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1.
Taiwan J Obstet Gynecol ; 59(1): 109-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039776

RESUMO

OBJECTIVE: The present study aimed to evaluate insulin-like growth factor 2 antisense (IGF2-AS) in the villi of human embryos and compared its expression between normal pregnancy and early pregnancy loss (EPL). MATERIALS AND METHODS: The present study conducted a microarray analysis to identify the expression profiles of lncRNAs in villi from EPL and normal controls (controls, n = 10 and EPL patients, n = 10). Embryonic villi were collected from women who underwent artificial abortion. QPCR was used to confirm the results. The DNA methylation patterns were analyzed using pyrosequencing and bisulfite sequencing polymerase chain reaction. The percentage of methylation was compared in chorionic villi from the two groups. RESULTS: A total of 57 deregulated differentially expressed lncRNAs were detected, of which 33 were upregulated, and 24 were downregulated. The expression of lncRNA IGF2-AS was downregulated significantly in EPL villi compared with the normal villi. Negative regulation of IGF2-AS may be involved in the development of EPL. Methprimer predicted that IGF2-AS promoter had CpG islands and dense CG sites. Increased methylation at CpG islands present in IGF2-AS gene promoter was observed in EPL villi. CONCLUSION: An increase in methylation of IGF2-AS likely leads to its downregulation in chorionic villi of EPL. The findings suggest that a deficiency of IGF2-AS in the villi is associated with human EPL.

2.
Behav Brain Res ; : 112550, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32057830

RESUMO

Genetic variations of COMT and KIBRA, which were reported to be expressed in the hippocampus, have been linked to memory function. However, their interaction on the hippocampal structure remains unknown. This study aimed to explore the interaction effects of COMT rs4680 and KIBRA rs17070145 on the hippocampal subfield volumes and test their associations with hippocampus-memory relationship in 187 healthy young adults. Two-way analysis of covariance was applied to the alterations in hippocampal subfield volumes among COMT and KIBRA genotypes. Significant interaction effects of these two genes were found in the right CA1 and CA3 subfields. Among KIBRA C-allele carriers, COMT Val/Val homozygotes showed greater volume in these regions than COMT Met-allele carriers. Furthermore, the slope of the correlation between right CA1 volume and immediate recall on the California Verbal Learning Test-II (CVLT-II) (F = 4.36, p = 0.041) as well as CVLT-II delayed recall (F = 6.44, p = 0.014) were significantly different between COMT Val/Val homozygotes and Met-allele carriers, which were positive or tend to be positive in COMT Val/Val group (CVLT immediate recall, r = 0.319, p = 0.040; CVLT delayed recall, r = 0.304, p = 0.051), but absent in COMT Met-allele carriers (CVLT immediate recall, r = -0.263, p = 0.205; CVLT delayed recall, r = -0.351, p = 0.086). These findings may provide a novel insight into the genetic effects upon the hippocampal structure and suggest that the conjoint effects of COMT and KIBRA played a modulatory role in the hippocampus-episodic memory correlation.

3.
Nucleic Acids Res ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31943080

RESUMO

Allele-specific protospacer adjacent motif (asPAM)-positioning SNPs and CRISPRs are valuable resources for gene therapy of dominant disorders. However, one technical hurdle is to identify the haplotype comprising the disease-causing allele and the distal asPAM SNPs. Here, we describe a novel CRISPR-based method (CRISPR-hapC) for haplotyping. Based on the generation (with a pair of CRISPRs) of extrachromosomal circular DNA in cells, the CRISPR-hapC can map haplotypes from a few hundred bases to over 200 Mb. To streamline and demonstrate the applicability of the CRISPR-hapC and asPAM CRISPR for allele-specific gene editing, we reanalyzed the 1000 human pan-genome and generated a high frequency asPAM SNP and CRISPR database (www.crispratlas.com/knockout) for four CRISPR systems (SaCas9, SpCas9, xCas9 and Cas12a). Using the huntingtin (HTT) CAG expansion and transthyretin (TTR) exon 2 mutation as examples, we showed that the asPAM CRISPRs can specifically discriminate active and dead PAMs for all 23 loci tested. Combination of the CRISPR-hapC and asPAM CRISPRs further demonstrated the capability for achieving highly accurate and haplotype-specific deletion of the HTT CAG expansion allele and TTR exon 2 mutation in human cells. Taken together, our study provides a new approach and an important resource for genome research and allele-specific (haplotype-specific) gene therapy.

4.
Nucleic Acids Res ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31980820

RESUMO

Therapeutic oligonucleotides are often modified using the phosphorothioate (PS) backbone modification which enhances stability from nuclease mediated degradation. However, substituting oxygen in the phosphodiester backbone with sulfur introduce chirality into the backbone such that a full PS 16-mer oligonucleotide is comprised of 215 distinct stereoisomers. As a result, the role of PS chirality on the performance of antisense oligonucleotides (ASOs) has been a subject of debate for over two decades. We carried out a systematic analysis to determine if controlling PS chirality in the DNA gap region can enhance the potency and safety of gapmer ASOs modified with high-affinity constrained Ethyl (cEt) nucleotides in the flanks. As part of this effort, we examined the effect of systematically controlling PS chirality on RNase H1 cleavage patterns, protein mislocalization phenotypes, activity and toxicity in cells and in mice. We found that while controlling PS chirality can dramatically modulate interactions with RNase H1 as evidenced by changes in RNA cleavage patterns, these were insufficient to improve the overall therapeutic profile. We also found that controlling PS chirality of only two PS linkages in the DNA gap was sufficient to modulate RNase H1 cleavage patterns and combining these designs with simple modifications such as 2'-OMe to the DNA gap resulted in dramatic improvements in therapeutic index. However, we were unable to demonstrate improved potency relative to the stereorandom parent ASO or improved safety over the 2'-OMe gap-modified stereorandom parent ASO. Overall, our work shows that while controlling PS chirality can modulate RNase H1 cleavage patterns, ASO sequence and design are the primary drivers which determine the pharmacological and toxicological properties of gapmer ASOs.

5.
Med Sci Monit ; 26: e918883, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31974331

RESUMO

BACKGROUND The structural remodeling of atrial architecture, especially increased amounts of fibrosis, is a critical substrate to atrial fibrillation (AF). Doxycycline (Doxy) has recently been shown to exert protective effects against fibrogenic response. This study investigated whether doxycycline (Doxy) can sufficiently ameliorate the fibrosis-induced changes of atrial conduction and AF vulnerability in a chronic intermittent hypoxia (CIH) rat model. MATERIAL AND METHODS Sixty rats were randomized into 3 groups: Control, CIH, and CIH with Doxy treatment (DOXY) group. CIH rats were exposed to CIH (6 h/d) and Doxy-treated rats were treated with Doxy during processing CIH. After 6 weeks, echocardiographic and hemodynamic parameters were measured. Isolated atrial epicardial activation mapping and heart electrophysiology were performed. The extent of atrial interstitial fibrosis were estimated by Masson's trichrome staining. The expression levels of TGF-ß1 and downstream factors were determined by real-Time PCR, immunohistochemistry, and Western blot analysis. RESULTS Compared to Control rats, the CIH rats showed significant atrial interstitial fibrosis, longer inter-atrial conduction time, and elevated conduction inhomogeneity and AF inducibility, and the expression of TGF-ß1, TGF-ßRI, TGF-ßRII, P-Smad2/3, alpha-SMA, CTGF, and Collagen I were significantly increased, whereas the velocity of atrial conduction and the expression of miR-30c were dramatically decreased. All of these changes were significantly improved by Doxy treatment. CONCLUSIONS The findings suggested that Doxy can profoundly mitigate atrial fibrosis, conduction inhomogeneity as well as high AF inducibility secondary to fibrosis in a CIH rat model through suppressing the TGF-ß1 signaling pathway.

6.
J Cell Biol ; 219(1)2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31816056

RESUMO

The development of cerebral cortex requires spatially and temporally orchestrated proliferation, migration, and differentiation of neural progenitor cells (NPCs). The molecular mechanisms underlying cortical development are, however, not fully understood. The neural cell adhesion molecule (NCAM) has been suggested to play a role in corticogenesis. Here we show that NCAM is dynamically expressed in the developing cortex. NCAM expression in NPCs is highest in the neurogenic period and declines during the gliogenic period. In mice bearing an NPC-specific NCAM deletion, proliferation of NPCs is reduced, and production of cortical neurons is delayed, while formation of cortical glia is advanced. Mechanistically, NCAM enhances actin polymerization in NPCs by interacting with actin-associated protein profilin2. NCAM-dependent regulation of NPCs is blocked by mutations in the profilin2 binding site. Thus, NCAM plays an essential role in NPC proliferation and fate decision during cortical development by regulating profilin2-dependent actin polymerization.

7.
Mol Genet Genomic Med ; 8(2): e1061, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31872983

RESUMO

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) is an essential enzyme that protects red blood cells from oxidative damage. Although G6PD-deficient alleles appear to confer a protective effect of malaria, the link with clinical protection against Plasmodium infection is conflicting. METHODS: A case-control study was conducted on Bioko Island, Equatorial Guinea and further genotyping analysis used to detect natural selection of the G6PD A- allele. RESULTS: Our results showed G6PD A- allele could significantly reduce the risk of Plasmodium falciparum infection in male individuals (adjusted odds ratio [AOR], 0.43; 95% confidence interval [CI], 0.20-0.93; p < .05) and homozygous female individuals (AOR, 0.11; 95% CI, 0.01-0.84; p < .05). Additionally, the parasite densities were significantly different in the individuals with different G6PD A- alleles and individual levels of G6PD enzyme activity. The pattern of linkage disequilibrium and results of the long-range haplotype test revealed a strong selective signature in the region encompassing the G6PD A- allele over the past 6,250 years. The network of inferred haplotypes suggested a single origin of the G6PD A- allele in Africans. CONCLUSION: Our findings demonstrate that glucose-6-phosphate dehydrogenase (G6PD) A- allele could reduce the risk of P. falciparum infection in the African population and indicate that malaria has a recent positive selection on G6PD A- allele.

8.
J Appl Toxicol ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31802521

RESUMO

The excellent optical property and relatively low toxicity of CdTe/ZnS core/shell quantum dots (QDs) make them an advanced fluorescent probe in the application of biomedicines, particularly in neuroscience. Thus, it is important to evaluate the biosafety of CdTe/ZnS QDs on the central nervous system (CNS). Our previous studies have suggested that the high possibility of CdTe/ZnS QDs being transported into the brain across the blood-brain barrier resulted in microglial activation and a shift of glycometabolism, but their underlying mechanism remains unclear. In this study, when mice were injected intravenously with CdTe/ZnS QDs through tail veins, the microglial activation, polarized into both M1 phenotype and M2 phenotype, and the neuronal impairment were observed in the hippocampus. Meanwhile, the increased pro- and anti-inflammatory cytokines released from BV2 microglial cells treated with CdTe/ZnS QDs also indicated that QD exposure was capable of inducing microglial activation in vitro. We further demonstrated that the glycolytic shift from oxidative phosphorylation switching into aerobic glycolysis was required in the microglial activation into M1 phenotype induced by CdTe/ZnS QD treatment, which was mediated through the mTOR signaling pathway. The findings, taken together, provide a mechanistic insight regarding the CdTe/ZnS QDs inducing microglial activation and the role of the glycolytic shift in it.

9.
Nucleic Acids Res ; 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31840180

RESUMO

Release of phosphorothioate antisense oligonucleotides (PS-ASOs) from late endosomes (LEs) is a rate-limiting step and a poorly defined process for productive intracellular ASO drug delivery. Here, we examined the role of Golgi-endosome transport, specifically M6PR shuttling mediated by GCC2, in PS-ASO trafficking and activity. We found that reduction in cellular levels of GCC2 or M6PR impaired PS-ASO release from endosomes and decreased PS-ASO activity in human cells. GCC2 relocated to LEs upon PS-ASO treatment, and M6PR also co-localized with PS-ASOs in LEs or on LE membranes. These proteins act through the same pathway to influence PS-ASO activity, with GCC2 action preceding that of M6PR. Our data indicate that M6PR binds PS-ASOs and facilitates their vesicular escape. The co-localization of M6PR and of GCC2 with ASOs is influenced by the PS modifications, which have been shown to enhance the affinity of ASOs for proteins, suggesting that localization of these proteins to LEs is mediated by ASO-protein interactions. Reduction of M6PR levels also decreased PS-ASO activity in mouse cells and in livers of mice treated subcutaneously with PS-ASO, indicating a conserved mechanism. Together, these results demonstrate that the transport machinery between LE and Golgi facilitates PS-ASO release.

10.
Front Immunol ; 10: 2707, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849936

RESUMO

Background: Accumulating evidence suggests inhibiting neuroinflammation as a potential target in therapeutic or preventive strategies for Alzheimer's disease (AD). MAPK-activated protein kinase II (MK2), downstream kinase of p38 mitogen activated protein kinase (MAPK) p38 MAPK, was unveiled as a promising option for the treatment of AD. Increasing evidence points at MK2 as involved in neuroinflammatory responses. MMI-0100, a cell-penetrating peptide inhibitor of MK2, exhibits anti-inflammatory effects and is in current clinical trials for the treatment of pulmonary fibrosis. Therefore, it is important to understand the actions of MMI-0100 in neuroinflammation. Methods: The mouse memory function was evaluated using novel object recognition (NOR) and object location recognition (OLR) tasks. Brain hippocampus tissue samples were analyzed by quantitative PCR, Western blotting, and immunostaining. Near-infrared fluorescent and confocal microscopy experiments were used to detect the brain uptake and distribution after intranasal MMI-0100 application. Results: Central MMI-0100 was able to ameliorate the memory deficit induced by Aß1-42 or LPS in novel object and location memory tasks. MMI-0100 suppressed LPS-induced activation of astrocytes and microglia, and dramatically decreased a series of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1ß, COX-2, and iNOS via inhibiting phosphorylation of MK2, but not ERK, JNK, and p38 in vivo and in vitro. Importantly, one of the reasons for the failure of macromolecular protein or peptide drugs in the treatment of AD is that they cannot cross the blood-brain barrier. Our data showed that intranasal administration of MMI-0100 significantly ameliorates the memory deficit induced by Aß1-42 or LPS. Near-infrared fluorescent and confocal microscopy experiment results showed that a strong fluorescent signal, coming from mouse brains, was observed at 2 h after nasal applications of Cy7.5-MMI-0100. However, brains from control mice treated with saline or Cy7.5 alone displayed no significant signal. Conclusions: MMI-0100 attenuates Aß1-42- and LPS-induced neuroinflammation and memory impairments via the MK2 signaling pathway. Meanwhile, these data suggest that the MMI-0100/MK2 system may provide a new potential target for treatment of AD.

11.
Med Sci Monit ; 25: 9811-9819, 2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31863577

RESUMO

BACKGROUND Ticagrelor is the first oral anti-platelet agent which has direct anti-platelet aggregation effect by combining with ADP P2Y12 receptors in platelets. It has been approved to reduce the incidence of thrombus cardiovascular events in acute coronary syndrome patients. However, the effects of ticagrelor on endothelial apoptosis have not been investigated. MATERIAL AND METHODS Oxidized low-density lipoprotein (ox-LDL) was used to establish a human umbilical vein endothelial cell (HUVEC) apoptosis model. To investigate the effects of ticagrelor on endothelial apoptosis, the HUVECs were treated with different dose of ticagrelor. Apoptosis rates of HUVECs was evaluated by flow cytometry, and the expression levels of Akt, p-Akt, Bcl-2, Bax, caspase-3, endothelial nitric oxide synthase (eNOS), and nitric oxide (NO) concentration were assessed. RESULTS After treatment with 50 ug/mL ox-LDL or 100 ug/mL ox-LDL, we found that the late apoptosis and necrosis rate and the expression levels of Bax and caspase-3 were significantly increased in HUVECs, whereas the expression levels of Akt, p-Akt, Bcl-2, eNOS, and NO were significantly decreased. Ticagrelor restored the apoptosis rate of ox-LDL-induced HUVECs in a dose-dependent manner. In addition, compared with ox-LDL group, ticagrelor treatment significantly increased the expression levels of Akt, p-Akt, Bcl-2, eNOS, and NO concentration, and significantly decreased the expression levels of Bax and caspase-3. CONCLUSIONS We found that ox-LDL induced significant apoptosis and necrosis in our model, which was dose-dependently improved by ticagrelor. These changes might be explained by alterations in apoptosis and antioxidant pathways.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31853785

RESUMO

To further understand the genetic structure that is associated with insulin (INS) and thyroid hormones (TH), including triiodothyronine (T3) and thyroxine (T4), in Chinese Holstein cows, we conducted a genome-wide association study (GWAS) of thyroid hormones and insulin in cows. We conducted GWAS analysis on 1217 Chinese Holstein cows raised in southern China and found 19 significant single nucleotide polymorphisms (SNPs) in this study: 10 SNPs were associated with INS, 5 SNPs were associated with T3, and 4 SNPs were associated with T4. In our study, the GWAS method was used for preliminary screening on related genes of traits, and due to insufficient relevant literature, a functional analysis of genes could only be based on human studies. We observed that DGKB from Bos taurus chromosome (BTA)4 is strongly associated with insulin secretion. We found that EXOC4 gene was significantly correlated with T3 and T4 traits. Another significant SNP was located in the CYP7A1 gene, which has been confirmed to be affected by thyroid hormones.

13.
Int Immunopharmacol ; : 105979, 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31771816

RESUMO

Chronic obstructive pulmonary fibrosis (COPD) is a chronic and fatal lung disease with few treatment options. Sodium hydrosulfide (NaHS), a donor of hydrogen sulfide (H2S), was found to alleviate cigarette smoke (CS)-induced emphysema in mice, however, the underlying mechanisms have not yet been clarified. In this study, we investigated its effects on COPD in a CS-induced mouse model in vivo and in cigarette smoke extract (CSE)-stimulated alveolar epithelial A549 cells in vitro. The results showed that NaHS not only relieved emphysema, but also improved pulmonary function in CS-exposed mice. NaHS significantly increased the expressions of tight junction proteins (i.e., ZO-1, Occludin and claudin-1), and reduced apoptosis and secretion of pro-inflammatory cytokines (i.e., TNF-α, IL-6 and IL-1ß) in CS-exposed mouse lungs and CSE-incubated A549 cells, indicating H2S inhibits CS-induced inflammation, injury and apoptosis in alveolar epithelial cells. NaHS also upregulated prolyl hydroxylase (PHD)2, and suppressed hypoxia-inducible factor (HIF)-1α expression in vivo and in vitro, suggesting H2S inhibits CS-induced activation of PHD2/HIF-1α axis. Moreover, NaHS inhibited CS-induced phosphorylation of ERK, JNK and p38 MAPK in vivo and in vitro, and treatment with their inhibitors reversed CSE-induced ZO-1 expression and inflammation in A549 cells. These results suggest that NaHS may prevent emphysema via the suppression of PHD2/HIF-1α/MAPK signaling pathway, and subsequently inhibition of inflammation, epithelial cell injury and apoptosis, and may be a novel strategy for the treatment of COPD.

14.
Medicine (Baltimore) ; 98(47): e17888, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764783

RESUMO

RATIONALE: Hemangiopericytoma (HPC) is a rare pediatric neoplasm with a high risk of bleeding, aggressive growth and high early relapse rates. Surgical excision remains the mainstream treatment, while the functions of chemotherapy and radiotherapy remain controversial. In particular, an infantile giant extracranial HPC located in the forehead has never been reported. PATIENT CONCERNS: A 3-day-old girl was delivered normally with a giant tumor localized mainly in the right frontal region. The surface of the mass was filled with vascularity. DIAGNOSIS: According to the results of imaging and pathological examinations, the diagnosis was HPC grade II. INTERVENTIONS: Gross total resection of the tumor and the invading partial frontal bone followed by skin scalp reconstruction was carried out without any blood transfusion. OUTCOMES: No recurrence was identified during 5 years of follow-up. And better outcomes can be achieved without adjuvant therapy. LESSONS: Multimodality imaging and a collaborative multidisciplinary approach are indispensable for the successful surgical management of infantile HPC, especially for giant tumors and their potential risk of life-threatening bleeding. Gross total resection is the optimal option for infantile HPC, and even without adjuvant therapy, it achieves better outcomes.


Assuntos
Neoplasias de Cabeça e Pescoço , Hemangiopericitoma , Neoplasias de Tecidos Moles , Pré-Escolar , Feminino , Seguimentos , Testa , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Hemangiopericitoma/patologia , Hemangiopericitoma/cirurgia , Humanos , Recém-Nascido , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Fatores de Tempo , Carga Tumoral
15.
Orthop Surg ; 11(6): 1209-1219, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31692295

RESUMO

OBJECTIVE: To use Gene Expression Omnibus (GEO) database coupled with Connectivity Map (CMap) databases to screen potential therapeutic drugs for osteonecrosis of femoral head (ONFH) rapidly. METHODS: Raw genetic data with accession number GSE74089 that contained eight hip articular cartilage specimens from four ONFH patients and four healthy controls were obtained from the Gene Expression Omnibus (GEO) database and were then integrated using R to identify differentially expressed genes (DEGs). Subsequently, to identify several potential small molecular compounds that were most strongly negatively correlated with ONFH, a search query of DEGs was explored by using CMap. RESULTS: Filtering revealed 1937 DEGs with log (fold-change) ≥1 and adjust P value < 0.001. Finally, a network of candidate targets for ONFH with 135 nodes and 660 edges was constructed through network topology analysis, including 96 up-regulated genes and 39 down-regulated genes. Several significant gene functions and signaling pathways associated with pathological processes of ONFH were identified via gene enrichment analysis. Based on the CMap database, some potential small molecular components that may be possible to counteract the effects of molecular signal imbalance for ONFH were identified. Neostigmine bromide with low CMap score and P value and specificity score was predicted to be the most candidate compound, involved in the "positive regulation of stem cell proliferation," "regulation of protein autophosphorylation," "VEGF signaling pathway," and "ECM-receptor interaction." CONCLUSIONS: The GEO and CMap databases can be effectively used in understanding the molecular changes in ONFH and provide a systematic manner to identify potential drugs for ONFH prevention and treatment. However, additional clinical and experimental research of the candidate compound is warranted.

16.
Pediatrics ; 144(6)2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31732547

RESUMO

BACKGROUND: Coronary artery aneurysms (CAAs) are a well-known complication of Kawasaki disease (KD), but there are no data on incidence or outcomes of systemic artery aneurysms (SAAs) in the current era. METHODS: From April 1, 2016, to March 31, 2019, we screened for SAAs in 162 patients with KD at risk for SAAs with magnetic resonance angiography or peripheral angiography and analyzed incidence and early outcomes of SAAs. RESULTS: Twenty-three patients had SAAs, demonstrating an incidence of 14.2% (23 of 162) in patients who were screened at 1 month after onset. The proportion of patients with SAAs was estimated to be 2% (23 of 1148) of all patients with KD. The median age at onset of KD with SAAs was 5 months. All patients with SAAs had CAAs, with z scores >8. Of patients with giant CAAs, 38.6% (17 of 44) had SAAs. A total of 129 SAAs occurred in 17 different named arteries. The most common sites for SAAs were the axillary (18.6%), common iliac (12.4%), and brachial (11.6%) arteries. During a median follow-up time of 6 months, 92.9% (79 of 85) of SAAs had some degree of regression, with 80% (68 of 85) of SAAs returning to normal. The overall regression rate was higher for medium to large SAAs than for medium to giant CAAs. CONCLUSIONS: Although the incidence of SAAs may not be as dramatically reduced as we expected compared with previous data, SAAs have a high regression rate during short-term follow-up.

17.
J Biol Chem ; 294(49): 18586-18599, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31636122

RESUMO

Gut microbial ß-glucuronidase (GUS) enzymes have been suggested to be involved in the estrobolome, the collection of microbial reactions involving estrogens. Furthermore, bacterial GUS enzymes within the gastrointestinal tract have been postulated to be a contributing factor in hormone-driven cancers. However, to date, there has been no experimental evidence to support these hypotheses. Here we provide the first in vitro analysis of the ability of 35 human gut microbial GUS enzymes to reactivate two distinct estrogen glucuronides, estrone-3-glucuronide and estradiol-17-glucuronide, to estrone and estradiol, respectively. We show that certain members within the Loop 1, mini-Loop 1, and FMN-binding classes of gut microbial GUS enzymes can reactivate estrogens from their inactive glucuronides. We provide molecular details of key interactions that facilitate these catalytic processes and present the structures of two novel human gut microbial GUS enzymes related to the estrobolome. Further, we demonstrate that estrogen reactivation by Loop 1 bacterial GUS enzymes can be inhibited both in purified enzymes and in fecal preparations of mixed murine fecal microbiota. Finally, however, despite these in vitro and ex vivo data, we show that a Loop 1 GUS-specific inhibitor is not capable of reducing the development of tumors in the PyMT mouse model of breast cancer. These findings validate that gut microbial GUS enzymes participate in the estrobolome but also suggest that the estrobolome is a multidimensional set of processes on-going within the mammalian gastrointestinal tract that likely involves many enzymes, including several distinct types of GUS proteins.

18.
Nanoscale ; 11(43): 20820-20836, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31657406

RESUMO

Silver selenide quantum dots (Ag2Se QDs) provide bright prospects for the application of QDs in the field of biomedicine because they contain low-toxic compounds and show great advantages in the imaging of deep tissues and tiny vascular structures. However, the biosafety of these novel QDs has not been thoroughly evaluated, especially in one main target for toxicity-the central nervous system (CNS). Our previous studies have suggested severe inflammatory responses to cadmium-containing QDs in the hippocampus, which gives us a hint regarding the risk assessment of Ag2Se QDs. In this study, microglial activation followed by enhanced levels of pro-inflammatory cytokines was observed in the hippocampus of mice intravenously injected with Ag2Se QDs. When using the microglial BV2 cells to investigate the underlying mechanisms, we found that the NLRP3 inflammasome activation was involved in the IL-1ß-mediated inflammation induced by Ag2Se QDs. On the one hand, Ag2Se QD-activated NF-κB participated in the NLRP3 inflammasome priming and assembly as well as the pro-IL-1ß upregulation. On the other hand, Ag2Se QD-induced ROS generation, particularly mtROS, triggered the NLRP3 inflammasome activation and resulted in active caspase-1 to process pro-IL-1ß into mature IL-1ß release. These findings not only indicated that it is important to evaluate the biosafety of novel QDs, even those containing low-toxic compounds, but also provided an unbiased and mechanism-based risk assessment of similar nanoparticles.

19.
Malar J ; 18(1): 317, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533747

RESUMO

BACKGROUND: Plasmodium falciparum apical membrane antigen-1 (PfAMA-1) is a promising candidate antigen for a blood-stage malaria vaccine. However, antigenic variation and diversity of PfAMA-1 are still major problems to design a universal malaria vaccine based on this antigen, especially against domain I (DI). Detail understanding of the PfAMA-1 gene polymorphism can provide useful information on this potential vaccine component. Here, general characteristics of genetic structure and the effect of natural selection of DIs among Bioko P. falciparum isolates were analysed. METHODS: 214 blood samples were collected from Bioko Island patients with P. falciparum malaria between 2011 and 2017. A fragment spanning DI of PfAMA-1 was amplified by nested polymerase chain reaction and sequenced. Polymorphic characteristics and the effect of natural selection were analysed using MEGA 5.0, DnaSP 6.0 and Popart programs. Genetic diversity in 576 global PfAMA-1 DIs were also analysed. Protein function prediction of new amino acid mutation sites was performed using PolyPhen-2 program. RESULTS: 131 different haplotypes of PfAMA-1 were identified in 214 Bioko Island P. falciparum isolates. Most amino acid changes identified on Bioko Island were found in C1L. 32 amino acid changes identified in PfAMA-1 sequences from Bioko Island were found in predicted RBC-binding sites, B cell epitopes or IUR regions. Overall patterns of amino acid changes of Bioko PfAMA-1 DIs were similar to those in global PfAMA-1 isolates. Differential amino acid substitution frequencies were observed for samples from different geographical regions. Eight new amino acid changes of Bioko island isolates were also identified and their three-dimensional protein structural consequences were predicted. Evidence for natural selection and recombination event were observed in global isolates. CONCLUSIONS: Patterns of nucleotide diversity and amino acid polymorphisms of Bioko Island isolates were similar to those of global PfAMA-1 DIs. Balancing natural selection across DIs might play a major role in generating genetic diversity in global isolates. Most amino acid changes in DIs occurred in predicted B-cell epitopes. Novel sites mapped on a three dimensional structure of PfAMA-1 showed that these regions were located at the corner. These results may provide significant value in the design of a malaria vaccine based on this antigen.


Assuntos
Antígenos de Protozoários/genética , Variação Genética , Proteínas de Membrana/genética , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Seleção Genética , Antígenos de Protozoários/metabolismo , Guiné Equatorial , Proteínas de Membrana/metabolismo , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo
20.
Nanomaterials (Basel) ; 9(9)2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31540191

RESUMO

The assistances of sodium dodecyl benzene sulfonate (SDBS) and aging treatment were introduced to further improve the room-temperature mechanochemical synthesis of the quantum-sized zinc sulfide (ZnS) nanocrystals. As a result, a green strategy for synthesizing the monodisperse nanocrystals with tunable size and crystallinity was developed, holding convenient, highly efficient and low pollution. Size evolution shows a gradually increasing trend along the aging-temperature. A model that the independent reaction cells constructed by SDBS-wrapped reactant packages (solid state vesicles, SSVs) for the confined growth of ZnS nanocrystals was proposed to access the formation mechanism of ZnS quantized crystal in a solid-state synthesis system. The band gaps and band-edge luminescent emissions of as-prepared ZnS nanocrystals experienced the size-dependent quantum confinement effect, while the trap-state emissions exhibited the lattice integrity-dependence. Furthermore, ZnS quantum-sized nanocrystals with narrower size distribution can be obtained by a batch-sorting process through adjusting the centrifugal speed.

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