , Microvessels/metabolism
19.
Acta cir. bras ; 34(2): e201900209, 2019. graf
Article in English | LILACS | ID: biblio-989056

ABSTRACT

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.


Subject(s)
Animals , Male , Rats , NF-kappa B/antagonists & inhibitors , Sepsis/complications , Protective Agents/therapeutic use , Acute Kidney Injury/prevention & control , Milk Proteins/therapeutic use , Antigens, Surface/therapeutic use , Signal Transduction/drug effects , Acute Kidney Injury/etiology , Mice, Inbred C57BL
20.
Braz. j. med. biol. res ; 52(10): e8391, 2019. tab, graf
Article in English | LILACS | ID: biblio-1039250

ABSTRACT

The effect of a short-term creatine supplementation on hindlimb suspension (HS)-induced muscle atrophy was investigated. Creatine monohydrate (5 g/kg b.w. per day) or placebo, divided in 2 daily doses, was given by oral gavage for 5 days. Rats were maintained in HS with dietary supplementation concomitantly for 5 days. Body weight, soleus and EDL muscle masses, and cross-sectional areas (CSA) of the muscle fibers were measured. Signaling pathways associated with skeletal muscle mass regulation (FST, MSTN, FAK, IGF-1, MGF, Akt, mTOR, atrogin-1, and MuRF1 expressions, and Akt, S6, GSK3B, and 4EBP1 proteins) were evaluated in the muscles. Soleus muscle exhibited more atrophy than the EDL muscle due to HS. Creatine supplementation attenuated the decrease of wet weight and increased p-4EBP1 protein in the EDL muscle of HS rats. Also, creatine increased mTOR and atrogin-1 expressions in the same muscle and condition. In the absence of HS, creatine supplementation increased FAK and decreased MGF expressions in the EDL muscle. Creatine attenuated the increase in FST expression due to HS in the soleus muscle. MuRF1 expression increased in the soleus muscle due to creatine supplementation in HS animals whereas atrogin-1 expression increased still further in this group compared with untreated HS rats. In conclusion, short-term creatine supplementation changed protein metabolism signaling in soleus and EDL muscles. However, creatine supplementation only slightly attenuated the mass loss of both muscles and did not prevent the CSA reduction and muscle strength decrease induced by HS for 5 days.


Subject(s)
Animals , Male , Rats , Muscular Atrophy/diet therapy , Hindlimb Suspension/adverse effects , Dietary Supplements , Creatine/administration & dosage , Muscular Atrophy/etiology , Signal Transduction/drug effects , Rats, Wistar , Muscle, Skeletal/drug effects , Disease Models, Animal
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