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1.
Environ Sci Technol ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31927955

RESUMO

Chlorinated polyfluoroalkylether sulfonic acids (Cl-PFESAs) have been shown to have potential thyroid hormone (TH) disruption effects. Here, we further investigated their estrogenic effects and underlying mechanisms. In vivo results revealed that exposure of zebrafish to Cl-PFESAs induced disorder of sex hormones during the early embryonic stages, and caused histopathological lesions in the gonads of adult zebrafish relative to control groups. To find out whether the estrogen receptor is the molecular target of Cl-PFESAs, the binding interaction between Cl-PFESAs and ERs were investigated using a series of in vitro assays. We found that all tested chemicals could bind directly to ERs and exhibit relatively weak agonistic activity toward ERs, suggesting that ER-mediated signaling pathway is directly involved in the estrogenic effects of Cl-PFESAs. The internal dose of 8:2 Cl-PFESA was significantly higher than the others, which explained why it obviously displayed an ER agonistic effect despite its weak ER binding affinity. Taken together, these results uncover that in addition to TH disruption effect, Cl-PFESAs might also cause estrogenic effects by activating ER pathways.

2.
Phytomedicine ; 67: 153138, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31881478

RESUMO

BACKGROUND: Hypoxia is commonly existed in tumors and lead to cancer cell chemo/radio-resistance. It is well-recognized that tumor hypoxia is a major challenge for the treatment of various solid tumors. Hyperoside (quercetin-3-O-galactoside, Hy) possesses antioxidant effects and has been reported to protect against hypoxia/reoxygenation induced injury in cardiomyocytes. Therefore, Hy may be attractive compound applicable to hypoxia-related diseases. PURPOSE: This study was designed to determine the role of Hy in hypoxia-induced proliferation of non-small cell lung cancer cells and the underlying mechanism. STUDY DESIGN AND METHODS: A549, a human non-small cell lung cancer (NSCLC) cell line, was used in the present study. 1% O2 was used to mimic the in vivo hypoxic condition of NSCLC. The potential mechanisms of Hy on hypoxia-induced A549 survival and proliferation, as well as the involvement of AMPK/HO-1 pathway were studied via CCK-8 assay, EdU staining, flow cytometry, qRT-PCR and western blot. RESULTS: We showed that pretreatment with Hy suppressed hypoxia-induced A549 survival and proliferation in dose-dependent manner. In terms of mechanism, hypoxia-treated A549 showed the lower AMPK phosphorylation and the reduced HO-1 expression, which were reversed by Hy pretreatment. Both AMPK inhibitor (Compound C) and HO-1 activity inhibitor (Zinc protoporphyrin IX) abolished Hy-evoked A549 cell death under hypoxia stimuli. Of note, Ferrous iron contributed to Hy-induced A549 cell death under hypoxia, while Hy had no effect on lipid peroxidation under hypoxia. CONCLUSION: Taken together, our results highlighted the beneficial role of Hy against hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31803728

RESUMO

Non-invasive tracking for monitoring the selective delivery and transplantation of biotargeted agents in vivo has been employed as one of the most effective tools in the field of nanomedicine. Different nanoprobes have been developed and applied to bioimaging tissues and the treatment of diseases ranging from inflammatory and cardiovascular diseases to cancer. Herein, we will review the recent advances in the development of optics-responsive nanomaterials, including organic and inorganic nanoparticles, for multimodal bioimaging and targeted therapy. The main focus is placed on nanoprobe fabrication, mechanistic illustrations, and diagnostic, or therapeutical applications. These nanomedicine strategies have promoted a better understanding of the biological events underlying diverse disease etiologies, thereby facilitating diagnosis, illness evaluation, therapeutic effect, and drug discovery.

5.
Front Physiol ; 10: 1282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680999

RESUMO

The immunological interaction between Drosophila melanogaster and its larval parasitoids has been thoroughly investigated, however, little is known about the interaction between the host and its pupal parasitoids. Pachycrepoideus vindemmiae, a pupal ectoparasitoid of D. melanogaster, injects venom into its host while laying eggs on the puparium, which regulates host immunity and interrupts host development. To resist the invasion of parasitic wasps, various immune defense strategies have been developed in their hosts as a consequence of co-evolution. In this study, we mainly focused on the host immunomodulation by P. vindemmiae and thoroughly investigated cellular and humoral immune response, including cell adherence, cell viability, hemolymph melanization and the Toll, Imd, and JAK/STAT immune pathways. Our results indicated that venom had a significant inhibitory effect on lamellocyte adherence and induced plasmatocyte cell death. Venom injection and in vitro incubation strongly inhibited hemolymph melanization. More in-depth investigation revealed that the Toll and Imd immune pathways were immediately activated upon parasitization, followed by the JAK/STAT pathway, which was activated within the first 24 h post-parasitism. These regulatory effects were further validated by qPCR. Our present study manifested that P. vindemmiae regulated the cellular and humoral immune system of host D. melanogaster in many aspects. These findings lay the groundwork for studying the immunological interaction between D. melanogaster and its pupal parasitoid.

6.
BMC Med Ethics ; 20(1): 73, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623624

RESUMO

BACKGROUND: Community advisory boards (CABs) have expanded beyond high-income countries (HICs) and play an increasing role in low- and middle-income country (LMIC) research. Much research has examined CABs in HICs, but less is known about CABs in LMICs. The purposes of this scoping review are to examine the creation and implementation of CABs in LMICs, including identifying frequently reported challenges, and to discuss implications for research ethics. METHODS: We searched five databases (PubMed, Embase, Global Health, Scopus, and Google Scholar) for publications describing or evaluating CABs in LMICs. Two researchers independently reviewed articles for inclusion. Data related to the following aspects of CABs were extracted from included publications: time, country, financial support, research focus, responsibilities, and challenges. Thematic analyses were used to summarize textual data describing challenges. RESULTS: Our search yielded 2005 citations, 83 of which were deemed eligible for inclusion. Most studies (65) were published between 2010 and 2017. Upper-middle-income countries were more likely to have studies describing CABs, with South Africa (17), China (8), and Thailand (7) having the greatest numbers. The United States National Institutes of Health was the main source of financial support for CABs. Many CABs (53/88, 60%) focused on HIV research. Thirty-four studies reported how CABs influenced the informed consent process for clinical trials or other aspects of research ethics. CAB responsibilities were related to clinical trials, including reviewing study protocols, educating local communities about research activities, and promoting the ethical conduct of research. Challenges faced by CABs included the following: incomplete ethical regulations and guidance; limited knowledge of science among members of communities and CABs; unstable and unbalanced power relationships between researchers and local communities; poor CAB management, including lack of formal participation structures and absence of CAB leadership; competing demands for time that limited participation in CAB activities; and language barriers between research staff and community members. Several challenges reflected shortcomings within the research team. CONCLUSIONS: Our findings examine the formation and implementation of CABs in LMICs and identify several ethical challenges. These findings suggest the need for further ethics training among CAB members and researchers in LMICs.

7.
J Paleontol ; n/a: 1937-2337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31631908

RESUMO

The lower-middle Hetang Formation (Cambrian Stage 2-3) deposited in slope-basinal facies in South China is well-known for its preservation of the earliest articulated sponge fossils, providing an important taphonomic window into the Cambrian explosion. However, the Hetang Formation also hosts a number of problematic animal fossils that have not been systematically described. This omission results in an incomplete picture of the Hetang biota and limits its contribution to the understanding of the early evolution of animals. Here we describe a new animal taxon, Cambrowania ovata Tang and Xiao, new genus new species, from the middle Hetang Formation in the Lantian area of southern Anhui Province, South China. Specimens are preserved as carbonaceous compressions, although some are secondarily mineralized. A comprehensive analysis using reflected light microscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy, and micro-CT reveals that the new species is characterized by a spheroidal to fusoidal truss-like structure consisting of rafter-like crossbars, some of which are secondarily baritized and may have been internally hollow. Some specimens have aperture-like structures that are broadly similar to oscula of sponges, whereas others show evidence of a medial split reminiscent of gaping carapaces. While the phylogenetic affinity of Cambrowania ovata Tang and Xiao, new genus new species remains problematic, we propose that it may represent carapaces of bivalved arthropods or more likely sponges in early life stages. Along with other problematic metazoan fossils such as hyolithids and sphenothallids, Cambrowania ovata Tang and Xiao, new genus new species adds to the diversity of the sponge-dominated Hetang biota in an early Cambrian deep-water slope-basinal environment.

8.
Toxicol Sci ; 172(2): 398-410, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504961

RESUMO

Carbon nanomaterials (CNMs) are widely used in industrial and medical sectors. The increasing exposure of CNMs necessitates the studies of their potential environmental and health effects. High-mobility group box-1 (HMGB1) is a nuclear DNA-binding protein, but when released from cells, may cause sustained inflammatory response and promote cell migration and invasion. In this work, we found that 7-day exposure of 2.5 mg/kg/day CNMs, including C60, single-walled carbon nanotubes, and graphene oxides significantly elevated the level of HMGB1 in blood and lung lavage fluids in C57BL/6 mice. Subsequently, cellular effects and underlying mechanism were explored by using Raw264.7. The results showed that noncytotoxic CNMs enhanced HMGB1 intracellular translocation and release via activating P2X7 receptor. Released HMGB1 further activated receptor for advanced glycation endproducts (RAGE) and downstream signaling pathway by upregulating RAGE and Rac1 expression. Simultaneously, CNMs prepared the cells for migration and invasion by modulating MMP2 and TIMP2 gene expression as well as cytoskeleton reorganization. Intriguingly, released HMGB1 from macrophages promoted the migration of nearby lung cancer cell, which can be efficiently inhibited by neutralizing antibodies against HMGB1 and RAGE. Taken together, our work demonstrated that CNMs stimulated HMGB1 release and cell migration/invasion through P2X7R-HMGB1-RAGE pathway. The revealed mechanisms might facilitate a better understanding on the inflammatory property and subsequent cell functional alteration of CNMs.

9.
Anal Chim Acta ; 1079: 103-110, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31387700

RESUMO

Characterization of carbonaceous nanomaterials (CNMs) exposure is a key step and of great importance towards a better understanding of their toxicity and underlying mechanisms. However, it has been bottlenecked for lack of valid methods capable of quantifying cell-associated CNMs. Here, we developed a new economical and convenient method based on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) that could accumulate graphene oxide (GO) at the interface between the loading well and the gel. The sharp black band formed there can be digitalized and the intensity quantified, which was proportional to the amount of GO loaded onto the gel. The method has a detection limit of 84.1 ng. We showed that the amount of GO in three different cell models, mouse macrophage cells (Raw264.7), human epithelial cells (A549) and mouse mesenchymal stem cells (MSC), could be accurately quantified by this assay, with the uptake rates decreasing in the order of MSC > Raw264.7 > A549. The results were consistent with the fluorescent imaging on cells exposed to fluorescence-labeled GO and TEM examination on ultrathin cell sections. The surprisingly highest uptake rate of MSC might be due to their abundant intracellular vesicles, which deserves further investigation. The novel method provides a complementary quantitative tool to the use of radioactive markers and fluorescent labeling of carbon nanomaterials and may facilitate the toxicological studies on carbon nanomaterials.


Assuntos
Eletroforese em Gel de Poliacrilamida/métodos , Grafite/análise , Células A549 , Animais , Corantes Fluorescentes/química , Grafite/metabolismo , Humanos , Limite de Detecção , Células-Tronco Mesenquimais , Camundongos , Células RAW 264.7
10.
Front Immunol ; 10: 1688, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379874

RESUMO

Endoparasitoid wasps, which lay eggs inside the bodies of other insects, use various strategies to protect their offspring from the host immune response. The hymenopteran species of the genus Leptopilina, parasites of Drosophila, rely on the injection of a venom which contains proteins and peculiar vesicles (hereafter venosomes). We show here that the injection of purified L. boulardi venosomes is sufficient to impair the function of the Drosophila melanogaster lamellocytes, a hemocyte type specialized in the defense against wasp eggs, and thus the parasitic success of the wasp. These venosomes seem to have a unique extracellular biogenesis in the wasp venom apparatus where they acquire specific secreted proteins/virulence factors and act as a transport system to deliver these compounds into host lamellocytes. The level of venosomes entry into lamellocytes of different Drosophila species was correlated with the rate of parasitism success of the wasp, suggesting that this venosome-cell interaction may represent a new evolutionary level of host-parasitoid specificity.

11.
Nat Commun ; 10(1): 3348, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350398

RESUMO

Most sponges have biomineralized spicules. Molecular clocks indicate sponge classes diverged in the Cryogenian, but the oldest spicules are Cambrian in age. Therefore, sponges either evolved spiculogenesis long after their divergences or Precambrian spicules were not amenable to fossilization. The former hypothesis predicts independent origins of spicules among sponge classes and presence of transitional forms with weakly biomineralized spicules, but this prediction has not been tested using paleontological data. Here, we report an early Cambrian sponge that, like several other early Paleozoic sponges, had weakly biomineralized and hexactine-based siliceous spicules with large axial filaments and high organic proportions. This material, along with Ediacaran microfossils containing putative non-biomineralized axial filaments, suggests that Precambrian sponges may have had weakly biomineralized spicules or lacked them altogether, hence their poor record. This work provides a new search image for Precambrian sponge fossils, which are critical to resolving the origin of sponge spiculogenesis and biomineralization.


Assuntos
Poríferos/metabolismo , Animais , Biomineralização , Fósseis , Paleontologia , Filogenia , Poríferos/classificação , Poríferos/ultraestrutura , Dióxido de Silício/metabolismo
12.
Pharm Biol ; 57(1): 453-459, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31311385

RESUMO

Context: Neuroligin-1 (NLGN1) is a cell adhesion protein located on the excitatory postsynaptic membrane. ß-Amyloid (Aß)-induced neuroinflammation decreases NLGN1 expression through epigenetic mechanisms. Triptolide (T10) and tripchlorolide (T4) exert protective effects on synapses in Alzheimer's disease (AD) mice, but the mechanisms remain unclear. Objective: The effects of T10 and T4 on hippocampal NLGN1 expression in AD mice and the epigenetic mechanisms were assessed using chromatin immunoprecipitation and methylated DNA immunoprecipitation. Materials and methods: Sixty APP/PS1 transgenic mice were randomly divided into an AD model group, a T10-treated group and a T4-treated group (n = 20); 20 wild-type littermates served as the control group. APP/PS1 transgenic mice were intraperitoneally injected with T10 (0.1 mg/kg) and T4 (25 µg/kg) once per day for 60 days. NLGN1 expression was examined using western blotting and quantitative PCR. Results: T10 and T4 increased the levels of the NLGN1 protein and mRNA in hippocampus of AD mice. T10 and T4 inhibited the binding of HDAC2 (p< 0.01) and MeCP2 (p< 0.01 and p< 0.05, respectively) to the NLGN1 promoter, and cytosine methylation (1.2305 ± 0.1482/1.2554 ± 0.3570 vs. 1.6578 ± 0.1818, p< 0.01) at the NLGN1 promoter in the hippocampus of AD mice. T10 and T4 increased the level of acetylated histone H3 (0.7733 ± 0.1611/0.8241 ± 0.0964 vs. 0.5587 ± 0.0925, p< 0.01) at the NLGN1 promoter in the hippocampus of AD mice. Conclusions: T10 and T4 may increase hippocampal NLGN1 expression in AD mice through epigenetic mechanisms, providing a new explanation for the mechanism underlying the protective effects of T10 and T4 on synapses.

13.
Arch Toxicol ; 93(9): 2661-2671, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31332466

RESUMO

Bisphenol analogues including bisphenol A and its derivatives are ubiquitous environmental contaminants and have been linked to adverse neurodevelopment effects on animals and humans. Most toxicological research focused on estrogen receptor mediated pathways and did not comprehensively clarify the observed toxicity. O-GlcNAcase (OGA), the highest level in brain, plays a critical role in controlling neuronal functions at multi-levels from molecule to animal behaviors. In this work, we intend to investigate the underlying molecular mechanisms for the neurotoxicity of bisphenol analogues by identifying their cellular targets and the resultant effects. The inhibitory actions of seven bisphenol analogues on the OGA activity at molecular level were investigated by our developed electrochemical biosensor. We found that their potency varied with substituent groups, in which tetrabromo bisphenol A (TBBPA) was the strongest. The seven bisphenol analogues (0-100 µM exposure) significantly inhibited OGA activity and up-regulated protein O-GlcNAcylation level in PC12 cells. Inhibition of OGA by bisphenol analogues further induced intracellular calcium, ROS, inflammation, repressed proliferation, interfered with cell cycle, induced apoptosis. And especially, 10 µM tetrabromo bisphenol A (TBBPA) exposure could impair the growth and development of neurite in human neural stem cells (hNSCs). Molecular docking for OGA/bisphenol analogue complexes revealed the hydrophobicity-dominated inhibition potency. OGA, as a new cellular target of bisphenol analogues, would illuminate the molecular mechanism of bisphenol analogues neurotoxicity.

14.
Environ Sci Technol ; 53(14): 8371-8380, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31251593

RESUMO

As alternatives to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide (HFPO) homologues, including hexafluoropropylene oxide dimer acid (HFPO-DA), hexafluoropropylene oxide trimer acid (HFPO-TA), and hexafluoropropylene oxide tetramer acid (HFPO-TeA), have been used in the fluoropolymer industry for a long period of time. These compounds have attracted widespread attention in recent years due to their environmental ubiquity and high bioaccumulation capability, as well as their toxicity. In our study, we evaluated the potential estrogenic effects of HFPOs in comparison to PFOA by ligand binding, transcriptional activity, and in vivo assays. Fluorescence ligand binding assays showed that both HFPO-TA and HFPO-TeA exhibited higher binding affinity to estrogen receptor ligand binding domains (ER-LBDs) than PFOA, with 2.5- and 57.5-fold higher affinity to ERα-LBD and 2.6- and 41.8-fold higher affinity to ERß-LBD, respectively, whereas HFPO-DA exhibited weaker binding affinity than PFOA. Unlike PFOA, HFPO-TA and HFPO-TeA exhibited antagonistic activity toward the ERs' signaling pathway, with HFPO-TeA displaying the strongest potency. In silico study revealed that while PFOA binds with ERs in a similar fashion as 17ß-estradiol, the HFPOs display an antagonistic binding mode. Using a zebrafish model, we further found that exposure to HFPO homologues significantly altered the levels of sex steroid hormones and vitellogenin. In general, both in vivo and in vitro results indicate that HFPO homologues might exert higher estrogenic effects than PFOA.


Assuntos
Estrogênios , Óxidos , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Transdução de Sinais
15.
Autism Res ; 12(7): 1057-1068, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31074587

RESUMO

Children with autism spectrum disorder (ASD) present with a high co-occurrence of anxiety and attention-deficit/hyperactivity disorder (ADHD). However, it remains unclear how the co-occurrence of anxiety and ADHD in children with ASD alters whole-brain functional networks. Here, we aimed to examine anxiety- and ADHD-related brain network centrality in children with ASD separately and their relationships with ASD symptoms. Clinical anxiety and ADHD levels in children with ASD, aged 6-13 years old, were assessed. Participants were categorized into four groups: ASD only (n = 28), ASD + anxiety (n = 19), ASD + ADHD (n = 25), and ASD + both anxiety and ADHD (n = 28). Subsequently, we compared voxel-wise network degree centrality (DC) among the four groups. We found that: (a) compared with ASD only, children with ASD + anxiety showed higher DC in the left middle temporal gyrus, right lingual gyrus, and left cuneus, and lower DC in the right precuneus; (b) children with ASD + ADHD presented higher DC in the right calcarine and left superior frontal gyrus (SFG) compared with ASD only; (c) children with ASD + both displayed higher DC in the right calcarine and lower centrality in the right middle occipital gyrus compared with ASD only; and (d) across all children with ASD, there was a positive correlation between DC of the right calcarine with nonverbal behavior scores, and DC of the left SFG was negatively correlated with social scores. Our findings suggest that the right calcarine, left SFG, and default mode network nodes play important roles in the co-occurrence of anxiety and ADHD among children with ASD. Autism Res 2019, 12: 1057-1068. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The co-occurrence of anxiety and attention-deficit/hyperactivity disorder (ADHD) has been shown to influence the brain function of children with ASD. In order to gain a better understanding of this, the present study compared degree centrality, the amount of effective brain functional connectivity that reflects the characteristics of brain networks, among four groups: ASD only, ASD + anxiety, ASD + ADHD, and ASD + both anxiety and ADHD. We found that some areas located in the language processing network and primary visual cortex were associated with the co-occurrence of ADHD, and some other areas located in the default mode network were associated with the co-occurrence of both anxiety and ADHD. These findings provide more knowledge about the neural basis underlying behavioral changes related to the co-occurrence of anxiety and ADHD in children with ASD.

16.
Gastroenterology ; 156(8): 2230-2241.e11, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30742832

RESUMO

BACKGROUND & AIMS: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. METHODS: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. RESULTS: Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. CONCLUSIONS: In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.


Assuntos
Causas de Morte , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Terminal/induzido quimicamente , Falência Hepática Aguda/induzido quimicamente , Sistema de Registros , Doença Aguda , Adulto , Distribuição por Idade , Idoso , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , China/epidemiologia , Doença Crônica , Estudos de Coortes , Intervalos de Confiança , Doença Hepática Terminal/epidemiologia , Doença Hepática Terminal/fisiopatologia , Feminino , Humanos , Incidência , Falência Hepática Aguda/epidemiologia , Falência Hepática Aguda/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Taxa de Sobrevida , Adulto Jovem
17.
J Environ Sci (China) ; 77: 198-209, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30573083

RESUMO

Graphene quantum dots (GQDs) possess great potential in various applications due to their superior physicochemical properties and wide array of available surface modifications. However, the toxicity of GQDs has not been systematically assessed, thus hindered their further development; especially, the risk of surface modifications of GQDs is largely unknown. In this study, we employed a lung carcinoma A549 cells as the model to investigate the cytotoxicity and autophagy induction of three types GQDs, including cGQDs (COOH-GQDs), hGQDs (OH-GQDs), and aGQDs (NH2-GQDs). The results showed hGQDs was the most toxic, as significant cell death was induced at the concentration of 100 µg/mL, determining by WST-1 assay as well as Annexin-V-FITC/PI apoptosis analysis, whereas cGQDs and aGQDs were non-cytotoxic within the measured concentration. Autophagy detection was performed by TEM examination, LC3 fluorescence tracking, and Western-blot. Both aGQDs and hGQDs induced cellular autophagy to various degrees except for cGQDs. Further analysis on autophagy pathways indicated all GQDs significantly activated p-p38MAPK; p-ERK1/2 was inhibited by aGQDs and hGQDs but activated by cGQDs. p-JNK was inhibited by aGQDs and cGQDs, while activated by hGQDs. Simultaneously, Akt was activated by hGQDs but inhibited by aGQDs. Inhibition of autophagy by 3-MA significantly increased the cytotoxicity of GQDs, suggesting that autophagy played a protective role against the toxicity of GQDs. In conclusion, cGQDs showed excellent biocompatibility and may be considered for biological applications. Autophagy induction may be included in the health risk assessment of GQDs as it reflects the stress status which may eventually lead to diseases.


Assuntos
Autofagia/efeitos dos fármacos , Citotoxinas/química , Citotoxinas/toxicidade , Grafite/química , Pontos Quânticos/química , Pontos Quânticos/toxicidade , Células A549 , Apoptose/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade , Propriedades de Superfície
18.
J Diabetes Res ; 2019: 1341963, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31930144

RESUMO

Aims/Introduction: The present study estimated the cost-effectiveness of bariatric surgery versus medication therapy for the management of recently diagnosed type 2 diabetes mellitus (T2DM) in obese patients from a Chinese health insurance payer perspective. Materials and Methods: A Markov model was established to compare the 40-year time costs and quality-adjusted life-years (QALYs) between bariatric surgery and medication therapy. The health-care costs in the bariatric surgery group, proportion of patients in each group with remission of diabetes, and state transition probabilities were calculated based on observed resource utilization from the hospital information system (HIS). The corresponding costs in the medication therapy group were derived from the medical insurance database. QALYs were estimated from previous literature. Costs and outcomes were discounted 5% annually. Results: In the base case analysis, bariatric surgery was more effective and less costly than medication therapy. Over a 40-year time horizon, the mean discounted costs were 86,366.55 RMB per surgical therapy patient and 113,235.94 CNY per medication therapy patient. The surgical and medication therapy patients lived 13.46 and 10.95 discounted QALYs, respectively. Bariatric surgery was associated with a mean health-care savings of 26,869.39 CNY and 2.51 additional QALYs per patient compared to medication therapy. Uncertainty around the parameter values was tested comprehensively in sensitivity analyses, and the results were robust. Conclusions: Bariatric surgery is a dominant intervention over a 40-year time horizon, which leads to significant cost savings to the health insurance payer and increases in health benefits for the management of recently diagnosed T2DM in obese patients in China.

19.
Neurochem Int ; 121: 69-74, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30248433

RESUMO

1,8-cineole is a natural monoterpene cyclic ether present in eucalyptus and has been reported to exhibit anti-inflammatory and antioxidant effects. The therapeutic effects of 1,8-cineole on neuropathic pain and the molecular mechanisms of its pharmacological actions remain largely unknown. In the present study, we investigated the analgesic mechanisms of orally administered 1,8-cineole in a rat model of chronic constriction injury (CCI) and examined the drug-induced modulation of P2X3 receptor expression in dorsal root ganglia. The mechanical withdrawal threshold and thermal withdrawal latency were measured in rats to assess behavioural changes 7 and 14 days after CCI surgery. Changes in P2X3 receptor mRNA expression of L4-5 dorsal root ganglia were analysed using quantitative real-time polymerase chain reaction at the 7th and 14th postoperative day. Additionally, we examined the expression of P2X3 receptor protein in L4-5 dorsal root ganglia 7 and 14 days after surgery using immunohistochemistry and western blots. We found that 1,8-cineole can alleviate pathological pain caused by P2X3 receptor stimulation and explored new methods for the prevention and treatment of neuropathic pain.


Assuntos
Eucaliptol/uso terapêutico , Gânglios Espinais/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Receptores Purinérgicos P2X3/biossíntese , Animais , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Relação Dose-Resposta a Droga , Eucaliptol/farmacologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Masculino , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos , Ratos Sprague-Dawley
20.
Arch Toxicol ; 92(10): 3131-3147, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30022264

RESUMO

Wide application of perfluoroalkyl acids (PFAAs) has raised great concerns on their side-effects on human health. PFAAs have been shown to accumulate mainly in the liver and cause hepatotoxicity. However, PFAAs can also deposit in lung tissues through air-borne particles and cause serious pulmonary toxicity. But the underlying mechanisms are still largely unknown. Autophagy is a type of programmed cell death parallel to necrosis and apoptosis, and may be involved in the lung toxicity of PFAAs. In this study, lung cancer cells, A549, were employed as the model to investigate the effects of three PFAAs with different carbon chain lengths on cell autophagy. Through Western blot analysis on LC3-I/II ratio of cells exposed to non-cytotoxic concentration (200 µM) and cytotoxic concentration (350 µM), we found concentration-dependent increase of autophagosomes in cells, which was further confirmed by TEM examination on ultra-thin section of cells and fluorescence imaging on autophagosomes in live cells. The abundance of p62 increased with the PFAAs concentration indicating the blockage of autophagy flux. Furthermore, we identified the mitochondrial autophagy (mitophagy) and endoplasmic reticulum autophagy (ER-phagy) morphologically as the major types of autophagy, suggesting the disruption on mitochondria and ERs. These organelle damages were confirmed by the overgeneration of ROS, hyperpolarization of mitochondrial membrane potential, as well as the up-regulation of ER-stress-related proteins, ATF4 and p-IRE1. Further analysis on the signaling pathways showed that PFAAs activated the MAPK pathways and inhibited the PI3K/Akt pathway, with potencies following the order of PFDA > PFNA > PFOA. Anti-oxidant (NAC) treatment did not rescue cells from death, indicating that oxidative stress is not the reason of cytotoxicity. Inhibition of autophagy by Atg5 siRNA and chloroquine even increased the toxicity of PFAAs, suggesting that PFAAs-autophagy was induced as the secondary effects of organelle damages and played a protective role during cell death.


Assuntos
Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fluorcarbonetos/toxicidade , Mitocôndrias/efeitos dos fármacos , Células A549 , Autofagia/fisiologia , Caprilatos/química , Caprilatos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Ácidos Decanoicos/química , Ácidos Decanoicos/toxicidade , Fluorcarbonetos/química , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo
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