The present study aimed to investigate the distribution and photodynamic therapeutic effect of chlorin e6 (Ce6) in the human tongue squamous cell carcinoma Tca8113 cell line in vitro. The distribution of Ce6 in the Tca8113 cells was observed in situ combined with mitochondrial and lysosomal fluorescent probes. Next, 630-nm semiconductor laser irradiation was performed. The MTS colorimetric method was used to determine cell survival. Annexin V fluorescein isothiocyanate/propidium iodide (PI) double staining was used to detect early apoptosis following photodynamic therapy (PDT). The flow cytometer was used to analyze the DNA content subsequent to PI-staining. It was observed that Ce6 could combine with the cellular membrane following 30 min of incubation with the Tca8113 cells. As the length of incubation increased, Ce6 gradually entered the cells in a particular distribution and reached saturation by 3 h. Co-localization analysis demonstrated that Ce6 was more likely to be present in the mitochondria than in the lysosomes. The cells incubated with 5 μg/ml Ce6 for 24 h exhibited a low toxicity of 5%, however, following light irradiation, Ce6-PDT was able to kill the Tca8113 cells in vitro. The cell toxicity was positively correlated with Ce6 concentration and light dose, therefore, the effect of Ce6 was concentration/dose-dependent (P<0.01). The lower Ce6 concentrations and light doses could significantly induce apoptosis in the Tca8113 cells, while higher doses increased necrosis/percentage of dead cells. In summary, Ce6 saturated the Tca8113 cells following 3 h of incubation. Furthermore, Ce6-PDT effectively killed the cultured Tca8113 cells in vitro at a safe concentration. At a low concentration and light dose, Ce6 is more likely to induce cell apoptosis via the mitochondria than the lysosomes.
photodynamic therapy; chlorin; mitochondria; human tongue squamous cell carcinoma; cell death
Clinical studies report that scopolamine, an acetylcholine muscarinic receptor antagonist, produces rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic response have not been determined. The present study examines the role of the mammalian target of rapamycin complex 1 (mTORC1) and synaptogenesis, which have been implicated in the rapid actions of NMDA receptor antagonists.
The influence of scopolamine on mTORC1 signaling was determined by analysis of the phosphorylated and activated forms of mTORC1 signaling proteins in the prefrontal cortex (PFC). The numbers and function of spine synapses were analyzed by whole cell patch clamp recording and 2-photon image analysis of PFC neurons. The actions of scopolamine were examined in the forced swim test in the absence or presence of selective mTORC1 and AMPA receptor inhibitors.
The results demonstrate that a single, low dose of scopolamine rapidly increases mTORC1 signaling and the number and function of spine synapses in layer V pyramidal neurons in the PFC. Scopolamine administration also produces an antidepressant response in the forced swim test that is blocked by pretreatment with the mTORC1 inhibitor or by a glutamate AMPA receptor antagonist.
Taken together, the results demonstrate that the antidepressant actions of scopolamine require mTORC1 signaling and are associated with increased glutamate transmission, and synaptogenesis, similar to NMDA receptor antagonists. These findings provide novel targets for safer and more efficacious rapid acting antidepressant agents.
Depression; acetylcholine; GABA; glutamate; ketamine; synaptic plasticity
Diffuse alveolar hemorrhage (DAH) is a life-threatening clinical pathologic syndrome caused by a variety of diseases. We report a case of DAH related to combination therapy of chemoradiotherapy and erlotinib. As to know, DAH following chemoradiotherapy was only reported among hematopoietic stem cell transplant recipients with hematologic malignancies till now. DAH associated with chemoradiotherapy for oesophageal carcinoma has not been reported. This is the first DAH report on erlotinib-combined chemoradiotherapy for esophageal cancer. The authors believe epidermal growth factor receptor tyrosine kinase inhibitor erlotinib increased the lung injury. Molecular targeted drugs are gradually applied to be combined with chemoradiation, whether this combination will cause the increase of serious adverse reactions need further study. This case can provide certain reference for erlotinib in the treatment. Meanwhile, after long term hormone therapy for DAH, the patient was diagnosed with pneumocystis carinii pneumonia. It reminds us to attach importance to the immunosuppressive diseases after long-term hormone treatment.
Diffuse alveolar hemorrhage; chemoradiotherapy; erlotinib; esophageal carcinoma
Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss (1). Clinical and pre-clinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions (2-9), but the molecular mechanisms underlying these morphological alterations have not yet been identified. Here, we show that stress increases levels of REDD1 (regulated in development and DNA damage responses 1), an inhibitor of mTORC1 (mammalian/mechanistic target of rapamycin complex 1) (10), in rat prefrontal cortex (PFC). This is concurrent with a decrease in phosphorylation of signaling targets of mTORC1, which is implicated in protein synthesis-dependent synaptic plasticity. We also found that REDD1 levels are increased in the postmortem PFC of human subjects with MDD relative to matched controls. Mutant mice with a deletion of REDD1 are resilient to the behavioral, synaptic, and mTORC1 signaling deficits caused by chronic unpredictable stress (CUS), while viral-mediated over expression of REDD1 in the rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and pre-clinical findings identify REDD1 as a critical mediator underlying the atrophy of neurons and depressive behavior caused by chronic stress exposure.
A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment-resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. Recent studies in medial prefrontal cortex (mPFC) show that the synaptogenic and antidepressant-like effects of a single standard dose of ketamine in rodents are dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. Here, we found that the synaptogenic and antidepressant-like effects of a single otherwise subthreshold dose of ketamine were potentiated when given together with a single dose of lithium chloride (a nonselective GSK-3 inhibitor) or a preferential GSK-3β inhibitor; these effects included rapid activation of the mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3β, increased synaptic spine density/diameter, increased excitatory postsynaptic currents in mPFC layer V pyramidal neurons, and antidepressant responses that persist for up to 1 week in the forced-swim test model of depression. The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine's antidepressant effects remains to be explored.
animal models; dendritic spines; EPSCs; Molecular & Cellular Neurobiology; mood/Anxiety/stress disorders; mTOR; NMDA; plasticity; prefrontal cortex; EPSCs; mTOR; NMDA; prefrontal; spines; synaptic
The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor in a variety of cancers, including breast cancer. Reduced WWOX expression is associated with the basal-like subtype and a relatively poor disease-free survival rate among breast cancer patients. Though several WWOX partners have been identified, the functional mechanisms of WWOX’s role in cancers have not been fully addressed to date. In the current study, we found WWOX suppresses expression of KLF5—an oncogenic transcription factor—at protein level, and suppresses cancer cell proliferation in both bladder and breast cancer cell lines. Furthermore, we demonstrated that WWOX physically interacts with KLF5 via the former’s WW domains and the latter’s PY motifs. Interestingly, we found the expression of WWOX negatively correlates with KLF5 expression in a panel of breast cancer cell lines. Taken together, we conjecture that WWOX may suppress cancer cell proliferation partially by reducing the expression of KLF5.
WW domain-containing oxidoreductase (WWOX); KLF5; breast cancer
Alterations in embryonic neural stem cells play crucial roles in the pathogenesis of amyotrophic lateral sclerosis. We hypothesized that embryonic neural stem cells from SOD1G93A individuals might be more susceptible to oxidative injury, resulting in a propensity for neurodegeneration at later stages. In this study, embryonic neural stem cells obtained from human superoxide dismutase 1 mutant (SOD1G93A) and wild-type (SOD1WT) mouse models were exposed to H2O2. We assayed cell viability with mitochondrial succinic dehydrogenase colorimetric reagent, and measured cell apoptosis by flow cytometry. Moreover, we evaluated the expression of the adenosine monophosphate-activated protein kinase (AMPK) α-subunit, paired box 3 (Pax3) protein, and p53 in western blot analyses. Compared with SOD1WT cells, SOD1G93A embryonic neural stem cells were more likely to undergo H2O2-induced apoptosis. Phosphorylation of AMPKα in SOD1G93A cells was higher than that in SOD1WT cells. Pax3 expression was inversely correlated with the phosphorylation levels of AMPKα. p53 protein levels were also correlated with AMPKα phosphorylation levels. Compound C, an inhibitor of AMPKα, attenuated the effects of H2O2. These results suggest that embryonic neural stem cells from SOD1G93A mice are more susceptible to apoptosis in the presence of oxidative stress compared with those from wild-type controls, and the effects are mainly mediated by Pax3 and p53 in the AMPKα pathway.
nerve regeneration; neuroderegeneration; embryonic neural stem cells; adenosine monophosphate-activated protein kinase α; paired box 3; p53; SOD1G93A mouse; amyotrophic lateral sclerosis; oxidative stress; hydrogen peroxide; apoptosis; NSFC grants; neural regeneration
We demonstrate for 24 metal oxide (MOx) nanoparticles that it is possible to use conduction band energy levels to delineate their toxicological potential at cellular and whole animal levels. Among the materials, the overlap of conduction band energy (Ec) levels with the cellular redox potential (−4.12 to −4.84 eV) was strongly correlated to the ability of Co3O4, Cr2O3, Ni2O3, Mn2O3 and CoO nanoparticles to induce oxygen radicals, oxidative stress and inflammation. This outcome is premised on permissible electron transfers from the biological redox couples that maintain the cellular redox equilibrium to the conduction band of the semiconductor particles. Both single parameter cytotoxic as well as multi-parameter oxidative stress assays in cells showed excellent correlation to the generation of acute neutrophilic inflammation and cytokine responses in the lungs of CB57 Bl/6 mice. Co3O4, Ni2O3, Mn2O3 and CoO nanoparticles could also oxidize cytochrome c as a representative redox couple involved in redox homeostasis. While CuO and ZnO generated oxidative stress and acute pulmonary inflammation that is not predicted by Ec levels, the adverse biological effects of these materials could be explained by their solubility, as demonstrated by ICP-MS analysis. Taken together, these results demonstrate, for the first time, that it is possible to predict the toxicity of a large series of MOx nanoparticles in the lung premised on semiconductor properties and an integrated in vitro/in vivo hazard ranking model premised on oxidative stress. This establishes a robust platform for modeling of MOx structure-activity relationships based on band gap energy levels and particle dissolution. This predictive toxicological paradigm is also of considerable importance for regulatory decision-making about this important class of engineered nanomaterials.
Metal oxide nanoparticles; band gap energy; surface dissolution; oxidative stress; in vitro and in vivo toxicity
Zebrafish is an aquatic organism that can be used for high content safety screening of engineered nanomaterials (ENMs). We demonstrate, for the first time, the use of high content bright-field and fluorescence-based imaging to compare the toxicological effect of transition metal oxide (CuO, ZnO, NiO and Co3O4) nanoparticles in zebrafish embryos and larvae. High content bright-field imaging demonstrated potent and dose-dependant hatching interference in the embryos, with the exception of Co3O4 which was relatively inert. We propose that the hatching interference was due to the shedding of Cu and Ni ions, compromising the activity of the hatching enzyme, ZHE1, similar to what we previously proposed for Zn2+. This hypothesis is based on the presence of metal–sensitive histidines in the catalytic center of this enzyme. Co-introduction of a metal ion chelator, diethylene triamine pentaacetic acid (DTPA), reversed the hatching interference of Cu, Zn and Ni. While neither the embryos nor larvae demonstrated morphological abnormalities, high content fluorescence-based imaging demonstrated that CuO, ZnO and NiO could induce increased expression of the heat shock protein 70:enhanced green fluorescence protein (hsp70:eGFP) in transgenic zebrafish larvae. Induction of this response by CuO required a higher nanoparticle dose than the amount leading to hatching interference. This response was also DTPA sensitive. In conclusion, we demonstrate that high content imaging of embryo development, morphological abnormalities and HSP70 expression can be used for hazard ranking and determining the dose-response relationships leading to ENM effects on the development of the zebrafish embryo.
high content imaging; transition metal oxide nanoparticle; dissolution; hsp70; zebrafish
Simultaneous multi-element imaging using NanoSIMS (nanoscale secondary ion mass spectrometry), exploiting the novel combination of 195Pt and 15N in platinum-am(m)ine antitumour drugs, provides information on the internalisation and subcellular localisation of both metal and ligands, and allows identification of ligand exchange.
Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2 treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associated β-galactosidase activity. Additionally, H2O2 treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated) retinoblastoma (Rb) protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.
Retinal neovascularization (NV) is a major cause of vision loss in ischemia-induced retinopathy. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor inducible–14 (Fn14), have been implicated in angiogenesis, but their role in retinal diseases is unknown. The goal of this study was to investigate the role of TWEAK/Fn14 pathway in retinal NV.
Studies were performed in a mouse model of oxygen-induced retinopathy (OIR) and in primary human retinal microvascular endothelial cells (HRMECs). Hyperoxia treatment was initiated on postnatal day (P)14. Immunohistochemistry and quantitative PCR (qPCR) were used to assess retinal vascular changes in relation to expression of Fn14 and TWEAK.
Fibroblast growth factor–inducible 14 mRNA was prominently increased from P13 to P17 in OIR retinas, whereas TWEAK level was slightly decreased. These alterations were normalized by hyperoxia treatment and were more striking in isolated retinal vessels. There was a discernible shift in the immunoreactivity of Fn14 and TWEAK from the neuronal layers in the healthy retina to the neovascular tufts in that of OIR. Blockade of TWEAK/Fn14 significantly prevented retinal NV while slightly accelerated revascularization. In contrast, activation of Fn14 positively regulated survival pathways in the B-cell lymphoma-2 (Bcl2) family and robustly enhanced HRMEC survival. Furthermore, gene analysis revealed the regulatory region of Fn14 gene contains several conserved hypoxia inducible factor (HIF)-1α binding sites. Overexpression of HIF-1α prominently induced Fn14 expression in HRMECs.
We found that the TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor inducible–14 (Fn14) pathway is involved in the development of pathologic retinal neovascularization. Hypoxia inducible factor–1α is likely implicated in the upregulation of Fn14.
We found that the TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor inducible–14 (Fn14) pathway is involved in the development of pathologic retinal neovascularization.
ischemia-induced retinopathy; neovascularization; TWEAK; Fn14; retina
Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor-expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. mBLA neurons activated by prefrontal D1 stimulation are CaMKII positive and closely juxtaposed to prefrontal D1 axon terminals. Finally, photostimulating these axons in the mBLA is sufficient to increase feeding, recapitulating the effects of mPFC D1 stimulation. These data describe a new circuit for top-down control of food intake.
The aims of this study were to assess the effect of transarterial chemoembolization (TACE) on circulating tumor cells (CTCs) in the peripheral blood and right atrium of patients with HCC and to evaluate whether perioperative shedding of CTCs affects time to progression of HCC. Before and after TACE, peripheral and right atrial blood samples (7.5 mL) were collected from 42 patients with HCC. CTCs were enriched using EpCAM antibody-conjugated magnetic beads. The number of CTCs was 0–30 and 0–54 in peripheral blood before and after TACE, respectively (P=0.166), and 0–65 and 0–98 in the right atrium before and after TACE, respectively (P=0.102). The number of CTCs was significantly different between the two samples both before (P=0.007) and after (P=0.021) TACE. There was no difference in time to progression between patients with and without an increase in the number of CTCs after TACE in either sample (P>0.05 for both). There were more CTCs in right atrial blood than in peripheral blood. The numbers of CTCs in both samples remained unchanged after TACE. Shedding of tumor cells did not affect time to progression of disease in patients with HCC.
hepatocellular carcinoma; transcatheter arterial chemoembolization; circulating tumor cells; metastasis; positive screening
Regulator of G-protein signaling 6 (RGS6), a member of a family of RGS proteins, has been reported to involve in multiple processes during tumor development. However, its role in pancreatic cancer has not been studied yet. In this study, we aimed to investigate the expression of RGS6 in pancreatic cancer and its role in predicting outcomes of patients with pancreatic cancer. We first measured the expression of RGS6 mRNA in 20 cases of tumor tissues and matched adjacent non-tumorous tissues by quantitative real-time PCR and examined RGS6 protein by immunohistochemistry in tissue microarrays containing 90 tumor and 90 paired adjacent non-tumor tissues. Decreased RGS6 mRNA detected in primary tumor, compared with their non-tumor counterparts. In addition, decreased RGS6 protein expression was associated with tumor differentiation (P = 0.027), pT classification (P = 0.034), smoking status (P = 0.041) and a poor survival (P = 0.007). Cox proportional hazards regression modeling analysis revealed that lymph node metastasis (P = 0.001; hazard ratio, 2.347, 95% CI, 1.387-3.972), tumor differentiation (P = 0.015; hazard ratio, 0.505, 95% CI, 0.291-0.876) and RGS6 expression (P = 0.048; hazard ratio, 0.567, 95% CI, 0.324-0.994) were three independent prognostic factors. Taken together, these date demonstrate that RGS6 decreases in tumor tissue and may serve as a novel biomarker for outcomes in pancreatic cancer patients and be a potential therapeutic target potential therapeutic target.
RGS protein; pancreatic neoplasms; clinical pathology; prognosis
High sleep quality promotes efficient performance in the following day. Sleep quality is influenced by environmental factors, such as temperature, light, sound and smell. Here, we investigated whether differences in the interface pressure distribution on healthy individuals during sleep influenced sleep quality. We defined four types of pressure models by differences in the area distribution and the subjective feelings that occurred when participants slept on the mattresses. One type of model was showed “over-concentrated” distribution of pressure; one was displayed “over-evenly” distributed interface pressure while the other two models were displayed intermediate distribution of pressure. A polysomnography analysis demonstrated an increase in duration and proportion of non-rapid-eye-movement sleep stages 3 and 4, as well as decreased number of micro-arousals, in subjects sleeping on models with pressure intermediately distributed compared to models with over-concentrated or over-even distribution of pressure. Similarly, higher scores of self-reported sleep quality were obtained in subjects sleeping on the two models with intermediate pressure distribution. Thus, pressure distribution, at least to some degree, influences sleep quality and self-reported feelings of sleep-related events, though the underlying mechanisms remain unknown. The regulation of pressure models imposed by external sleep environment may be a new direction for improving sleep quality. Only an appropriate interface pressure distribution is beneficial for improving sleep quality, over-concentrated or -even distribution of pressure do not help for good sleep.
Through a series of in vitro studies, the essential steps for intracellular drug delivery of paclitaxel using a pH-responsive nanoparticle system have been investigated in breast cancer cells. We successfully encapsulated paclitaxel within polymeric expansile nanoparticles (Pax-eNPs) at 5% loading via a miniemulsion polymerization procedure. Fluorescently tagged eNPs were readily taken up by MDA-MB-231 breast cancer cells grown in culture as confirmed by confocal microscopy and flow cytometry. The ability of the encapsulated paclitaxel to reach the cytoplasm was also observed using confocal microscopy and fluorescently labeled paclitaxel. Pax-eNPs were shown to be efficacious against three in vitro human breast adenocarcinoma cell lines (MDA-MB-231, MCF-7 and SK-BR-3) as well as cells isolated from the pleural effusions of two different breast cancer patients. Lastly, macropinocytosis was identified as the major cellular pathway responsible for eNP uptake, as confirmed using temperature-sensitive metabolic reduction, pharmacologic inhibitors, and fluid-phase marker co-localization.
drug delivery; nanoparticle; paclitaxel; breast cancer; cellular uptake; endocytosis
high throughput screening; metal oxide; hatching interference; predictive toxicology; zebrafish
Several reports indicate that melatonin alleviates bleomycin (BLM)-induced pulmonary fibrosis in rodent animals. Nevertheless, the exact mechanism remains obscure. The present study investigated the effects of melatonin on endoplasmic reticulum (ER) stress and epithelial-mesenchymal transition (EMT) during BLM-induced lung fibrosis. For the induction of pulmonary fibrosis, mice were intratracheally injected with a single dose of BLM (5.0 mg/kg). Some mice were intraperitoneally injected with melatonin (5 mg/kg) daily for a period of 3 wk. Twenty-one days after BLM injection, lung fibrosis was evaluated. As expected, melatonin significantly alleviated BLM-induced pulmonary fibrosis, as evidenced by Sirius red staining. Moreover, melatonin significantly attenuated BLM-induced EMT to myofibroblasts, as determined by its repression of α-SMA expression. Further analysis showed that melatonin markedly attenuated BLM-induced GRP78 up-regulation and elevation of the cleaved ATF6 in the lungs. Moreover, melatonin obviously attenuated BLM-induced activation of pulmonary eIF2α, a downstream target of the PERK pathway. Finally, melatonin repressed BLM-induced pulmonary IRE1α phosphorylation. Correspondingly, melatonin inhibited BLM-induced activation of XBP-1 and JNK, two downstream targets of the IRE1 pathway. Taken together, these results suggest that melatonin alleviates ER stress and ER stress-mediated EMT in the process of BLM-induced pulmonary fibrosis.
After reverse transcription, the HIV-1 proviral DNA is integrated into the host genome and thus subjected to transcription by the host RNA polymerase II (Pol II). With the identification and characterization of human P-TEFb in the late 1990s as a specific host cofactor required for HIV-1 transcription, it is now believed that the elongation stage of Pol II transcription plays a particularly important role in regulating HIV-1 gene expression. HIV-1 uses a sophisticated scheme to recruit human P-TEFb and other cofactors to the viral long terminal repeat (LTR) to produce full-length HIV-1 transcripts. In this process, P-TEFb is regulated by the reversible association with various transcription factors/cofactors to form several multi-subunit complexes (e.g., 7SK snRNP, super elongation complexes (SECs), and the Brd4-P-TEFb complex) that collectively constitute a P-TEFb network for controlling cellular and HIV-1 transcription. Recent progresses in HIV-1 transcription were reviewed in the paper, with the emphasis on the mechanism and factors that control HIV-1 transcription and latency activation.
HIV-1; Transcriptional elongation; RNA polymerase II; Tat; P-TEFb
Chronic obstructive pulmonary disease (COPD) is a common disease that severely threatens human health. Acute exacerbation of COPD (AECOPD) is a major cause of disease progression and death, and causes huge medical expenditures. This consensus statement represents a description of clinical features of AECOPD in the People’s Republic of China and a set of recommendations. It is intended to provide clinical guidelines for community physicians, pulmonologists and other health care providers for the prevention, diagnosis, and treatment of AECOPD.
COPD; AECOPD; recommendations; guidelines
This study aimed to explore the neural development status of the visual system of children (around 8 years old) using contrast sensitivity. We achieved this by eliminating the influence of higher order aberrations (HOAs) with adaptive optics correction. We measured HOAs, modulation transfer functions (MTFs) and contrast sensitivity functions (CSFs) of six children and five adults with both corrected and uncorrected HOAs. We found that when HOAs were corrected, children and adults both showed improvements in MTF and CSF. However, the CSF of children was still lower than the adult level, indicating the difference in contrast sensitivity between groups cannot be explained by differences in optical factors. Further study showed that the difference between the groups also could not be explained by differences in non-visual factors. With these results we concluded that the neural systems underlying vision in children of around 8 years old are still immature in contrast sensitivity.
A classification based cytotoxicity nano-structure-activity-realtionship (nano-SAR) is presented based on a set of nine metal oxide nanoparticles to which transformed bronchial epithelial cells (BEAS-2B) were exposed over a range of concentrations of 0.375–200 mg·L−1 and exposure times up to 24 h. The nano-SAR is developed using cytotoxicity data from high throughput screening (HTS) assay that was processed to identify and label toxic (in terms of the Propidium Iodide uptake of BEAS-2B cells) versus non-toxic events relative to unexposed control cell population. Starting with a set of fourteen intuitive but fundamental physicochemical nano-SAR input parameters, a number of models were identified which had classification accuracy above 95%. The best performing model had a 100% classification accuracy in both internal and external validation. This model is based on four descriptors including the atomization energy of the metal oxide, period of the nanoparticle metal, nanoparticle primary size, in addition to nanoparticle volume fraction (in solution). Notwithstanding the success of the present modeling approach with a relatively small nanoparticle library, it is important to recognize that a significantly larger data set would be needed in order to expand the applicability domain and increase the confidence and reliability of data-driven nano-SARs.
nanoparticle; metal oxides; cytotoxicity; nano-SAR; classification
Our objective was to explore the association between poor sleep quality and hs_CRP in an adult U.S. population.
This study focused on 9,317 participants in the National Health and Nutrition Examination Survey (NHANES) from 2005–2008 who were aged 20–85 years, completed a sleep disorder questionnaire, and had available information on serum hs_CRP. Sleep quality was classified into three categories (good, moderate, poor) based on the responses of participants to the NHANES sleep disorder questionnaire. High CRP was defined as hs-CRP >1 md/dL. Linear regression model was applied to investigate the association between poor sleep quality and log-transformed hs_CRP. And logistic regression model was fitted to evaluate the association between sleep quality and the risk of high CRP.
Females were more likely to report poor sleep quality than males (26% vs. 19%, p<0.0001). Each sleep disorder was significantly associated with increased hs_CRP and correlative to other sleep disorders. In fully-adjusted linear regression model, poor sleep quality was significantly associated with elevated hs_CRP (log transformed) among the overall sample and in females only (β = 0.10, se = 0.03, p<0.01 and β = 0.13, se = 0.04, p<0.01, respectively). In fully-adjusted logistics regression model, poor sleep quality was linked with risk of high CRP(OR: 1.42, 95%CI: 1.15–1.76 in overall sample and OR: 1.59, 95%CI: 1.18–2.14 in females, respectively).
We found that poor sleep quality was independently associated with elevated hs_CRP in females but not in males in a U.S. adult population.
Paroxetine, a selective serotonin reuptake inhibitor for counteracting depression, has been recently suggested as having a role in prevention of dopaminergic neuronal degeneration in substantia nigra, a hallmark of Parkinson’s disease (PD). The pathogenesis of this type of neurological disorders often involves the activation of microglia and associated inflammatory processes. Thus in this study we aimed to understand the role of paroxetine in microglia activation and to elucidate the underlying mechanism(s).
BV2 and primary microglial cells were pretreated with paroxetine and stimulated with lipopolysaccharide (LPS). Cells were assessed for the responses of pro-inflammatory mediator and cytokines, and the related signaling pathways were evaluated and analyzed in BV2 cells.
Paroxetine significantly inhibited LPS-induced production of nitric oxide (NO) and pro-inflammatory cytokines such as TNF-α and IL-1β. Further analysis showed inducible nitric oxide synthase (iNOS) and mRNA expression of TNF-α and IL-1β were attenuated by paroxetine pretreatment. Analyses in signaling pathways demonstrated that paroxetine led to suppression of LPS-induced JNK1/2 activation and baseline ERK1/2 activity, but had little effect on the activation of p38 and p65/NF-κB. Interference with specific inhibitors revealed that paroxetine-mediated suppression of NO production was via JNK1/2 pathway while the cytokine suppression was via both JNK1/2 and ERK1/2 pathways. Furthermore, conditioned media culture showed that paroxetine suppressed the microglia-mediated neurotoxicity.
Paroxetine inhibits LPS-stimulated microglia activation through collective regulation of JNK1/2 and ERK1/2 signaling. Our results indicate a potential role of paroxetine in neuroprotection via its anti-neuroinflammatory effect besides targeting for depression.
Paroxetine; Microglia; Lipopolysaccharide; Neuroinflammation; MAPK