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1.
Front Immunol ; 10: 1881, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507583

RESUMO

Growing evidence suggests that obesity is associated with the susceptibility and disease severity of multiple sclerosis. The chronic inflammation induced by obesity is believed to contribute to this process. However, the immune mechanisms connecting obesity to the prevalence and pathogenesis of MS are poorly defined. In this study, we show that high fat diet (HFD)-induced obese mice developed an exacerbated EAE as indicated by higher clinical scores and more severe pathological changes in spinal cord than the control mice fed with normal diet (ND), following immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. The exacerbation of EAE in HFD mice was associated with enhanced microglial activation and increased expansion of Th1 and Th17 cells. The HFD mice also showed aggravated disease in an adoptive T cell transfer EAE model. Mechanistically, HFD augmented the expression level of IL-6 and CCL-2 both in serum and brain, and blockade of IL-6 and CCL-2 signal ameliorated EAE with reduced T cells infiltration in CNS. Taken together, our results suggest that obesity promotes CNS inflammation in EAE through IL-6 and CCL-2 mediated the inflammatory cells infiltration.

2.
Nat Commun ; 10(1): 4067, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492885

RESUMO

ARID1A inactivation causes mitotic defects. Paradoxically, cancers with high ARID1A mutation rates typically lack copy number alterations (CNAs). Here, we show that ARID1A inactivation causes defects in telomere cohesion, which selectively eliminates gross chromosome aberrations during mitosis. ARID1A promotes the expression of cohesin subunit STAG1 that is specifically required for telomere cohesion. ARID1A inactivation causes telomere damage that can be rescued by STAG1 expression. Colony formation capability of single cells in G2/M, but not G1 phase, is significantly reduced by ARID1A inactivation. This correlates with an increase in apoptosis and a reduction in tumor growth. Compared with ARID1A wild-type tumors, ARID1A-mutated tumors display significantly less CNAs across multiple cancer types. Together, these results show that ARID1A inactivation is selective against gross chromosome aberrations through causing defects in telomere cohesion, which reconciles the long-standing paradox between the role of ARID1A in maintaining mitotic integrity and the lack of genomic instability in ARID1A-mutated cancers.

3.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502565

RESUMO

Bone marrow mesenchymal stem cells (BMSCs) play an important role in the process of bone repair. The present study investigated the effect of 5-azacytidine (AZA) and trichostatin A (TSA) on BMSC behaviors in vitro. The role of WNT family member 5A (WNT5A)/WNT family member 5A (WNT7A)/beta-catenin signaling was also investigated. BMSCs were isolated from a steroid-induced avascular necrosis of the femoral head (SANFH) rabbit model. The third-generation of BMSCs was used after identification. The results revealed obvious degeneration and necrosis in the SANFH rabbit model. AZA, TSA and TSA + AZA increased BMSC proliferation in a time-dependent fashion. AZA, TSA and TSA + AZA induced the cell cycle release from the G0/G1 phase and inhibited apoptosis in BMSCs. AZA, TSA and TSA + AZA treatment significantly decreased caspase-3 and caspase-9 activities. The treatment obviously increased the activity and relative mRNA expression of alkaline phosphatase. The treatment also significantly up-regulated the proteins associated with osteogenic differentiation, including osteocalcin and runt-related transcription factor 2 (RUNX2), and Wnt/beta-catenin signal transduction pathway-related proteins beta-catenin, WNT5A and WNT7A. The relative levels of Dickkopf-related protein 1 (an inhibitor of the canonical Wnt pathway) decreased remarkably. Notably, TSA + AZA treatment exhibited a stronger adjustment ability than either single treatment. Collectively, the present studies suggest that AZA, TSA and TSA + AZA promote cell proliferation and osteogenic differentiation in BMSCs, and these effects are potentially achieved via upregulation of WNT5A/WNT7A/b-catenin signaling.

4.
Dig Dis Sci ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31367877

RESUMO

BACKGROUND AND AIMS: Crohn's disease (CD) is a chronic inflammatory bowel disorder associated with intestinal dysbiosis. This study aimed to determine the efficacy and safety of different methods of fecal microbiota transplantation (FMT), a potential therapy for CD. METHODS: Patients with CD were randomized to receive FMT by gastroscopy or colonoscopy; a second transplantation was performed 1 week later. Patients were assessed by clinical evaluation and serum testing (at weeks 1, 2, 4, 6, and 8) and endoscopy (8 weeks after transplantation). Fecal DNA was extracted and analyzed using the Illuminal sequencing platform. RESULTS: Of the 27 patients included in the study, clinical remission was achieved in 18 (66.7%); no significant difference was seen between the two methods. 76.9% of gastroscopy group patients and 64.3% of colonoscopy group patients experienced mild adverse events during or shortly after treatment. Microbiota diversity analyses showed that, in comparison with the donors, patients had lower operational taxonomic units (OTU; 117 vs. 258, p < 0.05) and Shannon diversity index (2.05 vs. 3.46, p < 0.05). The CD patients showed a significant increase in OTU and Shannon diversity index 2 weeks after FMT. In comparison with the donors, CD patients had lower levels of Bacteroides, Eubacterium, faecalibacterium, and Roseburia, and higher levels of Clostridium, Cronobacter, Fusobacterium, and Streptococcus. CONCLUSIONS: FMT was seen to be safe and effective in this cohort of patients with CD. No significant differences in clinical remission rate and adverse events were seen between the gastroscopy and colonoscopy groups. FMT was seen to increase the species richness in CD patients.

5.
Soft Matter ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469148

RESUMO

Needle-induced cavitation (NIC) locally probes the elastic and fracture properties of soft materials, such as gels and biological tissues. Current NIC protocols tend to overestimate properties when compared to traditional techniques. New NIC methods are needed in order to address this issue. NIC measurements consist of two distinct processes, namely (1) the needle insertion process and (2) the cavitation process. The cavitation process is hypothesized to be highly dependent on the initial needle insertion process due to the influence of residual strain below the needle. Retracting the needle before pressurization to a state in which a cylindrical, tube-like fracture is left below the needle tip is experimentally demonstrated to reduce the impact of residual strain on NIC. Verification of the critical cavitation pressure equation in this new geometry is necessary before implementing this retraction NIC protocol. Complementary modeling shows that the change in initial geometry has little effect on the critical cavitation pressure. Together, these measurements demonstrate that needle retraction is a viable experimental protocol for reducing the influence of residual strain, thus enabling the confident measurement of local elastic and fracture properties in soft gels and tissues.

6.
J Agric Food Chem ; 67(36): 10222-10234, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31385700

RESUMO

The emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) critically requires alternative therapeutic options. New antibacterial drugs and strategies are urgently needed to combat MRSA-associated infections. Here, we investigated the antibacterial activity of flavones from Morus alba and the potential mode of action against MRSA. Kuwanon G, kuwanon H, mulberrin, and morusin displayed high efficiency in killing diverse MRSA isolates. On the basis of structure-activity analysis, the cyclohexene-phenyl ketones and isopentenyl groups were critical to increase the membrane permeability and to dissipate the proton motive force. Meanwhile, mechanistic studies further showed that kuwanon G displayed rapid bactericidal activity in vitrowith difficulty in developing drug resistance. Kuwanon G targeted phosphatidylglycerol and cardiolipin in the cytoplasmic membrane through the formation of hydrogen bonds and electrostatic interactions. Additionally, kuwanon G promoted wound healing in a mouse model of MRSA skin infection. In summary, these results indicate that flavones are promising lead compounds to treat MRSA-associated infections through disrupting the proton motive force and membrane permeability.

7.
Biomater Sci ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31380882

RESUMO

The homeostasis process in the gut tissue of humans relies on intestinal bacteria. However, the intestine is a complex structural tissue with a huge superficial area, and thus the effective application of probiotics in the treatment of Crohn's disease (CD) is still challenging. Herein, we show the feasibility of probiotic target delivery and retention using magnetic iron oxide nanoparticle-internalized Roseburia intestinalis, which can be easily directed by a magnetic field in vitro and in vivo. Subsequently, the increased colonization of this core profitable flora not only resulted in a better therapy effect than traditional intragastric administration but also altered the bacterial composition, leading to a higher diversity in microbial taxa in rats with colitis. Our findings illustrate the exciting opportunities that nanotechnology offers for alternative strategies to modulate biological systems remotely and precisely, which represent a step towards the wireless magnetic manipulation of living biological entities in microbiology.

8.
Autophagy ; : 1-15, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362587

RESUMO

Macroautophagy (autophagy) is a key catabolic pathway for the maintenance of proteostasis through constant digestion of selective cargoes. The selectivity of autophagy is mediated by autophagy receptors that recognize and recruit cargoes to autophagosomes. SQSTM1/p62 is a prototype autophagy receptor, which is commonly found in protein aggregates associated with major neurodegenerative diseases. While accumulation of SQSTM1 implicates a disturbance of selective autophagy pathway, the pathogenic mechanism that contributes to impaired autophagy degradation remains poorly characterized. Herein we show that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)-linked mutations of TBK1 and SQSTM1 disrupt selective autophagy and cause neurotoxicity. Our data demonstrates that proteotoxic stress activates serine/threonine kinase TBK1, which coordinates with autophagy kinase ULK1 to promote concerted phosphorylation of autophagy receptor SQSTM1 at the UBA domain and activation of selective autophagy. In contrast, ALS-FTLD-linked mutations of TBK1 or SQSTM1 reduce SQSTM1 phosphorylation and compromise ubiquitinated cargo binding and clearance. Moreover, disease mutation SQSTM1G427R abolishes phosphorylation of Ser351 and impairs KEAP1-SQSTM1 interaction, thus diminishing NFE2L2/Nrf2-targeted gene expression and increasing TARDBP/TDP-43 associated stress granule formation under oxidative stress. Furthermore, expression of SQSTM1G427R in neurons impairs dendrite morphology and KEAP1-NFE2L2 signaling. Therefore, our results reveal a mechanism whereby pathogenic SQSTM1 mutants inhibit selective autophagy and disrupt NFE2L2 anti-oxidative stress response underlying the neurotoxicity in ALS-FTLD. Abbreviations: ALS: amyotrophic lateral sclerosis; FTLD: frontotemporal lobar degeneration; G3BP1: GTPase-activating protein (SH3 domain) binding protein 1; GSTM1: glutathione S-transferase, mu 1; HMOX/HO-1: Heme oxygenase 1; IP: immunoprecipitation; KEAP1: kelch-like ECH associated protein 1; KI: kinase inactive; KIR: KEAP1 interaction region; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MBP: maltose binding protein; NBR1: NBR1, autophagy cargo receptor; NFE2L2/Nrf2: nuclear factor, erythroid derived 2, like 2; NQO1: NAD(P)H quinone dehydrogenase 1; SQSTM1/p62: sequestosome 1; SOD1: superoxide dismutase 1, soluble; S.S.: serum starvation; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK binding kinase 1; UBA: ubiquitin association; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.

9.
Chin Med J (Engl) ; 132(14): 1666-1672, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31268911

RESUMO

BACKGROUND: The detection of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome at early stage is challenging for neurologists. Since polyneuropathy could be the first manifestation, it could be misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). The present study aimed to determine the clinical and electrophysiological features of POEMS syndrome to distinguish from CIDP. METHODS: The data of a group of patients with POEMS (n = 17) and patients with CIDP (n = 17) in Zhongshan Hospital Fudan University from January 2015 to September 2017 were analyzed in this retrospective study. The clinical features, neurological symptoms, and electrophysiological findings were compared between the two groups. RESULTS: Clinically, patients with POEMS demonstrated significantly more neuropathic pain in the lower extremities than patients with CIDP (58.8% vs. 11.8%, P = 0.01). Multisystem features like edema, skin change, organomegaly, and thrombocytosis were also pointed towards the diagnosis of POEMS syndrome. Electrophysiologically, terminal latency index (TLI) was significantly higher in patients with POEMS than that in patients with CIDP (median nerve: 0.39 [0.17-0.52] vs. 0.30 (0.07-0.69), Z = -2.413, P = 0.016; ulnar nerve: 0.55 [0.23-0.78] vs. 0.42 [0.12-0.70], Z = -2.034, P = 0.042). Patients with POEMS demonstrated a higher frequency of absent compound muscle action potential of the tibial nerve (52.9% vs. 17.6%, P = 0.031), less conduction block (ulnar nerve: 0 vs. 35.3%, P = 0.018), and less temporal dispersion (median nerve: 17.6% vs. 58.8%, P = 0.032) than CIDP group. The combination of positive serum monoclonal protein and high TLI (if either one or both were present) discriminated POEMS from CIDP with a sensitivity of 94.1% and 47.1% and specificity of 76.5% and 100.0%, respectively. CONCLUSIONS: POEMS syndrome could be distinguished from CIDP through typical clinical and electrophysiological characteristics in practice. The combination of serum monoclonal protein and high TLI might raise the sensitivity of detecting POEMS syndrome.

10.
Org Biomol Chem ; 17(32): 7468-7473, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31361284

RESUMO

An unprecedented arylselenylation of aryl halides with trifluoromethyl aryl selenonium ylides in the presence of copper is described. The reaction proceeded at 100-140 °C under ligand- and additive-free conditions for 3-20 h to form a variety of unsymmetrical diaryl selenides in good to high yields. Arylselenylation is easy to operate, has good functional group tolerance, and demonstrates the different reaction profiles of trifluoromethyl aryl selenonium ylides from the homologous trifluoromethyl aryl sulfonium ylides.

11.
Anal Chem ; 91(16): 10772-10778, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31331164

RESUMO

There is still no good method for the diagnosis of colon cancer, so in this work we have presented a nanoscale metal-organic framework (NMOF)-based sensor array to effectively identify normal and pathological tissues. Moreover, this method can enable a rapid and accurate histopathological examination of colon cancer with simple and easy operation. The method is designed by making use of the different interactions between the overall intracellular proteome signatures of colonic tissues and three structurally stable NMOFs featuring characteristic surface chemistry. We have demonstrated that this sensor array can exhibit excellent performance to detect unknown specimens from low-dose tissue samples with clinically relevant specificity and accuracy. Collectively, the versatile detector array based on NMOFs offers a highly discerning and adaptive alternative for identifying colon cancer tissues, which exhibits wide-ranging prospects in medical diagnosis.

12.
Cancer Res ; 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311810

RESUMO

ARID1A, encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in over 50% of ovarian clear cell carcinoma (OCCC), a disease that currently has no effective therapy. Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of ARID1A-mutated tumors and modulates the tumor immune microenvironment. Here we show that inhibition of HDAC6 synergizes with anti-PD-L1 immune-checkpoint blockade in ARID1A-inactivated ovarian cancer. ARID1A directly repressed transcription of CD274, the gene encoding PD-L1. Reduced tumor burden and improved survival was observed in ARID1Aflox/flox/PIK3CAH1047R OCCC mouse treated with the HDAC6 inhibitor ACY1215 and anti-PD-L1 immune-checkpoint blockade as a result of activation and increased presence of interferon-gamma positive CD8 T cells. We confirmed that the combined treatment limited tumor progression in a cytotoxic T-cell-dependent manner as depletion of CD8+ T cells abrogated these antitumor effects. Together, these findings indicate that combined HDAC6 inhibition and immune-checkpoint blockade represents a potential treatment strategy for ARID1A-mutated cancers.

13.
Mol Med Rep ; 20(2): 1007-1016, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173202

RESUMO

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), has a complex etiology that may be associated with dysbiosis of the microbiota. Previously, our study revealed significant loss of Roseburia intestinalis from the gut of untreated patients with CD, and that R. intestinalis exerted anti­inflammatory functions in TNBS­induced colitis; however, the function of R. intestinalis supernatant is unknown. Therefore, LPS­induced macrophages, including RAW264.7 macrophages and bone marrow­derived macrophages were treated with R. intestinalis supernatant. The results indicated that R. intestinalis supernatant suppressed expression of interleukin (IL)­6 and signal transducer and activator of transcription 3 (STAT3) by macrophages. Additionally, these findings were further verified in vivo in DSS­ and TNBS­induced mouse models of colitis. It was observed that R. intestinalis supernatant ameliorated IBD colitis by reducing the number of inflammatory macrophages and Th17 cells in the colon, and by downregulating the expression of IL­6 and STAT3. Finally, the non­protein components of R. intestinalis supernatant were examined using gas chromatography­mass spectrometry analysis and identified the presence of short­chain fatty acids. In conclusion, the results of the present study indicated that R. intestinalis supernatant may regulate immune responses and ameliorate colitis.

14.
Neurologist ; 24(4): 111-114, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31246719

RESUMO

PURPOSE: To assess the impact of observer's experience on reliability of etiological classification systems in patients with ischemic stroke. PATIENTS AND METHODS: We retrospectively reviewed medical records of 80 patients with ischemic stroke in hospitals from August 2016 to March 2017 consecutively. Patients were classified by 4 observers with different clinical experiences and backgrounds (A, B, C, and D) according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST), Stop Stroke Study TOAST (SSS-TOAST), and ASCOD (A-atherosclerosis, S-small vessel disease, C-cardiac pathology, O-other cause, and D-dissection). The intraobserver reliability was assessed based on the initial and a second delayed assessment after 3 months, and the interobserver reliability of different pairs (A-B and C-D) and overall (A, B, C, and D) were compared based on the initial classification. RESULTS: The reliability values of the 3 classification systems were improved with observer's experience increasing, particularly in the TOAST system, in which the intraobserver reliability values of observers A, B, C, and D were 0.62, 0.73, 0.80, and 0.88, respectively, and slight differences were observed between the SSS-TOAST and ASCOD systems. The A-B pair had lower interobserver reliability value than the C-D pair, particularly in TOAST system with reliability values of 0.36 and 0.74, respectively, and a slight variation of interobserver reliability values were noted in the SSS-TOAST and ASCOD system. CONCLUSIONS: Observer's experience may affect the reliability of etiological classification systems in patients with ischemic stroke.

15.
Sci Adv ; 5(5): eaaw5294, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31131328

RESUMO

ARID1A, a subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex, localizes to both promoters and enhancers to influence transcription. However, the role of ARID1A in higher-order spatial chromosome partitioning and genome organization is unknown. Here, we show that ARID1A spatially partitions interphase chromosomes and regulates higher-order genome organization. The SWI/SNF complex interacts with condensin II, and they display significant colocalizations at enhancers. ARID1A knockout drives the redistribution of condensin II preferentially at enhancers, which positively correlates with changes in transcription. ARID1A and condensin II contribute to transcriptionally inactive B-compartment formation, while ARID1A weakens the border strength of topologically associated domains. Condensin II redistribution induced by ARID1A knockout positively correlates with chromosome sizes, which negatively correlates with interchromosomal interactions. ARID1A loss increases the trans interactions of small chromosomes, which was validated by three-dimensional interphase chromosome painting. These results demonstrate that ARID1A is important for large-scale genome folding and spatially partitions interphase chromosomes.

16.
Cancer Res ; 79(11): 2812-2820, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30967398

RESUMO

Despite the high initial response rates to PARP inhibitors (PARPi) in BRCA-mutated epithelial ovarian cancers (EOC), PARPi resistance remains a major challenge. Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of mRNA, yet the role of m6A modification in PARPi resistance has not previously been explored. Here, we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/ß-catenin pathway in BRCA-mutated EOC cells. Global m6A profile revealed a significant increase in m6A modification in FZD10 mRNA, which correlated with increased FZD10 mRNA stability and an upregulation of the Wnt/ß-catenin pathway. Depletion of FZD10 or inhibition of the Wnt/ß-catenin sensitizes resistant cells to PARPi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 was sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity, which correlated with an increase in homologous recombination activity. Moreover, combined inhibition of PARP and Wnt/ß-catenin showed synergistic suppression of PARPi-resistant cells in vitro and in vivo in a xenograft EOC mouse model. Overall, our results show that m6A contributes to PARPi resistance in BRCA-deficient EOC cells by upregulating the Wnt/ß-catenin pathway via stabilization of FZD10. They also suggest that inhibition of the Wnt/ß-catenin pathway represents a potential strategy to overcome PARPi resistance. SIGNIFICANCE: These findings elucidate a novel regulatory mechanism of PARPi resistance in EOC by showing that m6A modification of FZD10 mRNA contributes to PARPi resistance in BRCA-deficient EOC cells via upregulation of Wnt/ß-catenin pathway.

17.
J Cell Physiol ; 234(10): 19059-19072, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30993715

RESUMO

Retinoblastoma (RB) represents an aggressive malignancy in the eye during the period of infancy and childhood. We delineated the ability of microRNA-186 (miR-186) to influence viability, invasion, migration, angiogenesis, and apoptosis of RB via the Hedgehog signaling pathway by targeting AAA domain-containing protein 2 (ATAD2). The microarray-based analysis was adopted to identify differentially expressed genes (DEGs) related to RB. Subsequently, RB cells were treated with miR-186 mimic, miR-186 inhibitor, or si-ATAD2. The expression of miR-186, ATAD2, Hedgehog signaling pathway-related genes were evaluated, and the target relationship between miR-186 and ATAD2 was verified. Finally, cell proliferation, invasion, migration, apoptosis, and angiogenesis were assessed. ATAD2 was identified as a DEG and modulated by miR-186. Moreover, we revealed that ATAD2 was highly expressed, whereas miR-186 was lowly expressed, and the Hedgehog signaling pathway was activated in RB. Then, ATAD2 as a putative target of miR-186 was validated using a luciferase assay. miR-186 mimic or siRNA-ATAD2 in RB cells reduced cell viability, invasion, and migration coordinating with elevated apoptosis via impairing the Hedgehog signaling pathway, where repressed angiogenesis was observed. Overexpression of miR-186 attenuates RB via the inactivation of the Hedgehog signaling pathway by downregulating ATAD2.

18.
J Cell Biochem ; 120(8): 13792-13801, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31017714

RESUMO

Choroidal neovascularization (CNV), a characteristic of age-related macular degeneration, is an underlying cause of severe vision loss among elderly patients. Fibroblast growth factor (FGF) is suggested to exert an important role in the pathogenesis of CNV. However, the molecular mechanisms governing this event are not fully elucidated. Herein, we identified the potential role of FGF7 in CNV. To examine the roles of FGF7 in the progression of CNV, rat CNV models were established and treated with small interfering RNA (siRNA) against FGF7 or FGF7 overexpression, followed by identification of expression of FGF7 in the CNV modeled rats. Next, proliferation and migration, and in vitro tube formation of human umbilical vein endothelial cells, as well as expression of vascular endothelial growth factor (VEGF) and transforming growth factor-beta 2 (TGF-ß2) were evaluated. CNV led to upregulated FGF7 expression. Cells in the presence of FGF7 siRNA showed suppressed proliferation, migration, and tube formation, along with downregulated VEGF and TGF-ß2 expression. Taken together, functional suppression of FGF7 inhibited the onset of CNV, ultimately highlighting a novel therapeutic target for suppressing CNV progression.

19.
Nanotechnology ; 30(35): 354001, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31035266

RESUMO

Pyrolysis, which involves thermal decomposition of materials at elevated temperatures, has been commonly applied in the chemical industry. Here we explored the pyrolysis process for 3D nanofabrication. By strain engineering of nanomembranes on a thermal responsive polymer as the sacrificial layer, we demonstrated that diverse 3D rolled-up microstructures with different functions could be achieved without any additional solution and drying process. We carefully studied the effect of molecular weight of the polymer in the pyrolysis process and identified that the rapid breakdown of molecular backbone to a monomer is the key for nanomembrane releasing and rolling. Preferential rolling direction and corresponding dynamics were studied by analyzing the real-time video of the rolling process. We further demonstrated the versatile functions of the fabricated 3D structures as catalytic microengines and optical resonators. The simple fabrication methodology developed here may have great potential in producing functional 3D tubular micro-/nanostructures.

20.
Scand J Gastroenterol ; 54(4): 432-440, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946611

RESUMO

Objective: Levels of oncostatin M (OSM) and the composition of gut microbiota predict responses to anti-TNF agents used for IBD therapy. Here, the aim was to investigate the effects of Roseburia intestinalis, a gut microbiota, on OSM and on intestinal barrier in colitis. Methods: In the murine model of 3% dextran sulfate sodium (DSS)-induced colitis, we tested disease activity index (DAI), colon length, histological score and expression of tight junction (TJ) proteins (ZO-1, occludin and claudin-1), OSM, TNF-α and TLR5. In addition, a cellular model was used to examine the role of R. intestinalis during secretion of OSM by lipopolysaccharide (LPS)-induced bone marrow-derived macrophages (BMDMs) isolated from wild-type (WT) and TLR5 knockout (TLR5 KO) mice. Furthermore, we evaluated the impact of OSM on expressions of TJ proteins by Caco-2 cells. Results: R. intestinalis in DSS-induced colitis decreased DAI score (p < .001), colon length shortening (6.46 ± 0.36 cm vs 5.65 ± 0.47 cm, p = .022), histological score (2.667 ± 1.15 vs 5.33 ± 1.14, p = .018) and increased expression of TJ proteins (p < .05). In addition, R. intestinalis reduced expression of OSM (p < .05) and TNF-α (p < .05), while increasing expression of TLR5 (p < .05). Furthermore, R. intestinalis reduced secretion of OSM (p < .05) by LPS-induced BMDMs isolated from WT and TLR5 KO mice. Moreover, OSM downregulated expression of TJ proteins (p < .05) by Caco-2 cells in a concentration-dependent manner. Conclusions: These results indicate that R. intestinalis attenuates inflammation in IBD by decreasing secretion of OSM and by promoting intestinal barrier function. Taken together, the data provide insight into the role of the gut microbiota in patients with IBD who are resistant to anti-TNF therapy.

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