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1.
Br J Haematol ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33764511

RESUMO

Minimal residual disease (MRD) is an important independent prognostic factor for relapse and survival in acute lymphoblastic leukaemia (ALL). Compared with adult B-cell ALL, reports of adult T-cell ALL (T-ALL) MRD have been scarce and mostly based on molecular methods. We evaluated the prognostic value of multiparameter flow cytometry (FCM)-based MRD at the end of induction (EOI-MRD). The present retrospective study included 94 adult patients with T-ALL. MRD was detected by six- to eight-colour FCM. Patients who were EOI-MRD positive had a higher cumulative incidence of relapse (CIR) (87·6% vs. 38·8%, P = 0·0020), and a lower relapse-free survival (RFS) (5·4% vs. 61·0%, P = 0·0005) and overall survival (OS) (32·7% vs. 69·7%, P < 0·0001) than those who were EOI-MRD negative. Moreover, for patients who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) at their first remission, EOI-MRD positivity was predictive of post-transplant relapse (2-year CIR: 68·2% vs. 4·0%, P = 0·0003). Multivariate analysis showed that EOI-MRD was an independent prognostic factor for CIR [hazard ratio (HR) 2·139, P = 0·046], RFS (HR 2·125, P = 0·048) and OS (HR 2·987, P = 0·017). In conclusion, EOI-MRD based on FCM was an independent prognostic factor for relapse and survival in adult T-ALL. For patients who underwent HSCT, EOI-MRD could be used to identify patients with a high risk of relapse after allo-HSCT.

2.
J Vis Exp ; (168)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33645557

RESUMO

Ambient fine particulate matter (PM2.5) exposure can lead to cardiac developmental toxicity but the underlying molecular mechanisms are still unclear. 8-hydroxy-2'deoxygenase (8-OHdG) is a marker of oxidative DNA damage and γH2AX is a sensitive marker for DNA double strand breaks. In this study, we aimed to detect PM2.5-induced 8-OHdG and γH2AX changes in the heart of zebrafish embryos using an immunofluorescence assay. Zebrafish embryos were treated with extractable organic matters (EOM) from PM2.5 at 5 µg/mL in the presence or absence of antioxidant N-acetyl-L-cysteine (NAC, 0.25 µM) at 2 h post fertilization (hpf). DMSO was used as a vehicle control. At 72 hpf, hearts were dissected from embryos using a syringe needle and fixed and permeabilized. After being blocked, samples were probed with primary antibodies against 8-OHdG and γH2AX. Samples were then washed and incubated with secondary antibodies. The resulting images were observed under fluorescence microscopy and quantified using ImageJ. The results show that EOM from PM2.5 significantly enhanced 8-OHdG and γH2AX signals in the heart of zebrafish embryos. However, NAC, acting as a reactive oxygen species (ROS) scavenger, partially counteracted the EOM-induced DNA damage. Here, we present an immunofluorescence protocol for investigating the role of DNA damage in PM2.5-induced heart defects that can be applied to the detection of environmental chemical-induced protein expression changes in the hearts of zebrafish embryos.


Assuntos
Dano ao DNA , Embrião não Mamífero/efeitos dos fármacos , Imunofluorescência/métodos , Coração/embriologia , Material Particulado/toxicidade , Peixe-Zebra/embriologia , Animais , Embrião não Mamífero/metabolismo , Coração/efeitos dos fármacos , Cardiopatias Congênitas/embriologia
3.
Curr Neuropharmacol ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632102

RESUMO

Great progress has been made in specifically identifying the central neural circuits (CNCs) of the core body temperature (Tcore), sleep-wakefulness states (SWs), and general anesthesia states (GAs), mainly utilizing optogenetic or chemogenetic manipulations. We summarize the neuronal populations and neural pathways of these three CNCs, which gives evidence for the orchestration within these three CNCs, and the integrative regulation of these three CNCs by different environmental light signals. We also outline some transient receptor potential (TRP) channels that function in the CNCs-Tcore and are modulated by some general anesthetics, which makes TRP channels possible targets for addressing the general-anesthetics-induced-hypothermia (GAIH). We suggest this review will provide new orientations for further consummating these CNCs and elucidating the central mechanisms of GAIH.

4.
Toxicology ; 452: 152697, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33524428

RESUMO

Trichloroethylene (TCE), a prevalent environmental contaminant, has been shown to induce cardiac malformations. Resveratrol (RSV) is a natural polyphenolic compound exhibiting protective effects on heart development. To investigate if RSV could protect against TCE-induced heart defects, we exposed zebrafish embryos to TCE (10 ppb) in the presence or absence of RSV (1 µg/mL). Our results showed that RSV significantly attenuated TCE-induced heart defects in zebrafish embryos. The TCE-induced ROS (reactive oxygen species) generation, 8-OHdG (8-hydroxy-2`-deoxyguanosine) formation and cell proliferation were significantly counteracted by RSV. Moreover, RSV attenuated the TCE-induced changes in mRNA expression or activity of genes involved in AHR and Nrf2 signal pathways. We further showed that RSV might inhibit TCE-enhanced cell proliferation by rescuing the downregulation of the p53/p21 axis. In conclusion, our data demonstrates that RSV protects against the cardiac developmental toxicity of TCE by inhibiting AHR activity, oxidative stress and cell proliferation.

5.
Nat Commun ; 12(1): 107, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398061

RESUMO

Rapid 3D imaging of entire organs and organisms at cellular resolution is a recurring challenge in life science. Here we report on a computational light-sheet microscopy able to achieve minute-timescale high-resolution mapping of entire macro-scale organs. Through combining a dual-side confocally-scanned Bessel light-sheet illumination which provides thinner-and-wider optical sectioning of deep tissues, with a content-aware compressed sensing (CACS) computation pipeline which further improves the contrast and resolution based on a single acquisition, our approach yields 3D images with high, isotropic spatial resolution and rapid acquisition over two-order-of-magnitude faster than conventional 3D microscopy implementations. We demonstrate the imaging of whole brain (~400 mm3), entire gastrocnemius and tibialis muscles (~200 mm3) of mouse at ultra-high throughput of 5~10 min per sample and post-improved subcellular resolution of ~ 1.5 µm (0.5-µm iso-voxel size). Various system-level cellular analyses, such as mapping cell populations at different brain sub-regions, tracing long-distance projection neurons over the entire brain, and calculating neuromuscular junction occupancy across whole muscle, are also readily accomplished by our method.


Assuntos
Imageamento Tridimensional , Microscopia de Fluorescência/métodos , Especificidade de Órgãos , Animais , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Contagem de Células , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Músculos/diagnóstico por imagem , Junção Neuromuscular/diagnóstico por imagem , Neurônios/metabolismo , Frações Subcelulares
6.
Exp Cell Res ; 400(2): 112505, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33516666

RESUMO

Inflammation and alveolar bone destruction constitute the main pathological process of periodontitis. However, the molecular mechanisms of bone destruction under the inflammation environment remain unclear. This study aims to explore the role of Ephrin-B2/EphB4 signaling in osteogenic differentiation under the inflammation environment. Mouse pre-osteoblasts MC3T3-E1 were pretreated with lipopolysaccharide of Porphyromonas gingivalis (Pg-LPS). The Ephrin-B2/EphB4 signaling was activated, and the osteogenic differentiation of cells was examined. The results showed that activation of Ephrin-B2/EphB4 signaling promoted the expression levels of osteogenic differentiation-related genes, and also relieved the inhibitory effect of Pg-LPS on osteogenesis. Noticeably, the effect of Ephrin-B2/EphB4 signaling might be related to the mitogen-activated protein kinase (MAPK) pathway. While applying Ephrin-B2-Fc and EphB4-Fc to periodontitis mice, we observed the reduction of alveolar crest destruction. The current study revealed the possible role of Ephrin-B2/EphB4 signaling in reducing bone destruction in periodontitis and suggested its potential values for further research.

7.
J Oncol ; 2020: 2621308, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33293956

RESUMO

Background: Vitamin C (Vc) deficiency is frequently observed in cancer sites and has been proposed to have an antitumor effect. However, the mechanism of Vc's killing effect is not clear. Besides, epigenetic alterations exhibit significant effects on colorectal cancer (CRC). This study aimed to explore the mechanism of Vc's killing effect and its association to epigenetic alterations in CRC. Methods: Cell morphology, apoptosis, proliferation, and cycle were assayed to test Vc's suppressive function in CRC cell lines. Xenograft and peritoneal implantation metastasis models were performed to evaluate the high-dose Vc's inhibitory effect on tumor growth and metastasis. Immunohistochemistry was used to measure CD31 expression in solid tumors. A literature summary was applied for screening differently expressed long noncoding RNAs (lncRNAs) in CRC tissues and was closely associated with CRC progression. The qPCR was used to detect the expression of these lncRNAs. The association between Vc and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was evaluated in MALAT1-transfected CRC cells and a xenograft model. Results: Vc was confirmed to function in proliferation suppression, apoptosis induction, and S phase arresting in CRC cell lines. High-dose Vc, but not physiologically low-dose Vc, was identified as a suppressive function on tumor growth in xenograft models and an inhibitory effect on implantation metastasis in peritoneal implantation metastasis mice. Furthermore, a consistent downregulation of MALAT1 induced by Vc was verified among CRC cell lines and tumor tissues from both mouse models. Finally, experiments on MALAT1-knockdown CRC cells and its xenograft model suggested that Vc had a tendency in killing CRC with high MALAT1 expression. Conclusions: Our findings demonstrate that high-dose Vc has more efficiency in suppressing CRC with higher MALAT1 expression. It gives high-dose Vc the possibility of a better curative effect on CRC with overexpressed MALAT1. Further clinical studies are still needed.

8.
Cell Biol Toxicol ; 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33130971

RESUMO

Inflammatory bowel disease (IBD) is a chronic idiopathic disorder causing inflammation in the gastro-intestinal tract, which is lack of effective drug targets and medications. To identify novel therapeutic agents against consistent targets, we exploited a systems pharmacology-driven framework that incorporates drug-target networks of natural product and IBD disease genes. Our in silico approach found that Ligustilide (LIG), one of the major active components of Angelica acutiloba and Cnidium Officinale, potently attenuated IBD. The following in vivo and in vitro results demonstrated that LIG prevented experimental mice colitis induced by dextran sulfate sodium (DSS) via suppressing inflammatory cell infiltration, the activity of MPO and iNOS, and the expression and production of IL-1ß, IL-6, and TNF-α. Subsequently, the network analysis helped to validate that LIG alleviated colitis by inhibiting NF-κB and MAPK/AP-1 pathway through activating PPARγ, which were further confirmed in RAW 264.7 cells and bone marrow-derived macrophages in vitro. In summary, this study reveals that LIG activated PPARγ to inhibit the activation of NF-κB and AP-1 signaling thus eventually alleviated DSS-induced colitis, which has promising activities and may serve as a candidate for the treatment of IBD.Graphical abstract This study suggested novel computational and experimental pharmacology approaches to identify potential IBD therapeutic agents by exploiting polypharmacology of natural products. We demonstrated that LIG could attenuate inflammation in IBD by inhibiting NF-κB and AP-1 pathways via PPARγ activation to reduce the expression of pro-inflammatory cytokines in macrophages. These findings offer comprehensive pre-clinical evidence that LIG may serve as a promising candidate for IBD therapy in the future. Graphical headlights: 1. Systems pharmacology uncovered Ligustilide attenuates experimental colitis in mice. 2. Network-based analysis predicted the mechanism of Ligustilide against IBD, which was validated by inhibiting PPARγ-mediated inflammation pathways. 3. Ligustilide activated PPARγ to inhibit NF-κB and AP-1 activation thus eventually alleviated DSS-induced colitis.4. Ligustilide has promising activities and may serve as a candidate for the treatment of IBD.

9.
Front Neural Circuits ; 14: 55, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973462

RESUMO

Background: Monochromatic blue light (MBL), with a wavelength between 400-490 nm, can regulate non-image-forming (NIF) functions of light in the central nervous system. The suprachiasmatic nucleus (SCN) in the brain is involved in the arousal-promoting response to blue light in mice. Animal and human studies showed that the responsiveness of the brain to visual stimuli is partly preserved under general anesthesia. Therefore, this study aimed to investigate whether MBL promotes arousal from sevoflurane anesthesia via activation of the SCN in mice. Methods: The induction and emergence time of sevoflurane anesthesia under MBL (460 nm and 800 lux) exposure was measured. Cortical electroencephalograms (EEGs) were recorded and the burst-suppression ratio (BSR) was calculated under MBL during sevoflurane anesthesia. The EEGs and local field potential (LFP) recordings with or without locally electrolytic ablated bilateral SCN were used to further explore the role of SCN in the arousal-promoting effect of MBL under sevoflurane anesthesia. Immunofluorescent staining of c-Fos was conducted to reveal the possible downstream mechanism of SCN activation. Results: Unlike the lack of effect on the induction time, MBL shortened the emergence time and the EEG recordings showed cortical arousal during the recovery period. MBL resulted in a significant decrease in BSR and a marked increase in EEG power at all frequency bands except for the spindle band during 2.5% sevoflurane anesthesia. MBL exposure under sevoflurane anesthesia enhances the neuronal activity of the SCN. These responses to MBL were abolished in SCN lesioned (SCNx) mice. MBL evoked a high level of c-Fos expression in the prefrontal cortex (PFC) and lateral hypothalamus (LH) compared to polychromatic white light (PWL) under sevoflurane anesthesia, while it exerted no effect on c-Fos expression in the ventrolateral preoptic area (VLPO) and locus coeruleus (LC) c-Fos expression. Conclusions: MBL promotes behavioral and electroencephalographic arousal from sevoflurane anesthesia via the activation of the SCN and its associated downstream wake-related nuclei. The clinical implications of this study warrant further study.

10.
Oncol Lett ; 20(5): 230, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32968452

RESUMO

The aim of the present study was to establish a novel docetaxel-resistant prostate cancer cell line and investigate its biological characteristics. The human prostate cell line, PC-3, was exposed to docetaxel, the concentrations of which were increased in a stepwise manner in the medium to select the drug-resistant cell line, PC-3/DTX. The morphological features were observed using inverted microscopy. The growth curves of PC-3 and PC-3/DTX cells were drawn to calculate the doubling time. Flow cytometry was performed to determine cell-cycle distribution. A 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H tetrazolium bromide assay was performed to test the drug resistance of PC-3 and PC-3/DTX cells. Western blot analysis was conducted to determine the protein expression levels of the mammalian target of rapamycin (mTOR) signaling pathway, which may serve a role in regulating drug resistance in the two cell lines. PC-3/DTX cells exhibited changes in morphology, proliferation rate, doubling time and cell-cycle distributions, compared with PC-3 cells. PC-3/DTX cells were 10.9-fold resistant to docetaxel in comparison with PC-3 cells. The results showed that PC-3/DTX cells overexpressed Rictor and p-AKT(S473) proteins, which are specific subunits or downstream substrates of mTORC2. The new findings suggested that the mTORC2 signaling pathway may serve an important role in the regulation of docetaxel drug resistance of PC-3 cells. In conclusion, PC-3/DTX cells may be applied to study the resistance of anticancer drugs and to identify methods to overcome resistance.

11.
Front Pharmacol ; 11: 1264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903546

RESUMO

Hepatocellular carcinoma (HCC) is a fatal and dominant form of liver cancer that currently has no effective treatment or positive prognosis. In this study, we explored the antitumor effects of cryptotanshinone (CPT) against HCC and the molecular mechanisms underlying these effects using a systems pharmacology and experimental validation approach. First, we identified a total of 296 CPT targets, 239 of which were also HCC-related targets. We elucidated the mechanisms by which CPT affects HCC through multiple network analysis, including CPT-target network analysis, protein-protein interaction network analysis, target-function network analysis, and pathway enrichment analysis. In addition, we found that CPT induced apoptosis in Huh7 and MHCC97-H ells due to increased levels of cleaved PARP, Bax, and cleaved caspase-3 and decreased Bcl-2 expression. CPT also induced autophagy in HCC cells by increasing LC3-II conversion and the expression of Beclin1 and ATG5, while decreasing the expression of p62/SQSTM1. Autophagy inhibitors (3-methyladenine and chloroquine) enhanced CPT-induced proliferation and apoptosis, suggesting that CPT-induced autophagy may protect HCC cells against cell death. Furthermore, CPT was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Interestingly, activation of PI3K by insulin-like growth factor-I inhibited CPT-induced apoptosis and autophagy, suggesting that the PI3K/AKT/mTOR signaling pathway is involved in both CPT-induced apoptosis and autophagy. Finally, CPT was found to inhibit the growth of Huh7 xenograft tumors. In conclusion, we first demonstrated the antitumor effects of CPT in Huh7 and MHCC97-H cells, both in vitro and in vivo. We elucidated the potential antitumor mechanism of CPT, which involved inducing apoptosis and autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway. Our findings may provide valuable insights into the clinical application of CPT, serving as a potential candidate therapeutic agent for HCC treatment.

12.
Drug Des Devel Ther ; 14: 3131-3142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801649

RESUMO

Purpose: This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug. Materials and Methods: A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), the peak plasma concentration (Cmax), the time to achieve Cmax (Tmax), and the elimination half-life (t1/2). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs). Results: The values of t1/2 and Tmax for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of Cmax, AUC0-t, and AUC0-∞ between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events. Conclusion: This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption.

13.
Br J Anaesth ; 125(4): 548-559, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32807382

RESUMO

BACKGROUND: Circadian differences in the induction, maintenance, or emergence from volatile anaesthesia have not been well studied. METHODS: The minimal alveolar concentration (MAC) for preventing movement in response to a painful stimulus, MAC for loss of righting reflex (MACLORR), and MAC for recovery of righting reflex (MACRORR) in C57BL/6J male mice with isoflurane or sevoflurane exposure were measured during either the light or dark phase. Time to onset of loss of righting reflex (TimeLORR) and recovery of righting reflex (TimeRORR) upon exposure to 1 MAC of isoflurane or sevoflurane were determined. EEG was also monitored in the light and dark phase under isoflurane or sevoflurane exposure. The noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was used to deplete noradrenergic neurones in the locus coeruleus to explore the impact of norepinephrine on these measurements. RESULTS: MACLORR, TimeLORR, and MAC did not show light- or dark-phase-dependent variations for either isoflurane or sevoflurane exposure. However, MACRORR was higher and TimeRORR was shorter in the dark phase than in the light phase for both isoflurane and sevoflurane exposure. The EEG delta wave power was higher but theta wave power was lower in the light phase than that in the dark phase during the rest state and emergence of anaesthesia. These light- and dark-phase-dependent changes in emergence were abolished in DSP-4-treated mice. CONCLUSION: Our data show that circadian differences exist during emergence but not during induction or maintenance of sevoflurane or isoflurane anaesthesia. The locus coeruleus noradrenergic system may contribute to these differences.


Assuntos
Anestésicos Inalatórios/farmacologia , Ritmo Circadiano/fisiologia , Locus Cerúleo/fisiologia , Norepinefrina/fisiologia , Anestésicos Inalatórios/farmacocinética , Animais , Benzilaminas/farmacologia , Temperatura Corporal/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reflexo de Endireitamento/efeitos dos fármacos
14.
Am J Transl Res ; 12(6): 2843-2859, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655814

RESUMO

Brain responses to external stimuli such as light are preserved under general anesthesia. In nocturnal animals, acute light exposure can induce sleep, and acute dark can increase wakefulness. This study aims to investigate the effect of acute continuous nocturnal light exposure (ACNLE) on burst-suppression patterns under sevoflurane anesthesia using electroencephalogram (EEG) monitoring in mice. We set the initial sevoflurane dose to 2.0% and increased it by 0.5% every 20 min until it reached 4.0%. Burst-suppression ratio (BSR), EEG power and quantitative burst analysis were used to assess the effects of ACNLE on burst suppression patterns under sevoflurane anesthesia. Blood serum corticosterone measurement and c-Fos immunofluorescent staining of the suprachiasmatic nucleus (SCN) and ventrolateral preoptic nucleus (VLPO) were used to demonstrate the biological consequence induced by ACNLE. Compared to darkness, ACNLE caused significant changes in EEG power and decrease of BSR at 2.5%, 3.0% and 3.5% sevoflurane. ACNLE was also associated with an increase in burst duration and burst frequency as well as a decrease in burst maximum peak-to-peak amplitude and burst power in the beta (15-25 Hz) and gamma (25-80 Hz) bands. ACNLE increased the concentration of serum corticosterone and the expression of c-Fos in the SCN, while not changed c-Fos expression in the VLPO. These results demonstrated that ACNLE influences the BSR under sevoflurane anesthesia, possibly by activating light-sensitive nonvisual pathways including SCN and increasing of peripheral serum corticosterone levels.

15.
Toxicol Appl Pharmacol ; 398: 115029, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32376357

RESUMO

Resveratrol (RSV), a natural polyphenolic compound commonly found in food, has antioxidant and aryl hydrocarbon receptor (AHR) antagonist effects. We have recently demonstrated that AHR mediated reactive oxygen species (ROS) generation contributes to the cardiac developmental toxicity of ambient fine particle matter (PM2.5). Thus, we hypothesized that RSV protects against the cardiac developmental toxicity of PM2.5 by inhibiting ROS generation and AHR activity. To test this concept, we exposed zebrafish embryos to extractable organic matter (EOM) from PM2.5 in the presence or absence of RSV. We found that RSV significantly counteracted EOM-induced cardiac malformations in zebrafish embryos. The EOM-induced ROS production, DNA damage and apoptosis in the heart of zebrafish embryos were also counteracted by RSV supplementation. Furthermore, RSV attenuated EOM-induced changes in the expression of genes involved in cardiac development (nkx2.5, sox9b, axin2), oxidative stress (nrf2a, nrf2b, gstp1, gstp2, sod1, sod2, cat) and apoptosis (p53, bax). However, RSV did not suppress EOM-induced AHR activity. In conclusion, our data indicates that RSV protects against the PM2.5-induced heart malformations by inhibiting oxidative stress rather than through AHR antagonism.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/tratamento farmacológico , Material Particulado/efeitos adversos , Substâncias Protetoras/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Embrião não Mamífero/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/efeitos dos fármacos , Cardiopatias Congênitas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
16.
Chemosphere ; 251: 126610, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32443250

RESUMO

Trichloroethylene (TCE), a widely used organic solvent, is a common environmental pollutant. Increasing evidence indicates that maternal TCE exposure is associated with congenital cardiac defects, but the underlining mechanisms remain largely unknown. In this study, we revealed that TCE exposure significantly induced heart defects and dysfunctions in zebrafish embryos. Heart tissues were dissected and subjected to high throughput sequencing and qPCR to identify differentially expressed miRNAs and mRNAs. The effects of miRNA were further verified by microinjection of antagomir or agomir. Reactive Oxygen Species (ROS) and cell proliferation were measured by using dichlorodihydrofluorescein diacetate (DCFH-DA) and EdU staining, respectively. Our results showed that 19 miRNAs were downregulated whereas 48 miRNAs were upregulated in the heart of zebrafish embryos. The downregulation of miR-133a and the upregulation of miR-182 were further validated. Moreover, we found that miR-133a agomir significantly alleviated the TCE-induced heart defects while miR-133a antagomir mimicked the toxic effect of TCE on heart development. Furthermore, miR-133a agomir significantly counteracted TCE-induced ROS production and excessive cell proliferation in the heart of zebrafish embryos. In conclusion, our results indicate that miR-133a mediates TCE-induced ROS generation, leading to excessive cell proliferation and heart defects.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Coração/efeitos dos fármacos , MicroRNAs/genética , Tricloroetileno/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Cardiotoxicidade , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Coração/embriologia , Cardiopatias Congênitas/genética , Regulação para Cima
17.
J Cancer ; 11(9): 2580-2592, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32201528

RESUMO

Tumor associated neutrophils (TANs) play important roles in the progress of CRC. Since tumor microenvironments could influence the phenotypes of TANs, altering the tumor microenvironment to polarize the phenotype of TANs may be a new strategy for tumor treatment. This study aims to investigate the effect of anti-TGF-ß on the polarization of TANs from a pro-tumor phenotype towards an anti-tumor phenotype in CRC. In this work, CRC patients had more infiltration of TANs and higher expression of TGF-ß in CRC tissue when compared with the controls. In vitro, SW480 cells were co-cultured with primed neutrophils, which simulated the TANs in the tumor microenvironment, and TGF-ß was blocked by anti-TGF-ß (1D11) in order to polarize TANs. Anti-TGF-ß treatment increased the cytotoxicity of TANs and decreased the metastatic chemoattractants secreted by TANs, and ultimately increased the apoptosis of CRC cells significantly while remarkably suppressing the migration of tumor cells. The changes of signaling pathways in the TANs and tumor cells were explored. The results showed that anti-TGF-ß attenuated CRC may be partly mediated by suppression of PI3K/AKT signaling pathways in TANs and partly mediated by suppression of TGF-ß/Smad signaling pathways in tumor cells. Furthermore, the tumor in the mice treated with 1D11 was obviously smaller and had reverse tumorigenesis compared with the controls, while neutrophil depletion reduced the anti-tumor effect of 1D11. Our data suggest that anti-TGF-ß attenuates tumor growth via the polarization of TANs to an anti-tumor phenotype in CRC, which provides new strategies for CRC treatment.

19.
Med Sci Sports Exerc ; 52(8): 1710-1718, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32079925

RESUMO

PURPOSE: This study was to investigate the mechanism of intestinal physical and immune barriers in the occurrence of high-intensive exercise-induced gastrointestinal symptoms. METHODS: An overtraining model of male C57BL/6 mice was established by running-to-exhaustive exercise. Then, the mice were sacrificed, and a series of evaluation indicators, including the routine blood analysis as well as histological examinations, inflammatory factors, ultrastructure observation, and intestinal permeability of the gut, were measured based on this model. The expressions of inflammatory factors tumor necrosis factor α, interferon-γ, and interleukin (IL)-6 as well as the tight junction and adherence junction proteins ZO-1, Occludin, Claudin-1, and E-cadherin were measured, respectively. Furthermore, the mRNA level of IL-22 and the proportion of ILC3 and IL-22 produced in CD4 T cells in lamina propria lymphocytes (LPL) were analyzed by flow cytometry. Besides, the liver glycogen and the expressions of sirtuins-3 and hypoxia-inducible factor-1a, which were associated with the intestinal metabolism phenotype, were analyzed by Western blotting. RESULTS: Exhaustive exercise induced a disrupted intestinal barrier integrity, an aggravated intestinal inflammation, increased gut permeability, and the reduced IL-22 mRNA level. Compared with the nonexercise mice, the IL-22 produced in LPL was reduced followed by exhaustive exercise, whereas the proportion of IL-22 produced in CD4 T cells was still unchanged. Significantly, the proportion of ILC3 in the LPL was decreased obviously, including the NCR ILC3. Furthermore, the intestinal metabolism phenotype assessment showed lower liver glycogen and blood glucose as well as higher blood lactic acid and hypoxia-inducible factor-1a, respectively. CONCLUSIONS: The data indicated that the acute high-intensity running-induced gastrointestinal symptom is closely associated with a reduced percentage of ILC3 and IL-22 level in the LPL, possibly due to the glycogen exhaustion and intestinal mucosa hypoperfusion.

20.
Nat Commun ; 11(1): 642, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005799

RESUMO

Metastasis can occur following surgical resection of solid tumors and metastasis is the main cause of cancer death. The role of anesthetics used during surgery in cancer metastasis and the underlying mechanism remains largely unknown. Here we show that surgical dissection of primary tumors in mice under anesthesia with sevoflurane leads to significantly more lung metastasis than with propofol in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. Sevoflurane increases the level of serum IL-6, which activates STAT3 and the infiltration of CD11b+ myeloid cells into the lung. Interruption of IL-6/JAK/STAT3 pathway by a JAK inhibitor AZD1480 reverses the pro-metastatic effect of sevoflurane and the associated increase of both activated STAT3 and infiltrated CD11b+ cells in 4T1 model. Our study provides the preclinical evidence informing the distinct effects of anesthetics on metastasis of breast cancers through change of cytokines and the tumor microenvironment.


Assuntos
Anestésicos Gerais/efeitos adversos , Neoplasias da Mama/cirurgia , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Neoplasias Pulmonares/secundário , Fator de Transcrição STAT3/metabolismo , Anestésicos Gerais/administração & dosagem , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-6/genética , Janus Quinases/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Propofol/administração & dosagem , Propofol/efeitos adversos , Fator de Transcrição STAT3/genética , Sevoflurano/administração & dosagem , Sevoflurano/efeitos adversos
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