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1.
Mar Drugs ; 19(3)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803892

RESUMO

Unique fucosylated glycosaminoglycans (FG) have attracted increasing attention for various bioactivities. However, the precise structures of FGs usually vary in a species-specific manner. In this study, HfFG was isolated from Holothuria floridana and purified by anion exchange chromatography with the yield of ~0.9%. HfFG was composed of GlcA, GalNAc and Fuc, its molecular weight was 47.3 kDa, and the -OSO3-/-COO- molar ratio was 3.756. HfFG was depolymerized by a partial deacetylation-deaminative cleavage method to obtain the low-molecular-weight HfFG (dHfFG). Three oligosaccharide fragments (Fr-1, Fr-2, Fr-3) with different molecular weights were isolated from the dHfFG, and their structures were revealed by 1D and 2D NMR spectroscopy. HfFG should be composed of repeating trisaccharide units -{(L-FucS-α1,3-)d-GlcA-ß1,3-d-GalNAc4S6S-ß1,4-}-, in which sulfated fucose (FucS) includes Fuc2S4S, Fuc3S4S and Fuc4S residues linked to O-3 of GlcA in a ratio of 45:35:20. Furthermore, the heparanase inhibitory activities of native HfFG and oligosaccharide fragments (Fr-1, Fr-2, Fr-3) were evaluated. The native HfFG and its oligosaccharides exhibited heparanase inhibitory activities, and the activities increased with the increase of molecular weight. Additionally, structural characteristics such as sulfation patterns, the terminal structure of oligosaccharides and the presence of fucosyl branches may be important factors affecting heparanase inhibiting activity.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33741525

RESUMO

Coding regions have complex interaction among multiple selective forces, which are manifested as biases in nucleotide composition. Previous studies have revealed a decreasing GC gradient from the 5'- to 3'- ends of coding regions in various organisms. We confirmed that this gradient is universal in eukaryotic genes but the decrease only starts from the ∼25th codon. This trend is mostly found in nonsynonymous (ns) sites at which the GC gradient is universal across the eukaryotic genome. Increased GC contents at ns sites result in cheaper amino acids, indicating universal selection for energy efficiency toward the N-terminus of encoded proteins. Within a genome, the decreasing GC gradient intensifies from lowly- to highly-expressed genes (more and more protein products), further supporting this hypothesis. This reveals a conserved selective constraint for cheaper amino acids at the translation start that drives the increased GC contents at ns sites. Elevated GC contents can facilitate transcription but result in a more stable local secondary structure around the start codon and subsequently impede translation initiation. Conversely, the GC gradient at fourfold- and twofold- synonymous sites varied across species. They could decrease or increase, suggesting different constraints acting at the GC contents of different codon sites in different species. This study reveals that the overall GC contents at the translation start are consequences of complex interactions among several major biological processes that shaped the nucleotide sequences, especially efficient energy usage.

3.
Acta Otolaryngol ; : 1-7, 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33645422

RESUMO

BACKGROUND: A new floating piezoelectric microphone (NFPM), driven by the acoustic vibration of the ossicles, has been manufactured in the lab. OBJECTIVES: This study aimed at exploring the stability and bio-compatibility of this NFPM. MATERIALS AND METHODS: The NFPM was implanted into the cat tympanic cavity by clamping it to the handle of the malleus, and then a temporal bone computed tomography (CT) plain scan and three dimensional reconstruction were performed to observe its coupling with the handle of the malleus. After six months of implantation, cats' blood samples were taken for pro-inflammatory factor analysis. Then, the operative cavity was opened to check the NFPM, the auditory ossicular chain and some granulation tissue surrounding the NFPM. RESULTS: The NFPM was firmly clamped to the handle of the malleus of the cats during the six months of implantation. Besides, there was no obvious systemic inflammatory response in the experimental animals. In addition, local proliferation of granulation tissue occurred in the tympanic cavity without hampering the movement of the auditory ossicle,or causing ischemia of the auditory ossicle. CONCLUSION: The NFPM could be implanted in our experimental cats for a long period of time and had good bio-compatibility.

4.
PLoS Negl Trop Dis ; 15(3): e0009211, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33667230

RESUMO

Several studies have demonstrated that Zika virus (ZIKV) damages testis and leads to infertility in mice; however, the infection in the epididymis, another important organ of male reproductive health, has gained less attention. Previously, we detected lesions in the epididymis in interferon type I and II receptor knockout male mice during ZIKV infection. Herein, the pathogenesis of ZIKV in the epididymis was further assessed in the infected mice after footpad inoculation. ZIKV efficiently replicated in the epididymis, and principal cells were susceptible to ZIKV. ZIKV infection disrupted the histomorphology of the epididymis, and the effects were characterized by a decrease in the thickness of the epithelial layer and an increase in the luminal diameter, especially at the proximal end. Significant inflammatory cell infiltration was observed in the epididymis accompanied by an increase in the levels of interleukin (IL)-6 and IL-28. The expression of tight junction proteins was downregulated and associated with disordered arrangement of the junctions. Importantly, the expression levels of aquaporin 1 and lipocalin 8, indicators of the absorption and secretion functions of the epididymis, were markedly reduced, and the proteins were redistributed. These events synergistically altered the microenvironment for sperm maturation, disturbed sperm transport downstream, and may impact male reproductive health. Overall, these results provide new insights into the pathogenesis of the male reproductive damage caused by ZIKV infection and the possible contribution of epididymal injury into this process. Therefore, male fertility of the population in areas of ZIKV epidemic requires additional attention.

5.
World J Microbiol Biotechnol ; 37(4): 58, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33655368

RESUMO

Blakeslea trispora, a heterothallic Zygomycota with two mating types (termed "plus" and "minus"), is an ideal source of lycopene and ß-carotene. The lycopene and ß-carotene yields when the two type strains are used for fermentation separately are lower than those when they are joint together. To enhance the yield of lycopene and ß-carotene in B. trispora, protoplast fusion technology was carried out between ATCC 14,271 (+) and ATCC 14,272 (-). After protoplast preparation, protoplast fusion, fusion sorting, fusion regeneration, and high-throughput screening, two fusions (Fu-1and Fu-2) with high lycopene and ß-carotene yields were obtained. The lycopene yields of Fu-1 and Fu-2 were increased to 0.60 mg/gDW and 0.90 mg/gDW, which were respectively 3.62- and 5.44-fold those of 14,271 and 1.76- and 2.64-fold those of 14,272. The ß-carotene yields of Fu-1 and Fu-2 were increased to 22.07 mg/gDW and 36.93 mg/gDW, which were respectively 1.72- and 2.89-fold those of 14,271 and 1.23- and 2.06-fold those of 14,272. In this study, the protoplast fusion technique was successfully used in Blakeslea trispora, providing new ideas for improving lycopene and ß-carotene production.

6.
Pharmacol Res ; 166: 105527, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33667689

RESUMO

The invasion and metastasis of tumor cells are the hallmarks of malignant diseases and the greatest obstacle to overcome. Heparanase-mediated degradation of heparan sulfate (HS) is the critical process for tumor angiogenesis and metastasis, therefore, heparanase become an attractive target for cancer research. Herein, we reported a native fucosylated glycosaminoglycan (nHG) extracted from sea cucumber Holothuria fuscopunctata and a depolymerized nHG (dHG) and its contained oligosaccharides (hs17, hs14, hs11, hs8 and hs5), acting as heparanase inhibitors. nHG and its derivatives have the ability to bind with heparanase directly, leading to significant inhibition of heparanase activity. Moreover, their apparent binding affinity to heparanase was comparable to their inhibitory effect, which was elevated along with the increase of chain length, similar to the effect of heparins. In addition, oligosaccharides inhibited the migration and invasion of 4T1 mammary carcinoma cells and human umbilical vein endothelial cells (HUVECs) and also suppressed tube formation in Matrigel matrix and angiogenesis in the chick chorioallantoic membrane (CAM) assay. In the metastatic mouse model, oligosaccharides exhibited practical antimetastatic effects on 4T1 mammary carcinoma cells. According to the reported anticoagulant activity and the low bleeding tendency of dHG and its oligosaccharides, the use of the oligosaccharides may lead to better effects on tumor patients with thrombosis tendency.

7.
Anal Methods ; 13(8): 1043-1048, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33565542

RESUMO

Mercury is a highly toxic metal element, and the accumulation of mercury in the human body can cause great harm, including but not limited to brain damage, kidney damage and behavioral disorders. Therefore, an effective way to detect mercury ions in the environment is urgently needed. In this study, a novel fluorescent probe (CP-Hg) was synthesized with coumarin as the fluorophore and propanethiol as the recognition receptor. The probe was characterized with high sensitivity (detection limit is approximately 0.5 nM) and selectivity. Note that the probe can react with mercury ions with a distinct color change. In addition, it has been proved to have low toxicity and successfully applied to detect mercury in water samples, macrophages and zebrafish model.

8.
Environ Monit Assess ; 193(3): 151, 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33641075

RESUMO

Air and dust borne heavy metals can be deposited and bioaccumulated by plants; therefore, biomonitoring employing plants is an effective tool for environmental impact assessment in urban environments. In this study, in addition to road dust, leaves and bark were collected from four common tree species at roadside and urban park sampling sites within the metropolitan area of Hefei, China. A range of heavy metals were analyzed by ICP-MS and AFS. The metal accumulation index (MAI) was adopted to compare the bioaccumulation capacity. Results showed that Cd was highly enriched in road dust although its abundance was low in comparison with that of other elements. The MAI values presented a narrow range (1.8-2.7); however, significant differences (p < 0.05) were found for Al, Cu, Zn, and As among the tree species. Moreover, deciduous Platanus orientalis bioaccumulated more nonessential As than the other species and deserved further risk management. In addition, bark samples from Cinnamomum camphora bioaccumulated more heavy metals than the other species as a result of its morphological and anatomical characteristics. The distribution patterns of heavy metals in tree tissues showed obvious spatial heterogeneity, as impacted by anthropogenic activities to varying degrees. This study examined the biomonitoring potential of roadside trees and the distribution pattern of heavy metals in an urban area under rapid development. Results from the present study could provide baseline data for urban environmental impact assessment and the design of green belts.


Assuntos
Metais Pesados , Árvores , Monitoramento Biológico , China , Cidades , Poeira/análise , Monitoramento Ambiental , Metais Pesados/análise
9.
Medicine (Baltimore) ; 100(4): e23788, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33530176

RESUMO

ABSTRACT: Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related mortality globally. Abnormal DNA methylation is closely related to gastric cancer. The purpose of the study was to investigate the methylation of the SYNE1 and MAGI2 gene promoter and its relationship with the clinical-pathological factors, chemotherapy efficacy, and survival, thus providing a new biomarker for the prognosis and chemotherapy efficacy in gastric cancer.The methylation status of SYNE1 and MAGI2 in gastric cancer and adjacent tissues was detected by MSP method in 70 cases of advanced gastric cancer paraffin specimens.The methylation rate of the SYNE1 and MAGI2 gene promoter region was higher in gastric cancer tissues compared with adjacent tissues. The methylation status of SYNE1 was associated with the age at diagnosis and the size of the primary tumors, but no clinical or pathological factors have been found to be related with the methylation status of MAGI2 promoter. A high level of SYNE1 promoter methylation was associated with poorer chemotherapy efficacy in recurrent patients with gastric cancer. Thirty-three percent of the 70 patients exhibited highly methylated MAGI2; in this group, the median progression-free survival time was 4.1 months, shorter than those with negative methylated MAGI2 whose PFS was 5.1 months.MAGI2 is more methylated in gastric cancer than in adjacent tissues suggesting that hypermethylation changes in MAGI2 may be one of the mechanisms of tumorigenesis in gastric cancer. The methylation status of the SYNE1 and MAGI2 promoter regions may affect the chemotherapy efficacy of advanced gastric cancer. The prognosis of MAGI2-negative patients was better than that of positive ones, suggesting that MAGI2 may be an independent prognostic factor for PFS in patients with advanced gastric cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Citoesqueleto/genética , Metilação de DNA , Guanilato Quinases/genética , Proteínas do Tecido Nervoso/genética , Regiões Promotoras Genéticas , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(1): 32-37, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33554793

RESUMO

OBJECTIVE: To investigate the effect of norcantharidin (NCTD) to proliferation of leukemia cells through disrupting key regulators of sonic Hedgehog (SHH) pathway and its downstream transcription factor SOX2. METHODS: CCK8 was used to detected the HL60 and NB4 cells after inhibited by NCTD, SMO and GLI1 inhibitor for 24 hours. Expression level of SMO, GLI1 and SOX2 in HL60 cells with NCTD treatment was detected by immunoblot. HL60 cells were transfected with pcDNA3.1 plasmid expressing GLI1 or SOX2. Empty vector and pcDNA3. 1-EGFP were divided into negative and positive control group, respectively. The expression of exogenous GLI1 or SOX2 in HL60 cells was confirmed by immunoblot, and growth curve of HL60 cell was checked by CCK8. Proliferation of genetic modified HL60 cells treated by various dose of NCTD was detected. RESULTS: NCTD, SMO/GLI1 inhibitors could inhibit the proliferation of NB4 and HL60 cells in a dose-dependent manner. Compared with solvent (DMSO)-treated control group, NCTD remarkably decreased protein level of SMO, GLI1 and SOX2. GLI1 and SOX2 were overexpressed in HL60 cells as compared with pcDNA3.1 empty vector-transfected group. Growth curve demonstrated significant proliferative advantage of GLI1/SOX2-transfected cells. CCK8 assay indicated that GLI1/SOX2-overexpressed HL60 cells were more resistant to NCTD treatment. CONCLUSION: NCTD attenuates HL60 proliferation via targeting the Hedgehog/SOX2 axis.


Assuntos
Proteínas Hedgehog , Leucemia Mieloide Aguda , Compostos Bicíclicos Heterocíclicos com Pontes , Proliferação de Células , Células HL-60 , Humanos , Fatores de Transcrição SOXB1 , Proteína GLI1 em Dedos de Zinco
11.
Medicine (Baltimore) ; 100(3): e24412, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33546086

RESUMO

INTRODUCTION: Proliferative vitreous retinopathy (PVR) is characterized by proliferation of cells and contraction of membranes on either the retinal surface or in the vitreous cavity, which leads to retinal detachment and visual impairment. PVR is commonly seen in patients with rhegmatogenous retinal detachment and diabetic retinopathy, which seriously affects the patient's work and life. Previous studies indicated that Hirudo (Leech) or compound prescription containing Hirudo (Leech) for treatment of PVR would be effective. However, due to the lack of evidence, there are no specific methods or suggestions, so it is necessary to carry out systematic evaluations on Hirudo (Leech) for PVR and provide effective evidence for further research. METHODS AND ANALYSIS: The following 8 databases will be searched: Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, EMBASE, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, VIP Database, and Wanfang Database. All randomized controlled trials in English or Chinese related to Hirudo (Leech) for PVR will be included. Outcomes will include change in Vitreous opacity, Vision changes, production of the anterior macular membrane, and retinal detachment again. The incidence of adverse events will be assessed for safety evaluation. Study inclusion, data extraction and quality assessment will be performed independently by 2 reviewers. Assessment of risk of bias and data synthesis will be performed using Review Manager V.5.3. RESULTS: In this systematic review and meta-analysis, we will synthesize the studies to assess the safety and efficacy of Hirudo (Leech) for PVR. CONCLUSION: The summary of our study will clarify whether Hirudo (Leech) therapy could be an efficient and safe method for PVR, which can further guide the promotion and application of it. OPEN SCIENCE FRAMEWORK OSF REGISTRATION NUMBER: 10.17605/OSF.IO/FP7VG (https://osf.io/fp7vg).


Assuntos
Protocolos Clínicos , Aplicação de Sanguessugas/normas , Vitreorretinopatia Proliferativa/terapia , Animais , Humanos , Sanguessugas , Aplicação de Sanguessugas/efeitos adversos , Aplicação de Sanguessugas/métodos , Metanálise como Assunto , Revisões Sistemáticas como Assunto , Vitreorretinopatia Proliferativa/fisiopatologia
12.
Oxid Med Cell Longev ; 2021: 8839394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33542786

RESUMO

1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ), a potent nuclear factor-E2-related factor 2 (Nrf2) activator, has potent antioxidant activity by scavenging reactive oxygen species (ROS). However, the role of HTHQ on the development of preeclampsia (PE) and the underlying mechanisms have barely been explored. In the present study, PE model was induced by adenovirus-mediated overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1) in pregnant mice. The results showed that HTHQ treatment significantly relieved the high systolic blood pressure (SBP) and proteinuria and increased the fetal weight and fetal weight/placenta weight in preeclamptic mice. Furthermore, we found that HTHQ treatment significantly decreased soluble endoglin (sEng), endothelin-1 (ET-1), and activin A and restored vascular endothelial growth factor (VEGF) in preeclamptic mice. In addition, HTHQ treatment inhibited oxidative stress and endothelial cell apoptosis by increasing the levels of Nrf2 and its downstream haemoxygenase-1 (HO-1) protein. In line with the data in vivo, we discovered that HTHQ treatment attenuated oxidative stress and cell apoptosis in human umbilical vein endothelial cells (HUVECs) following hypoxia and reperfusion (H/R), and the HTHQ-mediated protection was lost after transfected with siNrf2. In conclusion, these results suggested that HTHQ ameliorates the development of preeclampsia through suppression of oxidative stress and endothelial cell apoptosis.

13.
Biomacromolecules ; 22(3): 1244-1255, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33616386

RESUMO

Glycosaminoglycans (GAGs) are conserved polysaccharides composed of linear repeating disaccharides and play crucial roles in multiple biological processes in animal kingdom. However, saccharide-branched GAGs are rarely found, except the fucose-branched one from sea cucumbers. There was conjecture about the presence of disaccharide-branched GAG since 30 years ago, though not yet confirmed. Here, we report a GAG containing galactose-fucose branches from Thelenota ananas. This unique branch was confirmed as d-Gal4S(6S)-α1,2-l-Fuc3S by structural elucidation of oligosaccharides prepared from T. ananas GAG. Bioassays indicated that oligomers with a larger degree of polymerization exhibited a potent anticoagulation by targeting the intrinsic tenase. Heptasaccharide was proven as the minimum fragment retaining the anticoagulant potential and showed 92.6% inhibition of venous thrombosis in vivo at sc. of 8 mg/kg with no obvious bleeding risks. These results not only solve a long-standing question about the presence of disaccharide-branched GAG in Holothuroidea, but open up new opportunities to develop safer anticoagulants.

14.
Kaohsiung J Med Sci ; 37(3): 172-180, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33554442

RESUMO

Psoriasis is one of the most common chronic inflammatory skin diseases that affects approximately 3% of the world's population. Hyper proliferation, infiltration of inflammatory cells and aberrant differentiation of keratinocytes are the three most important characteristics of psoriasis. Previous reports showed that NF-κBis the crucial mediator linking psoriatic keratinocytes and immune cell states through its effects on chemokine and cytokine production. To identify the role of NF-κB in psoriasis, we conducted ELISA assay to detect the activity of NF-κB in lesional skin and nonlesional skin of patients with psoriasis. Mounting evidence suggests that the interaction between long noncoding RNAs (lncRNAs) and microRNAs plays important role in the regulation of the initiation and development of various diseases. In this article, we identified that lncRNA UCA1 was down-regulated in lesional skin of patients with psoriasis. Further studies showed that lncRNA UCA1 could promote the expression of A20 by inhibitingmiR125a, and up-regulated A20 decreased the activity of NF-κB through its ubiquitin editing function. Taken together, we identified and demonstrated that lncRNA UCA1 negatively regulated NF-κB activity in psoriasis through the miR125a-A20 axis.

15.
Int J Audiol ; : 1-10, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33399499

RESUMO

OBJECTIVE: To assess any differences in spatial listening ability of cochlear implant recipients when using both or only one of two bilateral cochlear implants (BCIs) for stimuli originating from behind the subject. DESIGN: Twelve loudspeakers were placed in the rear horizontal plane of the subjects to test the sound localisation performance of BCI users and normal-hearing listeners (NHLs) with or without interfering noise. Stimuli were presented via two rear loudspeakers simultaneously during the speech recognition test. In the tone recognition test, another anechoic chamber was used with stimuli presenting from a loudspeaker behind the participants. STUDY SAMPLE: Twenty-seven NHLs and eleven BCI users. RESULTS: Average root-mean-square (RMS) error for the bilateral condition was significantly lower than that for the right and left cochlear implant (CI) conditions with or without interfering noises (p < 0.05). Average speech or tone recognition scores for the bilateral condition and the right and left CI conditions were not statistically significant (p > 0.05). CONCLUSION: Sound localisation with BCIs was significantly more accurate than with either implant alone. Speech and tone recognition scores were not better with two compared to those of one activated implant. Given the small number of subjects, the results should be considered as preliminary.

16.
Carbohydr Polym ; 256: 117513, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33483034

RESUMO

Marine sulfated polysaccharides have aroused widespread concern for their various structures and bioactivities. Peroxide depolymerization is a common strategy in analysis of structures and structure-activity relationships of polysaccharides. However, confirming the depolymerization process and exact structures of the degradation products is still a considerable challenge. This study reported the structures of a fucan sulfate (FS) from sea cucumber Stichopus herrmanni and its depolymerized products (dFS) prepared by peroxide degradation. The FS was elucidated with a highly regular structure, {-3)-L-Fuc2S-(α1-}n. Structure analysis of oligosaccharides purified from dFS suggested that peroxide degradation involved in cleavage of glycosidic bonds and oxidative modification of reducing end of sugar residue, while no break in sugar ring was observed. Both FS and series of dFSs exhibited significant anticoagulant activities due to their anti-thrombin effects in presence of heparin cofactor II and their potencies were related to their molecular sizes, dFS with ∼ 20 kDa showed the strongest activity.


Assuntos
Anticoagulantes/química , Coagulação Sanguínea/efeitos dos fármacos , Peróxidos/química , Polissacarídeos/química , Stichopus/química , Animais , Anticoagulantes/isolamento & purificação , Anticoagulantes/farmacologia , Organismos Aquáticos , Testes de Coagulação Sanguínea , Sequência de Carboidratos , Cofator II da Heparina/farmacologia , Humanos , Hidrólise , Peso Molecular , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Stichopus/fisiologia , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores , Trombina/metabolismo
17.
Toxicol Appl Pharmacol ; 412: 115389, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33385404

RESUMO

Cytochrome P450 (CYP) gene expression exhibits large interindividual variation attributable to diverse regulatory factors including microRNAs (miRNAs) and hepatic transcription factors (TFs). We used real-time qPCR with 106 human liver samples to measure the expression and interindividual variation of seven miRNAs and four TFs that have been reported to regulate the expression of CYPs; we also identified factors that influence their expression. The results show that expression of the seven miRNAs and the four TFs exhibits a non-normal distribution and the expression variability is high (89- to 618-fold for miRNA and 12- to 85-fold for TFs). Age contributed to the interindividual variation for miR-148a, miR-27b and miR-34a, whereas cigarette smoking and alcohol consumption significantly reduced HNF4α mRNA levels. Association analysis showed significant correlations among the seven miRNAs as well as the four TFs. Furthermore, we systematically evaluated the impact of the seven miRNAs and four TFs on protein content, mRNA levels, translation efficiency and activity of 10 CYPs. The results show that numerous associations (positive and negative) are present between the seven miRNAs or the four TFs and the 10 CYP phenotypes (as indicated by mRNA, protein and activity); specifically, miR-27b, miR-34a and all four TFs played key roles in the interindividual variation of CYPs. Our results extend previous findings and suggest that miR-27b and miR-34a may be potential direct or indirect master regulators of CYP expression and thereby contribute to the interindividual variations in CYP-mediated drug metabolism.

18.
Drug Deliv ; 28(1): 252-260, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33501870

RESUMO

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator used to treat osteoporosis in postmenopausal women. RLX fails to be developed into injectable dosage forms due to poor solubility. Although oral formulations are clinically available, the lower bioavailability (<2%) embarrasses the pharmaceutists. This work reported a bioadhesive nanosystem intended for oral delivery of RLX to enhance its oral bioavailability and address the formulation challenge. The bioadhesive nanosystem refers to polymer-lipid hybrid nanoparticles made up of Carbopol 940, glyceryl distearate, and TGPS. RLX was solidly encapsulated into bioadhesive nanoparticles (bNPs) through a nanoprecipitation technique along with synchronous desalting of RLX·HCl. The resultant RLX-loaded bNPs (RLX-bNPs) were characterized by particle size, ζ potential, morphology, and entrapment efficiency. The in vitro release and in vivo oral bioavailability of RLX-bNPs in rats were comparatively investigated with RLX-loaded common lipid nanoparticles (RLX-cNPs). The preferred formulation possesses a particle size of 150 nm around with a polydispersity index (PDI) of 0.282. RLX-bNPs exhibited slower drug release than RLX-cNPs owing to the presence of an adhesive layer. After oral administration, RLX-bNPs resulted in significant enhancement in the bioavailability of RLX, up to 556.9% relative to RLX suspensions, while it was merely 244.7% for RLX-cNPs. Cellular testing and ex vivo transport imaging demonstrated that bNPs were endowed with excellent intestinal epithelial affinity and absorbability. Our study affords an alternative option for designing a suitable oral delivery system specific to amphiphobic drugs like RLX·HCl.

19.
Spectrochim Acta A Mol Biomol Spectrosc ; 249: 119279, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33341742

RESUMO

Mercury, as a highly toxic heavy metal, can cause very serious harm to human health and even death in severe cases. Therefore, we synthesized a novel ratiometric fluorescent probe for detecting mercury ions, with mercaptoethanol as the recognition receptor. Probe CMER could determine mercury ions in 0-1.6 µM and the detection limit is 7.6 nM. Moreover, CMER manifested a fast response for Hg2+ (within 5 s) and simultaneously observed that the color changed from light yellow to orange by naked eye. In addition to these preeminent spectral properties, the probe also had satisfactory bioimaging results in RAW 264.7 macrophage cells and zebrafish.

20.
Mol Biol Rep ; 47(12): 9739-9747, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33200314

RESUMO

Dengue virus (DV) is the most rapidly spreading arbovirus in the world. Our previous studies indicated that Rac1, a kind of Rho GTPase, was related with the increased vascular permeability in DV infection. However, the molecular mechanisms that regulate the activity of the Rac1 pathway during DV infection is not fully understood yet. Recently, Rho-specific guanine nucleotide dissociated inhibitors (Rho GDIs), as a pivotal upstream regulator of Rho GTPase, attract our attention. To identify the role of GDI-1 in DV2 infection, the expression of GDI in Eahy926 cells was detected. Moreover, a GDI-1 down-regulated cell line was constructed to explore the correlation between GDI-1 and Rac1 and to further evaluate the function of GDI in DV life cycle. Our results indicated that DV2 infection could up-regulate GDI-1 expression, and down-regulation of GDI enhanced the activity of Rac1. In addition, down-regulated GDI-1 significantly inhibited all steps of DV2 replication cycle. GDI-1 plays an important role in DV2 infection via negatively regulating the activation of the Rac1-actin pathway. These results not only contribute to our further understanding of the pathogenesis of severe dengue but also provide further insight into the development of antiviral drugs.

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