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1.
Asian J Pharm Sci ; 15(5): 646-660, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33193866

RESUMO

Multiple drug resistance (MDR) is a tough problem in developing hepatocellular carcinoma (HCC) therapy. Here, we developed TPGS-coated cationic liposomes with Bcl-2 siRNA corona to load doxorubicin (Dox) i.e., Bcl-2 siRNA/Dox-TPGS-LPs, to enhance anticancer effect of Dox in HCC-MDR. TPGS i.e., d-α-tocopheryl polyethylene glycol 1000 succinate, inhibited P-glycoprotein (P-gp) efflux pump and Bcl-2 siRNA suppressed anti-apoptotic Bcl-2 protein. The Bcl-2 siRNA loaded in the liposomal corona was observed under transmission electron microscopy. The stability and hemolysis evaluation demonstrated Bcl-2 siRNA/Dox-TPGS-LPs had good biocompatibility and siRNA-corona could protect the liposomal core to avoid the attachment of fetal bovine serum. In drug-resistant cells, TPGS effectively prolonged intracellular Dox retention time and siRNA-corona did improve the internalization of Dox from liposomes. In vitro and in vivo anticancer effect of this dual-functional nanostructure was examined in HCC-MDR Bel7402/5-FU tumor model. MTT assay confirmed the IC50 value of Dox was 20-50 fold higher in Bel7402/5-FU MDR cells than that in sensitive Bel7402 cells. Bcl-2 siRNA corona successfully entered the cytosol of Bel7402/5-FU MDR cells to downregulate Bcl-2 protein levels in vitro and in vivo. Bcl-2 siRNA/Dox-TPGS-LPs showed superior to TPGS- (or siRNA-) linked Dox liposomes in cell apoptosis and cytotoxicity assay in Bel7402/5-FU MDR cells, and 7-fold greater effect than free Dox in tumor growth inhibition of Bel7402/5-FU xenograft nude mice. In conclusion, TPGS-coated cationic liposomes with Bcl-2 siRNA corona had the capacity to inhibit MDR dual-pathways and subsequently improved the anti-tumor activity of the chemotherapeutic agent co-delivered to a level that cannot be achieved by inhibiting a MDR single way.

2.
Int J Mol Med ; 46(6): 2235-2250, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33125123

RESUMO

The roles of the Hippo­Yes­associated protein (YAP) pathway in lung injury and repair remain elusive. The present study examined the effects of systemic inhibition or stimulation of YAP activity on lung injury, repair and inflammation in a mouse model of lipopolysaccharide (LPS)­induced lung injury. Mice were treated with or without YAP inhibitor, verteporfin, or with or without YAP stimulator, XMU­MP­1, and intraperitoneally injected with LPS (7.5 mg/kg). Lung injury and repair were evaluated by histological analysis and by testing for markers of lung injury. Lung inflammation was assessed by measuring tissue levels of inflammatory mediators. Lung injury was associated with a decreased, whereas lung repair was associated with an increased YAP activity evidenced by nuclear translocation. Lung injury was associated with a high level of lung inflammation and epithelial adherens junction disassembly, but not with cell proliferation or epithelial cell regeneration. The injury phase was defined as 0­48 h post­LPS injection, and the 48­168 h time period was considered the repair phase. Inhibition of YAP activity at the injury phase, using verteporfin, exacerbated, whereas its stimulation, using XMU­MP­1, alleviated lung injury, lung inflammation and epithelial adherens junction disassembly. Inhibition or stimulation of YAP activity at the injury phase had no effects on cell proliferation or epithelial regeneration. By contrast, lung repair was associated with inflammation resolution, increased cell proliferation, epithelial regeneration and reassembly of epithelial adherens junctions. Inhibition of YAP activity at the repair phase delayed inflammation resolution, impeded lung recovery, inhibited cell proliferation and epithelial regeneration, and inhibited epithelial adherens junction reassembly. Stimulation of YAP activity at the repair phase reversed all these processes. The results of the current study demonstrated that the Hippo­YAP activity serves a protective role against endotoxemic lung injury. The Hippo­YAP activity alleviated lung inflammation and injury at the injury phase and promoted inflammation resolution and lung repair at the repair phase.

3.
Front Genet ; 11: 809, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849809

RESUMO

High-altitude acclimatization is a representative example of vertebrates' acclimatization to harsh and extreme environments. Previous studies reported sufficient evidence for a molecular genetic basis of high-altitude acclimatization, and genomic patterns of genetic variation among populations and species have been widely elucidated in recent years. However, understanding of the miRNA role in high-altitude acclimatization have lagged behind, especially in non-model species. To investigate miRNA expression alterations of goats that were induced by high-altitude stress, we performed comparative miRNA transcriptome analysis on six hypoxia-sensitive tissues (heart, kidney, liver, lung, skeletal muscle, and spleen) in two goat populations from distinct altitudes (600 and 3000 m). We obtained the expression value of 1391 mature miRNAs and identified 138 differentially expressed (DE) miRNAs between high and low altitudes. Combined with tissue specificity analysis, we illustrated alterations of expression levels among altitudes and tissues, and found that there were coexisting tissue-specific and -conserved mechanisms for hypoxia acclimatization. Notably, the interplay between DE miRNA and DE target genes strongly indicated post-transcriptional regulation in the hypoxia inducible factor 1, insulin, and p53 signaling pathways, which might play significant roles in high-altitude acclimatization in domestic goats. It's also worth noting that we experimentally confirmed miR-106a-5p to have a negative regulation effect on angiogenesis by directly targeting FLT-1. These results provide insight into the complicated miRNA expression patterns and regulatory mechanisms of high-altitude acclimatization in domestic goats.

4.
Front Genet ; 11: 845, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849828

RESUMO

Local hypoxia has recently been reported to occur in the white adipose tissue (WAT) microenvironment during obesity. Adipocytes have a unique life cycle that reflects the different stages of adipogenesis in the WAT niche. Long non-coding RNAs (lncRNAs) play an important role in the cellular response to hypoxia. However, the differentially hypoxic responses of preadipocytes during adipogenesis and the potential role of lncRNAs in this process remain to be elucidated. Here, we evaluated the differentially hypoxic responses of primary hamster preadipocytes during adipogenesis and analyzed mRNA and lncRNA expression in same Ribo-Zero RNA-seq libraries. Hypoxia induced HIF-1α protein during adipogenesis and caused divergent changes of cell phenotypes. A total of 10,318 mRNAs were identified to be expressed in twenty libraries (five timepoints), and 3,198 differentially expressed mRNAs (DE mRNAs) were detected at five timepoints (hypoxia vs. normoxia). Functional enrichment analysis revealed the shared and specific hypoxia response pathways in the different stages of adipogenesis. Hypoxia differentially modulated the expression profile of adipose-associated genes, including adipokines, lipogenesis, lipolysis, hyperplasia, hypertrophy, inflammatory, and extracellular matrix. We also identified 4,296 lncRNAs that were expressed substantially and detected 1,431 DE lncRNAs at five timepoints. Two, 3, 5, 13, and 50 DE mRNAs at D0, D1, D3, D7, and D11, respectively, were highly correlated and locus-nearby DE lncRNAs and mainly involved in the cell cycle, vesicle-mediated transport, and mitochondrion organization. We identified 28 one-to-one lncRNA-mRNA pairs that might be closely related to adipocyte functions, such as ENSCGRT00015041780-Hilpda, TU2105-Cdsn, and TU17588-Ltbp3. These lncRNAs may represent the crucial regulation axis in the cellular response to hypoxia during adipogenesis. This study dissected the effects of hypoxia in the cell during adipogenesis, uncovered novel regulators potentially associated with WAT function, and may provide a new viewpoint for interpretation and treatment of obesity.

5.
ACS Appl Mater Interfaces ; 12(35): 38906-38917, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32805820

RESUMO

Manganese dioxide (MnO2) nanostructures have aroused great interest among analytical and biological medicine researchers as a unique type of tumor microenvironment (TME)-responsive nanomaterial. However, reliable approaches for synthesizing yolk-shell nanostructures (YSNs) with mesoporous MnO2 shell still remain exciting challenges. Herein, a YSN (size, ∼75 nm) containing a mesoporous MnO2 shell and Er3+-doped upconversion/downconversion nanoparticle (UCNP) core with a large cavity is demonstrated for the first time. This nanostructure not only integrates diverse functional components including MnO2, UCNPs, and YSNs into one system but also endows a size-controllable hollow cavity and thickness-tunable MnO2 layers, which can load various guest molecules like photosensitizers, methylene blue (MB), and the anticancer drugs doxorubicin (DOX). NIR-II fluorescence and photoacoustic (PA) imaging from UCNP and MB, respectively, can monitor the enrichment of the nanomaterials in the tumors for guiding chemo-photodynamic therapy (PDT) in vivo. In the TME, degradation of the mMnO2 shell by H2O2 and GSH not only generates Mn2+ for tumor-specific T1-MR imaging but also releases O2 and drugs for tumor-specific treatment. The result confirmed that imaging-guided enhanced chemo-PDT combination therapy that benefited from the unique structural features of YSNs could substantially improve the therapeutic effectiveness toward malignant tumors compared to monotherapy.

6.
Neurosci Bull ; 36(9): 1023-1034, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32812127

RESUMO

Joubert syndrome is characterized by unique malformation of the cerebellar vermis. More than thirty Joubert syndrome genes have been identified, including ARL13B. However, its role in cerebellar development remains unexplored. We found that knockdown or knockout of arl13b impaired balance and locomotion in zebrafish larvae. Granule cells were selectively reduced in the corpus cerebelli, a structure homologous to the mammalian vermis. Purkinje cell progenitors were also selectively disturbed dorsomedially. The expression of atoh1 and ptf1, proneural genes of granule and Purkinje cells, respectively, were selectively down-regulated along the dorsal midline of the cerebellum. Moreover, wnt1, which is transiently expressed early in cerebellar development, was selectively reduced. Intriguingly, activating Wnt signaling partially rescued the granule cell defects in arl13b mutants. These findings suggested that Arl13b is necessary for the early development of cerebellar granule and Purkinje cells. The arl13b-deficient zebrafish can serve as a model organism for studying Joubert syndrome.

7.
Acta Biomater ; 115: 358-370, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32798720

RESUMO

Heat-treated cancer cells have thermo-resistance due to the up-regulated levels of heat shock proteins (HSP) resulting in low therapeutic efficiency and ineffective ablation of tumors. In this work, we report pH-responsive Ag2S nanodots (Ag2S NDs) loaded with HSP70 inhibitor (QE-PEG-Ag2S) for enhanced photothermal cancer therapy. QE-PEG-Ag2S was easily prepared via self-assembly of hydrophobic Ag2S NDs, amphiphilic pH-responsive PEG5k-PAE10k polymer, and an HSP70 inhibitor quercetin (QE). QE-PEG-Ag2S has ideal water-solubility and biocompatibility, can rapidly enter cells, and preferentially accumulate in cell lysosomes. The slightly acidic environment of tumor cells and the acidity of lysosomes as well as the high temperature generated by photothermal therapy under irradiation of NIR light (808 nm) promote the release of the inhibitor molecules to reduce the heat resistance of cancer cells and improve the in vivo photothermal therapy efficiency. Moreover, QE-PEG-Ag2S has good photoacoustic imaging (PAI) ability; this QE-PEG-Ag2S concentration dependent signal can precisely follow the accumulation of the nanomaterials in tumors and dictate the correct time for light therapy. As a result, QE-PEG-Ag2S achieved complete tumor ablation effect with no recurrence when only irradiated with NIR light for 10 min. This approach offers a new approach for the theranostic applications of Ag2S NDs. STATEMENT OF SIGNIFICANCE: In this work, pH-responsive Ag2S nanodots loaded with the heat shock protein inhibitor for enhanced photothermal cancer therapy have been simply prepared via self-assembly process. This nanoagent possesses ideal water-solubility and biocompatibility, can rapidly enter cells, and preferentially accumulate in cell lysosomes. The acidic environment of tumor cells and the acidity of lysosomes, as well as the high temperature generated by photothermal therapy under irradiation of NIR light promote the release of the inhibitor molecules from the nanoagent to improve the in vivo photothermal therapy efficiency. Moreover, the photoacoustic imaging (PAI) of the nanoagent can precisely follow the accumulation of the nanomaterials in tumors and dictate the light therapy time to guarantee the complete tumor ablation effect with no recurrence.

8.
Nanoscale ; 12(31): 16451-16461, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32790812

RESUMO

Multidrug resistance (MDR) remains a huge obstacle during cancer treatment. One of the most studied MDR mechanisms is P-glycoprotein (P-gp) mediated drug efflux. Based on the three-dimensional structural characteristics of P-gp, gold nanoparticles (AuNPs) with average sizes of 4.1 nm and 5.4 nm were designed for the construction of nanodrug delivery systems (NanoDDSs), with the anticancer molecules 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) and 6-mercaptopurine (6-MP) modified on the AuNP surfaces through the thiol group. In vitro cytotoxicity results suggested that the larger sized AuNPs can effectively decrease the drug resistance index of MCF-7/ADR cells to ∼2. Verapamil and P-gp antibody competitive experiments, combined with the cellular uptake of AuNPs, indicated that larger NanoDDSs were more conducive to intracellular drug accumulation and thus had improved anticancer activities, due to a size mismatch between the nanoparticles and the active site of P-gp, and, therefore, reduced drug efflux was seen. Measurements of ATPase activity and intracellular ATP levels indicated that the larger nanoparticles do not bind well to P-gp, thus avoiding effective recognition by P-gp. This was further evidenced by the observation that 4.1 nm and 5.4 nm NanoDDS-treated MCF-7/ADR cells showed remarkable differences in energy-related metabolic pathways. Therefore, the critical size of AuNPs for overcoming MDR was identified to be between 4.1 nm and 5.4 nm. This provides a more accurate description of the composite dimension requirements for NanoDDSs that are designed to overcome MDR.

9.
ACS Sens ; 5(8): 2457-2466, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32702967

RESUMO

Early detection of drug-induced acute kidney injury (AKI) is crucial for effective treatment and prevention of further injury. It remains challenging, however, because of the lack of activatable indicators with multimodality imaging capability that could increase the accuracy of diagnosis by mutual verification. Herein, we report an activatable probe, FDOCl-22, that enabled dual-modality detection of the early-stage drug-induced AKI. FDOCl-22 was completely soluble in water and highly sensitive to hypochlorous acid (HOCl). Dramatic increases of both near-infrared (NIR) emission and absorption were observed after reaction with HOCl. A correlation between HOCl concentration and drug-induced AKI was established using FDOCl-22 as a tool. As a consequence, the HOCl-activated probe was able to detect the early-stage drug-induced AKI by dual-modality imaging, irrespective of the drug stimulation time or dosage, by combining NIR fluorescence and photoacoustic imaging.

10.
Anal Chem ; 92(16): 10971-10978, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32674562

RESUMO

Detecting myeloperoxidase (MPO) activity in living organisms is important because MPO contributes to the pathogenesis of many diseases such as rheumatoid arthritis and other inflammatory diseases, artherosclerosis, neurodegenerative disease, and some cancers. However, rapid and effective methods for the detection of basal MPO activity in living systems have not yet been reported. Herein, we report a near-infrared (NIR) emissive "turn-on" probe FD-301 that can specifically bind to MPO and accurately measure MPO activity in living cells and in vivo via a rapid response to initial hypochlorous acid (HOCl), produced by MPO. Notably, FD-301 could detect the basal level of MPO activity in human promyelocytic leukemia cells (HL-60) and could discriminate between MPO high-expression and low-expression cells. Furthermore, FD-301 was successfully applied to in vivo imaging of MPO in MPO-dependent diseases, such as arthritis and inflammatory bowel disease.

11.
J Cell Mol Med ; 24(17): 9658-9666, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32667746

RESUMO

Endometriosis is a common, chronic gynaecologic disease affecting up to 10% of women in their reproductive age and leading to pain and infertility. Oestrogen (E2 )-induced epithelial-mesenchymal transition (EMT) process has been considered as a key factor of endometriosis development. Recently, the dysregulated circular RNAs (circRNAs) have been discovered in endometriosis tissues. However, the molecular mechanism of circRNAs on the E2 -induced EMT process in endometriosis is still unknown. Here, we demonstrated that circ_0004712 up-regulated by E2 treatment in endometrial epithelial cells. Knock-down the expression of circ_0004712 significantly suppressed E2 -induced cell migration activity. Meanwhile, we identified miR-148a-3p as a potential target miRNA of circ_0004712. Inhibited the expression of miR-148a-3p could recovered the effect of circ_0004712 knock-down in E2 -treated endometrial epithelial. Furthermore, Western blot assay showed that E2 treatment could increase the expression and activity of ß-catenin, snail and N-cadherin and reduce the expression of E-cadherin. The expression and activity of ß-catenin pathway were recovered by circ_0004712 knock-down or miR-148a-3p overexpression. Altogether, the results demonstrate that circ_0004712/miR-148a-3p plays an important role in E2 -induced EMT process in the development of endometriosis, and the molecular mechanism may be associated with the ß-catenin pathway. This work highlighted the importance of circRNAs in the development of endometriosis and provide a new biomarker for diagnosis and therapies.

12.
Analyst ; 145(12): 4196-4203, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32501463

RESUMO

Hydrogen peroxide (H2O2), one of the reactive oxygen species (ROS), plays vital roles in diverse physiological processes. Thus, herein, to improve the signal-to-noise ratio, a new near-infrared region (NIR) fluorophore (PCN) based on reduced phenazine was developed. PCN was further designed as a "turn on" fluorescent probe (PCN-BP) for the detection of H2O2 by introducing p-boratebenzyl. After H2O2 was added, the p-boratebenzyl group in PCN-BP was oxidized to p-hydroxy benzyl; it then self-departed, forming PCN, which displayed 24-fold NIR emission at 680 nm with a large Stokes shift (more than 200 nm). This probe presented an excellent linear relation with the concentration of H2O2 and good selectivity to various ions, ROS and biothiols; thus, it can be utilized as a colorimetric and fluorescence turn-on probe. More importantly, the probe was also employed for the exogenous and endogenous imaging of H2O2 in RAW 264.7 cells.

13.
J Org Chem ; 85(11): 7045-7059, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32393036

RESUMO

We reported a novel two-step stereoselective synthesis of functionalized pyrrolidines from homopropargylic sulfonamides and nucleophiles via an isolable N,O-acetal intermediates. This reaction features mild conditions and good scope of substrates. In addition, the use of hexafluoroisopropanol, acting as a solvent, an additive, a weak nucleophile, and a good leaving group, is pivotal to the success of the method. Moreover, reactions of chiral homopropargylic sulfonamides afford only 2,5-cis-disubstituted pyrrolidines with high diastereoselectivity (up to >99:1 dr) and enantioselectivity (up to >99% ee). The overall reaction constitutes a formal 1,1-bifunctionalization of terminal alkynes, which has hitherto been reported only rarely. Additionally, this method provides efficient access to pharmaceutical intermediate and to carry out postmodification of natural products.

14.
Front Microbiol ; 11: 555, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32318039

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) is recognized as one of the serious pathogen that causes acquired infections worldwide. Its emerging need to discover novel, safe and potent anti-MRSA drugs. In this study, primary screening by anti-MRSA activity assay found one strain WA5-2-37 isolated from the intestinal tract of Periplaneta americana, exhibited great activity against MRSA ATCC 43300. The strain WA5-2-37 produced actinomycin X2 and collismycin A which showed strong inhibition of MRSA with minimum inhibitory concentration (MIC) values of 0.25 and 8 µg/mL. The structures of the pure compounds were elucidated by analysis of mass spectrometry (MS), 1H and 13C nuclear magnetic resonance (NMR). The strain WA5-2-37 was considered as Streptomyces globisporus on the basis of morphological characteristics, genotypic data, and phylogenetic analysis. This is the first reported naturally occurring strain of S. globisporus isolated from the intestinal tract of P. americana, whereas it has almost been found from plants, marine, and soil previously. Moreover, S. globisporus has not been reported to produce any anti-MRSA substances previously, such as actinomycin X2 and collismycin A. In conclusion, the insect-derived strain of S. globisporus WA5-2-37 was considered of great potential as a new strain of producing actinomycin X2, collismycin A or other anti-MRSA compounds.

15.
Gene ; 744: 144591, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32220601

RESUMO

Polycystic ovary syndrome (PCOS) is a kind of endocrine disease among women across the global. Recently, many researches have reported circular RNAs can act as significant molecular biomarkers for diseases, especially in tumors. Several Circular RNAs are reported to be aberrantly expressed in PCOS patients. Here, we investigated the biological effects of hsa_circ_0118530 on human granulosa cells, KGN. We observed that hsa_circ_0118530 was greatly elevated in PCOS patients and granulosa cells (including KGN and COV434 cells) compared to normal IOSE80 cells. hsa_circ_0118530 siRNA was transfected into KGN cells. We found that KGN cell viability was repressed, cell apoptosis was induced while cell migration was greatly inhibited. TGF-ß1 was utilized to induce EMT process. As shown, loss of hsa_circ_0118530 significantly enhanced E-cadherin mRNA and protein levels while depressed N-cadherin expression. Furthermore, we indicated that decrease of hsa_circ_0118530 was able to inhibit ROS accumulation, MDA levels while induced SOD activity. Next, it was demonstrated that releases of inflammatory cytokine were suppressed by hsa_circ_0118530 down-regulation. Additionally, miR-136 was predicted and confirmed as the target of hsa_circ_0118530. For another, the functions of hsa_circ_0118530 on KGN cell progression, oxidative stress and inflammation releases were obviously reversed by miR-136 suppression. In conclusion, knockdown of hsa_circ_0118530 repressed PCOS progression via sponging miR-136.


Assuntos
Células da Granulosa/metabolismo , MicroRNAs/metabolismo , Síndrome do Ovário Policístico/genética , RNA Circular/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Células da Granulosa/citologia , Humanos , Mediadores da Inflamação/metabolismo , Estresse Oxidativo/genética , Síndrome do Ovário Policístico/metabolismo , RNA Circular/biossíntese
16.
Sci Data ; 6(1): 192, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586122

RESUMO

Animals that lived at high altitudes have evolved distinctive physiological traits that allow them to tolerate extreme high-altitude environment, including higher hemoglobin concentration, increased oxygen saturation of blood and a high energy metabolism. Although previous investigations performed plenty of comparison between high- and low-altitude mammals at the level of morphology, physiology and genomics, mechanism underlying high-altitude adaptation remains largely unknown. Few studies provided comparative analyses in high-altitude adaptation, such as parallel analysis in multiple species. In this study, we generated high-quality small RNA sequencing data for six tissues (heart, liver, spleen, lung, kidney and muscle) from low- and high-altitude populations of four typical livestock animals, and identified comparable numbers of miRNAs in each species. This dataset will provide valuable information for understanding the molecular mechanism of high-altitude adaptation in vertebrates.


Assuntos
Adaptação Fisiológica/genética , Gado/genética , MicroRNAs/genética , Transcriptoma , Altitude , Animais , Bovinos , Galinhas , Carneiro Doméstico , Suínos
17.
Chem Commun (Camb) ; 55(79): 11872-11875, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31528875

RESUMO

We have developed a new cell-penetrating peptide (CPP) using a repeated protease (furin) substrate. This CPP can not only deliver cargo into cells but can also be cleaved by furin in cells and release the cargo. Cell-impermeable antitumor pro-apoptotic peptide KLAKLAKKLAKLAK (KLA) and chemotherapy drug chlorambucil were chosen to be delivered by the CPP into live cancer cells and their cytotoxicity was greatly enhanced for in vivo cancer treatment.

18.
Front Genet ; 10: 505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191617

RESUMO

Mammalian mitochondrial biogenesis is a complex process involving mitochondrial proliferation and differentiation. Mitochondrial DNA transcription factor A (TFAM), which encodes a major component of a protein-mitochondrial DNA (mtDNA) complex, is regulated by peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Testosterone is the primary male sex hormone and plays an increasingly important role in mammalian development through its interaction with androgen receptor (AR). However, the function of AR in mitochondrial biogenesis induced by testosterone deficiency has not been investigated. Here, we explored the molecular mechanism underlying the effect of testosterone deficiency on mitochondrial biogenesis using a Yorkshire boar model. Testosterone deficiency caused by castration induced changes in mtDNA copy numbers in various tissues, and AR showed the opposite tendency to that of mtDNA copy number, particularly in adipose tissues and muscle tissues. In addition, castration weakened the correlation of PGC1α and mtDNA copy number, while AR and TFAM showed a relatively high correlation in both control and castrated pigs. Furthermore, luciferase assays revealed that AR binds to potential AR elements in the TFAM promoter to promote TFAM expression. Taken together, testosterone may be involved in the pathway linking PGC1α to mitochondrial biogenesis through the interaction between AR and TFAM.

19.
Funct Integr Genomics ; 19(5): 827-838, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31111266

RESUMO

Botia superciliaris, an endemic cobitid fish in China, is widely accepted by Chinese consumers because its edibility. Recently, the black and yellow stripes of B. superciliaris skin have made this species increasingly popular as a novel ornamental fish. However, the genetic basis of the stripe patterns in B. superciliaris skin has not been extensively studied. In this study, Illumina sequencing was employed to identify the mRNAs and miRNAs involved in stripe pattern formation in B. superciliaris skin. A total of 147.25 and 155.15 million (M) high-quality transcriptome reads were generated from three black and yellow skin libraries respectively, which resulted in 159,327 unigenes that were used as reference sequences. A total of 3169 genes exhibited significantly differential expression patterns (fold-change ≥ 2 or ≤ 0.5 and q ≤ 0.05), including 1891 upregulated genes (59.67%) and 1278 downregulated genes (40.33%) in black vs yellow skin. These genes were enriched in 50 GO terms and 10 KEGG pathways (q ≤ 0.05), including melanogenesis, with 21 upregulated genes and 5 downregulated genes in black vs yellow skin. Based on the zebrafish genome, miRNA-seq identified a total of 355 miRNAs, which included 38 novel miRNAs. Furthermore, 87 differentially expressed miRNAs including 50 upregulated and 37 downregulated miRNAs were identified in different color skin (fold-change ≥ 2 or ≤ 0.5 and q ≤ 0.05). Then, target prediction revealed a variety of putative target genes; differentially expressed mRNAs and miRNAs patterns of high-throughput sequencing were validated in 5 mRNAs and miR-217-5p by qRT-PCR. In vivo tests and dual-luciferase reporter assay revealed that overexpression of miR-217-5p can inhibit pheomelanin formation by targeting Zgc. In this study, a comparative analysis was conducted to profile the transcriptome of black and yellow skin for B. superciliaris, and we detected key genes and important miRNAs involved in the B. superciliaris skin pigmentation process. These results will enhance understanding of molecular mechanisms underlying skin pigmentation and facilitate molecular-assisted selection of highly valued skin colors.


Assuntos
Padronização Corporal/genética , Proteínas de Peixes/genética , Peixes/genética , Redes Reguladoras de Genes , MicroRNAs/genética , RNA Mensageiro/genética , Pele/química , Animais , Peixes/fisiologia , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de RNA , Pele/metabolismo , Transcriptoma
20.
J Clin Lab Anal ; 33(7): e22922, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31115929

RESUMO

BACKGROUND: Liver biopsy is the criterion standard for diagnosing liver fibrosis, but it is not widely used to monitor liver fibrosis because of the invasiveness, risk of complications, and sample errors. Therefore, it is necessary to involve other techniques to monitor liver fibrosis or cirrhosis during clinical practice. The objective was to explore noninvasive indicators to predict advanced liver fibrosis in autoimmune hepatitis (AIH) patients. METHODS: A total of 45 AIH patients and 47 healthy controls were recruited to this retrospective study. Complete blood count and liver function tests were performed for all subjects. AIH patients were divided into "no/minimal fibrosis" group and "advanced fibrosis" group based on liver biopsy. RESULTS: AIH patients demonstrated significantly higher monocytes, MCV, RDW-CV, RDW-SD, NLR, RDW-CV/PLT, RDW-SD/PLT, TBIL, DBIL, GLB, ALT, AST, GGT, ALP, and GPR and lower WBC, neutrophils, lymphocytes, RBC, HGB, HCT, LMR, TP, ALB, and AAR compared with healthy controls. Patients with advanced fibrosis showed remarkably higher RDW-CV, RDW-SD, RDW-CV/PLT, RDW-SD/PLT, AAR, and FIB-4 and lower RBC, PLT, PCT, and ALB compared with the no/minimal fibrosis group. Logistic regression analysis showed that RDW-SD/PLT was an independent risk factor for advanced fibrosis with an OR (95% CI) of 2.647 (1.383-5.170). Receiver operating characteristic (ROC) analysis revealed that RDW-SD, RDW-CV/PLT, RDW-SD/PLT, FIB-4, and AAR had an area under the ROC curve (AUC) above 0.700 and RDW-SD/PLT had the largest AUC of 0.785 with a cutoff value of 0.239. CONCLUSION: RDW-SD, RDW-CV/PLT, RDW-SD/PLT, FIB-4, and AAR were excellent noninvasive biomarkers and RDW-SD/PLT was an independent risk factor for predicting advanced fibrosis in AIH patients.


Assuntos
Hepatite Autoimune/complicações , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Estudos de Casos e Controles , Feminino , Hepatite Autoimune/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Curva ROC , Fatores de Risco
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