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1.
Cytokine ; 128: 155001, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32035329

RESUMO

Neutrophilic granule protein (NGP) belongs to the cystatin superfamily. Even though this superfamily is critically involved in cancer biology and adaptive immunity, the relationship of macrophage NGP to inflammation and phagocytosis remains poorly understood. In this study, we observed a significant increase of NGP in peritoneal macrophages (PMs) isolated from mice challenged with E. coli or lipopolysaccharide (LPS), as judged by NGP mRNA microarray. We also found changes in NGP to be mainly Toll-like receptor 4 (TLR4)-dependent. By western blot and electrophoretic mobility shift assay, we demonstrated NGP overexpression to reduce TNF-α and IL-1ß production by LPS-induced RAW264.7 cells (RAW) via suppression of the NF-κB (p65 and p50) signalling pathway, rather than the JNK1/AP-1 (fos and jun) signalling pathway. NGP overexpression by LPS-induced RAW also induced IL-10, an anti-inflammatory cytokine, which was partially involved in the anti-inflammatory effect produced by NGP overexpression. Moreover, upregulated NGP enhanced the phagocytosis of E. coli by RAW. Taken together, these results demonstrated NGP to be an important host defense component that regulates inflammatory responses and phagocytosis by activated macrophages. As such, NGP may be useful for the treatment of inflammatory based disease.

2.
Cell Immunol ; : 104047, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-32019673

RESUMO

The polarization of macrophages is critical to inflammation and tissue repair, with unbalanced macrophage polarization associated with critical dysfunctions of the immune system. Cytochrome P450 1A1 (CYP1A1) is a hydroxylase mainly controlled by the inflammation-limiting aryl hydrocarbon receptor (AhR), which plays a critical role in mycoplasma infection, oxidative stress injury, and cancer. Arginase-1 (Arg-1) is a surrogate for polarized alternative macrophages and is important to the production of nitric oxide (NO) by the modulation of arginine. In the present study, we found CYP1A1 to be upregulated in IL-4-stimulated mouse peritoneal macrophages (PMs) and human peripheral blood monocytes. Using CYP1A1-overexpressing RAW264.7 cells (CYP1A1/RAW) we found that CYP1A1 augmented Arg-1 expression by strengthening the activation of the JAK1/STAT6 signaling pathway in macrophages treated with IL-4. 15(S)-HETE, a metabolite of CYP1A1 hydroxylase, was elevated in IL-4-induced CYP1A1/RAW cells. Further, in macrophages, the loss-of-CYP1A1-hydroxylase activity was associated with reduced IL-4-induced Arg-1 expression due to impaired 15(S)-HETE generation. Of importance, CYP1A1 overexpressing macrophages reduced the inflammation associated with LPS-induced peritonitis. Taken together, these findings identified a novel signaling axis, CYP1A1-15(S)-HETE-JAK1-STAT6, that may be a promising target for the proper maintenance of macrophage polarization and may also be a means by which to treat immune-related disease due to macrophage dysfunction.

3.
Inflammation ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31802382

RESUMO

Ellipticine, a natural product from Ochrosia elliptica, has been broadly investigated for its anticancer effects. Although inflammation has been clearly identified as a key factor in the onset and progression of cancer, the relationship between ellipticine and inflammation remains unknown. Hence, the aims of the present study were to assess the effects of ellipticine on the inflammatory responses to lipopolysaccharide (LPS)-induced macrophages and to potentially identify the underlying mechanisms involved. Viability testing showed that ellipticine was not significantly toxic to Raw264.7 cells and actually conveyed protective effects to LPS-stimulated Raw264.7 cells and human peripheral blood monocytes by decreasing the secretion of inflammatory factors (TNF-α and IL-6). The results of western blot analysis and electrophoretic mobility shift assays showed that ellipticine markedly suppressed LPS-induced activation of the JNK/AP-1 (c-Fos and c-Jun) signaling pathway, but not ERK/p38/NF-κB pathway (p65 and p50) activation. Furthermore, ellipticine reduced the inflammatory response and mortality in a mouse model of LPS-induced endotoxic shock. Collectively, these data indicate that ellipticine may be a potential therapeutic agent for the treatment of inflammation-associated diseases.

4.
Org Lett ; 21(9): 3310-3313, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30998376

RESUMO

The α-regioselective asymmetric [3 + 2] annulation reaction of Morita-Baylis-Hillman carbonates from isatins and activated ortho-vinylbenzaldehyses was developed by the catalysis of a chiral tertiary amine. The sequential N-heterocyclic carbene-mediated intramolecular Stetter reaction was conducted to finally furnish the bridged 5,8-methanobenzo[7]annulen-9-one architectures incorporating a spirooxindole motif with excellent stereoselectivity.

5.
Org Lett ; 20(24): 8000-8003, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30525703

RESUMO

The asymmetric dearomative formal [4 + 2] cycloaddition reaction of activated N,4-dialkylpyridinium salts and acyclic α,ß-unsaturated ketones was developed by the cascade iminium ion-enamine catalysis of a cinchona-derived amine. A spectrum of valuable azaspiro[5.5]undecane architectures was efficiently constructed with high to excellent diastereoselectivity and enantioselectivity.

6.
Stem Cell Res Ther ; 9(1): 306, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30409193

RESUMO

BACKGROUND: Cardiovascular complications, especially myocardial infarctions (MIs), are the leading mortality cause in diabetic patients. The transplantation of stem cells into damaged hearts has had considerable success as a treatment for MI, although whether antidiabetic drugs affect the therapeutic efficacy of stem cell transplantation is still unknown. This study aims to understand whether and how metformin, one of the first-line drugs used to treat type 2 diabetes mellitus (T2DM), induces mesenchymal stromal cell (MSC) apoptosis and dampens their cardioprotective effect after transplantation into infarcted hearts. METHODS: A mouse MI model was generated via permanent ligation of the left anterior descending (LAD) coronary artery. MSCs with or without metformin treatment were transplanted after MI in diabetic mice. Echocardiography was used to assess cardiac function and determine cardiac remodeling, and TTC staining was performed to evaluate infarction size. A mouse gavage model was performed to evaluate bone marrow MSCs for flow cytometry assay. RESULTS: Metformin dampened MSC therapeutic efficacy, which increased infarct size and restricted functional cardiac recovery. Specifically, metformin induced the activation of AMP-activated protein kinase (AMPK)-mediated apoptosis through the inhibition of S6K1-Bad-Bcl-xL cell survival signaling, resulting in the upregulated expression of apoptosis-associated proteins and increased MSC apoptosis. Accordingly, counteracting AMPK attenuated metformin-induced apoptosis in MSCs and partially restored their cardioprotective effects in diabetic mice with MI. Furthermore, a decrease in peripheral blood MSCs was found in patients with T2DM who had a metformin medication history. CONCLUSIONS: Our results highlight an unexpected adverse effect of metformin-induced MSC apoptosis through AMPK-mediated mTOR suppression, which is attenuated by an AMPK inhibitor. Moreover, AMPK inhibition may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI in diabetes.


Assuntos
Apoptose/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Metformina/farmacologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Adenilato Quinase/metabolismo , Animais , Cardiotônicos/metabolismo , Diabetes Mellitus Experimental , Feminino , Humanos , Masculino , Camundongos , Resultado do Tratamento
7.
Org Lett ; 20(19): 6279-6283, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30256122

RESUMO

The in-situ-generated zwitterionic allylic ylides between Morita-Baylis-Hillman carbonates from isatins and chiral tertiary amine catalysts underwent highly regioselective and enantioselective 1,3-oxo-ethynylation or 1,3-amino-sulfenylation reactions with silyl ethynyl-1,2-benziodoxol-3( 1H)-ones or N-(aryl or alkylthio)imides, respectively, giving densely functionalized products bearing a quaternary stereogenic center. An array of diversely structured scaffolds were efficiently constructed from the products, showing the synthetic versatility of the current catalytic strategy.

8.
Nan Fang Yi Ke Da Xue Xue Bao ; 38(6): 652-660, 2018 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-29997086

RESUMO

OBJECTIVE: To investigate whether exogenous agmatine inhibits lipopolysaccharide (LPS)-induced activation and dysfunction of human umbilical vein endothelial cells (HUVECs) by modulating nuclear factor-κB (NF-κB) and MAPK signal pathways and the production of reactive oxygen species (ROS). METHODS: Cultured HUVECs were treated with agmatine at the optimized concentration of 1.0 mmolγL, LPS (10 µgγmL), and LPS + agmatine, with or without pretreatment with the inhibitors of NF-κB (PDTC), p38 (SB203580), and ERK (PD98059) for 1 h. The levels of soluble vascular cell adhesion molecule 1 (VCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), soluble E-selectin and monocyte chemoattractant protein 1 (MCP-1) in the supernatant were determined using ELISA, and their mRNA expressions, along with heme oxygenase-1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO-1), were assessed using real-time PCR. ROS production in the cells was determined using 2, 7-dichlorofluoresce in diacetate (DCFH-DA) as the fluorescence probe. The protein expressions of VCAM-1, ICAM-1, p65, phospho-p65 (p-p65), IκBα, p-IκBα, ERK, p-ERK, p38, p-p38, JNK, and p-JNK were detected using Western blotting. RESULTS: LPS stimulation for 6 and 24 h significantly increased the levels of sVCAM-1, sICAM-1, sE-selectin and MCP-1 in the supernatant, intracellular ROS production, and the mRNA expressions of these molecules (P<0.05). Intervention with 1 mmolγL agmatine, similar with pretreatment with p38, ERK and NF-κB inhibitors, obviously inhibited such effects of LPS in HUVECs (P<0.05). Agmatine significantly up-regulated the mRNA expression of HO-1 (P<0.05), inhibited LPS-induced phosphorylation of p38, ERK, nuclear p65 and cytoplasmic IκBα, and up-regulated the protein expression of cytoplasmic IκBα. CONCLUSION: Agmatine inhibits LPS-induced activation and dysfunction of HUVECs by modulating NF-κB and MAPK signal pathways to down-regulate the expressions of adhesion molecules and chemokines and by up-regulating the expression of HO-1 to reduce ROS production.


Assuntos
Agmatina/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Células Cultivadas , Quimiocina CCL2/análise , Selectina E/análise , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/análise , Espécies Reativas de Oxigênio/metabolismo , Molécula 1 de Adesão de Célula Vascular/análise , Proteínas Quinases p38 Ativadas por Mitógeno/análise
9.
Mil Med Res ; 5(1): 21, 2018 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-29970166

RESUMO

The characteristics and treatment of pelvic fractures vary between general conditions and modern war. An expert consensus has been reached based on pelvic injury epidemiology and the concepts of battlefield treatment combined with the existing levels of military medical care in modern warfare. According to this consensus, first aid, emergency treatment and early treatment of pelvic fractures are introduced in three separate levels. In Level I facilities, simple triage and rapid treatment following the principles of advanced trauma life support are recommended to evaluate combat casualties during the first-aid stage. Re-evaluation, further immobilization and fixation, and hemostasis are recommended at Level II facilities. At Level III facilities, the main components of damage control surgery are recommended, including comprehensive hemostasis, a proper resuscitation strategy, the treatment of concurrent visceral and blood vessel damage, and battlefield intensive care. The grading standard for evidence evaluation and recommendation was used to reach this expert consensus.


Assuntos
Consenso , Fraturas Ósseas/cirurgia , Medicina Militar/normas , Ossos Pélvicos/cirurgia , Ferimentos e Lesões/terapia , China , Hemostasia , Humanos , Ossos Pélvicos/lesões , Ressuscitação , Guerra
10.
J Cell Biochem ; 118(12): 4230-4239, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28419526

RESUMO

Sepsis is one of the most challenging health problems worldwide. Our previous study showed that chronic schistosoma japonica (SJ) infection might increase serum anti-inflammatory factors to play a protective role, thus improving the survival rate of septic mice. Further research revealed that SJ infection promoted J774A.1 macrophage differentiation into M2 macrophages; suppressed LPS-induced activation of M1 macrophages; up-regulated CD163, IL-10, and TGF-ß1 expression; inhibited TNF-α and iNOS expression; and blocked the effect of LPS-promoted TNF-α and iNOS expression. Furthermore, adoptive transfer of ex vivo programed M2 macrophages significantly increased the survival rate of septic mice. In vitro studies suggested that soluble egg antigen (SEA) from SJ played the same role as worm infection but had no impact on M1 macrophages. SEA reduced LPS-induced TNF-α and iNOS expression, decreased the inhibitory effect of LPS on IL-10 and TGF-ß1 expression, increased STAT6 phosphorylation, and up-regulated PI3K and Akt expression but inhibited SOCS1 expression. When PI3K inhibitors were added, SEA-induced expression of CD163, IL-10, and arg1 might be reduced. Therefore, worm infection has a protective effect in septic mice in which SEA may play a key role via the STAT6 and PI3K pathways. This finding may provide a favorable solution for the treatment of sepsis, especially early cases. J. Cell. Biochem. 118: 4230-4239, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Antígenos de Helmintos/imunologia , Citocinas , Macrófagos/metabolismo , Esquistossomose Japônica/complicações , Sepse/complicações , Transdução de Sinais , Animais , Macrófagos/imunologia , Camundongos , Óxido Nítrico Sintase Tipo II , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Transcrição STAT6/metabolismo , Esquistossomose Japônica/imunologia , Esquistossomose Japônica/metabolismo , Sepse/mortalidade , Taxa de Sobrevida
11.
Inflammation ; 40(3): 1012-1027, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28337636

RESUMO

Evodiamine (EVO), an important alkaloidal component extracted from the fruit of Evodiae fructus, has been known to possess anti-tumor, anti-inflammatory, anti-oxidative, and other therapeutic capabilities. In the present study, the effects of EVO on zymosan-induced inflammation and its underlying mechanism were investigated both in vitro and in vivo. Our results showed that EVO effectively suppressed both protein and mRNA expression of interleukin-1ß, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in vitro. Zymosan-induced DNA-binding activity of nuclear factor-kappa B (NF-κB) was attenuated by EVO, which was achieved through inhibitory effects on the phosphorylation of inhibitory κB α and p65 nuclear translocation, but there was very little association with mitogen-activated protein kinase activation. In vivo, treatment with EVO markedly decreased TNF-α and IL-6 levels in plasma. EVO also repressed inflammatory cytokine expression and ameliorated the abnormal state in both lung and intestine tissues by inactivation of NF-κB. Furthermore, EVO significantly reduced the mortality caused by zymosan. In summary, these results suggested that EVO could effectively suppress inflammatory responses in vitro and in vivo, and may be a potential therapeutic agent against inflammatory disorders.


Assuntos
Inflamação/prevenção & controle , Inibidor de NF-kappaB alfa/metabolismo , Quinazolinas/farmacologia , Citocinas/sangue , Citocinas/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Mucosa Intestinal/metabolismo , Pulmão/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Zimosan
12.
Oncotarget ; 8(6): 9035-9052, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-28118617

RESUMO

Suppressed adaptive immune function is one of the major concerns responsible for the development of opportunistic infections and subsequent sepsis with high mortality in severe burns. Endoplasmic reticulum stress (ERS) is the endogenous self-protective mechanism, and it plays an important role in almost every process of living by regulating the balance between homeostasis and apoptosis. The current study investigated the involvement of ERS in the pathogenesis of dysfunction of dendritic cells (DCs) in burn mice. Our results show a significant ERS response in splenic DC after burn injury. Treatment with salubrinal (Sal, reported to protect cells against ERS-induced apoptosis.) decrease the apoptotic rate of DC induced by burns, and promote maturation and activation of DC, as well as the ability to promote T cell proliferation and polarization towards Th1 immunity (all P<0.05). Gene silence of XBP-1 (key molecular in ERS response) results in the increased apoptosis and suppressed phenotypical maturation of splenic DC in burn mice. These results show that the excessive ERS is essential for immunosuppression during severe thermal injury. XBP-1 plays a pivotal role in DC functional immunomodulation in burn mice. Inhibition of apoptotic ERS response benefits mice from major burns.


Assuntos
Imunidade Adaptativa , Queimaduras/imunologia , Células Dendríticas/imunologia , Estresse do Retículo Endoplasmático , Baço/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Apoptose , Queimaduras/tratamento farmacológico , Queimaduras/metabolismo , Queimaduras/patologia , Células Cultivadas , Cinamatos/farmacologia , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ativação Linfocitária , Masculino , Camundongos Endogâmicos BALB C , Fenótipo , Interferência de RNA , Índice de Gravidade de Doença , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Células Th1/imunologia , Células Th1/metabolismo , Tioureia/análogos & derivados , Tioureia/farmacologia , Fatores de Tempo , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/imunologia , Proteína 1 de Ligação a X-Box/metabolismo
13.
Mil Med Res ; 3: 33, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27833759

RESUMO

Trauma still represents one of the major causes of death worldwide. Despite the reduction of post-traumatic sepsis over the past two decades, the mortality of septic trauma inpatients is still high (19.5-23 %). Early prevention of sepsis development can aid in the subsequent treatment of patients and help improve their outcomes. To date, the prevention of trauma-related infection/sepsis has mainly included infection prevention (e.g., surgical management, prophylactic antibiotics, tetanus vaccination, immunomodulatory interventions) and organ dysfunction prevention (e.g., pharmaceuticals, temporary intravascular shunts, lung-protective strategies, enteral immunonutrition, acupuncture). Overall, more efficient ways should be developed to prevent trauma-related infection/sepsis.


Assuntos
Traumatismo Múltiplo/complicações , Sepse , Infecção dos Ferimentos , Humanos , Sepse/etiologia , Sepse/prevenção & controle , Infecção dos Ferimentos/etiologia , Infecção dos Ferimentos/prevenção & controle
14.
Biomed Res Int ; 2015: 903720, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25821827

RESUMO

Sepsis, the leading cause of mortality in intensive care unit, is characterized by hyperinflammatory response in the early stage and followed by a period of immunosuppression. This immune disorder is believed to be the potent factor that is tightly associated with high mortality in sepsis. Dendritic cells (DCs) serve as professional antigen-presenting cells that play a vital role in immune response by activating T lymphocytes. During the progression of sepsis, DCs have been reported to take part in the aberrant immune response and be necessary for survival. Therefore, a better understanding of the DCs pathology will be undoubtedly beneficial for resolving the problems occurring in sepsis. This review discusses effects of sepsis on DCs number and function, including surface molecules expression, cytokines secretion, and T cell activation, and the underlying mechanism as well as some potential therapeutic strategies.


Assuntos
Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Sepse/imunologia , Sepse/patologia , Linfócitos T/imunologia , Animais , Humanos , Modelos Imunológicos , Linfócitos T/patologia
15.
Chin J Traumatol ; 18(4): 223-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26764544

RESUMO

PURPOSE: To evaluate the usefulness and information collecting ability of speckle tracking imaging techniques in the assessment of myocardial regional ventricular contractility in a rabbit model with blunt cardiac injury. METHODS: Fifteen healthy New Zealand rabbits weighing (2.70 ±0.28) kg were anesthetized (3% pentobarbital sodium/i.v) and impacted using the BIM-II biological impact machine to induce myocardial contusion (MC). Hemodynamic parameters, such as heart rate, systolic pressure, mean arterial pressure, diastolic pressure and central venous pressure, were determined before and after MC. Further, parameters reflecting left ventricular functions, such as left ventricular end systolic pressure, left ventricular end diastolic pressure, isovolumic pressure (IP) and the maximal increasing/decreasing rate of left intraventricular pressure (±dp/dtmax), were also determined before and after MC. Left ventricular functions were determined either by two dimensional transthoracic echocardiography or by speckle tracking imaging for segmental abnormal ventricular wall motions. RESULTS: Heart rate, systolic pressure, diastolic pressure and mean arterial pressure decreased significantly but transiently, while central venous pressure markedly increased after MC. In contrast to significant changes in diastolic functions, there was no significant change in cardiac systolic functions after MC. The speckle tracking imaging demonstrated that strain values of different myocardial segment significantly decreased post impact, and that of the ventricular segment decreased from segment to segment. CONCLUSION: Speckle tracking imaging is useful and informative to assess myocardial regional dysfunctions post MC.


Assuntos
Ecocardiografia , Traumatismos Cardíacos/fisiopatologia , Função Ventricular , Ferimentos não Penetrantes/fisiopatologia , Animais , Feminino , Traumatismos Cardíacos/diagnóstico por imagem , Hemodinâmica , Masculino , Contração Miocárdica , Coelhos , Ferimentos não Penetrantes/diagnóstico por imagem
16.
PLoS One ; 9(6): e100457, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24971752

RESUMO

Small ubiquitin-like modifier (SUMO) proteins regulate many important eukaryotic cellular processes through reversible covalent conjugation to target proteins. In addition to its many well-known biological consequences, like subcellular translocation of protein, subnuclear structure formation, and modulation of transcriptional activity, we show here that SUMO-2 also plays a role in mRNA translation. SUMO-2 promoted formation of the active eukaryotic initiation factor 4F (eIF4F) complex by enhancing interaction between Eukaryotic Initiation Factor 4E (eIF4E) and Eukaryotic Initiation Factor 4G (eIF4G), and induced translation of a subset of proteins, such as cyclinD1 and c-myc, which essential for cell proliferation and apoptosis. As expected, overexpression of SUMO-2 can partially cancel out the disrupting effect of 4EGI-1, a small molecule inhibitor of eIF4E/eIF4G interaction, on formation of the eIF4F complex, translation of the cap-dependent protein, cell proliferation and apoptosis. On the other hand, SUMO-2 knockdown via shRNA partially impaired cap-dependent translation and cell proliferation and promoted apoptosis. These results collectively suggest that SUMO-2 conjugation plays a crucial regulatory role in protein synthesis. Thus, this report might contribute to the basic understanding of mammalian protein translation and sheds some new light on the role of SUMO in this process.


Assuntos
Fator de Iniciação 4E em Eucariotos/metabolismo , Fator de Iniciação 4G em Eucariotos/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Apoptose/genética , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Células HCT116 , Humanos , Hidrazonas/farmacologia , Complexos Multiproteicos/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Capuzes de RNA , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Tiazóis/farmacologia
17.
Recent Pat CNS Drug Discov ; 8(2): 142-60, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23597305

RESUMO

Ischemic brain damage remains a major cause of disability at all ages. This review examines the efficacy, mode of action and mechanisms of insulin-like growth factor (IGF)-1 and its derivatives in animal models of acute brain injury and neurodegenerative conditions, their potential in pharmaceutical developments. IGF-1 reduces cell loss and improves long-term neurological function in animal models. IGF-1 needs to be given within a few hours of the insult. However, the therapeutic window can be extended by mild hypothermia, likely by delaying apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential limit clinical translation. Thus, recent studies have examined related compounds. For example, intravenous infusion of the N-terminal tripeptide of IGF-1 (glycine- proline-glutamate, GPE) can alleviate brain injury and improve long-term function in rats, with a broad effective dose range and a 3-7 hour therapeutic window, but has a short half-life. G-2meth-PE(G-2mPE), a GPE analogue with a longer half-life, is also neuroprotective. GPE/G-2mPE do not interact with IGF receptors and may act by modulating postinjury inflammation, astrogliosis and vascular remodeling. Cyclo-glycyl-proline (cGP), an endogenous diketopiperazine possibly derived from GPE is also neuroprotective. An analogue, cyclo-L-glycyl-L-2-allylproline (NNZ-2591) improves long-term somatosensory-motor function and histology after ischemic injury. Treatment with NNZ-2591 after 6-hypdroxydopamine injection in adult rats improves neurogenesis and long-term motor function. Further, oral administration of NNZ-2591 also prevents scopolamine-induced acute memory impairment. These beneficial effects may mediated by improved neuroplasticity. This review is an updated version of a previous publication in Recent Pat CNS Drug Discov.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Fator de Crescimento Insulin-Like I/análogos & derivados , Fator de Crescimento Insulin-Like I/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos
18.
Neuroimmunomodulation ; 20(2): 87-98, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23257628

RESUMO

OBJECTIVE: Immune cells are key mediators of secondary damage following spinal cord injury (SCI), and dendritic cell (DC)-based vaccines have received considerable interest for treatment of SCI. We previously showed that vaccination with DCs pulsed with homogenate proteins of the spinal cord (hpDCs) promotes functional recovery from SCI in mice. However, the underlying molecular mechanisms remain unclear. Here, changes of neurotrophins, cytokines and T cells at the site of SCI in mice after vaccination with hpDCs were investigated and correlated with recovery from SCI. METHODS: hpDCs, DCs (control) or PBS (control) were injected intraperitoneally into injured mouse spinal cords. Functional recovery of the spinal cord was measured weekly using the Basso Mouse Scale (BMS) and confirmed by histological and immunohistochemical analysis. Brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), interleukin-4 (IL-4) and interferon-γ (IFN-γ) levels in T cell culture supernatants and spinal cord tissues were determined by ELISA. RESULTS: Eighty-four days after immunization, the BMS score of the hpDCs group (6.92 ± 0.20) was significantly higher than those of the DCs and PBS groups (p < 0.01). Meanwhile, the injury area and number of cysts in the hpDCs group decreased significantly compared with control groups. BDNF, NT-3, IL-4 and IFN-γ levels at the injured site as well as BDNF and NT-3 levels in the supernatant of cultured T cells from the hpDCs group were significantly higher than in control groups (p < 0.05). CONCLUSION: These results reveal that vaccination with hpDCs can promote SCI repair potentially by upregulating BDNF, NT-3, IL-4 and IFN-γ at the injury site.


Assuntos
Citocinas/biossíntese , Células Dendríticas/transplante , Fatores de Crescimento Neural/biossíntese , Traumatismos da Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Proteínas/imunologia , Proteínas/metabolismo , Recuperação de Função Fisiológica , Medula Espinal/imunologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/terapia , Vacinação
19.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 25(12): 720-4, 2013 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-24620385

RESUMO

OBJECTIVE: To observe the effect of agmatine ( AGM) on lipopolysaccharide ( LPS )-induced acute hepatic injury in mice, and to explore its related mechanism. METHODS: Sixty C57BU6 mice were randomly divided into control group ( n = 20, with intra-peritoneal injection of phosphate buffer saline 10 mg/kg), model group ( n = 20, with intra-peritoneal injection of LPS 10 mg/kg), and AGM group (n=20, with intra-peritoneal injection of LPS 10 mg/kg and AGM 200 mg/kg). Ten mice in each group were sacrificed at 6 hours and 24 hours, respectively, after modeling, blood samples were collected for the determination of tumor necrosis factor-a ( TNF -a) and interleukin ( IL-113 and IL-6) by enzyme linked immunosorbent assay (ELISA) at 6 hours after modeling , and for determination of alanine aminotransferase (ALT), aspartate transaminase (AST) and total bilirubin (TBil) by automatic biochemistry analyzer at 24 hours after modeling. Hepatic homogenate was also collected for determining the endo nuclear nuclear factor-KB ( NF -KB) p65 by Western blotting at 6 hours after modeling, and for observation of pathological changes at 24 hours after modeling. RESULTS: At 6 hours after modeling, .the mice in model group became lethargic and quiet, and their food and water assumption was reduced, but AGM was found to be able to greatly improve the general status of animals in AGM group. AGM was found to lower the contents of serum TNF-a ( IJ.g/L: 296.3 ± 42.5 vs. 627.2 ± 81.3, t=7.327, P=0.002), IL-113 ( f.Lg/L: 109.1 ± 12.3 vs. 264.2 ± 18.8, t= 11.958, P=0.001), IL-6 ( mg/L: 11.4 ± 1.9 vs. 23.6 ± 2.5, t=6.729, P=0.003), ALT (U!L: 107.9 ± 8.5 vs. 189.9 ± 13.6, t=8.856, P=0.001 ), AST (UIL: 347.4 ± 24.9 vs. 716.8 ± 60.4, t=9.793, P=0.001) and TBil ( f.Lmol!L: 8.3 ± 0.9 vs. 10.6 ± 0.5, t=3.869, P=0.018) in mice with acute hepatic injury induced by LPS. AGM also depressed TNF -a ( ng/g: 287.4 ± 32.5 vs. 461.5 ± 31.4, t=6.673, P= 0.003), IL-113 (pg/g: 146.7 ± 13.5 vs. 351.6 ± 28.7, t=11.190, P=0.001) and intranuclear NF-KB p65 level (NF-KBp65/TBP: 0.515 ± 0.060 vs. 0.853 ± 0.080, t=5.849, P=0.004) in liver tissue. Histological examination demonstrated that AGM significantly reduced liver injury caused by LPS, as manifested in amelioration of hepatocytes swelling, necrosis and neutrophil infiltration. CONCLUSION: Agmatine can reduce LPS-induced acute hepatic injury in mice via suppressing NF-κB translocation and reduction of the synthesis and release of cytokines.


Assuntos
Agmatina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fígado/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/sangue , Lipopolissacarídeos/efeitos adversos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fator de Transcrição RelA/metabolismo
20.
Oncol Rep ; 29(2): 481-90, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23135406

RESUMO

Autophagy is a self-defense mechanism that provides nutrition and energy for cell survival by recycling the cytoplasm and organelles. Hence, chemotherapy is rendered less effective against cancer cells. Evodiamine is a previously described biological agent that possesses a cytotoxic activity in multiple cancer cells. However, little is known about evodiamine-induced autophagy in Lewis lung carcinoma (LLC) cells. In this study, LLC cells and a xenograft model were used. By use of a panel of techniques such as MTT assay, flow cytometry, western blotting, immunocytochemistry and TUNEL assay, the effects on the induction of apoptosis and autophagy were evaluated. We demonstrated that evodiamine inhibited LLC cell growth and induced apoptosis through caspase-independent manner in vitro and caspase-dependent pathway in vivo. In addition, we showed for the first time that evodiamine promoted autophagosome formation by enhancing the conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II and upregulating the expression of autophagy-specific genes (Atgs). Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, attenuated evodiamine-induced autophagy through decreasing the conversion of LC3-I to LC3-II. The inhibition of autophagy was found to increase cell death and enhance evodiamine-induced apoptosis in vitro in a caspase-independent manner and in vivo in a caspase-dependent manner. In conclusion, evodiamine promoted autophagy in LLC cells and autophagy inhibition enhanced evodiamine-induced apoptosis in vitro and in vivo. These results demonstrate that evodiamine-induced autophagy plays a cytoprotective role in LLC cells and evodiamine combined with autophagy inhibitor therapy could increase the chemosensitivity of LLC cells.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Lewis/metabolismo , Quinazolinas/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagia/genética , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Quinazolinas/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
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