RESUMO
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is present in almost all cells and regulates the activity of innate immune responses in both intracellular and extracellular settings. Current evidence suggests that HMGB1 plays a pivotal role in human pathological and pathophysiological processes such as the inflammatory response, immune reactions, cell migration, aging, and cell death. Sepsis is a systemic inflammatory response syndrome (SIRS) that occurs in hosts in response to microbial infections with a proven or suspected infectious etiology and is the leading cause of death in intensive care units worldwide, particularly in the aging population. Dysregulated systemic inflammation is a classic characteristic of sepsis, and suppression of HMGB1 may ameliorate inflammation and improve patient outcomes. Here, we focus on the latest breakthroughs regarding the roles of HMGB1 in sepsis and sepsis-related organ injury, the ways by which HMGB1 are released, and the signaling pathways and therapeutics associated with HMGB1. This review highlights recent advances related to HMGB1: the regulation of HMBG1 might be helpful for both basic research and drug development for the treatment of sepsis and sepsis-related organ injury.
Assuntos
Proteína HMGB1/metabolismo , Insuficiência de Múltiplos Órgãos/patologia , Sepse/patologia , Autofagia/fisiologia , Transtornos da Coagulação Sanguínea/patologia , Síndrome da Liberação de Citocina/patologia , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Mitocôndrias/patologia , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Sepse/tratamento farmacológico , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismoRESUMO
BACKGROUND: Diabetic cardiomyopathy is one of the leading causes of death in diabetes mellitus (DM) patients. This study aimed to explore the therapeutic implication of N-acetyl-L-cysteine (NAC, an antioxidant and glutathione precursor) and the possible underlying mechanism. METHODS: Thirty five 12-week-old male C57BL/6 mice were included. Twenty-five diabetic mice were induced by intraperitoneal injection of streptozocin (STZ, 150 mg/kg, Sigma-Aldrich) dissolved in a mix of citrate buffer after overnight fast. Mice with a blood glucose level above 13.5 mmol/L were considered diabetic. As a non-DM (diabetic) control, mice were injected with equal volume of citrate buffer. The 25 diabetic mice were divided into 5 groups with 5 animals in each group: including DM (diabetes without NAC treatment), and 4 different NAC treatment groups, namely NAC1, NAC3, NAC5 and NAC7, with the number defining the start time point of NAC treatment. In the 10 non-DM mice, mice were either untreated (Ctrl) or treated with NAC for 5 weeks (NAC only). Echocardiography was performed 12 weeks after STZ injection. Heart tissue were collected after echocardiography for Hematoxylin Eosin (HE) and Trichrome staining and ROS staining. Cardiac fibroblast cells were isolated, cultured and treated with high glucose plus NAC or the vehicle. qPCR analysis and CCK-8 assay were performed to observe fibrotic gene expression and cell proliferation. RESULTS: We found that both cardiac systolic function and diastolic function were impaired, coupled with excessive reactive oxygen stress and cardiac fibrosis 12 weeks after STZ induction. NAC significantly reduced ROS generation and fibrosis, together with improved cardiac systolic function and diastolic function. Strikingly, NAC1 treatment, which had the earlier and longer treatment, produced significant improvement of cardiac function and less fibrosis. In the cardiac fibroblasts, NAC blocked cardiac fibroblast proliferation and collagen synthesis induced by hyperglycemia. CONCLUSIONS: Our study indicates that NAC treatment in diabetes effectively protects from diabetic cardiomyopathy, possibly through inhibiting the ROS production and fibrosis, which warrants further clarification.
Assuntos
Acetilcisteína/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Acetilcisteína/farmacologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Fibrose/metabolismo , Fibrose/patologia , Fibrose/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologiaRESUMO
Mariculture effluent polishing with microalgal biofilm could realize effective nutrients removal and resolve the microalgae-water separation issue via biofilm scraping or in-situ aquatic animal grazing. Ubiquitous existence of antibiotics in mariculture effluents may affect the remediation performances and arouse ecological risks. The influence of combined antibiotics exposure at environment-relevant concentrations towards attached microalgae suitable for mariculture effluent polishing is currently lack of research. Results from suspended cultures could offer limited guidance since biofilms are richer in extracellular polymeric substances that may protect the cells from antibiotics and alter their transformation pathways. This study, therefore, explored the effects of combined antibiotics exposure at environmental concentrations towards seawater Chlorella sp. biofilm in terms of microalgal growth characteristics, nutrients removal, anti-oxidative responses, and antibiotics removal and transformations. Sulfamethoxazole (SMX), tetracycline (TL), and clarithromycin (CLA) in single, binary, and triple combinations were investigated. SMX + TL displayed toxicity synergism while TL + CLA revealed toxicity antagonism. Phosphorus removal was comparable under all conditions, while nitrogen removal was significantly higher under SMX and TL + CLA exposure. Anti-oxidative responses suggested microalgal acclimation towards SMX, while toxicity antagonism between TL and CLA generated least cellular oxidative damage. Parent antibiotics removal was in the order of TL (74.5-85.2 %) > CLA (60.8-69.5 %) > SMX (13.5-44.1 %), with higher removal efficiencies observed under combined than single antibiotic exposure. Considering the impact of residual parent antibiotics, CLA involved cultures were identified of high ecological risks, while medium risks were indicated in other cultures. Transformation products (TPs) of SMX and CLA displayed negligible aquatic toxicity, the parent antibiotics themselves deserve advanced removal. Four out of eight TPs of TL could generate chronic toxicity, and the elimination of these TPs should be prioritized for TL involved cultures. This study expands the knowledge of combined antibiotics exposure upon microalgal biofilm based mariculture effluent polishing.
Assuntos
Antibacterianos , Biofilmes , Chlorella , Água do Mar , Poluentes Químicos da Água , Chlorella/fisiologia , Chlorella/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Antibacterianos/toxicidade , Poluentes Químicos da Água/toxicidade , Água do Mar/química , Medição de Risco , Eliminação de Resíduos Líquidos/métodos , Aquicultura , Microalgas/efeitos dos fármacos , Microalgas/fisiologiaRESUMO
BACKGROUND: Few data on the combined effects of bifurcation and calcification on coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI) are available. This study evaluated the impact of main vessel (MV) calcification on the procedural and long-term outcomes in patients with CAD who underwent provisional single stent PCI. METHODS: This is a multicenter, prospective, observational study. Patients with bifurcation lesions were enrolled at 10 PCI centers in China from January 2015 to December 2017. Intravascular ultrasound or optical coherence tomography was performed in all patients to evaluate the MV calcification. Patients were treated with provisional single stent strategy using drug eluting stents and followed-up at 1 month, 6 months and 12 months after discharge by telephone contact or outpatient visit. Repeated coronary imaging was performed within one year. We compared the procedural success rates in MV and in side branch (SB), and target lesion failure (TLF), defined as a composite of cardiac death, non-fatal myocardial infarction, definite or possible stent thrombosis and target lesion revascularization between patients with and without MV calcification. RESULTS: A total of 185 subjects were enrolled according to the inclusion and exclusion criteria of this study. MV calcification was detected in 119 (64.3%, calcification group) and not found in 66 (35.7%, non-calcification group) patients. The angiographic success rate of MV was 95.8% in the calcification group and 97.0% in the non-calcification group (P = 0.91); the angiographic success rate of SB was 32.8% in the calcification group and 53.0% in the non-calcification group (P < 0.05). During the one-year follow-up period, TLF occurred in 14 (11.8%) patients in the calcification group and in 13 (19.7%) in the non-calcification group (P = 0.31). Multivariate regression analysis showed the same result (HR = 1.23, 95% CI: 0.76-1.52, P = 0.47). Calcification on group had higher recurrent angina than non-calcification group (13.51% vs. 17.65%, P < 0.05). CONCLUSIONS: In patients with coronary bifurcation lesion treated with provisional one stent approach, calcification of MV is associated with lower SB procedural success rate, it could increase recurrence of angina; however, it was not associated with an increased risk of TLF.
RESUMO
BACKGROUND: Clearance of coronary arterial thrombosis is necessary in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing urgent percutaneous coronary intervention (PCI). There is currently no highly-recommended method of thrombus removal during interventional procedures. We describe a new method for opening culprit vessels to treat STEMI: intracoronary arterial retrograde thrombolysis (ICART) with PCI. METHODS & RESULTS: Eight patients underwent ICART. The guidewire was advanced to the distal coronary artery through the occlusion lesion. Then, we inserted a microcatheter into the distal end of the occluded coronary artery over the guidewire. Urokinase (5-10 wu) mixed with contrast agents was slowly injected into the occluded section of the coronary artery through the microcatheter. The intracoronary thrombus gradually dissolved in 3-17 min, and the effect of thrombolysis was visible in real time. Stents were then implanted according to the characteristics of the recanalized culprit lesion to achieve full revascularization. One patient experienced premature ventricular contraction during vascular revascularization, and no malignant arrhythmias were seen in any patient. No reflow or slow flow was not observed post PCI. Thrombolysis in myocardial infarction flow grade and myocardial blush grade post-primary PCI was 3 in all eight patients. No patients experienced bleeding or stroke. CONCLUSIONS: ICART was accurate and effective for treating intracoronary thrombi in patients with STEMI in this preliminary study. ICART was an effective, feasible, and simple approach to the management of STEMI, and no intraprocedural complications occurred in any of the patients. ICART may be a breakthrough in the treatment of acute STEMI.
RESUMO
Efflux of monocaroxylates like lactate, pyruvate, and ketone bodies from astrocytes through monocarboxylate transporter 4 (MCT4) supplies the local neuron population with metabolic intermediates to meet energy requirements under conditions of increased demand. Disruption of this astroglial-neuron metabolic coupling pathway may contribute to epileptogenesis. We measured MCT4 expression in temporal lobe epileptic foci excised from patients with intractable epilepsy and in rats injected with pilocarpine, an animal model of temporal lobe epilepsy (TLE). Cortical MCT4 expression levels were significantly lower in TLE patients compared with controls, due at least partially to MCT4 promoter methylation. Expression of MCT4 also decreased progressively in pilocarpine-treated rats from 12 h to 14 days post-administration. Underexpression of MCT4 in cultured astrocytes induced by a short hairpin RNA promoted apoptosis. Knockdown of astrocyte MCT4 also suppressed excitatory amino acid transporter 1 (EAAT1) expression. Reduced MCT4 and EAAT1 expression by astrocytes may lead to neuronal hyperexcitability and epileptogenesis in the temporal lobe by reducing the supply of metabolic intermediates and by allowing accumulation of extracellular glutamate.
Assuntos
Astrócitos/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Neurônios/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Masculino , Ratos Sprague-Dawley , Lobo Temporal/metabolismoRESUMO
Chloride (Clâ») channels participate in the regulation of cardiac function in response to stress although the underlying regulatory mechanism remains poorly understood. This study was designed to examine the impact of the pro-apoptotic stimulus staurosporine (STS) on the volume-sensitive outwardly rectifying Clâ» current (I(Cl,Vol)) in cardiomyocytes and possible regulatory mechanism involved with a focus on phosphatidylinositol-3 kinase (PI3K)/Akt. Primary cultured rat neonatal cardiomyocytes were subjected to hypotonic and isotonic environment in the presence or absence of STS prior to whole-cell voltage-clamp evaluation of Clâ» current. Whole-cell recordings revealed that STS activated an outwardly rectifying Clâ» current with phenotypic properties reminiscent of I(Cl,Vol). These currents were outwardly rectifying with a time-dependent inactivation at positive potentials and were sensitive to 4,4'-diisothiocya-natostilbene- 2,2'- disulfonicacid (DIDS), a non-selective Clâ» channel blocker, and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl)oxybutyric acid (DCPIB), a selective VSOR Clâ» channel blocker. DIDS and DCPIB inhibited I(Cl,Vol) by 92.6% ± 7.3% and 78.4% ± 5.5%, respectively. Our data further revealed that the PI3K inhibitor LY294002 facilitated the current with the peak amplitude of 19.54 ± 2.70 pA/pF. To the contrary, insulin partially inhibited the current amplitude with the peak current amplitude of 15.4 ± 2.13 pA/pF. Taken together, our data depicted staurosporine is capable of activating I(Cl,Vol) channel in cardiomyocytes via possibly a PI3K/Akt-dependent mechanism.
Assuntos
Agonistas dos Canais de Cloreto , Moduladores de Transporte de Membrana/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estaurosporina/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Células Cultivadas , Canais de Cloreto/antagonistas & inibidores , Canais de Cloreto/metabolismo , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Soluções Hipotônicas , Insulina/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Moduladores de Transporte de Membrana/agonistas , Moduladores de Transporte de Membrana/antagonistas & inibidores , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Fosfatidilinositol 3-Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase , Ratos , Ratos Sprague-Dawley , Estaurosporina/agonistas , Estaurosporina/antagonistas & inibidoresRESUMO
The majority of renal cell carcinomas (RCCs) are characterized by loss of function of the tumor suppressor gene von Hippel Lindau (VHL), which acts as ubiquitin ligase for hypoxia-inducible factor-1α (HIF-1α). In the absence of VHL, HIF-1α protein becomes stabilized and contributes to tumorigenesis. Recent data demonstrate the antitumor efficacy of VHL promoter in RCC cells. This study demonstrates that N-Myc downstream-regulated gene 2 (NDRG2) is a potential regulator of VHL. NDRG2 is involved in proliferation and invasion of cancer cell, furthermore it is frequently down-regulated in renal cell carcinoma. Herein we evaluated the effect of NDRG2 overexpression on proliferation and invasion in human renal cancer cells. The human renal cancer cell line 786-O and A498 were infected with Ad-NDRG2 or Ad-LacZ. Overexpression of NDRG2 not only inhibited the growth of the cells, but also suppressed the invasion. Further study showed that the tumor suppressor gene VHL were up-regulated, whereas transcription factor HIF-1a and vascular endothelial growth factor (VEGF) were down-regulated in 786-O cells infected by Ad-NDRG2. Finally, in a nude mouse model, intratumoral injections of Ad-NDRG2 every 3 days for a total of seven times significantly inhibited the growth and angiogenesis of xenografted 786-O tumors. In conclusion, these data indicate that NDRG2 may be involved in proliferation and invasion by impacting the expression of VHL and HIF-1α. NDRG2 may be an attractive therapeutic target for renal cell carcinoma.
RESUMO
Gliomas are the leading cause of death among adults with primary brain malignancies. Treatment for malignant gliomas remains limited, and targeted therapies have been incompletely explored. In this study, we found that the protein expression of presenilin 2 (PS2) was significantly increased in glioma tissues, at least partially because of promoter demethylation. We further evaluated the biological functions of PS2 in U251 glioma cell proliferation, migration, invasion, and tumor growth in vivo by specific inhibition of PS2 using short hairpin RNA (shRNA). We found that PS2 depletion inhibited glioma cell growth as the result of inhibited proliferation and induced apoptosis. PS2 depletion also decreased the invasive capability of glioma cells and anchorage-independent colony formation in soft agar. Moreover, suppression of PS2 expression significantly impaired the growth of glioma xenografts in nude mice. Finally, the decrease in glioma cell growth caused by PS2 depletion seems to involve Nrg1/ErbB signaling. In summary, our data highlight the use of RNA interference (RNAi) as a tool to better understand the molecular basis of PS2 in glioma progression and to uncover new targets for the treatment of glioma.