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1.
Dalton Trans ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33416817

RESUMO

Self-assembly of polyoxometalates, Ni(ii)/Ag(i) cations and tetra-[5-(mercapto)-1-methyltetrazole]-thiacalix[4]arene (L) yielded three inorganic-organic hybrids, namely, [Ni3L2(CH3OH)6(H2O)4][PMo12O40]2·3CH3OH·2H2O (1), [Ni3L2(CH3OH)6(H2O)4][PW12O40]2·3CH3OH·2H2O (2) and [Ag3L(PMo12O40)] (3). In hybrids (1) and (2), Ni(ii) cations are linked by L ligands to produce layered frameworks, and H bonds among the [PMo12O40]3-/[PW12O40]3- anions and L ligands lengthen the structures to form 3D supramolecular architectures. Hybrid (3) exhibits a 3D architecture, of which Ag(i) cations not only coordinated with the N and O atoms of L ligands and [PMo12O40]3- anions simultaneously, but also connected each other by Ag-Ag interactions. It is worth mentioning that 1 and 3 as recyclable catalysts show excellent heterogeneous catalytic activity in oxidation desulfurization reactions.

2.
Clin Nephrol ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33433320

RESUMO

OBJECTIVE: Electron microscopy (EM) was used to observe the deposition and ultrastructural characteristics of amyloids in abdominal adipose tissue, which provided a reliable basis for pathological diagnosis of systemic amyloidosis. MATERIALS AND METHODS: 42 patients with established amyloidosis and 8 controls underwent surgical biopsy of subcutaneous abdominal fat. The fat tissues were submitted concurrently in 4% buffered neutral formalin for histological sections preparation, in glutaraldehyde fixative for EM studies, and in saline solutions for immunofluorescence tests. RESULTS: Light microscopy revealed marked brick-red staining in 11 of 42 samples, 6 moderate and 11 slight staining in the septum of cells, medium and small sized vessel, and apple green double refraction under polarized light microscopy. There were no significant differences in fat biopsies between the systemic amyloidosis and normal subjects in 14 cases. The EM showed approximate 10-nm-thick straight filaments in adipose tissue in all 42 cases with amyloidosis. The positive rate of diagnosis was 100%. Congo red stained sections alone in cases with scant amyloid led to false negative results, but the EM was able to characterize the amyloid protein in all cases. CONCLUSION: Therefore, preliminary diagnosis of suspected cases can be made by Congo red staining, but the final diagnosis requires an electron microscopic examination.

3.
Nat Commun ; 12(1): 74, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397965

RESUMO

The effective storage of lipids in white adipose tissue (WAT) critically impacts whole body energy homeostasis. Many genes have been implicated in WAT lipid metabolism, including tripartite motif containing 28 (Trim28), a gene proposed to primarily influence adiposity via epigenetic mechanisms in embryonic development. However, in the current study we demonstrate that mice with deletion of Trim28 specifically in committed adipocytes, also develop obesity similar to global Trim28 deletion models, highlighting a post-developmental role for Trim28. These effects were exacerbated in female mice, contributing to the growing notion that Trim28 is a sex-specific regulator of obesity. Mechanistically, this phenotype involves alterations in lipolysis and triglyceride metabolism, explained in part by loss of Klf14 expression, a gene previously demonstrated to modulate adipocyte size and body composition in a sex-specific manner. Thus, these findings provide evidence that Trim28 is a bona fide, sex specific regulator of post-developmental adiposity and WAT function.


Assuntos
Adipócitos/metabolismo , Deleção de Genes , Glucose/metabolismo , Obesidade/patologia , Proteína 28 com Motivo Tripartido/genética , Células 3T3-L1 , Tecido Adiposo Branco/metabolismo , Adiposidade , Animais , Peso Corporal , Dieta , Dieta Hiperlipídica , Metabolismo Energético , Feminino , Redes Reguladoras de Genes , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Fenótipo , Triglicerídeos/metabolismo , Proteína 28 com Motivo Tripartido/deficiência
4.
Acta Pharm ; 71(1): 99-114, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32697747

RESUMO

Eplerenone is a drug that protects the cardiovascular system. 11α-Hydroxycanrenone is a key intermediate in eplerenone synthesis. We found that although the cytochrome P450 (CYP) enzyme system in Aspergillus ochraceus strain MF018 could catalyse the conversion of canrenone to 11α-hydroxycanrenone, its biocatalytic efficiency is low. To improve the efficiency of 11α-hydroxycanrenone production, the CYP monooxygenase-coding gene of MF018 was predicted and cloned based on whole-genome sequencing results. A recombinant A. ochraceus strain MF010 with the high expression of CYP monooxygenase was then obtained through homologous recombination. The biocatalytic rate of this recombinant strain reached 93 % at 60 h without the addition of organic solvents or surfactants and was 17-18 % higher than that of the MF018 strain. Moreover, the biocatalytic time of the MF010 strain was reduced by more than 30 h compared with that of the MF018 strain. These results show that the recombinant A. ochraceus strain MF010 can overcome the limitation of substrate biocatalytic efficiency and thus holds a high poten tial for application in the industrial production of eplerenone.

5.
Chemosphere ; 267: 129146, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33338725

RESUMO

The effects of ambient fine particulate matter (PM2.5) exposure on blood pressure have been widely reported. However, there remains uncertainty regarding the underlying roles of particulate matter components. We aimed to investigate the association between ambient PM2.5 exposure and blood pressure, as well as the potential effects of trace metal(loid)s, in a repeated-measurement study that enrolled women of childbearing age. Our study included 35 participants from Hebei Province, China, each of whom was visited for five times. During each visit, we conducted questionnaire surveys, measured blood pressure, and collected blood. The daily PM2.5 exposure of participants was estimated according to their residential addresses using a spatiotemporal model that combined monitoring data with satellite measurements and chemical-transport model simulations. This model was used to calculate average PM2.5 concentrations in 1, 3, 7, 15, 30, and 60 days prior to each visit. Serum concentrations of various trace metal(loid)s were measured. A linear mixed-effects model was used to investigate associations among study variables. Overall, the mean (standard deviation) 60 days PM2.5 concentration over all five visits was 108.1(43.3) µg/m3. PM2.5 concentration was positively associated with both systolic and diastolic blood pressures. Likewise, ambient PM2.5 concentration was positively associated with serum concentrations of manganese and arsenic, and negatively associated with serum concentrations of nickel, tin, and chromium. Only the serum concentration of molybdenum was negatively associated with systolic blood pressure. We concluded that ambient PM2.5 exposure may contribute to elevated blood pressure, potentially by interfering with internal intake of various metal(loid)s in the human body.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Pressão Sanguínea , China , Exposição Ambiental , Feminino , Humanos , Metais , Material Particulado/análise
6.
Signal Transduct Target Ther ; 5(1): 283, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277466

RESUMO

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33289538

RESUMO

The development of intelligent and multifunctional hydrogels having photothermal properties, good mechanical properties, sustained drug release abilities with low burst release, antibacterial properties, and biocompatibility is highly desirable in the biomaterial field. Herein, mesoporous polydopamine (MPDA) nanoparticles wrapped with graphene oxide (GO) were physically cross-linked in cellulose nanofibril (CNF) hydrogel to obtain a novel MPDA@GO/CNF composite hydrogel for controllable drug release. MPDA nanoparticles exhibited a high drug loading ratio (up to 35 wt %) for tetracycline hydrochloride (TH). GO was used to encapsulate MPDA nanoparticles for extending the drug release time and reinforcing the physical strength of the obtained hydrogel. The mechanical strength of the as-fabricated MPDA@GO/CNF composite hydrogel was five times greater compared to that of the pure CNF hydrogel. Drug release experiments demonstrated that burst release behavior was significantly reduced by adding MPDA@GO. The drug release time of the MPDA@GO/CNF composite hydrogel was 3 times and 7.2 times longer than that of the polydopamine/CNF hydrogel and pure CNF hydrogel, respectively. The sustained and controlled drug release behaviors of the composite hydrogel were highly dependent on the proportion of MPDA and GO. Moreover, the rate of drug release could be accelerated by near-infrared (NIR) light irradiation and pH value change. The drug release kinetics of the as-prepared composite hydrogel was well described by the Korsmeyer-Peppas model, and the drug release mechanism of TH from the composite hydrogel was anomalous transport. Importantly, this carefully designed MPDA@GO/CNF composite hydrogel showed good biocompatibility through an in vitro cytotoxicity test. In particular, the toxicity of GO was well shielded by the CNF hydrogel. Therefore, this novel MPDA@GO/CNF composite hydrogel with an encapsulation structure for controllable drug release and toxicity shielding of GO could be used as a very promising controlled drug delivery carrier, which may have potential applications for chemical and physical therapies.

8.
Chemosphere ; 265: 129153, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33302207

RESUMO

The abuse of antibiotics has brought out serious bacterial resistance, which threatens the ecological environment and human health. Quorum sensing inhibitors (QSIs), as a new kind of potential antibiotic substitutes that are theoretically difficult to trigger bacterial resistance, are recommended to individually use or jointly use with traditional antibiotics. However, there are few studies on the resistance risk in the use of QSIs. In this study, the influence of QSIs alone or in combination with sulfonamides (SAs) on conjugative transfer and mutation of Escherichia coli (E. coli) was investigated to explore whether QSIs have the potential to induce bacterial resistance. The results show that QSIs may facilitate plasmid RP4 conjugative transfer by binding with SdiA protein to regulate pilus expression, and interact with LsrR protein to increase SOS gene expression, inducing gene mutation. The QSIs-SAs mixtures could promote plasmid RP4 conjugative transfer and mutation in E. coli, and the main joint effects are synergism and antagonism. Furthermore, there is a good correlation among conjugative transfer, mutation, and growth inhibition of QSIs-SAs to E. coli. It could be speculated that bacteria may delay cell division to provide sufficient energy and time for regulating conjugative transfer and mutation under the stress of QSIs and their combined exposure with antibiotics, which is essentially a balance between bacterial resistance and toxicity. This study provides a reference for the resistance risk assessment of QSIs and benefits the clinical application of QSIs.

9.
Technol Cancer Res Treat ; 19: 1533033820980117, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33349156

RESUMO

Accumulating evidence have suggested that long non-coding RNAs (lncRNAs) act as a critical regulator in tumorgenesis. LncRNA KCNQ1OT1 (KCNQ1OT1) has been recently shown to be dysregulated in many cancers. This study was aimed to explore the biological role of KCNQ1OT1 in hepatocellular carcinoma (HCC). In our study, we first observed the expression level of KCNQ1OT1 was distinctly up-regulated in HCC tissues and cell lines compared with adjacent non-cancer tissues and normal liver cell line. And clinical results indicated that higher expression of KCNQ1OT1 was correlated with poor prognosis of patients with HCC. Next, functional studies revealed that knockdown of KCNQ1OT1 induced apoptosis and repressed proliferation, migration and invasion of HCC cells. In addition, knockdown of KCNQ1OT1 suppressed xenograft tumor growth in vivo. Mechanically, we found that KCNQ1OT1 can promote the expression of IGF1R by functioning as a competing endogenous RNA of miR-148a-3p. In conclusion, our results shown the oncogenic role of KCNQ1OT1 in HCC by regulating the miR-148a-3p/IGF1R axis and may provide a new insight and a potential therapeutic target for HCC.

10.
Front Neurol ; 11: 585977, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193049

RESUMO

Anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis is a rare autoimmune encephalitis (AE). We investigated the clinical features and gut microbial alterations of anti-LGI1 encephalitis. Fifteen patients newly diagnosed with anti-LGI1 encephalitis were recruited in the study prior to the administration of immunotherapy. The control group contains 25 well-matched healthy controls (HCs). All participants were Han Chinese from South China. Their clinical data and fecal samples were collected. The diversity and composition of gut microbiota were analyzed by 16S ribosomal RNA (16S rRNA) gene sequencing. The results showed that anti-LGI1 encephalitis was characterized by cognitive impairment, faciobrachial dystonic seizures, hyponatremia, and psychiatric symptoms. Abnormal EEG and brain MRI were presented in 9 and 10 patients, respectively. Compared to HCs, the anti-LGI1 encephalitis patients exhibited a decreased microbial diversity and an altered overall composition of gut microbiome. At the phylum level, anti-LGI1 encephalitis patients exhibited a higher abundance of Proteobacteria and a lower abundance of Firmicutes. The alterations in the phylum level were associated with autoimmune and inflammatory disorders. At the genus level, there was an increase in Sphingomonas, Anaerofustis, Succinvibrio, Clostridium, and SMB53 (genera related to movement disorders, psychiatric diseases, and with proinflammatory effects). However, the Faecalibacterium, Roseburia, Lachnospira, Ruminococcus, and Blautia [genera with ability to produce short-chain fatty acids (SCFAs)] were obviously reduced in the patient group. Our results suggest that anti-LGI1 encephalitis is characterized by special clinical features and is accompanied by alterations in specific gut microbiota. For the limited sample size and non-applicability to other populations, further studies are warranted to explore the relationships between gut microbiota and anti-LGI1 encephalitis.

11.
Mol Brain ; 13(1): 161, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33228784

RESUMO

Previous studies have shown that CCL2 may cause chronic pain, but the exact mechanism of central sensitization is unclear. In this article, we further explore the presynaptic role of CCL2. Behavioral experiments show that intervertebral foramen injection CCR2 antagonists into dorsal root ganglion (DRG) can inhibit the inflammatory pain caused by CCL2 in spinal cord. We raised the question of the role of presynaptic CCR2 in the spinal dorsal horn. Subsequent electron microscopy experiments showed that CCR2 was expressed in the presynaptic CGRP terminal in the spinal dorsal horn. CCL2 can enhance presynaptic calcium signal. Whole-cell patch-clamp recordings showed that CCL2 can enhance NMDAR-eEPSCs through presynaptic effects, and further application of glutamate sensor method proved that CCL2 can act on presynaptic CCR2 to increase the release of presynaptic glutamate. In conclusion, we suggest that CCL2 can directly act on the CCR2 on presynaptic terminals of sensory neurons in the spinal dorsal horn, leading to an increase in the release of presynaptic glutamate and participate in the formation of central sensitization.

12.
Sci Rep ; 10(1): 19524, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33177654

RESUMO

Salvia miltiorrhiza has numerous compounds with extensive clinical application. "Sweating", a processing method of Traditional Chinese Medicine (TCM), results in great changes in pharmacology and pharmacodynamics. Previously, chromatogram of 10 characteristic metabolites in S. miltiorrhiza showed a significant difference after "Sweating". Due to the complexity of TCM, changes in metabolites should be investigated metabolome-wide after "Sweating". An untargeted UPLC/MS-based metabolomics was performed to discover metabolites profile variation of S. miltiorrhiza after "Sweating". Multivariate analysis was conducted to screen differential metabolites. Analysis indicated distinct differences between sweated and non-sweated samples. 10,108 substance peaks had been detected altogether, and 4759 metabolites had been identified from negative and positive ion model. 287 differential metabolites were screened including 112 up-regulated and 175 down-regulated and they belong to lipids and lipid-like molecules, and phenylpropanoid and polyketides. KEGG analysis showed the pathway of linoleic acid metabolism, and glyoxylate and dicarboxylate metabolism were mainly enriched. 31 and 49 identified metabolites were exclusively detected in SSM and NSSM, respectively, which mainly belong to carboxylic acids and derivatives, polyketides and fatty acyls. By mapping tanshinones and salvianolic acids to 4759 identified metabolites library, 23 characteristic metabolites had been identified, among which 11 metabolites changed most. We conclude that "Sweating'' has significant effect on metabolites content and composition of S. miltiorrhiza.

13.
Circulation ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33207953

RESUMO

Background: Aberrant expression of circular RNA (CircRNA) contributes to human diseases. CircRNAs regulate gene expression by sequestering specific microRNAs (miRNAs). In this study, we investigated whether CircMAP3K5 could act as a competing endogenous miR-22-3p sponge and regulate neointimal hyperplasia. Methods: CircRNA profiling from genome-wide RNA sequencing data was compared between human coronary artery smooth muscle cells (HCASMCs) treated with or without PDGF. Expression levels of circular MAP3K5 (CircMAP3K5) was assessed in human coronary arteries from autopsies on patients with dilated cardiomyopathy (DCM) or coronary heart disease (CHD). The role of CircMAP3K5 in intimal hyperplasia was further investigated in mice with AAV9-mediated CircMAP3K5 transfection. SMC-specific Tet2 knockout mice and global miR-22-3p knockout mice were used to delineate the mechanism by which CircMAP3K5 attenuated neointimal hyperplasia using the femoral arterial wire injury model. Results: RNA sequencing demonstrated that treatment with PDGF-BB significantly reduced expression of CircMAP3K5 in HCASMCs. Wire-injured mouse femoral arteries and diseased arteries from CHD patients (where PDGF-BB is increased) confirmed in vivo downregulation of CircMAP3K5 associated with injury and disease. Lentivirus-mediated overexpression of CircMAP3K5 inhibited the proliferation of HCASMCs. In vivo AAV9-mediated transfection of CircMap3k5 specifically inhibited SMC proliferation in the wire-injured mouse arteries, resulting in reduced neointima formation. Using a luciferase reporter assay and RNA pull-down, CircMAP3K5 was found to sequester miR-22-3p, which in turn inhibited the expression of TET2. Both in vitro and in vivo results demonstrate that the loss of miR-22-3p recapitulated the anti-proliferative effect of CircMap3k5 on VSMCs. In SMC-specific Tet2 knockout mice, loss of Tet2 abolished the CircMap3k5-mediated anti-proliferative effect on VSMCs. Conclusions: We identify CircMAP3K5 as a master regulator of TET2-mediated VSMC differentiation. Targeting the CircMAP3K5/miR-22-3p/TET2 axis may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia including restenosis and atherosclerosis.

14.
Int Immunopharmacol ; : 107192, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33214096

RESUMO

BACKGROUND: Random skin flaps are often used for plastic repair because they are convenient and flexible. However, necrosis of flaps is a common complication that may lead to disastrous consequences. Exenatide, a glucagon-like peptide 1 receptor agonist, can enhance angiogenesis and ameliorate ischemia/reperfusion injury. Our experiments explored random skin flap outcomes after its use. METHODS: We established modified dorsal McFarlane flaps on 54 Sprague-Dawley rats and divided the rats into three groups (control, Exe-I, and Exe-II). We intraperitoneally injected either 4 or 8 µg/kg/day exenatide into the rats of the Exe-I and Exe-II groups, respectively. On the seventh day after the operation, we measured the levels of superoxide dismutase (SOD) and malondialdehyde (MDA). Tissue sections were obtained for histopathological and immunohistochemical analyses, and we evaluated the expression of vascular endothelial growth factor (VEGF), interleukin (IL) 6, IL-1ß, nuclear factor kappa beta (NF-κB), Toll-like receptor 4 (TLR4), and tumor necrosis factor α (TNF-α). We measured blood flow reconstruction and angiogenesis using laser Doppler blood flowmetry and lead oxide/gelatin angiography, respectively. RESULTS: Exenatide increased the average survival area of the flap and improved microvascular density and blood flow intensity in a dose-dependent manner. Meanwhile, the SOD level was up-regulated and the MDA level down-regulated. Exenatide also enhanced the expression of VEGF and reduced the expression of inflammatory cytokines (IL-6, IL-1ß, NF-κB, TLR4, and TNF-α), thereby promoting angiogenesis and inhibiting inflammation. CONCLUSIONS: Exenatide potentially inhibits necrosis in our rat random skin flap model.

15.
ACS Omega ; 5(41): 26486-26496, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33110976

RESUMO

Recent advances in MXenes with high carrier mobility show great application prospects in the surface-enhanced Raman scattering (SERS) field. However, challenges remain regarding the improvement of the SERS sensitivity. Herein, an effective strategy considering charge-transfer resonance for semiconductor-based substrates is presented to optimize the SERS sensitivity with the guidance of the density functional theory calculation. The theoretical calculation predicted that the excellent SERS enhancement for methylene blue (MeB) on Ti3C2 MXene can be excited by both 633 and 785 nm lasers, and the Raman enhanced effect is mainly originated from the charge-transfer resonance enhancement. In this work, the Ti3C2 MXenes exhibit an excellent SERS sensitivity with an enhancement factor of 2.9 × 106 and a low detection limit of 10-7 M for MeB molecules. Furthermore, the SERS enhancement of Ti3C2 and Au-Ti3C2 substrates exhibit higher selectivity on different molecules, which contributes to the detection of target molecules in complex solution environments. This work can provide some theoretical and experimental basis for the research on SERS activity of other MXene materials.

16.
Materials (Basel) ; 13(21)2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33114557

RESUMO

Silicon carbide (SiC) ceramics with Y2O3-Er2O3 as sintering additives were prepared by spark plasma sintering (SPS). The effects of sintering temperatures and Y2O3-Er2O3 contents on the microstructure, thermal conductivity, electrical, and mechanical properties were investigated. The increasing of sintering temperatures promoted the densification of SiC ceramics, thus increasing the thermal conductivity and electrical resistivity. With the increase of the sintering additive contents, the electrical resistivity increased due to the formation of the electrical insulating network; and the thermal conductivity first increased and then decreased, which was related to the content and distribution of the secondary phase among the SiC grains. The SiC ceramics sintered at 2000 °C with 9 wt.% Y2O3-Er2O3 exhibited higher electrical resistivity and thermal conductivity, which were 4.28 × 109 Ω·cm and 96.68 W/m·K, respectively.

17.
Onco Targets Ther ; 13: 9887-9899, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116574

RESUMO

Purpose: LncRNAs play an important role in tumorigenesis and cancer progression in liver cancer. Although many lncRNAs have been reported, the role of MIR194-2HG and the underlying mechanism mediated by it are still largely unknown in HCC. This study aimed to investigate the biological role and mechanism of MIR194-2HG in liver cancer. Materials and Methods: The expression of MIR194-2HG was determined in liver cancer tissues and cells by RT-qPCR. The overall survival rate of MIR194-2HG was analyzed by Kaplan-Meier survival analysis. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, and Transwell assays were carried out to detect cell migration and invasion. Western blotting was used to quantify the levels of all proteins. The regulatory mechanism of the MIR194-2HG/miR-1207-5p/TCF19 axis in liver cancer was investigated by dual-luciferase activity reporter assay, Kaplan-Meier survival analysis, and Western blotting. Results: MIR194-2HG was upregulated in liver cancer tissues and cell lines. Liver cancer patients with higher expression of MIR194-2HG revealed poor overall survival compared with those who had lower expression of MIR194-2HG. MIR194-2HG promoted the proliferation, migration, and invasion of HepG2 and Huh7 cells by acting as a ceRNA mechanism for the miR-1207-5p/TCF19 axis to activate the Wnt/ß-catenin signaling pathway. Conclusion: MIR194-2HG acts in an oncogenic role and activates the Wnt/ß-catenin signaling pathway via a miR-1207-5p/TCF19 axis-mediated mechanism, which provides a novel avenue for diagnostic or therapeutic interventions in liver cancer.

18.
Chin Med ; 15: 113, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33110441

RESUMO

Background: Yuzhi Zhixue Granule (YZG) is a traditional Chinese patent medicine for treating excessive menstrual flow caused by ovulatory dysfunctional uterine bleeding (ODUB) accompanied by heat syndrome. However, the underlying molecular mechanisms, potential targets, and active ingredients of this prescription are still unknown. Therefore, it is imperative to explore the molecular mechanism of YZG. Methods: The active compounds in YZG were screened by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The putative targets of YZG were collected via TCMSP and Search Tool for Interacting Chemicals (STITCH) databases. The Therapeutic Target Database (TTD) and Pharmacogenomics Knowledgebase (PharmGKB) databases were used to identify the therapeutic targets of ODUB. A protein-protein interaction (PPI) network containing both the putative targets of YZG and known therapeutic targets of ODUB was built. Furthermore, bioinformatics resources from the database for annotation, visualization and integrated discovery (DAVID) were utilized for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Finally, molecular docking was performed to verify the binding effect between the YZG screened compounds and potential therapeutic target molecules. Results: The study employed a network pharmacology method, mainly containing target prediction, network construction, functional enrichment analysis, and molecular docking to systematically research the mechanisms of YZG in treating ODUB. The putative targets of YZG that treat ODUB mainly involved PTGS1, PTGS2, ALOX5, CASP3, LTA4H, F7 and F10. The functional enrichment analysis suggested that the produced therapeutic effect of YZG against ODUB is mediated by synergistical regulation of several biological pathways, including apoptosis arachidonic acid (AA) metabolism, serotonergic synapse, complement and coagulation cascades and C-type lectin receptor signaling pathways. Molecular docking simulation revealed good binding affinity of the seven putative targets with the corresponding compounds. Conclusion: This novel and scientific network pharmacology-based study holistically elucidated the basic pharmacological effects and the underlying mechanisms of YZG in the treatment of ODUB.

19.
Sci Rep ; 10(1): 16933, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037257

RESUMO

The increased application of graphene oxide (GO), a new carbon-based engineered nanomaterial, has generated a potential toxicity in humans and the environment. Previous studies have identified some dysregulated microRNAs (miRNAs), such as up-regulated mir-235, in organisms exposed to GO. However, the detailed mechanisms of the dysregulation of miRNA underlying GO toxicity are still largely elusive. In this study, we employed Caenorhabditis elegans as an in vivo model to investigate the biological function and molecular basis of mir-235 in the regulation of GO toxicity. After low concentration GO exposure, mir-235 (n4504) mutant nematodes were sensitive to GO toxicity, implying that mir-235 mediates a protection mechanism against GO toxicity. Tissue-specific assays suggested that mir-235 expressed in intestine is required for suppressing the GO toxicity in C. elegans. daf-12, a gene encoding a member of the steroid hormone receptor superfamily, acts as a target gene of mir-235 in the nematode intestine in response to GO treatment, and RNAi knockdown of daf-12 suppressed the sensitivity of mir-235(n4503) to GO toxicity. Further genetic analysis showed that DAF-12 acted in the upstream of DAF-16 in insulin/IGF-1 signaling pathway and PMK-1 in p38 MAPK signaling pathway in parallel to regulate GO toxicity. Altogether, our results revealed that mir-235 may activate a protective mechanism against GO toxicity by suppressing the DAF-12-DAF-16 and DAF-12-PMK-1 signaling cascade in nematodes, which provides an important molecular basis for the in vivo toxicity of GO at the miRNA level.

20.
Sheng Li Xue Bao ; 72(5): 559-565, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33106826

RESUMO

The pre-Bötzinger complex (pre-BötC) residing in the ventrolateral medulla oblongata, is thought to be the kernel of respiratory rhythmogenesis. Episodic hypoxia exerts respiratory long-term facilitation, being recognized as electrophysiological characteristic of respiratory motor neuroplasticity. Our previous study demonstrated up-regulated expression of phospho-protein kinase C θ (P-PKCθ) in the pre-BötC of rats receiving chronic intermittent hypoxic (CIH) challenge. The present study was aimed to examine subcellular distribution of P-PKC substrates (P-PKCsub) and explore PKC down-stream targeting proteins in the pre-BötC in normoxic and CIH rats. Using neurokinin-1 receptor (NK1R) as a marker of the pre-BötC, P-PKCsub immunoreactivity was revealed by immunofluorescence and immuno-electron microscopic double-labeling in the pre-BötC. Western blot was applied to analyze P-PKCsub proteins in ventrolateral medulla, containing the pre-BötC. The results showed that NK1R immunoreactivity (NK1R-ir) was expressed mainly along plasma membranes of somata and processes, outlining pre-BötC neurons under the light microscope. P-PKCsub immunoreactive (P-PKCsub-ir) fluorophores in dot-like appearance appeared in somata and processes. Some were in close apposition to plasma membranes. A majority of P-PKCsub-ir neurons was found with NK1R-ir. CIH challenge up-regulated the expression of P-PKCsub proteins in the ventrolateral medulla. Under the electron microscope, NK1R-ir product was found to distribute along the inner membrane surfaces of somata and dendrites. P-PKCsub-ir gold particles were located in somata and dendrites, and some were distributed along the inner membrane surfaces, as well as in the endoplasmic reticulum and postsynaptic dense body. These results suggest that CIH challenge up-regulates the expression of P-PKCsub proteins, probably including some receptor proteins in the postsynaptic membrane, which may contribute to respiratory neuroplasticity via activation of PKCθ in the pre-BötC.


Assuntos
Bulbo , Receptores da Neurocinina-1 , Animais , Hipóxia , Bulbo/metabolismo , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores da Neurocinina-1/metabolismo
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