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1.
J Cell Physiol ; 235(1): 380-393, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31232476

RESUMO

Atherosclerosis (AS), a chronic disorder of large arteries, is the underlying pathological process of heart disease and stroke. Former researchers have found that microRNAs (miRs) are involved in the several key processes of AS. Apolipoprotein E knockout (ApoE-/- ) mice fed a high-fat-diet (HFD) to establish AS model. The expression of miR-103 was characterized in the mice model. The effects of miR-103 on inflammation and endoplasmic reticulum stress (ERS) were analyzed when the expression of miR-103 was inhibited in ApoE -/- mice fed an HFD and human aortic endothelial cells (HAECs) exposed to oxidized low-density lipoprotein (ox-LDL). The relationship between miR-103 and phosphatase and tensin homolog (PTEN) was identified by luciferase activity detection and real-time quantitative polymerase chain reaction (RT-qPCR). Gain- and loss-function approaches were further applied for investigating the regulatory effects of miR-103 and PTEN on ERS. Role of MAPK signaling was then analyzed using PD98059 to block this pathway. miR-103 was highly expressed in the ApoEApoE -/- mice fed an HFD. Downregulation of miR-103 suppressed inflammation and ERS in endothelial cells isolated from ApoE -/- mice fed a HFD and ox-LDL-exposed HAECs. In addition, miR-103 can target PTEN and downregulate its expression. Overexpression of PTEN reversed the miR-103-induced activation of MAPK signaling. Moreover, PTEN upregulation or MAPK signaling inhibition ease miR-103-induced inflammation and ERS in vivo and in vitro. Thus, miR-103 depletion restrains the progression of AS through blocking PTEN-mediated MAPK signaling.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31493078

RESUMO

Cell culture liquid waste containing antibiotic resistance genes (ARGs) and microbial community were still not received enough recognition, which pose potential risks to human health. Sixty-eight resistance genes and intl1 were detected in eight samples by Quantitative real-time PCR, while intl1 was only detected in hospital group. Meanwhile, the bacterial community was complex and diverse in each sample by 16S rRNA gene high-throughput sequencing, in addition, Morganella and Enterococcus presented a significant difference between two groups. Whole genome shotgun sequencing revealed that Morganella morganii had more resistance genes and virulence factors in hospital group, and three extended-spectrum beta-lactamase (ESBL) genotypes were found to be blaDHA-5, blaOXA-1, and blaTEM-1. This study provided a preliminary report on ARGs and resistant strains, which reminded people attention to the health risks of potential pathogens in this waste.

3.
Opt Express ; 27(18): 25560-25572, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31510427

RESUMO

Artificial intelligence (AI) techniques such as deep learning (DL) for computational imaging usually require to experimentally collect a large set of labeled data to train a neural network. Here we demonstrate that a practically usable neural network for computational imaging can be trained by using simulation data. We take computational ghost imaging (CGI) as an example to demonstrate this method. We develop a one-step end-to-end neural network, trained with simulation data, to reconstruct two-dimensional images directly from experimentally acquired one-dimensional bucket signals, without the need of the sequence of illumination patterns. This is in particular useful for image transmission through quasi-static scattering media as little care is needed to take to simulate the scattering process when generating the training data. We believe that the concept of training using simulation data can be used in various DL-based solvers for general computational imaging.

4.
Nat Commun ; 10(1): 4044, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492850

RESUMO

Acute graft-versus-host disease (GVHD) remains a major obstacle for the wider usage of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an effective therapy for hematopoietic malignancy. Here we show that caspase-11, the cytosolic receptor for bacterial endotoxin (lipopolysaccharide: LPS), enhances GVHD severity. Allo-HSCT markedly increases the LPS-caspase-11 interaction, leading to the cleavage of gasdermin D (GSDMD). Caspase-11 and GSDMD mediate the release of interleukin-1α (IL-1α) in allo-HSCT. Deletion of Caspase-11 or Gsdmd, inhibition of LPS-caspase-11 interaction, or neutralizing IL-1α uniformly reduces intestinal inflammation, tissue damage, donor T cell expansion and mortality in allo-HSCT. Importantly, Caspase-11 deficiency does not decrease the graft-versus-leukemia (GVL) activity, which is essential to prevent cancer relapse. These findings have major implications for allo-HSCT, as pharmacological interference with the caspase-11 signaling might reduce GVHD while preserving GVL activity.

5.
Shock ; 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31486774

RESUMO

Sepsis can be simulated in animals by perforating the cecum via a surgical procedure termed "cecal ligation and puncture" (CLP), which induces similar inflammatory responses as observed during the clinical course of human sepsis. In addition to anesthetic agents, many Institutional Animal Care and Use Committees (IACUC) often recommend the use of additional analgesic agents (such as opioid) to further augment the initial anesthetic effects. However, emerging evidence suggest that a commonly recommended opioid, buprenorphine, dramatically elevated circulating IL-6 levels and reduced animal survival in male C57BL/6 mice, but not in female mice possibly due to the complex interference of estrous cycles, fueling an ongoing debate regarding the possible impact of analgesic administration on the sepsis-induced systemic inflammation. As per the recommendation of a local government agency, we performed a pilot study and confirmed that repetitive administration of buprenorphine indeed markedly elevated circulating levels of four sepsis surrogate markers (e.g., IL-6, KC, MCP-1 and G-CSF) in 20- 60% of septic animals. This complication may adversely jeopardize our ability to use the CLP model to reliably simulate human sepsis, and to understand the complex mechanism underlying the pathogenesis of lethal sepsis. Thus, for experimental sepsis studies set to survey systemic inflammation and animal lethality at relatively later stages (e.g., at 24 h post CLP and beyond), we strongly recommend not to repetitively administer buprenorphine to eliminate its potential complication to animal sepsis models.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.

6.
Environ Sci Technol ; 53(18): 10676-10684, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31418557

RESUMO

In contrast to summer smog, the contribution of photochemistry to the formation of winter haze in northern mid-to-high latitude is generally assumed to be minor due to reduced solar UV and water vapor concentrations. Our comprehensive observations of atmospheric radicals and relevant parameters during several haze events in winter 2016 Beijing, however, reveal surprisingly high hydroxyl radical oxidation rates up to 15 ppbv/h, which is comparable to the high values reported in summer photochemical smog and is two to three times larger than those determined in previous observations during winter in Birmingham (Heard et al. Geophys. Res. Lett. 2004, 31, (18)), Tokyo (Kanaya et al. J. Geophys. Res.: Atmos. 2007, 112, (D21)), and New York (Ren et al. Atmos. Environ. 2006, 40, 252-263). The active photochemistry facilitates the production of secondary pollutants. It is mainly initiated by the photolysis of nitrous acid and ozonolysis of olefins and maintained by an extremely efficiently radical cycling process driven by nitric oxide. This boosted radical recycling generates fast photochemical ozone production rates that are again comparable to those during summer photochemical smog. The formation of ozone, however, is currently masked by its efficient chemical removal by nitrogen oxides contributing to the high level of wintertime particles. The future emission regulations, such as the reduction of nitrogen oxide emissions, therefore are facing the challenge of reducing haze and avoiding an increase in ozone pollution at the same time. Efficient control strategies to mitigate winter haze in Beijing may require measures similar as implemented to avoid photochemical smog in summer.

7.
Anal Chem ; 91(16): 10687-10693, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31364843

RESUMO

We describe an open-path cavity-enhanced absorption spectroscopy (OP-CEAS) technique for the ambient measurement of nitrate radicals (NO3) near 662 nm. Compared with the closed type of CEAS system with a sampling line, the OP-CEAS features high accuracy due to the lack of NO3 loss in the sampling line and cavity. On the basis of a 0.84 m long open-path cavity, the effective absorption length of ∼5 km is achieved by mirrors with a reflectivity of 0.99985 at 662 nm. The detection limit of OP-CEAS for the measurement of NO3 is 3.0 pptv (2σ) in 30 s, and the uncertainty is 11-15%. The instrument was successfully applied in a field measurement under low particulate matter (PM) loading conditions. As the sensitivity would be decreased due to strong PM extinction under heavy PM pollution conditions, we highlight the feasibility of this OP-CEAS configuration for field application in clean and moderate PM condition, such as forested regions affected by anthropogenic emissions. This technique is also appropriate for the field detection of other reactive trace gases in future studies.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31243880

RESUMO

Gastric carcinoma (GC) is a pernicious neoplasm with high morbidity and mortality. Sinomenine (SIN) has long been exploited to heal rheumatoid arthritis. Recently, SIN has been discovered to exert the antitumour functions in diverse cancers. However, the impacts of SIN on GC remain indistinct. We attempted to expose the antitumour effect of SIN on GC. MKN45 and SGC-7901 cells were administered with SIN for 24 hours, cell viability, proliferation, apoptosis, migration, invasion and the associated proteins in the above processes were examined via exploiting CCK-8, BrdU, flow cytometry, Transwell and Western blot. MiR-204 expression in GC tumour tissues, different GC cell lines and SIN-stimulated GC cells was investigated by executing RT-qPCR. The above cell biological processes were reassessed after transfection with miR-204 inhibitor. The latent mechanisms were probed by examining AMPK and Wnt/ß-catenin pathways. We found that SIN memorably repressed cell proliferation, evoked apoptosis and affected CyclinD1, Bcl-2, Bax and cleaved-caspase-3 expression in MKN45 and SGC-7901 cells. Cell migration, invasion and expression of MMP-9 and Vimentin were all restrained by SIN stimulation. The increase of miR-204 was discovered in GC tissues and SIN-treated MKN45 and SGC-7901 cells. But suppression of miR-204 was observed in AGS, MKN28, MKN45 and SGC-7901 cells. Suppression of miR-204 overturned the inhibitory functions of SIN in MKN45 and SGC-7901 cells. Besides, SIN prohibited AMPK and Wnt/ß-catenin pathways via enhancement of miR-204. In conclusion, these findings suggested that SIN exerted the antitumour activity in GC cells by hindering AMPK and Wnt/ß-catenin pathways via enhancement of miR-204.

10.
Sci Adv ; 5(5): eaav5562, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31131320

RESUMO

The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11-dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. l-adrenaline-induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11-mediated proteolytic maturation of interleukin-1ß, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 (Casp11-/- ), or Gsdmd inactivation (GsdmdI105N/I105N ) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.

11.
Curr Neurovasc Res ; 16(2): 142-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30977449

RESUMO

BACKGROUND: Cognitive impairment can occur after aneurysmal subarachnoid hemorrhage (aSAH) though it commonly tends to be neglected. Red blood cell (RBC) indices are associated with long-term functional outcomes, while it is unclear whether RBC indices could be a potential predictor of cognitive decline after aSAH. We aimed to investigate the association between RBC indices and post-aSAH cognitive impairment at 1 year. METHODS: Patients with aSAH received neuropsychological test by the Montreal Cognitive Assessment (MoCA) and underwent serum and cerebrospinal fluid (CSF) samples test. To determine the association between RBC indices and cognitive impairment after acute aSAH, we adjusted for demographic and vascular risk factors using multivariate logistic regression analysis. RESULTS: Of the 126 patients included in this study, 33% (42/126) of them were diagnosed with cognitive impairment (MoCA<26). After adjustment for potential confounders, increased mean corpuscular volume (MCV) (OR: 1.36, 95%CI: 1.19-1.55) and mean corpuscular hemoglobin (MCH) (OR: 1.61, 95%CI: 1.25-2.08), reflecting systemic iron status, are more likely to be associated with cognitive impairment after aSAH. CONCLUSION: In this aSAH population, our data shows the positive association between MCH and MCV and cognitive impairment at 1 year.

12.
J Biol Chem ; 294(22): 8872-8884, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31000631

RESUMO

Receptor-interacting protein kinase 3 (RIPK3) is a key regulator of programmed cell death and inflammation during viral infection or sterile tissue injury. Whether and how bacterial infection also activates RIPK3-dependent immune responses remains poorly understood. Here we show that bacterial lipids (lipid IVa or lipid A) form a complex with high mobility group box 1 (HMGB1), released by activated immune cells or damaged tissue during bacterial infection, and that this complex triggers RIPK3- and TIR domain-containing adapter-inducing IFN-ß (TRIF)-dependent immune responses. We found that these responses lead to macrophage death, interleukin (IL)-1α release, and IL-1ß maturation. In an air-pouch inflammatory infiltration model, genetic deletion of Ripk3, Trif, or IL-1 receptor (Il-1R), or monoclonal antibody-mediated HMGB1 neutralization uniformly attenuated inflammatory responses induced by Gram-negative bacteria that release lipid IVa and lipid A. These findings uncover a previously unrecognized mechanism by which host factors and bacterial components work in concert to orchestrate immune responses.

13.
Biochimie ; 160: 113-121, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30831151

RESUMO

BACKGROUND: Increased DAN protein (Grem1, Grem2, Grem3, Cerberus, NBL1, SOST, and USAG1) levels are often associated with severe disease-states in adult kidneys. Grem1, SOST, and USAG1 have been demonstrated to be upregulated and play a critical role in the progression of diabetic nephropathy (DN); however, the expression and the role of other DAN family members in DN have not been reported yet. In this study, we investigated the expression and the role of Grem2 in the development of renal lesions in mice with type 2 DN. METHODS: Fourteen-week-old BTBRob/ob (a mouse model of type 2 diabetes mellitus) and control (BTBR, wild type) mice were evaluated for renal functional and structural biomarkers. Urine was collected for protein content assay, and renal tissues were harvested for molecular analysis with real-time PCR, Western blotting, and immunohistochemistry. In vitro studies, human podocytes were transfected with Grem2 plasmid and were evaluated for apoptosis (morphologic assay and Western blotting). To evaluate the Grem2-mediated downstream signaling, the phosphorylation status of Smad2/3 and Smad1/5/8 was assessed. To establish a causal relationship, the effect of SIS3 (an inhibitor for Samd2/3) and BMP-7 (an agonist for Smad1/5/8) was evaluated on Germ2-induced podocyte apoptosis. RESULTS: BTBRob/ob mice showed elevated urinary protein levels. Renal tissues of BTBRob/ob mice showed an increased expression of Grem2; both glomerular and tubular cells displayed enhanced Grem2 expression. In vitro studies, high glucose increased Grem2 expression in cultured human podocytes, whereas, Grem2 silencing partially protected podocyte from high glucose-induced apoptosis. Overexpression of Grem2 in podocytes not only increased Bax/Bcl2 expression ratio but also promoted podocyte apoptosis; moreover, an overexpression of Grem2 increased the phosphorylation of Smad2/3 and decreased the phosphorylation of Smad1/5/8; furthermore, SIS3 and BMP-7 attenuated Grem2-induced podocyte apoptosis. CONCLUSIONS: High glucose increases Grem2 expression in kidney cells. Grem2 mediates podocyte apoptosis through Smads.


Assuntos
Apoptose , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/patologia , Glucose/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Podócitos/patologia , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos , Camundongos Obesos , Fosforilação , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Transdução de Sinais , Edulcorantes/farmacologia , Regulação para Cima
14.
Med Sci Monit ; 25: 2257-2264, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30917108

RESUMO

BACKGROUND This study investigated the risk factors of infliximab (IFX)-related infusion reactions (IR) in Chinese patients with inflammatory bowel disease (IBD). MATERIAL AND METHODS The medical records of 330 consecutive IBD patients treated with IFX between 2009 and 2017 were reviewed. The incidence of IR and adverse effects were recorded in detail, and the potential risk factors related to IR were analyzed by univariate and logistic regression analysis. RESULTS The 330 patients received a total of 2108 IFX infusions, with a median follow-up of 29 months. Eighteen patients (5.5%) experienced IR: 15 were immediate (2 severe) and 3 were late (0 severe). The patients who were treated with episodic IFX without concomitant IM therapy and at the 2nd IFX series (all P<0.001) had higher incidence of IR. Logistic regression revealed the 2nd IFX treatment series (OR=0.017, P<0.001) and episodic use of IFX (OR=0.113, P<0.001) as the significant predictors. Antibodies against infliximab (ATI) were highly positive in 10 of 14 patients (71%) with IR. Sixty-seven percent of patients finished infusions after IR through appropriate management. CONCLUSIONS IFX infusions were accompanied by IR in about 5% of Chinese IBD patients. Severe IR was rare. The patients with the 2nd series or episodic use of IFX should be monitored closely during infusion.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/efeitos adversos , Adolescente , Adulto , Anticorpos Monoclonais/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , China , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Seguimentos , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/fisiopatologia , Infliximab/uso terapêutico , Reação no Local da Injeção/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
15.
Aging Cell ; 18(3): e12955, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909324

RESUMO

Advanced maternal age has been reported to impair oocyte quality; however, the underlying mechanisms remain to be explored. In the present study, we identified the lowered NAD+ content and decreased expression of NMNAT2 protein in oocytes from old mice. Specific depletion of NMNAT2 in mouse oocytes disturbs the meiotic apparatus assembly and metabolic activity. Of note, nicotinic acid supplementation during in vitro culture or forced expression of NMNAT2 in aged oocytes was capable of reducing the reactive oxygen species (ROS) production and incidence of spindle/chromosome defects. Moreover, we revealed that activation or overexpression of SIRT1 not only partly prevents the deficient phenotypes of aged oocytes but also ameliorates the meiotic anomalies and oxidative stress in NMNAT2-depleted oocytes. To sum up, our data indicate a role for NMNAT2 in controlling redox homeostasis during oocyte maturation and uncover that NMNAT2- NAD+ -SIRT1 is an important pathway mediating the effects of maternal age on oocyte developmental competence.

16.
Environ Sci Technol ; 53(7): 3517-3525, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30811937

RESUMO

As nitrous acid (HONO) photolysis is an important source of hydroxyl radical (OH), apportionment of the ambient HONO sources is necessary to better understand atmospheric oxidation. Based on the data HONO-related species and various parameters measured during the one-month campaign at Wangdu (a rural site in North China plain) in summer 2014, a box model was adopted with input of current literature parametrizations for various HONO sources (nitrogen dioxide heterogeneous conversion, photoenhanced conversion, photolysis of adsorbed nitric acid and particulate nitrate, acid displacement, and soil emission) to reveal the relative importance of each source at the rural site. The simulation results reproduced the observed HONO production rates during noontime in general but with large uncertainty from both the production and destruction terms. NO2 photoenhanced conversion and photolysis of particulate nitrate were found to be the two major mechanisms with large potential of HONO formation but the associated uncertainty may reduce their importance to be nearly negligible. Soil nitrite was found to be an important HONO source during fertilization periods, accounted for (80 ± 6)% of simulation HONO during noontime. For some episodes of the biomass burning, only the NO2 heterogeneous conversion to HONO was promoted significantly. In summary, the study of the HONO budget is still far from closed, which would require a significant effort on both the accurate measurement of HONO and the determination of related kinetic parameters for its production pathways.


Assuntos
Dióxido de Nitrogênio , Ácido Nitroso , China , Nitritos , Óxidos de Nitrogênio
17.
Cell Transplant ; 28(6): 684-690, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30654640

RESUMO

Mechanical thrombectomy (MT) is effective in managing patients with acute ischemic stroke (AIS) caused by large-vessel occlusions and allows for valuable histological analysis of thrombi. However, whether bridging therapy (pretreatment with intravenous thrombolysis before MT) provides additional benefits in patients with middle cerebral artery (MCA) occlusion remains unclear. Therefore, this study aimed to compare the effects of direct MT and bridging therapy, and to elucidate the correlation between thrombus composition and stroke subtypes. Seventy-three patients with acute ischemic stroke who received MT, were eligible for intravenous thrombolysis, and had MCA occlusion were included. We matched 21 direct MT patients with 21 bridging therapy patients using propensity score matching and compared their 3rd-month clinical outcomes. All MCA thrombi (n = 45) were histologically analyzed, and the red blood cell (RBC) and fibrin percentages were quantified. We compared the clot composition according to stroke etiology (large-artery atherosclerosis and cardioembolism) and intravenous thrombolysis application. The baseline characteristics showed no difference between groups except for a higher atrial fibrillation rate and NIHSS score on admission in the direct MT group. We performed a supportive analysis using propensity score matching but could not find any differences in the functional outcome, mortality, and intracerebral hemorrhage. In the histological clot analysis, the cardioembolic clots without intravenous thrombolysis pretreatment had higher RBC (P = 0.042) and lower fibrin (P = 0.042) percentages than the large-artery atherosclerosis thrombi. Similar findings were observed in the thrombi treated with recombinant tissue plasminogen activator (P = 0.012). In conclusion, there was no difference in the functional outcomes between the direct MT and bridging therapy groups. However, randomized trials are needed to elucidate the high ratio of cardioembolism subtype in our group of patients. The histological MCA thrombus composition differed between cardioembolism and large-artery atherosclerosis, and this finding provides valuable information on the underlying pathogenesis and thrombus origin.

18.
Sci Rep ; 9(1): 160, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655582

RESUMO

We have recently reported an important role of Connexin 43 (Cx43) hemichannels in the pathogenesis of lethal sepsis through facilitating ATP efflux to potentiate the double-stranded RNA-activated protein kinase R (PKR)-dependent macrophage activation. Here we further elucidated the possible role of Pannexin 1 (Panx1) hemichannel in lethal sepsis by assessing its expression along with the impact of a Panx1-specific mimetic inhibitory peptide, 10Panx, on macrophage hemichannel activity in vitro and animal sepsis lethality in vivo. Both crude bacterial lipopolysaccharide (LPS) and purified serum amyloid A (SAA) effectively induced the expression and extracellular release of Panx1 by macrophages or monocytes as judged by Western blotting and immunocytochemistry assays. In animal model of lethal sepsis, Panx1 expression levels were significantly elevated in the heart, but reduced in the kidney, lung, spleen, and blood. At relatively lower doses (10, 50, and 100 mg/kg), the Panx1 mimetic peptide, 10Panx, reproducibly exacerbated the sepsis-induced animal lethality, reducing survival rates from 60-70% to 0-10%. Consistently, 10Panx did not inhibit, but rather promoted, the LPS-induced elevation of Lucifer Yellow dye uptake, ATP release, and Nitric Oxide (NO) production. Collectively, these findings suggested that elevated macrophage Panx1 expression and hemichannel activation contribute to the pathogenesis of lethal sepsis.

19.
J Biomed Nanotechnol ; 15(1): 62-76, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30480515

RESUMO

High energy ray in medical diagnosis and therapy can benefit to patients, but can also cause the significant damages to biomolecules such as DNA, as well as free radical generation, inevitably leading to numerous side effects. Small molecular radioprotectors provide an effective route to preserve the healthy tissue and whole body from ionizing radiation, but always have a short circulation time in body. Inorganic nanoparticles show major protection effect but their heavy metal components considerably jeopardize translational promise due to suboptimal biocompatibility. Herein, we report a novel protein nanoparticle that can overcome limitations of both small molecular and inorganic nanoparticle radioprotectors and can be used as a radioprotector with spontaneous biocompatibility, outstanding pharmacokinetics and improvement on survival rate under exposure to γ-ray irradiation. PHA-L protein nanoparticle serves to clear excessive reactive oxygen species in vivo, prevents radiation-induced hematopoietic and gastrointestinal damages and boosts the survival rate of irradiated mice to ∼70%. A detailed study of the mechanism shows PHA-L protein nanoparticle can target and activate the toll-like receptor 5 in vitro and in vivo, and thus protect irradiated cells by immune response. Importantly, the PHA-L protein nanoparticle can perform highly efficient clearance while eliciting negligible toxicological response.


Assuntos
Nanopartículas , Animais , Camundongos , Fito-Hemaglutininas , Protetores contra Radiação , Receptor 5 Toll-Like
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