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1.
Behav Genet ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32048109

RESUMO

Fragile X syndrome (FXS) is a heritable mental retardation disease caused by unstable trinucleotide repeat sequences in FMR1. FXS is characterized by delayed development, hyperactivity, and autism behavior. Zebrafish is an excellent model to study FXS and the underlying function of fmr1. However, at present, fmr1 function is mainly studied via morpholinos or generated mutants using targeting induced local lesions in genomes. However, both of these methods generate off-target effects, making them suboptimal techniques for studying FXS. In this study, CRISPR/Cas9 technology was used to generate two zebrafish fmr1 mutant lines. High-throughput behavior analysis, qRT-PCR, and alcian blue staining experiments were employed to investigate fmr1 function. The fmr1 mutant line showed abnormal behavior, learning memory defects, and impaired craniofacial cartilage development. These features are similar to the human FXS phenotype, indicating that the fmr1 mutant generated in this study can be used as a new model for studying the molecular pathology of FXS. It also provides a suitable model for high-throughput screening of small molecule drugs for FXS therapeutics.

2.
Aging (Albany NY) ; 122020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32074085

RESUMO

In this study, we evaluated the function and regulation of the long non-coding RNA (lncRNA) FAM83H-AS1 in triple-negative breast cancer (TNBC). Our data show that the FAM83H-AS1 levels are increased in human TNBC cells and tissues. Proliferation, migration, and invasion of TNBC cells are decreased by FAM83H-AS1 suppression, but increased by FAM83H-AS1 overexpression. Bioinformatics analysis revealed that miR-136-5p is a potential target of FAM83H-AS1. MiR-136-5p expression is decreased in TNBC tissues, and its overexpression suppresses TNBC cell proliferation, migration, and invasion. MiR-136-5p suppression reverses the FAM83H-AS1 silencing-mediated inhibition of TNBC cell proliferation, migration, and invasion, suggesting that FAM83H-AS1 exerts its oncogenic effect by inhibiting miR-136-5p. Our data identify metadherin (MTDH) as the target gene of miR-136-5p, and demonstrate that the MTDH expression is increased in human TNBC tissues, which induces proliferation, migration, and invasion of TNBC cells. Importantly, our in vivo data show that FAM83H-AS1 also promotes tumor growth in TNBC mouse xenografts. Together, our results demonstrate that FAM83H-AS1 functions as an oncogenic lncRNA that regulates miR-136-5p and MTDH expression during TNBC progression, and suggest that targeting the FAM83H-AS1/miR-136-5p/MTDH axis may serve as a novel therapeutic target in TNBC.

3.
Anal Bioanal Chem ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32030494

RESUMO

Due to its important role in tumor development and treatment, hyaluronidase (HAase) has been widely investigated in vitro and in vivo. However, such investigation was limited by the absence of sensitive and in situ detection methods. Herein, a hyaluronic acid (HA) hydrogel based on the fluorescence resonance energy transfer (FRET) effect was constructed for the detection of HAase. FITC and AuNPs were covalently coupled with two HA derivatives respectively to form a fluorescent donor-acceptor pair. In the presence of HAase, the hydrogel established by cross-linking of HA derivatives was hydrolyzed specifically. The FRET effect in the hydrogel disappeared and the fluorescence intensity increased proportionally with the changes in the concentration of the HAase. Experiments proved that the HAase sensing system had a wide response range (0.5-100 U/mL), good anti-interference, and excellent biocompatibility. When the hydrogel was used for 3D culture of lung cancer cells, in situ fluorescent response could be achieved. Graphical abstract.

4.
Brain ; 143(2): 570-581, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953931

RESUMO

At least 50% of patients with tuberous sclerosis complex present with intractable epilepsy; for these patients, resective surgery is a treatment option. Here, we report a nationwide multicentre retrospective study and analyse the long-term seizure and neuropsychological outcomes of epilepsy surgery in patients with tuberous sclerosis complex. There were 364 patients who underwent epilepsy surgery in the study. Patients' clinical data, postoperative seizure outcomes at 1-, 4-, and 10-year follow-ups, preoperative and postoperative intelligence quotients, and quality of life at 1-year follow-up were collected. The patients' ages at surgery were 10.35 ± 7.70 years (range: 0.5-47). The percentage of postoperative seizure freedom was 71% (258/364) at 1-year, 60% (118/196) at 4-year, and 51% (36/71) at 10-year follow-up. Influence factors of postoperative seizure freedom were the total removal of epileptogenic tubers and the presence of outstanding tuber on MRI at 1- and 4-year follow-ups. Furthermore, monthly seizure (versus daily seizure) was also a positive influence factor for postoperative seizure freedom at 1-year follow-up. The presence of an outstanding tuber on MRI was the only factor influencing seizure freedom at 10-year follow-up. Postoperative quality of life and intelligence quotient improvements were found in 43% (112/262) and 28% (67/242) of patients, respectively. Influence factors of postoperative quality of life and intelligence quotient improvement were postoperative seizure freedom and preoperative low intelligence quotient. The percentage of seizure freedom in the tuberectomy group was significantly lower compared to the tuberectomy plus and lobectomy groups at 1- and 4-year follow-ups. In conclusion, this study, the largest nationwide multi-centre study on resective epilepsy surgery, resulted in improved seizure outcomes and quality of life and intelligence quotient improvements in patients with tuberous sclerosis complex. Seizure freedom was often achieved in patients with an outstanding tuber on MRI, total removal of epileptogenic tubers, and tuberectomy plus. Quality of life and intelligence quotient improvements were frequently observed in patients with postoperative seizure freedom and preoperative low intelligence quotient.

5.
AAPS J ; 22(2): 22, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900688

RESUMO

Immuno-PET is a molecular imaging technique utilizing positron emission tomography (PET) to measure the biodistribution of an antibody species labeled with a radioactive isotope. When applied as a clinical imaging technique, an immuno-PET imaging agent must be manufactured with quality standards appropriate for regulatory approval. This paper describes methods relevant to the chemistry, manufacturing, and controls component of an immuno-PET regulatory filing, such as an investigational new drug application. Namely, the production, quality control, and characterization of the immuno-PET clinical imaging agent, ZED8, an 89Zr-labeled CD8-specific monovalent antibody as well as its desferrioxamine-conjugated precursor, CED8, is described and evaluated. PET imaging data in a human CD8-expressing tumor murine model is presented as a proof of concept that the imaging agent exhibits target specificity and comparable biodistribution across a range of desferrioxamine conjugate loads.

6.
Chem Commun (Camb) ; 56(3): 344-347, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31808481

RESUMO

Exploiting synergistic remote participation effects of acyl groups at the O3 and O6 positions was key to the complete α-selectivity during the total synthesis of the unique (1 → 2)- and (1 → 3)-linked α-oligoglucosides from the Helicobacter pylori O2 O-antigen. Acyl remote participation and solvent effects were found to counteract during α-stereoselective glucosylations for the first time. The resulting antigen is a lead for the development of a carbohydrate-conjugate vaccine.


Assuntos
Helicobacter pylori/metabolismo , Antígenos O/química , Oligossacarídeos/síntese química , Oligossacarídeos/química , Sorogrupo , Solventes/química , Estereoisomerismo , Vacinas Conjugadas/química
7.
Ann Rheum Dis ; 79(1): 132-140, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31662318

RESUMO

OBJECTIVES: Diverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to (1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome. METHODS: The stools from a case-control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray. RESULTS: Previous reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients. CONCLUSION: These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.

8.
J Biol Chem ; 295(3): 717-728, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31819005

RESUMO

Cellular membranes contain many lipids, some of which, such as sphingolipids, have important structural and signaling functions. The common sphingolipid glucosylceramide (GlcCer) is present in plants, fungi, and animals. As a major plant sphingolipid, GlcCer is involved in the formation of lipid microdomains, and the regulation of GlcCer is key for acclimation to stress. Although the GlcCer biosynthetic pathway has been elucidated, little is known about GlcCer catabolism, and a plant GlcCer-degrading enzyme (glucosylceramidase (GCD)) has yet to be identified. Here, we identified AtGCD3, one of four Arabidopsis thaliana homologs of human nonlysosomal glucosylceramidase, as a plant GCD. We found that recombinant AtGCD3 has a low Km for the fluorescent lipid C6-NBD GlcCer and preferentially hydrolyzes long acyl-chain GlcCer purified from Arabidopsis leaves. Testing of inhibitors of mammalian glucosylceramidases revealed that a specific inhibitor of human ß-glucosidase 2, N-butyldeoxynojirimycin, inhibits AtGCD3 more effectively than does a specific inhibitor of human ß-glucosidase 1, conduritol ß-epoxide. We also found that Glu-499 and Asp-647 in AtGCD3 are vital for GCD activity. GFP-AtGCD3 fusion proteins mainly localized to the plasma membrane or the endoplasmic reticulum membrane. No obvious growth defects or changes in sphingolipid contents were observed in gcd3 mutants. Our results indicate that AtGCD3 is a plant glucosylceramidase that participates in GlcCer catabolism by preferentially hydrolyzing long-acyl-chain GlcCers.

9.
ACS Omega ; 4(22): 19969-19976, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31788630

RESUMO

P-O-H polycondensation -O-Cu-O- ion-bonded bridges were formed in copper phosphate thermal insulation materials by mixing Al(OH)3 dissolved in H3PO4 with CuO filler and Al2O3, SiC, ZrC, and Cr2O3 as curing accelerators, alone or in combination. The effects of different additive combinations on the curing behavior and thermal stability of the copper phosphate thermal insulation material matrixes were compared using thermogravimetry/differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy. The copper phosphate materials exhibit good thermal stabilities and low thermal conductivities. The thermal weight losses before and after ceramic reinforcement were 4-19.8 and 3.8-9.4%, respectively, and the thermal conductivities of the P-O-H polycondensation -O-Cu-O- ion-bonded bridges formed in the copper phosphate thermal insulation materials were in the range of 0.656-1.824 W/(m·K).

10.
J Appl Toxicol ; 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31883144

RESUMO

The interactions between adenosine triphosphate-binding cassette (ABC) transporters and nano-sized materials are attracting increasing attention, due to their great potential in overcoming the multidrug resistance (MDR) phenomena in cancer treatment. However, the inner mechanisms involved in the interactions are largely unknown. In this study, two commercial quantum dots (QDs), CdSe/ZnS-MPA and CdSe/ZnS-GSH, were tested for their interactions with P-glycoprotein (P-gp), as well as the relating mechanisms in lung cancer (A549) cells. Both QDs significantly suppressed the gene and protein expressions of P-gp in A549 cells. To explain this, the gene expressions of nine relating microRNAs (miRNAs) were evaluated. The results indicated a shared up-regulation of miR-34b and miR-185 by both QDs. Furthermore, mimics and inhibitors of miR-34b and miR-185 significantly enhanced and suppressed the gene and protein expressions of P-gp, respectively, confirming the modulatory function of these two miRNAs on P-gp. Interestingly, expressions of both miRNAs were suppressed during treatment with Cd2+ and doxorubicin, which induced the expression of P-gp, indicating the universality of these miRNAs-related mechanisms. Thus, as miR-34b and miR-185 participated in the suppression of P-gp functions in A549 cells they could be interesting targets for the treatment of lung cancer.

11.
BMC Geriatr ; 19(1): 367, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870318

RESUMO

BACKGROUND: Sarcopenia is a decrease in skeletal muscle mass, physical performance, and muscle strength in older people. In this study, we aimed to explore the correlation between comorbidity and skeletal muscle mass and physical performance in older people. METHODS: This retrospective study included 168 subjects. Their medical history, physical function, computed tomography (CT) chest scans, and blood tests for nutrition were evaluated. The patients were divided into two groups: (1) a low muscle mass group and (2) a normal muscle mass group. Multivariate analysis of variance was used to compare multiple sets of mean vectors. RESULTS: Overall, 72.02% of the subjects had a low skeletal muscle index (SMI) and low gait speed. The patients with low skeletal muscle mass and physical performance were older, had more serious comorbidities, and had longer average hospitalization periods and lower albumin and hemoglobin levels. Subjects with a high Charlson comorbidity index (CCI) were more likely to be in the sarcopenic group than in the non-sarcopenic group. In addition, there was a linear correlation between the CCI and SMI (r = - 0.549, P < 0.05), and between the CCI and gait speed (r = - 0.614, P < 0.05). The area under the curve (AUC) value for low skeletal muscle mass with the CCI was 0.879. CONCLUSIONS: We identified an independent association between comorbidity and skeletal muscle mass/physical performance by researching the correlation between the CCI and SMI/gait speed. Our results suggested that the CCI score may have important clinical diagnostic value for sarcopenia.

12.
BMJ Open ; 9(12): e032945, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843846

RESUMO

INTRODUCTION: Available patient-reported outcome (PRO) studies are mainly from single institution or of small sample size, and the variations across hospitals and regions were not fully analysed. A multicentre, prospective, patient-reported outcome-reconstruction and oncoplastic cohort (PRO-ROC) will be planned to assess the PROs of Chinese patients with breast cancer who will undergo breast reconstruction (BR) or oncoplastic breast-conserving surgery (OBCS). METHODS AND ANALYSIS: The inclusion criteria are female patients with breast cancer aged >18 years old who will undergo BR or OBCS. This cohort will include at least 10 000 consecutive patients (about 5000 patients who will undergo BR and 5000 patients who will undergo OBCS). The exposures were surgery types: BR and OBCS regardless of the techniques and materials used. The primary endpoint will be PROs, which include BREAST-Q and quality of life (European Organisation for Research and Treatment (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and EORTC QoL Breast Cancer-specific version (QLQ-BR23)). All patients will be followed up to 24 months after operations. All data will be prospectively collected using an app software. Data will be analysed using SPSS and Stata software. ETHICS AND DISSEMINATION: This study follows the Helsinki Declaration. All patients will be asked to sign an informed consent before enrolment. The results of this study will be presented at national and international meetings and published in a scientific peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04030845; Pre-results.

13.
Sci Rep ; 9(1): 17765, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31780743

RESUMO

Phylogenetic relationships of basal insects remain a matter of discussion. In particular, the relationships among Ephemeroptera, Odonata and Neoptera are the focus of debate. In this study, we used a next-generation sequencing approach to reconstruct new mitochondrial genomes (mitogenomes) from 18 species of basal insects, including six representatives of Ephemeroptera and 11 of Odonata, plus one species belonging to Zygentoma. We then compared the structures of the newly sequenced mitogenomes. A tRNA gene cluster of IMQM was found in three ephemeropteran species, which may serve as a potential synapomorphy for the family Heptageniidae. Combined with published insect mitogenome sequences, we constructed a data matrix with all 37 mitochondrial genes of 85 taxa, which had a sampling concentrating on the palaeopteran lineages. Phylogenetic analyses were performed based on various data coding schemes, using maximum likelihood and Bayesian inferences under different models of sequence evolution. Our results generally recovered Zygentoma as a monophyletic group, which formed a sister group to Pterygota. This confirmed the relatively primitive position of Zygentoma to Ephemeroptera, Odonata and Neoptera. Analyses using site-heterogeneous CAT-GTR model strongly supported the Palaeoptera clade, with the monophyletic Ephemeroptera being sister to the monophyletic Odonata. In addition, a sister group relationship between Palaeoptera and Neoptera was supported by the current mitogenomic data.

14.
Int J Neurosci ; : 1-7, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31721620

RESUMO

Purpose: The aim of this study was to explore the mechanism of neurological changes underlying the toxicity of nicotine.Materials and methods: Rat pheochromocytoma 12 (PC12) cells and human neuroglia (HM) cells were used. The ROS levels of the cells were detected by the FACScan. Autophagy flux was monitored by a tandem monomeric RFP-GFP-tagged LC3 lentivirus. The autophagic proteins LC3, SQSTM1/p62 and Beclin1 were detected by western blot assay. In order to evaluate the effects of nicotine and melatonin on the morphological changes of neurons, primary cortical neurons were obtained and immunocytochemistry of TUBB3 tubulin were conducted.Results: Nicotine increased the levels of reactive oxygen species (ROS) in PC12 and HM cells in a concentration-dependent manner. Microscopy showed increased autophagic flux in nicotine-treated PC12 cells. Subsequent western blotting results showed that nicotine induced increase in the levels of LC3B-II and Beclin1, and decreased SQSTM1/p62 in a concentration-dependent manner. Finally, nicotine treatment reduced the length of TUBB3-positive axons and dendrites. Melatonin, a mitochondrially targeted antioxidant, reduced the ROS level, and blocked autophagy activation and the morphologic structural changes induced by nicotine.Conclusions: Our results suggested that the role of nicotine in neuronal toxicity maybe through the induction of ROS and the subsequent activation of autophagy. These effects could be restored by melatonin.

15.
J Biochem Mol Toxicol ; 33(12): e22408, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617658

RESUMO

In this study, gene expression alterations of phase I to III enzymes, transcription factors, and microRNA (miRNA) in embryonic zebrafish fibroblasts (ZF4) cells after the treatment of Pb(NO3 )2 and AgNO3 were investigated, to illustrate the possible detoxification pathway of heavy metal ions. It was observed that both metals caused concentration-dependent death and moderate elevation of oxidative stress in ZF4 cells. In response to such toxicity, upregulation of multidrug resistance protein (mdr)4 and multiresistance-associated protein (mrp)1 were found. However, enhanced expression of glutathione S-transferase (gst) and cytochrome P450 (cyp)1a could only be detected during the exposure of Pb2+ . In addition, both metals induced extensive upregulation of pregnane X receptor (pxr), but only moderate elevation of E2-related factor (nrf2), while they suppressed the expression of miR-122 and miR-126. In conclusion, Pb2+ and Ag+ shared the same detoxification mechanism including ABC transporters, Pxr, and miRNA in ZF4 cells, which needs further investigation.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Chumbo/toxicidade , Nitratos/toxicidade , Nitrato de Prata/toxicidade , Peixe-Zebra/embriologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação da Expressão Gênica , Glutationa Transferase/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
16.
Neurochem Res ; 44(12): 2746-2754, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31630316

RESUMO

Spinal cord ischemia and reperfusion (SCIR) injury can induce autophagy, which is involved in the survival of neurons. However, whether autophagy plays a neuroprotective or a detrimental role in SCIR injury remains controversial. Angiopoietin-1 (Ang-1), an endothelial growth factor, has been shown to have neuroprotective effects. The present study aimed to explore the neuroprotective mechanisms of Ang-1 in neuronal cells in a rat model of SCIR injury in vivo. Ang-1 protein and rapamycin were injected intrathecally. Basso Beattie Bresnahan (BBB) scoring and hematoxylin and eosin staining were used to assess the degree of SCIR injury. Proteins that reflected the level of autophagy expression, such as Beclin-1 and LC3, were evaluated by western blotting. The results indicated that SCIR injury resulted in loss in lower limb motor function. Ang-1 protein inhibited the expression of Beclin-1 and LC3, which improved the BBB score and alleviated spinal cord injury. In contrast, rapamycin, an autophagy activator, caused the opposite effect. This study provides evidence that Ang-1 plays a neuroprotective role by inhibiting of autophagy expression in SCIR injury. Overall, findings could be useful for the treatment of SCIR injury.

17.
Environ Pollut ; 255(Pt 2): 113329, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31600704

RESUMO

Transcription factors including pregnane X receptor (Pxr) and nuclear factor-erythroid 2-related factor-2 (Nrf2) are important modulators of Adenosine triphosphate-binding cassette (ABC) transporters in mammalian cells. However, whether such modulation is conserved in zebrafish embryos remains largely unknown. In this manuscript, pxr- and nrf2-deficient models were constructed with CRISPR/Cas9 system, to evaluate the individual function of Pxr and Nrf2 in the regulation of ABC transporters and detoxification of heavy metal ions like Cd2+ and Ag+. As a result, both Cd2+ and Ag+ conferred extensive interactions with ABC transporters in wild type (WT) embryos: their accumulation and toxicity were affected by the activity of ABC transporters, and they significantly induced the mRNA expressions of ABC transporters. These induction effects were reduced by the mutation of pxr and nrf2, but elevations in the basal expression of ABC transporters compensated for the loss of their inducibility. This could be an explanation for remaining transporter function in both mutant models as well as the unaltered toxicity of metal ions in pxr-deficient embryos. However, mutation of nrf2 disrupted the production of glutathione (GSH), resulting in the enhanced toxicity of Cd2+/Ag+ in zebrafish embryos. In addition, elevated expressions of other transcription factors like aryl hydrocarbon receptor (ahr) 1b, peroxisome proliferator-activated receptor (ppar)-ß, and nrf2 were found in pxr-deficient models without any treatment, while enhanced induction of ahr1b, ppar-ß and pxr could only be seen in nrf2-deficient embryos after the treatment of metal ions, indicating different compensation phenomena for the absence of transcription factors. After all, pxr-deficient and nrf2-deficient zebrafish embryos are useful tools in the functional investigation of Pxr and Nrf2 in the early life stages of aquatic organisms. However, the compensatory mechanisms should be taken into consideration when interpreting the results and need in-depth investigations.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Metais Pesados/toxicidade , Fator 2 Relacionado a NF-E2/genética , Receptor de Pregnano X/genética , Peixe-Zebra/embriologia , Animais , Glutationa/metabolismo , Inativação Metabólica , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Esteroides/genética , Fatores de Transcrição/metabolismo , Proteínas de Peixe-Zebra/metabolismo
18.
Chem Commun (Camb) ; 55(86): 12904-12907, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31584577

RESUMO

A novel type of hydrogen peroxide (H2O2)-activated diazeniumdiolate based on an α-ketoamide moietey was developed as a nitric oxide (NO) donor. KA-NO-4 inhibited lung cancer cells with submicromolar activity. The H2O2-responsive behaviour of KA-NO-4 was thoroughly investigated. The NO-centered mechanism of action of KA-NO-4 was intracellularly studied.


Assuntos
Amidas/química , Antineoplásicos/química , Compostos Azo/química , Peróxido de Hidrogênio/química , Doadores de Óxido Nítrico/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Azo/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia
19.
Chem Sci ; 10(30): 7156-7162, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31588282

RESUMO

Leveraging the elevated levels of hydrogen peroxide (H2O2) in cancer, inflammatory diseases and cardiovascular disorders, H2O2-activated promoieties have been widely used in drugs and biomaterials design. However, the overwhelming majority of the promoieties only share the common structure of a H2O2-responsive arylboronic acid/ester moiety with low diversity. We report here an unprecedented strategy to construct novel H2O2-responsive prodrugs based on an α-ketoamide structure. As a proof of concept, we designed and synthesized a panel of α-ketoamide based nitrogen mustard prodrugs, among which KAM-2 showed potent growth inhibitory activity and high selectivity toward cancer cells. The H2O2-trigged decomposition of KAM-2 was validated, and the DNA damaging and apoptosis promoting activity attributed to the released nitrogen mustard were demonstrated. Our work unveils α-ketoamide as a new scaffold for prodrug design and may quickly inspire future developments.

20.
Behav Pharmacol ; 30(8): 730-737, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31625977

RESUMO

Chronic inflammation plays an important role in the mechanisms underpinning the development of anesthesia-induced cognitive dysfunction. However, less is known about how anesthesia causes inflammation. One possibility is that the inflammation is related to alteration of the activity of the alpha 7 nicotinic acetylcholine receptor cholinergic anti-inflammatory pathway. This study analyzed the effect of sevoflurane administration on the cognitive function by using a novel object recognition test and Y-maze test, and on acetylcholinesterase activity and expression in hippocampal tissue by using an acetylcholinesterase assay kit and quantitative real-time PCR. This study also evaluated the effect of alpha 7 nicotinic acetylcholine receptor agonist PNU-282987 and antagonist methyllycaconitine on cognitive function and the level of hippocampal tumor necrosis factor-α in aged rats exposed to sevoflurane anesthesia. We found that 3% sevoflurane significantly impaired cognitive function and increased acetylcholinesterase activity by upregulating its expression in hippocampal tissue. Sevoflurane-induced impairment of cognitive function was significantly rescued by PNU-282987 but aggravated by methyllycaconitine. In addition to impairment of cognitive function, sevoflurane also significantly increased tumor necrosis factor-α level in plasma and hippocampal tissue. Similarly, this sevoflurane-induced change of tumor necrosis factor-α level in rats was antagonized by PNU-282987 but amplified by methyllycaconitine. In conclusion, our data show that the development of inflammation in sevoflurane-induced cognitive decline is associated with the downregulation of alpha 7 nicotinic acetylcholine receptor cholinergic anti-inflammatory pathway in aged rats.

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