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1.
Mediators Inflamm ; 2020: 2431705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32317861

RESUMO

CXCL14 is a relatively novel chemokine with a wide spectrum of biological activities. The present study was designed to investigate whether CXCL14 overexpression attenuates sepsis-associated acute kidney injury (AKI) in mice. Sepsis model has been established by cecal ligation and puncture (CLP). CLP induced AKI in mice as assessed by increased renal neutrophil gelatinase-associated lipocalin (NGAL) expression and serum creatinine levels. We found that renal CXCL14 expression in the kidney was significantly decreased at 12 hours after CLP. Correlation analysis demonstrated a negative association between renal CXCL14 expression and AKI markers including serum creatinine and renal NGAL. Moreover, CXCL14 overexpression reduced cytokine (TNF-α, IL-6, and IL-1ß) production and NGAL expression in the kidney and decreased serum creatinine levels. In vivo and in vitro experiments found that CXCL14 overexpression inhibited M1 macrophage polarization but increased M2 polarization. Together, these results suggest that CXCL14 overexpression attenuates sepsis-associated AKI probably through the downregulation of macrophages-derived cytokine production. However, further studies are required to elucidate the underlying mechanism.

2.
Chin Med J (Engl) ; 133(5): 505-508, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142490
3.
Chin Med J (Engl) ; 133(5): 590-596, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32032080

RESUMO

Enhanced recovery after cesarean (ERAC) delivery is an evidence-based, multi-disciplinary approach throughout pre-, intra-, post-operative period. The ultimate goal of ERAC is to enhance recovery and improve the maternal and neonatal outcomes. This review highlights the role of anesthesiologist in ERAC protocols. This review provided a general introduction of ERAC including the purposes and the essential elements of ERAC protocols. The tool used for evaluating the quality of ERAC (ObsQoR-11) was discussed. The role of anesthesiologist in ERAC should cover the areas including management of peri-operative hypotension, prevention and treatment of intra- and post-operative nausea and vomiting, prevention of hypothermia and multi-modal peri-operative pain management, and active pre-operative management of unplanned conversion of labor analgesia to cesarean delivery anesthesia. Although some concerns still remain, ERAC implementation should not be delayed. Regular assessment and process improvement should be imbedded into the protocol. Further high-quality studies are warranted to demonstrate the effectiveness and efficacy of the ERAC protocol.

4.
Int Immunopharmacol ; 81: 106257, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32044659

RESUMO

The activation of NLRP3 inflammasome and NF-κB pathway, associating with oxidativestress, have been implicated in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). NecroX-5 has been reported to exhibit theeffectsofanti-oxidation and anti-stress in various diseases. However, the role of NecroX-5 in ALI has not been explicitly demonstrated. The aim of this study was to explore the therapeutic effects and potential mechanism action of NecroX-5 on ALI. Here, we found that NecroX-5 pretreatment dramatically diminished the levels of IL-1ß, IL-18 and ROS in in RAW264.7 cells challenged with LPS and ATP. Furthermore, NecroX-5 suppressed the activation of NLRP3 inflammasome and NF-κB signalpathway. In addition, NecroX-5 also inhibited the thioredoxin-interacting protein (TXNIP) expression. In vivo, NecroX-5 reduced the LPS-induced lung histopathological injury, the number of TUNEL-positive cells, lung wet/dry (W/D) ratio, levels of total protein and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) in mice. Additionally, LPS-induced upregulation of myeloperoxidase (MPO), ROS production and malondialdehyde (MDA) were inhibited by NecroX-5 administration. Thus, our results demonstrate that NecroX-5 protects against LPS-induced ALI by inhibiting TXNIP/NLRP3 and NF-κB.

6.
Med Sci Monit ; 26: e918523, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31995551

RESUMO

BACKGROUND Intrathecal dexmedetomidine (DEX) can improve the blockade of spinal anesthesia, but there is no clear conclusion on whether it has an effect on the fetus during cesarean section. Our meta-analysis evaluated the safety and efficacy of intrathecal DEX in cesarean delivery. MATERIAL AND METHODS We searched Cochrane, Embase, PubMed, and CBM for eligible studies, and used the Revised Cochrane Risk of Bias Tool (RoB 2.0) to assess the risk of bias of each study. RevMan was used for statistical analyses. We have registered this meta-analysis on PROSPERO (CRD42019120995). RESULTS The meta-analysis included 10 RCTs, but only 5 were prospectively registered. The results of preregistration studies, including the 1- or 5-min Apgar score (mean difference [MD], -0.03; 95% confidence intervals [CI], -0.16 to 0.10; P=0.64 or MD, 0.00; 95% CI, -0.09 to 0.09; P=1), the umbilical arterial oxygen or carbon dioxide partial pressure (MD, 0.90; 95% CI, -4.92 to 6.72; P=0.76 or MD, 1.20; 95% CI, -2.06 to 4.46; P=0.47), and the cord blood pH (MD, -0.01; 95% CI, -0.05 to 0.03; P=0.72), showed that intrathecal DEX had no significant difference in neonatal outcomes compared with placebo. In maternal outcomes, intrathecal DEX significantly prolonged postoperative pain-free period and reduced the incidence of postoperative shivering, which did not increase spinal anesthesia-associated adverse effects. CONCLUSIONS Intrathecal DEX is safe for the fetus during cesarean section and can improve the blockade effects of spinal anesthesia on puerperae.

7.
Chin Med J (Engl) ; 133(2): 183-189, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31929368

RESUMO

BACKGROUND: Obstetric hemorrhage is a major cause of maternal death during cesarean delivery. The objective of this retrospective observational study was to evaluate the efficacy and safety of intra-operative cell salvage (IOCS) in cesarean section. METHODS: We included a total of 361 patients diagnosed with central placenta previa who underwent cesarean section from May 2016 to December 2018. In this study, 196 patients received autologous transfusion using IOCS (IOCS group) and 165 patients accepted allogeneic blood transfusion (ABT group). Propensity score matched analysis was performed to balance differences in the baseline variables between the IOCS group and ABT group. Patients in the IOCS group were matched 1:1 to patients in the ABT group. RESULTS: After propensity score matching, 137 pairs of cases between the two groups were successfully matched and no significant differences in baseline characteristics were found between the IOCS group and ABT group. Patients in the IOCS group were associated with significantly shorter length of hospital stay, compared with ABT group (8.9 ±â€Š4.1 days vs. 10.3 ±â€Š5.2 days, t = -2.506, P = 0.013). The postoperative length of hospital stay was 5.3 ±â€Š1.4 days for patients in the IOCS group and 6.6 ±â€Š3.6 days for those in the ABT group (t = -4.056, P < 0.001). The post-operative hemoglobin level in the IOCS group and ABT group was 101.3 ±â€Š15.4 and 96.3 ±â€Š16.6 g/L, respectively, which were significantly different (t = 2.615, P = 0.009). Allogeneic red blood cell transfusion was significantly lower at 0 unit (range: 0-11.5 units) in the IOCS group when compared with 2 units (range: 1-20 units) in the ABT group (P < 0.001). CONCLUSIONS: This retrospective observational study using propensity score matched analysis suggested that IOCS was associated with shorter length of postoperative hospital stay and higher post-operative hemoglobin levels during cesarean delivery.

9.
Front Pharmacol ; 10: 1323, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787899

RESUMO

Acute kidney injury (AKI) is one of the most common and serious complications of sepsis in which the inflammatory cascade plays a crucial role. There is now increasing evidence that lipid mediators derived from the omega-3 fatty acid docosahexaenoic acid (DHA) have potent anti-inflammatory effects that promote the timely regression of acute inflammation. In this study, we investigated the protective effects and molecular mechanism of a novel DHA-derived lipid mediator Maresin 1 (MaR1) on AKI in septic mice. The cecal ligation and puncture (CLP) was used to establish a sepsis mice model. As a result, we found that MaR1 significantly increased the 7-day survival rate of septic mice and the anti-inflammatory factor IL-10 while reducing bacterial load and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß). In addition, MaR1 dose dependently reduced renal injury scores and serum creatinine and urea nitrogen levels in septic mice while inhibiting renal neutrophil infiltration and myeloperoxidase (MPO) activity. In terms of signaling pathway, we found that MaR1 inhibits the expression of phosphorylated p65, Stat3, JNK, ERK, and p38 and significantly reduces nuclear translocation of p65. In conclusion, our results indicate that MaR1 is able to reduce neutrophil infiltration and inhibit nuclear factor-kappa B/signal transducer and activator of transcriptor 3/mitogen-activated protein kinase (NF-κB/STAT3/MAPK) activity and regulate inflammatory cytokine level to inhibit inflammatory response and thereby weaken sepsis-associated AKI in mice.

10.
Lab Invest ; 99(8): 1143-1156, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30911150

RESUMO

Acute respiratory distress syndrome (ARDS) is a uniform progression of overwhelming inflammation in lung tissue with extensive infiltration of inflammatory cells. Neutrophil apoptosis is thought to be a significant process in the control of the resolution phase of inflammation. It has been proved that 5-Aza-2'-deoxycytidine (Aza) can inhibit cancer by activating death-associated protein kinase 1 (DAPK1) to promote apoptosis. However, the effect of DAPK1 on neutrophil apoptosis is unclear, and research on the role of Aza in inflammation is lacking. Here, we investigated whether Aza can regulate DAPK1 expression to influence the fate of neutrophils in ARDS. In vitro, we stimulated neutrophil-like HL-60 (dHL-60) cells with different concentrations of Aza for different durations and used RNA interference to up- or downregulate DAPK1 expression. We observed that culturing dHL-60 cells with Aza increased apoptosis by inhibiting NF-κB activation to modulate the expression of Bcl-2 family proteins, which was closely related to the levels of DAPK1. In vivo, ARDS was evoked by intratracheal instillation of lipopolysaccharide (LPS; 3 mg/kg). One hour after LPS administration, mice were treated with Aza (1 mg/kg, i.p.). To inhibit DAPK1 expression, mice were intraperitoneally injected with a DAPK1 inhibitor. Aza treatment accelerated inflammatory resolution in LPS-induced ARDS by suppressing pulmonary edema, alleviating lung injury and decreasing the infiltration of inflammatory cells in bronchoalveolar lavage fluid (BALF). Moreover, Aza reduced the production of proinflammatory cytokines. However, administration of the DAPK1 inhibitor attenuated the protective effects of Aza. Similarly, the proapoptotic function of Aza was prevented when DAPK1 was inhibited either in vivo or in vitro. In summary, Aza promotes neutrophil apoptosis by activating DAPK1 to accelerate inflammatory resolution in LPS-induced ARDS. This study provides the first evidence that Aza prevents LPS-induced neutrophil survival by modulating DAPK1 expression.

11.
Int J Mol Med ; 42(6): 3083-3092, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30280199

RESUMO

Pulmonary fibrosis is an aggressive end­stage disease. Transforming growth factor­ß1 (TGF­ß1) mediates lung fibroblast activation and is essential for the progress of pulmonary fibrosis. BML­111, a lipoxinA4 (LXA4) receptor (ALX) agonist, has been reported to possess anti­ï¬brotic properties. The present study aimed to elucidate whether BML­111 inhibits TGF­ß1­induced mouse embryo lung fibroblast (NIH3T3 cell line) activation in vitro and bleomycin (BLM)­induced pulmonary fibrosis in vivo. In vitro experiments demonstrated that BML­111 treatment inhibits TGF­ß1­induced NIH3T3 cell viability and the expression of smooth muscle α actin (α­SMA), fibronectin and total collagen. Furthermore, this suppressive effect was associated with mothers against decapentaplegic homolog (Smad)2/3, extracellular signal­regulated kinase (ERK) and Akt phosphorylation interference. In vivo experiments revealed that BML­111 treatment markedly improved survival rate and ameliorated the destruction of lung tissue structure. It also reduced interleukin­1ß (IL­1ß), tumor necrosis factor­α (TNF­α) and TGF­ß1 expression in the BLM intratracheal mouse model. In addition, the expression ofα­SMA and extracellular matrix (ECM) deposition (total collagen, hydroxyproline and fibronectin) were also suppressed following BML­111 treatment. However, BOC­2, an antagonist of ALX, partially weakened the effects of BML­111. In conclusion, these results indicated that BML­111 inhibits TGF­ß1­induced fibroblasts activation and alleviates BLM­induced pulmonary fibrosis. Therefore, BML­111 may be used as a potential therapeutic agent for pulmonary fibrosis treatment.


Assuntos
Fibroblastos/metabolismo , Ácidos Heptanoicos/farmacologia , Fibrose Pulmonar/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Masculino , Camundongos , Células NIH 3T3 , Prognóstico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Resultado do Tratamento
12.
Curr Med Sci ; 38(4): 672-678, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30128877

RESUMO

Mechanical ventilation (MV) with large tidal volumes can increase lung alveolar permeability and initiate inflammatory responses, resulting in ventilator-induced lung injury (VILI). The mechanisms of the injurious effects of MV and the genetic susceptibility remain unclear. VILI-related genes such as cysteine-rich angiogenic inducer 61 (Cyr61) have been demonstrated to play a detrimental role in the aggressive ventilation strategies. In the present study, we investigated the involvement of Cyr61 in the VILI and the underlying mechanism. A549 cells were exposed to cyclic stretch of varying durations and then the mRNA and protein levels of Cyr61 were measured by real-time PCR and Western blotting, respectively. Additionally, after exposure of A549 cells to cyclic stretch for 5 min to 1 h,the expression levels of nuclear factor kappaB (NF-κB) and IL-8 were detected by E L I S A and Western blotting. Thereafter, Cyr61 expression was depressed in A549 cells with the siRNA pGenesil1.1-Cyr61-3 before the cyclic stretch, and IL-8 secretion and the activation of NF-κB pathways were probed by ELISA and Western blotting, respectively. Moreover, A NF-κB inhibitor (PDTC) and an activator (TNF) were used before mechanical stretch. Realtime PCR and ELISA were performed to detect the mRNA and protein of IL-8, respectively. The results showed that the mechanical cyclic stretch led to increased Cyr61 expression at mRNA and protein levels in A549 cells. Additionally, cyclic stretch also mobilized NF-κB from the cytoplasm to the nucleus and increased IL-8 secretion in A549 cells. The inhibition of Cyr61 blocked the NF-κB activation and IL-8 secretion in response to cyclic stretch. Inhibition of NF-κB attenuated the mRNA and protein expression of IL-8 in A549 cells transfected with Cyr61 siRNA. It was suggested that Cyr61/NF-κB signaling pathway mediates the upregulation of IL-8 in response to cyclic stretch in A594 cells. These findings support the hypothesis that Cyr61 plays a critical role in acute lung inflammation triggered by mechanical strain.


Assuntos
Proteína Rica em Cisteína 61/metabolismo , Mecanotransdução Celular , Transporte Ativo do Núcleo Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proteína Rica em Cisteína 61/genética , Humanos , Interleucina-8/metabolismo , NF-kappa B/metabolismo
13.
Chin Med J (Engl) ; 131(10): 1214-1219, 2018 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-29722341

RESUMO

Objective: Exposure to halogens, such as chlorine or bromine, results in environmental and occupational hazard to the lung and other organs. Chlorine is highly toxic by inhalation, leading to dyspnea, hypoxemia, airway obstruction, pneumonitis, pulmonary edema, and acute respiratory distress syndrome (ARDS). Although bromine is less reactive and oxidative than chlorine, inhalation also results in bronchospasm, airway hyperresponsiveness, ARDS, and even death. Both halogens have been shown to damage the systemic circulation and result in cardiac injury as well. There is no specific antidote for these injuries since the mechanisms are largely unknown. Data Sources: This review was based on articles published in PubMed databases up to January, 2018, with the following keywords: "chlorine," "bromine," "lung injury," and "ARDS." Study Selection: The original articles and reviews including the topics were the primary references. Results: Based on animal studies, it is found that inhaled chlorine will form chlorine-derived oxidative products that mediate postexposure toxicity; thus, potential treatments will target the oxidative stress and inflammation induced by chlorine. Antioxidants, cAMP-elevating agents, anti-inflammatory agents, nitric oxide-modulating agents, and high-molecular-weight hyaluronan have shown promising effects in treating acute chlorine injury. Elevated free heme level is involved in acute lung injury caused by bromine inhalation. Hemopexin, a heme-scavenging protein, when administered postexposure, decreases lung injury and improves survival. Conclusions: At present, there is an urgent need for additional research to develop specific therapies that target the basic mechanisms by which halogens damage the lungs and systemic organs.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Halogênios/toxicidade , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Animais , Cloro/toxicidade , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia
14.
Chin Med J (Engl) ; 131(10): 1225-1231, 2018 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-29553050

RESUMO

Objective: Mechanical ventilation (MV) has long been used as a life-sustaining approach for several decades. However, researchers realized that MV not only brings benefits to patients but also cause lung injury if used improperly, which is termed as ventilator-induced lung injury (VILI). This review aimed to discuss the pathogenesis of VILI and the underlying molecular mechanisms. Data Sources: This review was based on articles in the PubMed database up to December 2017 using the following keywords: "ventilator-induced lung injury", "pathogenesis", "mechanism", and "biotrauma". Study Selection: Original articles and reviews pertaining to mechanisms of VILI were included and reviewed. Results: The pathogenesis of VILI was defined gradually, from traditional pathological mechanisms (barotrauma, volutrauma, and atelectrauma) to biotrauma. High airway pressure and transpulmonary pressure or cyclic opening and collapse of alveoli were thought to be the mechanisms of barotraumas, volutrauma, and atelectrauma. In the past two decades, accumulating evidence have addressed the importance of biotrauma during VILI, the molecular mechanism underlying biotrauma included but not limited to proinflammatory cytokines release, reactive oxygen species production, complement activation as well as mechanotransduction. Conclusions: Barotrauma, volutrauma, atelectrauma, and biotrauma contribute to VILI, and the molecular mechanisms are being clarified gradually. More studies are warranted to figure out how to minimize lung injury induced by MV.


Assuntos
Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Barotrauma/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Ferimentos e Lesões/metabolismo
15.
Chin Med J (Engl) ; 131(10): 1167-1173, 2018 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-29553051

RESUMO

Background: Acute lung injury (ALI) is a severe disease with high mortality and poor prognosis. Protectin DX (PDX), a pro-resolving lipid mediator, exhibits protective effects in ALI. Our experiment aimed to explore the effects and related mechanisms of PDX in mice with ALI induced by lipopolysaccharide (LPS). Methods: BALB/c mice were randomly divided into five groups: sham, LPS, LPS plus 1 ng of PDX (LPS + PDX-1 ng), LPS plus 10 ng of PDX (LPS + PDX-10 ng), and LPS plus 100 ng of PDX (LPS + PDX-100 ng). Bronchoalveolar lavage fluids (BALFs) were collected after 24 h, and total cells, polymorphonuclear leukocytes, monocyte-macrophages, and lymphocytes in BALF were enumerated. The concentration of interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein (MIP)-1α, and MIP-2 in BALF was determined, and histopathological changes of the lung were observed. The concentration of protein in BALF and lung wet/dry weight ratios were detected to evaluate pulmonary edema. After determining the optimal dose of PDX, neutrophil-platelet interactions in whole blood were evaluated by flow cytometry. Results: The highest dose of PDX (100 ng/mouse) failed to provide pulmonary protective effects, whereas lower doses of PDX (1 ng/mouse and 10 ng/mouse), especially 1 ng PDX, alleviated pulmonary histopathological changes, mitigated LPS-induced ALI and pulmonary edema, inhibited neutrophil infiltration, and reduced pro-inflammatory mediator (IL-1ß, IL-6, TNF-α, and MIP-1α) levels. Meanwhile, 1 ng PDX exhibited pro-resolving functions in ALI including upregulation of monocyte-macrophage numbers and anti-inflammatory mediator IL-10 levels. The flow cytometry results showed that PDX could inhibit neutrophil-platelet interactions in ALI. Conclusion: PDX exerts protective effects in LPS-induced ALI by mitigating pulmonary inflammation and abrogating neutrophil-platelet interactions.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Lipopolissacarídeos/toxicidade , Animais , Quimiocina CXCL2/metabolismo , Citometria de Fluxo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/metabolismo
16.
Cell Death Discov ; 3: 17054, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28845299

RESUMO

Enriched environment (EE) is shown to promote angiogenesis, neurogenesis and functional recovery after ischemic stroke. However, the underlying mechanisms remain unclear. C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion, after which mice were housed in either standard environment (SE) or EE. Here we found that post-ischemic EE exhibited decreased depression and anxiety-like behavior, and promoted angiogenesis and functional recovery compared to SE mice. EE mice treated with high-mobility group box-1 (HMGB1) inhibitor glycyrrhizin had an increased post-stroke depression and anxiety-like behavior, and the angiogenesis and functional recovery were decreased. HMGB1 and interleukin-6 (IL-6) expression in astrocyte were increased in EE mice. EE mice treated with glycyrrhizin decreased, whereas EE mice treated with recombinant HMGB1 (rHMGB1) increased the levels of IL-6 and p-AKT. Blockade of IL-6 with anti-IL-6-neutralizing antibody in EE mice attenuated EE-mediated angiogenesis and functional recovery. Furthermore, our in vitro data revealed that in primary astrocyte cultures rHMGB1 promoted the expression of IL-6 in activated astrocytes. PI3K/AKT signaling pathway was involved in HMGB1-mediated expression of astrocytic IL-6. Thus, our results reveal a previously uncharacterized property of HMGB1/IL-6 signaling pathway in EE-mediated angiogenesis and functional recovery after ischemic stroke.

17.
Int J Mol Med ; 40(1): 31-38, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28498464

RESUMO

S100A8/A9, a heterodimer of the two calcium-binding proteins S100A8 and S100A9, has emerged as an important proinflammatory mediator in acute and chronic inflammation. However, whether S100A8/A9 is implicated in microglial­induced neuroinflammatory response remains unclear. Here, we found that S100A8/A9 significantly increased the secretion of proinflammatory cytokines inclu-ding tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured BV-2 microglial cells. Inhibition of the Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) with C225 and a RAGE-blocking antibody, respectively significantly reduced the secretion of TNF-α and IL-6 from S100A8/A9-stimulated BV-2 microglial cells. Furthermore, S100A8/A9 markedly enhanced the nuclear translocation of NF-κB p65 and the DNA-binding activities of NF-κB in BV-2 microglial cells, and suppression of ERK and JNK/MAPK signaling pathways by PD98059 or SP600125 significantly inhibited NF-κB activity and the release of TNF-α and IL-6 in the S100A8/A9-treated BV-2 microglial cells. Our data also showed that inhibition of NF-κB with pyrrolidine dithiocarbamate (PDTC) significantly reduced the secretion of TNF-α and IL-6 from BV-2 microglial cells treated with S100A8/A9. Taken together, our data suggest that S100A8/A9 acts directly on BV-2 microglial cells via binding to TLR4 and RAGE on the membrane and then stimulates the secretion of proinflammatory cytokines through ERK and JNK-mediated NF-κB activity in BV-2 microglial cells. Targeting S100A8/A9 may provide a novel therapeutic strategy in microglial-induced neuroinflammatory diseases.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Microglia/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Animais , Linhagem Celular Transformada , Citocinas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Camundongos , Microglia/patologia
18.
J Huazhong Univ Sci Technolog Med Sci ; 36(3): 428-433, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27376816

RESUMO

This study aimed to establish a new propofol target-controlled infusion (TCI) model in animals so as to study the general anesthetic mechanism at multi-levels in vivo. Twenty Japanese white rabbits were enrolled and propofol (10 mg/kg) was administrated intravenously. Artery blood samples were collected at various time points after injection, and plasma concentrations of propofol were measured. Pharmacokinetic modeling was performed using WinNonlin software. Propofol TCI within the acquired parameters integrated was conducted to achieve different anesthetic depths in rabbits, monitored by narcotrend. The pharmacodynamics was analyzed using a sigmoidal inhibitory maximal effect model for narcotrend index (NI) versus effect-site concentration. The results showed the pharmacokinetics of propofol in Japanese white rabbits was best described by a two-compartment model. The target plasma concentrations of propofol required at light anesthetic depth was 9.77±0.23 µg/mL, while 12.52±0.69 µg/mL at deep anesthetic depth. NI was 76.17±4.25 at light anesthetic depth, while 27.41±5.77 at deep anesthetic depth. The effect-site elimination rate constant (ke0) was 0.263/min, and the propofol dose required to achieve a 50% decrease in the NI value from baseline was 11.19 µg/mL (95% CI, 10.25-13.67). Our results established a new propofol TCI animal model and proved the model controlled the anesthetic depth accurately and stably in rabbits. The study provides a powerful method for exploring general anesthetic mechanisms at different anesthetic depths in vivo.


Assuntos
Anestésicos Intravenosos/farmacocinética , Modelos Estatísticos , Propofol/farmacocinética , Anestésicos Intravenosos/sangue , Animais , Monitoramento de Medicamentos , Infusões Intravenosas , Propofol/sangue , Coelhos , Software
19.
J Huazhong Univ Sci Technolog Med Sci ; 36(4): 576-583, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27465336

RESUMO

The aim of this study was to investigate the possible beneficial role of telmisartan in cerebral edema after traumatic brain injury (TBI) and the potential mechanisms related to the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) pyrin domain-containing 3 (NLRP3) inflammasome activation. TBI model was established by cold-induced brain injury. Male C57BL/6 mice were randomly assigned into 3, 6, 12, 24, 48 and 72 h survival groups to investigate cerebral edema development with time and received 0, 5, 10, 20 and 40 mg/kg telmisartan by oral gavage, 1 h prior to TBI to determine the efficient anti-edemic dose. The therapeutic window was identified by post-treating 30 min, 1 h, 2 h and 4 h after TBI. Blood-brain barrier (BBB) integrity, the neurological function and histological injury were assessed, at the same time, the mRNA and protein expression levels of NLRP3 inflammasome, IL-1ß and IL-18 concentrations in peri-contused brain tissue were measured 24 h post TBI. The results showed that the traumatic cerebral edema occurred from 6 h, reached the peak at 24 h and recovered to the baseline 72 h after TBI. A single oral dose of 5, 10 and 20 mg/kg telmisartan could reduce cerebral edema. Post-treatment up to 2 h effectively limited the edema development. Furthermore, prophylactic administration of telmisartan markedly inhibited BBB impairment, NLRP3, apoptotic speck-containing protein (ASC) and Caspase-1 activation, as well as IL-1ß and IL-18 maturation, subsequently improved the neurological outcomes. In conclusion, telmisartan can reduce traumatic cerebral edema by inhibiting the NLRP3 inflammasome-regulated IL-1ß and IL-18 accumulation.


Assuntos
Edema Encefálico/tratamento farmacológico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Interleucina-18/biossíntese , Interleucina-1beta/biossíntese , Proteína 3 que Contém Domínio de Pirina da Família NLR/biossíntese , Animais , Benzimidazóis/administração & dosagem , Benzoatos/administração & dosagem , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/genética , Edema Encefálico/patologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Caspase 1/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/efeitos adversos , Inflamassomos/genética , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transdução de Sinais/efeitos dos fármacos , Telmisartan
20.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 37(5): 541-8, 2015 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-26564505

RESUMO

OBJECTIVE: To identify the incidence and risk factors of perioperative major adverse cardiac events (MACE) in elderly patients with coronary heart disease (CHD) undergoing non-cardiac surgery. METHODS: We prospectively analyzed the clinical data of 360 CHD patients who aged 75 years or older undergoing elective intermediate-to high-risk surgery in five medical centers across China from January 2008 to January 2010. The clinical variables included the 12-lead ECG and Troponin I levels after surgery. The combined outcome was defined as all the perioperative MACE in hospital. The risk factors of MACE and their indexes were analyzed with univariate analysis and multivariable logistic regression in SPSS software,together with a risk scoring and stratification system established. RESULTS: Perioperative MACE occurred in 11.94% of elderly CHD patients undergoing non-cardiac surgery. Seven independent risk factors of perioperative MACE for this population were identified,which included angina within 6 months (P=0.001), hypertension(P=0.014), preoperative haematocrit (HCT) <40% (P=0.050), serum creatinine (Scr)>150 mmol/L (P=0.014), ejection fraction(EF) <50% (P=0.019), intraoperative hyoxemia (P=0.019), and operative time>150 min (P=0.001). The risk indexes of these factors were 4,3,3,6,4,5, and 4, respectively. The rate of perioperative MACE increased significantly as the level of risk stratification elevated. CONCLUSIONS: Elderly CHD patients undergoing non-cardiac surgery are at high risk of perioperative MACE. Angina within 6 months,hypertension, preoperative HCT<40%, Scr>150 mmol/L, EF<50%, intraoperative hyoxemia, and operative time>150 min can increase the risk of MACE. The risk scoring and stratification system based on the risk factor index can be a valuable parameter for assessing the perioperative cardiac risk of noncardiac surgery for elderly CHD patients.


Assuntos
Doença das Coronárias , Idoso , China , Procedimentos Cirúrgicos Eletivos , Eletrocardiografia , Humanos , Incidência , Modelos Logísticos , Assistência Perioperatória , Fatores de Risco
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