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Flare and multiple recurrences pose significant challenges in gouty arthritis. Traditional treatments provide temporary relief from inflammation but fail to promptly alleviate patient pain or effectively prevent subsequent recurrences. It should also be noted that both anti-inflammation and metabolism of uric acid are necessary for gouty arthritis, calling for therapeutic systems to achieve these two goals simultaneously. In this study, we propose a biomimetic integrated nanozyme, HMPB-Pt@MM, comprising platinum nanozyme and hollow Prussian blue. It demonstrates anti-inflammatory properties by eliminating reactive oxygen species and reducing infiltration of inflammatory macrophages. Additionally, it rapidly targets inflamed ankles through the camouflage of macrophage membranes. Furthermore, HMPB-Pt@MM exhibits urate oxidase-like capabilities, continuously metabolizing locally elevated uric acid concentrations, ultimately inhibiting multiple recurrences of gouty arthritis. In summary, HMPB-Pt@MM integrates ROS clearance with uric acid metabolism, offering a promising platform for the treatment of gouty arthritis.
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There have been concerns raised about the environmental effects of perfluoroalkyl substances (PFASs) because of their toxicity, widespread distribution, and persistence. Understanding the occurrences and ecological risk posed by PFASs is essential, especially for the short-chain replacements perfluorobutanoic acid (PFBA) and perfluorobutane sulfonic acid (PFBS), which are now becoming predominant PFASs. The lack of aquatic life criteria (ALC), however, prevents an accurate assessment of the ecological risks of PFBA and PFBS. This study thus investigated the occurrence of 15 PFASs at 29 sampling sites in Shaying River Basin (in China) systematically, conducted the toxicity tests of PFBA and PFBS on eight resident aquatic organisms in China, and derived the predicted non-effect concentration (PNEC) values for PFBA and PFBS for two environmental media in China. The results showed that the total PFASs concentrations (ΣPFASs) ranged from 5.07 to 20.32 ng/L (average of 10.95 ng/L) in surface water, whereas in sediment, ΣPFASs ranged from 6.46 to 20.05 ng/g (dw) (average of 11.51 ng/g). The presence of PFBS was the most prominent PFASs in both water (0.372-8.194 ng/L) and sediment (4.54-15.72 ng/g), demonstrating that short-chain substitution effects can be observed in watersheds. The PNEC values for freshwater and sediment were 6.60 mg/L and 8.30 mg/kg (ww), respectively, for PFBA, and 14.04 mg/L, 37.08 mg/kg (ww), respectively, for PFBS. Ecological risk assessment of two long-chain PFASs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), and two short-chain PFASs, PFBA and PFBS, using the hazard quotient method revealed that Shaying River and other major River Basins in China were at risk of PFOS contamination. This study contributes to a better understanding of the presence and risk of PFASs in the Shaying River and first proposes the ALCs for PFBA and PFBS in China, which could provide important reference information for water quality standards.
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Ácidos Alcanossulfônicos , Fluorocarbonos , Poluentes Químicos da Água , Rios , Monitoramento Ambiental , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise , Exposição Ambiental , Ácidos Alcanossulfônicos/toxicidade , Ácidos Alcanossulfônicos/análise , Fluorocarbonos/toxicidade , Fluorocarbonos/análise , ChinaRESUMO
Stormwater wetlands play a crucial role in the urban environment, providing many ecosystem services. In this work, a stormwater wetland was developed to study the effects on the removal of pollutants and the characteristics of dissolved organic matter (DOM) under different operating conditions, such as hydraulic retention time (HRT) and water depth. The results showed that the stormwater wetland exhibited excellent pollutant-removal performance, such as NH4+_N, TN, TP, COD, and suspended solids (SS). The removal rates for these substances reached 79.1%, 73.2%, 89.0%, 84.3%, 80.4%, and 73.77, respectively, with 24 h of HRT and 15 cm of water depth. An increase in HRT can improve the removal rates of TN, TP, COD, and TOC. The removal rates for these parameters decreased with increasing water depth, though, except for TP; the UV-VIS spectral parameters indicated that an obvious decrease occurred in the degrees of humification and aromaticity of DOM with increasing HRT and water depth after the stormwater wetland treatment. Parallel factor (PARAFAC) analysis identified six fluorescent components (one combination of freshly produced biologically labile matter and a tryptophan-like component, one fulvic-like, one humic-like, and three tryptophan-like), whose fluorescence intensity was weakened after the stormwater wetland treatment. The lowest intensity appeared with 24 h of HRT and 15 cm of water depth. This study could be beneficial for understanding and managing stormwater wetlands, thus alleviating the impacts of pollutants on urban environments.
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Poluentes Ambientais , Matéria Orgânica Dissolvida , Áreas Alagadas , Ecossistema , Triptofano , Espectrometria de Fluorescência , Substâncias Húmicas/análiseRESUMO
The aim of this study was to prepare HY-038 solid dispersions (SDs) with single carrier at high drug loading and then forming a tablet to enhance solubility, dissolution, and bioavailability via spray drying technology. At the same time, we hope to develop a more convenient in vitro method to predict the absorption behavior of different formulations in vivo. Different solid dispersions, varying in drug/polymer ratios, were prepared. Infrared spectroscopy, differential scanning calorimetry, scanning electron microscope, and X-ray diffraction were used to perform solid-state characterizations of the pure drug and SDs. Contact angle of water, dissolution in pH = 6.8 phosphate buffer, and in vivo absorption in dogs were studied. As a result, solid-state characterization demonstrated the transformation of the crystalline HY-038 to an amorphous state in the solid dispersions, and the in vivo exposure followed with the trend of the dissolution curve combined with contact angle. Compared with the prototype formulation, the Cmax and AUC0-∞ of optimized formulation SD2 (HY-038-HPMCAS 3:1) increased by about 5 ~ 9 times at the same dose. More importantly, the SD2 formulation showed approximately linear increases in Cmax and AUC0-∞ as the dose increased from 50 to 100 mg, while the prototype formulation reached absorption saturation at 50 mg. SD2 (HY-038-HPMCAS 3:1) was selected as the best formulation for the downstream development.
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Secagem por Atomização , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Cães , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Comprimidos , Difração de Raios XRESUMO
Current Chinese surface water environmental quality standard GB3838-2002 for ammonia fails to take water quality factors and native organism distributions in different basins into consideration. In this study, ammonia toxicity tests were performed using three aquatic organisms native to the Shaying River Basin (China). Published ammonia toxicity data with pH and temperature, and toxicity data acquired in this study were used to establish water quality criteria. The final criterion maximum concentration (CMC) and criterion continuous concentration (CCC) for the Shaying River Basin were 5.09 and 1.36 (mg total ammonia nitrogen (TAN))/L (pH 7 and 20 °C), respectively. In addition, based on the corresponding relationship between ammonia toxicity and temperature and pH, the ecological risk assessment of ammonia was conducted in different seasons for the Shaying River using a tiered approach of both hazard quotient (HQ) and the joint probability (JPC) methods. Two methods gave consistent results: the ecological risks of ammonia to aquatic species in the Shaying River Basin were severe and the risk could be ranked as wet season > flat season > dry season. It is therefore indicating that monitoring, evaluation, and early warning of ammonia pollution need to be taken to prevent and control the risks posed by ammonia pollution, especially for wet season (because of high temperatures and pH) or flat season (because of high pH values). We hope the present work could provide valuable information to manage and control ammonia pollution in the Shaying River Basin.
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Amônia/análise , Poluentes Químicos da Água/análise , Amônia/toxicidade , Organismos Aquáticos , China , Monitoramento Ambiental/métodos , Nitrogênio , Medição de Risco/métodos , Rios/química , Estações do Ano , Testes de Toxicidade , Poluentes Químicos da Água/toxicidade , Qualidade da Água/normasRESUMO
BACKGROUND: Acute respiratory distress syndrome (ARDS) causes substantial mortalities. Alveolar epithelium is one of the main sites of cell injuries in ARDS. As an important kind of microRNAs (miRNAs), microRNA-145 (miR-145) has been studied in various diseases, while its role in ARDS has not been investigated. METHODS: Lipopolysaccharide (LPS) was intratracheally instilled to establish a rat ARDS model. Cytokines from bronchoalveolar lavage fluid (BALF) were measured using rat tumor necrosis factor-α and interleukin-6 enzyme-linked immunosorbent assay kits (R&D Systems), and the pathological structures were evaluated using hematoxylin and eosin (H&E) staining and transmission electron microscope; the lung miR-145 messenger RNA (mRNA) was detected using quantitative polymerase chain reaction. Bioinformatics focused on the target genes and possible pathways of gene regulation. RESULTS: A rat model of LPS-induced ARDS was successfully established. The miR-145 was down-regulated in the LPS-induced ARDS lung, and mitochondrial dysfunction was observed in alveolar epithelial cells, most obviously at 72 hours after LPS. TargetScan and miRDB databases were used to predict the target genes of miR-145. A total of 428 overlapping genes were identified, seven genes were associated with mitochondrial function, and Ogt, Camk2d, Slc8a3, and Slc25a25 were verified. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, and Gene Ontology (GO) biological process was mainly enriched in signal transduction and transcription regulation. CONCLUSIONS: The miR-145 is down-regulated in LPS-induced ARDS, and affects its downstream genes targeting mitochondrial functions.
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ETHNOPHARMACOLOGICAL RELEVANCE: Xuanbai Chengqi decoction (XBCQ), a traditional Chinese medicine formulation, was reported to have a protective role in a variety of pulmonary infection diseases. However, its mechanism remains uncertain. In the current study, we investigated the potential mechanism of XBCQ, its therapeutic effects on organ injuries induced by sepsis and gut microbiota modulation. MATERIAL AND METHODS: 80 Male Sprague Dawley rats were performed cecal ligation and puncture (CLP) for sepsis model and 60 of them were treated with different doses of XBCQ (3.78, 7.56, 15.12 g/Kg, 20 rats per group) twice per day. After the most valid dose was determined, another 40 rats were divided randomly into four groups: sham group, sham + XBCQ group, sepsis group, sepsis + XBCQ group. The sepsis + XBCQ group was treated with XBCQ by intragastric administration and then twice per day. Feces of the rats were collected and the gut microbiota constituents were analyzed by 16S rDNA sequencing. Histological changes were observed by H&E staining. Occludin content in the colon was determined by immunohistochemical analysis. The concentrations of cytokines were determined by enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: The survival rate of septic rats was increased significantly at the dose of 7.56 g/Kg from 50% to 80% at 72 h. The gut microbiota richness and composition were disturbed in septic rats. XBCQ altered the gut microbiota, involving alpha diversity changes, significantly reducing the relative abundance of Bacteroidaceae and ClostridiumXI and increasing that of Firmicutes and Actinobacteria. Furthermore, the relative abundances of Lactobacillus, Butyricicoccus and Bifidobacterium were increased by XBCQ. Moreover, the gut barrier dysfunction was improved by XBCQ through restoring the impaired tight conjunction protein Occludin. The concentration of diamine oxidase was decreased, while the D-lactate level was elevated. Meanwhile, the level of myeloperoxidase (MPO) in the lung tissue of the XBCQ-treated group was reduced. Lung injury was also alleviated by decreased levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and interleukin 10 (IL-10) in bronchoalveolar lavage fluids (BALFs). The relative abundance of potential microbial biomarkers in four groups significantly correlated with the concentration of inflammatory factors in BALFs. CONCLUSIONS: Our results suggested that XBCQ had a protective role against sepsis by modulating the gut microbiota, restoring the intestinal epithelial barrier and decreasing inflammatory responses.
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Anti-Inflamatórios/farmacologia , Bactérias/efeitos dos fármacos , Colo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Lesão Pulmonar/prevenção & controle , Pulmão/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Bactérias/crescimento & desenvolvimento , Líquido da Lavagem Broncoalveolar , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Disbiose , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/microbiologia , Lesão Pulmonar/patologia , Masculino , Permeabilidade , Ratos Sprague-Dawley , Sepse/metabolismo , Sepse/microbiologia , Sepse/patologiaRESUMO
In order to study the pollution source and ecological risk assessment of polycyclic aromatic hydrocarbons (PAHs) in the Jiaxing river network, PAHs were analyzed by GC-MS. The results show that with the influence of rainfall and surface runoff in the wet season, the types and mass concentrations of PAHs in the river network of Jiaxing differ from the dry season. Ten and 16 priority PAHs were detected in the dry season and wet season, respectively. The average mass concentration of PAHs in the dry season was 143.83ng·L-1 and 73.47ng·L-1 in the wet season. The range of mass concentration of PAHs in the dry and wet season was 77.32-283.76ng·L-1 and 13.05-133.02ng·L-1, respectively, and 2-ring and 3-ring PAHs accounted for 79.18% in the dry season and 73.60% in the wet season. PAHs pollution in the river network of Jiaxing was at a low level compared with the domestic and foreign areas. The isomer ratio and principal component analysis found that the PAHs in the Jiaxing river network mainly come from urban non-point source pollution, combustion source, and traffic pollution in the dry season and wet season. The results of the Kalf risk entropy method show that in the dry season, naphthalene(Nap), acenaphthylene(Acy), acenaphthene(Ace), fluorene(Flu), phenanthrene(Phe), anthracene(Ant), fluoranthene(Fla), pyrene(Pyr), and benzo(a)anthracene(BaA) are at moderate ecological risk. In the wet season, Nap, Acy, Flu, Phe, Fla, Pyr, BaA, benzo(b)fluoranthene(BbF), benzo(k)fluoranthene(BkF), benzo(a)pyrene(BaP), indeno(1,2,3-cd)pyrene(InP), and benzo(g,h,i)perylene(BghiP) are at moderate ecological risk. In the dry season, ∑PAHs are at moderate ecological risk, and low in the wet season. On the whole, PAHs pollution in the Jiaxing river network presents moderate ecological risk levels, and measures to reduce the ecological risk of PAHs in the river network should be taken by the Departments concerned.
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Hidrocarbonetos Policíclicos Aromáticos , Monitoramento Ambiental , Poluição Ambiental , Hidrocarbonetos Policíclicos Aromáticos/análise , Medição de Risco , Rios , Estações do AnoRESUMO
(1) Background: It is common practice in the treatment of respiratory diseases to mix different inhalation solutions for simultaneous inhalation. At present, a small number of studies have been published that evaluate the physicochemical compatibility and aerosol characteristics of different inhalation medications. However, none of them studied Atrovent®. Our work aims to address the lack of studies on Atrovent®. (2) Methods: Portions of admixtures were withdrawn at certain time intervals after mixing and were tested by pH determination, osmolarity measurement, and high-performance liquid chromatography (HPLC) assay of each active ingredient as measures of physicochemical compatibility. The geometrical and aerosol particle size distribution, active drug delivery rate, and total active drug delivered were measured to characterize aerosol behaviors. (3) Results: During the testing time, no significant variation was found in the pH value, the osmotic pressure, or the active components of admixtures. With the increase in nebulization volume after mixing, fine particle dose (FPD) and total active drug delivered showed statistically significant improvements, while the active drug delivery rate decreased compared to the single-drug preparations. (4) Conclusions: These results endorse the physicochemical compatibility of Atrovent® over 1 h when mixed with other inhalation medications. Considering aerosol characteristics, simultaneous inhalation is more efficient.
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Hardness is one important water quality parameter that influences the toxicity of cadmium. Several studies have derived water quality criteria (WQC) for cadmium, but most of these studies did not consider environmental factors. Moreover, few studies considered environmental factors when carrying out ecological risk assessments (ERA) based on environmental factors. In this research, six native aquatic organisms in the Shaying River were adopted to conduct toxicity tests for cadmium. By combining published toxicity data for cadmium with hardness values and toxicity data from this study, hardness-dependent WQC were established. When normalized to a hardness of 100 mg/L CaCO3, the criterion maximum concentration (CMC) of 6.46 µg/L and criterion continuous concentration (CCC) of 1.49 µg/L in the Shaying River Basin were derived according to the USEPA guidelines. The acute predicted no effect concentrations (PNECs) derived by species sensitivity distribution (SSD) methods based on log-logistic, log-normal and Burr Type III models were 1.03, 2.41 and 1.66 µg/L, respectively. Recommended WQC values finally expressed as a function of hardness: (1) CMC=(1.136672-0.041838 × lnH) × e0.9969×lnH-2.6676; and (2) CCC=(1.101672-0.041838 × lnH) × e1.0083×lnH-6.1156. In addition, three tiers of ERA of cadmium in surface waters were conducted based on hardness obtained during different seasons in the Shaying River using the hazard quotient (HQ), the margin of safety (MOS10), and the joint probability (JPC) methods. In tiered 1, 2, and 3 ERA, cadmium exposure concentrations were standardized to a hardness of 100 mg/L. The three levels of the ERA method in the tiered framework gave consistent results: the ecological risks of cadmium in the Shaying River Basin were at acceptable levels. The present study provides a reference for the derivation of WQC and risk assessment of pollution affected by differences in aquatic species and water quality factors such as hardness.
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Cádmio/análise , Monitoramento Ambiental/métodos , Poluentes Químicos da Água/análise , Organismos Aquáticos , China , Dureza , Medição de Risco/métodos , Rios , Estações do Ano , Testes de Toxicidade , Qualidade da Água/normasRESUMO
PURPOSE: Cancer chemotherapy effect has been largely limited by cell autophagy and little drug accumulation at the action sites. Herein, we designed an intelligent strategy involving paclitaxel (PTX) polymer micelles in response to biological functions of ambroxol (Ax). The amphiphilic polymers polyethyleneglycol-polylactic acid (PEG-PLA) and Pluronic P105 were selected as nanocarriers to encapsulate PTX to form into lung affinity PEG-PLA/P105/PTX micelles. Ax which can up-regulate the secretion of pulmonary surfactant (PS) and inhibit autophagy was hired to change the microenvironment of the lung, thereby promoting the lung accumulation and increasing cell-killing sensitivity of the micelles. METHODS: The physical and chemical properties of the micelles were characterized including size, morphology, critical micellar concentration (CMC) and in vitro drug release behavior. The therapeutic effects of the combination regimen were characterized both in vitro and in vivo including study on Ax in promoting the secretion of pulmonary surfactant, in vitro cytotoxicity, cellular uptake, Western blotting, in vivo biodistribution, in vivo pharmacokinetics and in vivo antitumor efficacy. RESULTS: The PEG-PLA/P105/PTX micelles showed a particle size of 16.7 ± 0.5 nm, a nearly round shape, small CMC and sustained drug release property. Moreover, the in vitro results indicated that Ax could increase PS and LC3 protein secretion and enhance the cytotoxicity of PEG-PLA/P105/PTX micelles toward A549 cells. The in vivo results indicated that the combination therapeutic regimen could promote the micelles to distribute in lung and enhance the therapeutic effect on lung cancer. CONCLUSION: This multifunctional approach of modulating the tumor microenvironment to enhance drug transportation and cell-killing sensitivity in the action sites might offer a new avenue for effective lung cancer treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , Ambroxol/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Micelas , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Tamanho da Partícula , Poloxâmero/química , Polietilenoglicóis/química , Polímeros/química , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Hepatocellular carcinoma (HCC) is a prevalent and highly malignant cancer throughout the world. Effective treatment of this disease is impeded by the high rate of metastasis, recurrence, and chemoresistance. Recent studies have revealed the close relationship between the malignant phenotype of HCC and cancer stem cells (CSCs). Therefore, CSC-targeted therapy is considered a promising strategy to eradicate HCC. Traditional Chinese medicine (TCM) can be effective in preventing recurrence and metastasis of some advanced HCC. A growing amount of literature has discovered that extracts or compounds derived from TCM exert an anti-CSC effect. This review introduces some formulas and chemical compounds derived from TCMs that have been reported to inhibit CSCs of HCC; these TCM-related drugs may help to provide an alternative approach to help manage cancers, especially for HCC which has a great potential of metastasis, recurrence, and chemoresistance.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Medicina Tradicional Chinesa , Células-Tronco Neoplásicas , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/terapiaRESUMO
BACKGROUND: We report a case of giant gastroduodenal trichobezoar, an extremely rare upper gastrointestinal bezoar due to trichotillomania and trichophagia. CASE SUMMARY: The patient was a 10-year-old girl who presented with an abdominal mass that was discovered at palpation and noninvasive imaging examinations. Computed tomography (CT) showed a well-circumscribed heterogeneous mass extending from the stomach into the duodenum. The patient underwent a laparotomy to pull out the trichobezoar. Although these imaging findings are nonspecific, trichobezoar should be included in the differential diagnosis of gastric mass, especially with the history of an irresistible urge to pull out and swallow their hair. CONCLUSION: Laparotomy is useful and practical for the management of giant gastroduodenal trichobezoar.
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BACKGROUND: Secondary infection has a higher incidence in septic patients and affects clinical outcomes. This study aims to investigate the clinical characteristics, risk factors, immune status and prognosis of secondary infection of sepsis. METHODS: A four-year retrospective study was carried out in Zhongshan Hospital, Fudan University, enrolling septic patients admitted between January, 2014 and January, 2018. Clinical data were acquired from medical records. CD14+ monocyte human leukocyte antigen-D related (HLA-DR) expression and serum cytokines levels were measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: A total of 297 septic patients were enrolled, 92 of whom developed 150 cases of secondary infections. Respiratory tract was the most common site of secondary infection (n = 84, 56%) and Acinetobacter baumanii the most commonly isolated pathogen (n = 40, 31%). Urinary and deep venous catheterization increased the risk of secondary infection. Lower HLA-DR expression and elevated IL-10 level were found in secondary infection group. The expected prolonged in-hospital stay owing to secondary infection was 4.63 ± 1.87 days. Secondary infection was also associated with higher in-hospital, 30-day and 90-day mortality. Kaplan-Meier survival analysis and Log-rank test revealed that secondary infection group had worse survival between day 15 and day 90. CONCLUSIONS: Urinary and deep venous catheterization increased the risk of secondary infection, in which underlying immunosuppression might also play a role. Secondary infection affected the prognosis of septic patients and prolonged in-hospital length of stay.
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Coinfecção/epidemiologia , Citocinas/sangue , Sepse/epidemiologia , Idoso , Coinfecção/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Sepse/imunologia , Sepse/mortalidadeRESUMO
Organophosphorus pesticides are effective, cheap, and used extensively but can harm aquatic organism and human health. Here, water quality criteria (WQCs) for dichlorvos (DDVP) and malathion (MAL) were derived. Nine aquatic organisms native to China were used in toxicity tests. Published toxicity data for aquatic organisms native and non-native to China were also analyzed. DDVP and MAL WQCs were derived using (log-normal model) species sensitivity distributions. Species sensitivity distribution curves indicated native and non-native species have different sensitivities to DDVP. The sensitivities of native and non-native species to MAL were not different because non-native species data for fewer than eight genera were available, so further research is required. The results indicated that native species need to be considered when deriving WQCs. The criteria maximum concentration (CMC) and criteria continuous concentration (CCC) were 1.33 and 0.132 µg/L, respectively, for DDVP, and 0.100 and 0.008 µg/L, respectively, for MAL. The CMCs for DDVP and MAL derived using ETX 2.0 software and species sensitivity ranks were different from the CMCs obtained using the SSD method because of parameter uncertainties. The DDVP and MAL WQCs were significantly lower than Chinese surface water quality standard thresholds. The results provide basic data for revising these thresholds.
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Diclorvós/análise , Malation/análise , Praguicidas/análise , Poluentes Químicos da Água/análise , Qualidade da Água/normas , Animais , Organismos Aquáticos , China , Humanos , Testes de ToxicidadeRESUMO
Hepatocyte growth factor (HGF) was encapsulated into sterically stabilized liposomes (SSL) in order to protect it from in vivo degradation. Cyclic Arg-Gly-Asp (RGD) peptides were combined with maleimide-[poly (ethylene glycol)]-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (MAL-PEG-DOPE) incorporated into SSL. The average percentage of HGF encapsulated into liposomes was 32.38%, the size of liposomes was 91.56 nm and the polydispersity index was 0.164. In vivo, histological observation of the rat livers revealed that injection of RGD-SSL-HGF induced more significant remission of liver cirrhosis than injection of SSL-HGF, HGF alone, HGF plus RGD-SSL and saline. When the histological score, the collagen surface density, the hydroxyproline content and the expression of procollagen alpha1 (I) and alpha1 (III) mRNA in the liver were evaluated, all values were smallest in the RGD-SSL-HGF group. In contrast, an increase in apoptotic alpha-SMA-positive cells was noted in the RGD-SSL-HGF group. Together, this data suggests that targeted liposomes encapsulating HGF is a promising therapeutic modality in terms of promoting the remission of liver cirrhosis by promoting collagen fiber digestion, inhibiting collagen production, and promoting apoptosis of alpha-SMA-positive cells in rats with cirrhosis.
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Fator de Crescimento de Hepatócito/uso terapêutico , Lipossomos/uso terapêutico , Cirrose Hepática Experimental/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Colágeno Tipo I/análise , Cadeia alfa 1 do Colágeno Tipo I , Portadores de Fármacos/síntese química , Portadores de Fármacos/uso terapêutico , Fator de Crescimento de Hepatócito/administração & dosagem , Fator de Crescimento de Hepatócito/metabolismo , Hidroxiprolina/análise , Lipossomos/síntese química , Lipossomos/química , Fígado/química , Fígado/efeitos dos fármacos , Maleimidas/síntese química , Oligopeptídeos/síntese química , Oligopeptídeos/química , Fosfatidiletanolaminas/síntese química , Fosfatidiletanolaminas/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , RatosRESUMO
Targeting hepatic stellate cells (HSCs) has been challenging due to the lack of specific receptors or motifs on the cells. The aim of the present study was to develop a HSC-specific system for improving drug delivery to HSCs. The affinity of a cyclic peptide containing Arg-Gly-Asp (cRGD) to collagen type VI receptor on HSCs was examined in both in vitro and in vivo experiments. Sterically stable liposomes (SSLs) were modified with this peptide to yield a new carrier, cRGD-SSL. The targeting efficiency of this carrier in delivering interferon (IFN)-alpha1b was investigated in a rat model of liver fibrosis induced by bile duct ligation (BDL). When incubating HSCs or hepatocytes with cyclic RGD peptide, the peptide was bound preferentially to activated HSCs. Biodistribution study showed that the accumulation of cRGD peptide-labeled liposomes in HSCs isolated from BDL rats was 10-fold more than unlabeled SSLs. BDL rats receiving injections of IFN-alpha1b entrapped in cRGD-SSL exhibited significantly reduced extent of liver fibrosis compared with BDL control rats or BDL rats treated with IFN-alpha1b entrapped in SSLs. Thus, cRGD-SSL is an efficient drug carrier, which selectively targets activated HSCs and improves drug therapy for liver fibrosis to a significant extent. This liposomal formulation represents a new means of targeting drug carrier for the treatment of liver fibrosis, and it may have potential clinical applications.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Interferon-alfa/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Pericitos/metabolismo , Alanina Transaminase/sangue , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colestase Extra-Hepática/complicações , Colestase Extra-Hepática/tratamento farmacológico , Colestase Extra-Hepática/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Endocitose/fisiologia , Expressão Gênica/efeitos dos fármacos , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hidroxiprolina/metabolismo , Interferon-alfa/química , Interferon-alfa/farmacologia , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Masculino , Maleimidas/química , Oligopeptídeos/química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Pericitos/efeitos dos fármacos , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos , Ratos Wistar , Lipossomas Unilamelares/químicaRESUMO
OBJECTIVE: To evaluate the antifibrotic effect of receptor-mediated sterical stability liposome (SSL) targeting hepatic stellate cells (HSCs) and containing recombinant human interferon-alpha 1b (IFNalpha-1b) on hepatic cirrhosis. METHODS: The ligand, cyclo (RGD) with specific affinity to HSCs, was incorporated via PEG into the lipid bilayers of SSL. Forty male SD rats were randomly divided into 4 equal groups: liver fibrosis model group undergoing double ligation and cutting of the common bile duct (BDL group), BDL + IFN-SSL group, undergoing BDL and injection of IFN 50,000 IU per week via caudal vein for 4 times; IFN-RGD-SSL treatment group, undergoing BDL and injection of IFN-RGD-SSL (equal to 50,000 IU per week) via caudal vein for 4 times; and sham operation group used as control. The rats were killed 24 hours after the last injection. Their livers and serum samples were collected. Pathological changes of the liver were observed with HE and alpha-SMA immunohistochemical staining. Biochemical automatic analyzer was used to test the serum indices of liver function: ALT, AST, total bilirubin (TBIL), alkaline phosphatase, and gamma-glutamine (gamma-GT). Radioimmunoassay method was used to examine the s serum index of liver fibrosis: HA, procollagen III (PCIII), LN, and CIV. Colorimetry was used to examine the level of hydroxyl proline (Hyp). RT-PCR was used to detect the mRNA expression of type I collagen. Western blotting was used to examine the protein expression of alpha-SMA of HSC. RESULTS: Compared with the control group, liver fibrosis was seen in the other 3 groups, especially in the BDL group. In comparison with the sham operation group, the levels of serum indices of liver fibrosis, liver hydroxyl proline content, and expression of type I collagen mRNA and alpha-SMA protein in liver were significantly higher in the other groups (all P < 0.05), being significantly lower in the BDL + IFN-RGD-SSL group than in the BDL + IFN-SSL group (all P < 0.05). CONCLUSION: The receptor-mediated IFN-RGD-SSL displays good targeting antifibrotic effects on liver fibrosis.
Assuntos
Interferon Tipo I/uso terapêutico , Cirrose Hepática Experimental/terapia , Oligopeptídeos/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Actinas/biossíntese , Actinas/genética , Animais , Colágeno Tipo I/biossíntese , Colágeno Tipo I/genética , Lipossomos , Testes de Função Hepática , Masculino , RNA Mensageiro/biossíntese , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteínas RecombinantesRESUMO
OBJECTIVE: To investigate the binding characteristics between an artificial Arg-Gly-Asp (RGD)-containing cyclic peptide [cyclo(CGRGDSPK)] and rat hepatic stellate cells (HSC). METHODS: An artificial RGD-containing cyclic peptide was labeled with fluorescein isothiocyanate (FITC). HSCs were isolated by collagenase in situ liver recirculating and purified by density gradient centrifugation from normal rats. The cells were cultured for 5 days of primary culture (quiescent phenotype) or for 7 days of secondary culture (activated phenotype). To access the binding and uptake, HSCs were incubated with FITC-cRGD of different concentrations at 4 degree C or 37 degree C, and then the binding and uptake were investigated by flow cytometry. The location of FITC-cRGD in HSC was investigated by fluorescent microscopy. Kd and maximal binding sites per cell were calculated by radioligand binding assay (RBA) of receptors using 3H-cRGD. In the interim, FITC-cAGA was used as a peptide control devoid of any binding site. RESULTS: The binding between FITC-cRGD and HSC was saturable, time- and dose-dependent and could compete with overdosed unlabeled cRGD. The fluorescence was mainly distributed in cytoplasma, especially near the nuclei. Kd was 7.05 x 10(-9) mol/L and Bmax per cell was nearly 6.79 x 10(5). CONCLUSIONS: The results demonstrate that cRGD are specifically taken up by HSC through a receptor-mediated pathway. The information is useful for understanding the ligand-receptor interaction of HSC. FITC labeled cyclic RGD-peptides meet the standards of special ligands and FITC does not change the binding activation of cyclic RGD-peptides.