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1.
Front Immunol ; 10: 1824, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428103

RESUMO

Macrophages play a critical role in the pathogenesis of endotoxin shock by producing excessive amounts of pro-inflammatory cytokines. A pan-caspase inhibitor, zVAD, can be used to induce necroptosis under certain stimuli. The role of zVAD in both regulating the survival and activation of macrophages, and the pathogenesis of endotoxin shock remains not entirely clear. Here, we found that treatment of mice with zVAD could significantly reduce mortality and alleviate disease after lipopolysaccharide (LPS) challenge. Notably, in LPS-challenged mice, treatment with zVAD could also reduce the percentage of peritoneal macrophages by promoting necroptosis and inhibiting pro-inflammatory responses in macrophages. In vitro studies showed that pretreatment with zVAD promoted LPS-induced nitric oxide-mediated necroptosis of bone marrow-derived macrophages (BMDMs), leading to reduced pro-inflammatory cytokine secretion. Interestingly, zVAD treatment promoted the accumulation of myeloid-derived suppressor cells (MDSCs) in a mouse model of endotoxin shock, and this process inhibited LPS-induced pro-inflammatory responses in macrophages. Based on these findings, we conclude that treatment with zVAD alleviates LPS-induced endotoxic shock by inducing macrophage necroptosis and promoting MDSC-mediated inhibition of macrophage activation. Thus, this study provides insights into the effects of zVAD treatment in inflammatory diseases, especially endotoxic shock.

2.
Am J Transl Res ; 11(5): 3029-3038, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31217872

RESUMO

Immune-mediated liver injury plays a crucial role in the pathogenesis of liver diseases, which can result from viral infections, autoimmunity, alcohol intake, and drug use. Concanavalin A (Con A)-induced hepatitis is a well-characterized murine model with similar pathophysiology to that of human viral and autoimmune hepatitis. Capsaicin, a selective agonist of the transient potential vanilloid subfamily member 1 (TRPV1) receptor, exhibits anti-inflammatory effects on various causes of inflammation. In the present study, we investigated the effect of capsaicin on Con A-induced hepatitis. Capsaicin (1 mg/kg body weight) was administered by intraperitoneal injection, after which (30 minutes), the mice were challenged intravenously with Con A (20 µg/g body weight). We collected serum for plasma transaminase analysis. Pro-inflammatory cytokine levels and hepatocyte apoptosis were assayed by ELISA and TUNEL, respectively. Liver samples were collected for real-time PCR, hematoxylin and eosin staining, and measuring oxidative stress and myeloperoxidase levels. Activation of splenocytes and hepatic mononuclear cells was analyzed by flow cytometry. Compared with control, the capsaicin-treated group showed significantly decreased aminotransferase levels and markedly prolonged mouse survival. Capsaicin pretreatment also attenuated hepatocyte apoptosis and oxidative stress. Furthermore, tumor necrosis factor-α and interferon-γ levels in serum and liver were significantly suppressed, while the percentage of myeloid-derived suppressor cells increased after capsaicin pretreatment. Our findings indicate that capsaicin pretreatment protects mice from Con A-induced hepatic damage and is partially involved in inhibiting hepatocyte apoptosis, oxidative stress, and inflammatory mediators as well as regulating activation and recruitment of intrahepatic leukocytes.

3.
J Cell Mol Med ; 23(7): 4738-4745, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31062436

RESUMO

Long non-coding RNA MIR503 host gene (MIR503HG) is located on chromosome Xq26.3, and has been found to be deregulated in many types of human malignancy and function as tumour suppressor or promoter based on cancer types. The role of MIR503HG in breast cancer was still unknown. In our study, we found MIR503HG expression was significantly decreased in triple-negative breast cancer tissues and cell lines. Furthermore, we observed low MIR503HG expression was correlated with late clinical stage, lymph node metastasis and distant metastasis. In the survival analysis, we observed that triple-negative breast cancer patients with low MIR503HG expression had a statistically significant worse prognosis compared with those with high MIR503HG expression, and low MIR503HG expression was a poor independent prognostic factor for overall survival in triple-negative breast cancer patients. The study in vitro suggested MIR503HG inhibits cell migration and invasion via miR-103/OLFM4 axis in triple negative breast cancer. In conclusion, MIR503HG functions as a tumour suppressive long non-coding RNA in triple negative breast cancer.

4.
Front Immunol ; 10: 215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809230

RESUMO

Dysregulation of macrophage has been demonstrated to contribute to aberrant immune responses and inflammatory diseases. CD11b, expressed on macrophages, plays a critical role in regulating pathogen recognition, phagocytosis, and cell survival. In the present study, we explored the effect of leukadherin-1 (LA1), an agonist of CD11b, on regulating LPS-induced pro-inflammatory response in macrophages and endotoxic shock. Intriguingly, we found that LA1 could significantly reduce mortalities of mice and alleviated pathological injury of liver and lung in endotoxic shock. In vivo studies showed that LA1-induced activation of CD11b significantly inhibited the LPS-induced pro-inflammatory response in macrophages of mice. Moreover, LA1-induced activation of CD11b significantly inhibited LPS/IFN-γ-induced pro-inflammatory response in macrophages by inhibiting MAPKs and NF-κB signaling pathways in vitro. Furthermore, the mice injected with LA1-treated BMDMs showed fewer pathological lesions than those injected with vehicle-treated BMDMs in endotoxic shock. In addition, we found that activation of TLR4 by LPS could endocytose CD11b and activation of CD11b by LA1 could endocytose TLR4 in vitro and in vivo, subsequently blocking the binding of LPS with TLR4. Based on these findings, we concluded that LA1-induced activation of CD11b negatively regulates LPS-induced pro-inflammatory response in macrophages and subsequently protects mice from endotoxin shock by partially blocking LPS-TLR4 interaction. Our study provides a new insight into the role of CD11b in the pathogenesis of inflammatory diseases.

5.
Biochim Biophys Acta Mol Basis Dis ; 1865(3): 535-546, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30557700

RESUMO

Myeloid-derived suppressor cells (MDSCs) play an immunosuppressive role in the pathogenesis of inflammatory diseases. CD180, a TLR-like protein, can regulate the proliferation and activation of immune cells. However, the roles of CD180 in regulating the accumulation and function of MDSCs have not been investigated. Here, we found that, compared with non-treated controls, the expression of CD180 was significantly elevated in MDSCs, especially granulocytic MDSCs (G-MDSCs), from mice challenged with lipopolysaccharide (LPS). Ligation of CD180 by the anti-CD180 antibody not only blocked the expansion of MDSCs by preventing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), but also reduced the immunosuppressive activity of MDSCs on M1 macrophage polarization through inhibition of Arg-1 expression in vitro. In vivo studies showed that injection of anti-CD180 antibody significantly aggravated pathological lesions in mice challenged with LPS. Furthermore, injection of anti-CD180 antibody inhibited the accumulation of G-MDSCs in mice challenged with LPS and reduced the immunosuppressive activity of G-MDSCs on M1 macrophage polarization. Based on these findings, we conclude that ligation of CD180 contributes to the pathogenesis of endotoxic shock by inhibiting the accumulation and immunosuppressive activity of G-MDSCs, thus providing insight into the function of CD180 in inflammatory diseases.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Células Supressoras Mieloides/imunologia , Fator de Transcrição STAT3/fisiologia , Choque Séptico/induzido quimicamente , Choque Séptico/imunologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/efeitos dos fármacos , Ligação Proteica , Choque Séptico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
6.
Inflammation ; 41(6): 2090-2100, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30143931

RESUMO

Endotoxin shock is a life-threatening response caused by a disordered immune response to an infection. MDSCs are accumulated and play a protective role in the pathogenesis of endotoxin shock. However, the regulation of MDSCs by small molecule remains unrevealed. Here, we report that arctigenin, a small molecule extracted from Arctium lappa, induces accumulation of functional MDSCs. Arctigenin was able to ameliorate LPS-induced inflammation through accumulating MDSCs, especially granulocytic MDSCs (G-MDSCs), and enhancing the immunosuppressive function of MDSCs in vivo and in vitro. Mechanistically, arctigenin promoted the accumulation of MDSCs through upregulating miR-127-5p which targets the 3'UTR of interferon regulatory factor-8 (IRF8) mRNA. In addition, arctigenin enhanced the immunosuppressive activity of MDSCs on M1 macrophage polarization by elevating the expression of arginase 1 (Arg-1) and inducible nitric oxide synthase (iNOS). Our study provides new insights into the regulation of functional MDSCs by arctigenin in exerting immune responses and pathogenesis of inflammatory diseases.


Assuntos
Furanos/farmacologia , Inflamação/prevenção & controle , Lignanas/farmacologia , Células Supressoras Mieloides/imunologia , Choque Séptico/patologia , Animais , Arginase/metabolismo , Furanos/uso terapêutico , Fatores Reguladores de Interferon/genética , Lignanas/uso terapêutico , Lipopolissacarídeos , Camundongos , MicroRNAs/efeitos dos fármacos , Células Supressoras Mieloides/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro , Choque Séptico/metabolismo
7.
Am J Transl Res ; 10(5): 1552-1561, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29887968

RESUMO

Cancer stem cells (CSCs) play important roles in tumor initiation, metastasis, and progression. They are also mainly responsible for high treatment failure rates. Identification and characterization of CSCs are crucial for facilitating the detection, prevention, or therapy of cancer. Great efforts have been paid to develop an effective method and the ideal method for CSCs research is still in the going. In our study, we created an ultra-low concentration of serum and non-adhesive (ULCSN) culture system to enrich CSCs from murine lewis lung cancer cell line LL/2 with cell spheres structure and characterize the LL/2 CSCs properties. Their characteristics were investigated through colony formation, spheres formation, chemoresistance, flow cytometry for putative stem cell markers, such as CD133, CD34 and CD45, immunofluorescence staining and tumor initiation capacity in vivo. Tumor spheres were formed within 7-10 days under the condition of ULCSN culture system. Compared with adherent parental LL/2 cells, the colony capacity, chemo-resistance, and expression of stem cell markers increased significantly in addition to tumor-initiating capability in the tumor sphere cells. Using the ULCSN culture system, an available isolation method of lewis lung CSCs was established, which is simple, effective, and inexpensive compared with the cytokines attachment serum free culture method. The stem cell properties of the tumor sphere LL/2 cells reflected the CSCs phenotypes. We developed a useful CSCs model for basic and pre-clinical studies for lung cancer and other types of cancer.

8.
Gerontology ; 64(5): 457-465, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29804119

RESUMO

BACKGROUND: Tetrahydroxystilbene glucoside (TSG) is a main bioactive component of Polygonum multiflorum, a traditional Chinese medicine known for certain anti-aging effects. Since TSG has been found to extend lifespan in the nematode Caenorhabditis elegans, we hypothesized that TSG might produce anti-aging benefits in mammals. OBJECTIVE: The aim was to evaluate the anti-aging potential of TSG and to explore its relative molecular mechanism. METHODS: Mice were maintained on standard diet, high-calorie diet (HC), or high-calorie plus TSG diet. Survival rates and body weight changes were recorded weekly. Rotarod analysis was performed to assess the physical fitness of mice. Bone mineral density was assessed using micro-computed tomography. Hematoxylin and eosin staining was used for the histological examination of heart, liver, and kidney pathology. The mRNA and protein expression of target genes were analyzed by quantitative real-time polymerase chain reaction and western blotting, respectively. Mitotracker deep red staining and high-content analysis were used to quantify cellular mitochondrial mass and function. RESULTS: In this study, we found that TSG improved the physiology of aged mice consuming excess calories and delayed senile symptoms. The anti-aging benefits of TSG were mediated at least in part by the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) signaling cascade, leading to significant improvement in motor function, bone mineral density, HC-induced organ pathology, and mitochondrial function. CONCLUSION: Our findings show that TSG could be a potential drug candidate for the treatment of aging- and high-calorie intake-associated disorders.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Glucosídeos/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Estilbenos/farmacologia , Envelhecimento/patologia , Animais , Densidade Óssea/efeitos dos fármacos , Linhagem Celular , Medicamentos de Ervas Chinesas/farmacologia , Ingestão de Energia , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
9.
Front Pharmacol ; 9: 312, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29681850

RESUMO

Shuxuening injection (SXNI) is a widely prescribed herbal medicine of Ginkgo biloba extract (EGB) for cerebral and cardiovascular diseases in China. However, its curative effects on ischemic stroke and heart diseases and the underlying mechanisms remain unknown. Taking an integrated approach of RNA-seq and network pharmacology analysis, we compared transcriptome profiles of brain and heart ischemia reperfusion injury in C57BL/6J mice to identify common and differential target genes by SXNI. Models for myocardial ischemia reperfusion injury (MIRI) by ligating left anterior descending coronary artery (LAD) for 30 min ischemia and 24 h reperfusion and cerebral ischemia reperfusion injury (CIRI) by middle cerebral artery occlusion (MCAO) for 90 min ischemia and 24 h reperfusion were employed to identify the common mechanisms of SXNI on both cerebral and myocardial ischemia reperfusion. In the CIRI model, ischemic infarct volume was markedly decreased after pre-treatment with SXNI at 0.5, 2.5, and 12.5 mL/kg. In the MIRI model, pre-treatment with SXNI at 2.5 and 12.5 mL/kg improved cardiac function and coronary blood flow and decreased myocardial infarction area. Besides, SXNI at 2.5 mL/kg also markedly reduced the levels of LDH, AST, CK-MB, and CK in serum. RNA-seq analysis identified 329 differentially expressed genes (DEGs) in brain and 94 DEGs in heart after SXNI treatment in CIRI or MIRI models, respectively. Core analysis by Ingenuity Pathway Analysis (IPA) revealed that atherosclerosis signaling and inflammatory response were top-ranked in the target profiles for both CIRI and MIRI after pre-treatment with SXNI. Specifically, Tnfrsf12a was recognized as an important common target, and was regulated by SXNI in CIRI and MIRI. In conclusion, our study showed that SXNI effectively protects brain and heart from I/R injuries via a common Tnfrsf12a-mediated pathway involving atherosclerosis signaling and inflammatory response. It provides a novel knowledge of active ingredients of Ginkgo biloba on cardio-cerebral vascular diseases in future clinical application.

10.
Endocrine ; 47(3): 901-12, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24760659

RESUMO

The regulation of the transcriptional activity of the estrogen receptor-related receptor a (ERRa) has not yet been clearly documented. Aromatase is a direct target gene of ERRa, and we previously reported that prostaglandin E2 (PGE2) increased the expression of ERRa in the prostate stromal cell line WPMY-1, which ultimately promoted estradiol production by enhancing aromatase gene transcription. Here, we show that PGE2 also affects aromatase expression by regulating ERRa transcriptional activity in prostate stromal cells. When the cells were cultured in serum-free medium, the expression of aromatase was not proportional to the ERRa protein level, if no other stimulation occurred, indicating the absence of a factor that activates ERRa. PGE2 could upregulate aromatase and ERRa response element (ERRE)-reporter expression and also enhance ERRa phosphorylation and nuclear localization. PGE2 functions through the PGE2 receptors (EP) 2 and EP4, which couple to adenylate cyclase. The activation of adenylate cyclase with Forskolin mimicked the PGE2-mediated enhancement of extracellular signal-regulated kinase (ERK) phosphorylation and ERRa target gene expression. Experiments using specific signaling pathway inhibitors showed that both phosphatidylinositol 3-kinase (PI3K) and ERK are involved in ERRa activation, and the PI3K inhibitor was shown to abolish ERK activation. Our results suggest that PGE2 is a modulator of ERRa transcriptional activity. Furthermore, PGE2 activates the EP2/EP4-cAMP-PI3K-ERK signaling pathway, which enhanced ERRa transcriptional potentiality by increasing ERRa phosphorylation and nuclear translocation, subsequently promoting the expression of its target genes, such as aromatase.


Assuntos
Dinoprostona/farmacologia , Próstata/efeitos dos fármacos , Receptores Estrogênicos/metabolismo , Células Estromais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Aromatase/genética , Aromatase/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Próstata/citologia , Próstata/metabolismo , Receptores Estrogênicos/genética , Transdução de Sinais/efeitos dos fármacos , Células Estromais/citologia , Células Estromais/metabolismo
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