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1.
Theranostics ; 10(2): 829-840, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903153

RESUMO

Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed. Methods: A tissue microarray was performed to assess ASS1 expression in surgical specimens of pancreatic ductal adenocarcinoma (PDAC) and its correlation with disease prognosis. An RNA-Seq analysis examined the role of ASS1 in regulating the global gene transcriptome. A high throughput screen of FDA-approved oncology drugs identified synthetic lethality between histone deacetylase (HDAC) inhibitors and Arg deprivation in PDAC cells with low ASS1 expression. We examined HDAC inhibitor panobinostat (PAN) and Arg deprivation in a panel of human PDAC cell lines, in ASS1-high and -knockdown/knockout isogenic models, in both anchorage-dependent and -independent cultures, and in multicellular complex cultures that model the PDAC tumor microenvironment. We examined the effects of combined Arg deprivation and PAN on DNA damage and the protein levels of key DNA repair enzymes. We also evaluated the efficacy of PAN and ADI-PEG20 (an Arg-degrading agent currently in Phase 2 clinical trials) in xenograft models with ASS1-low and -high PDAC tumors. Results: Low ASS1 protein level is a negative prognostic indicator in PDAC. Arg deprivation in ASS1-deficient PDAC cells upregulated asparagine synthetase (ASNS) which redirected aspartate (Asp) from being used for de novo nucleotide biosynthesis, thus causing nucleotide insufficiency and impairing cell cycle S-phase progression. Comprehensively validated, HDAC inhibitors and Arg deprivation showed synthetic lethality in ASS1-low PDAC cells. Mechanistically, combined Arg deprivation and HDAC inhibition triggered degradation of a key DNA repair enzyme C-terminal-binding protein interacting protein (CtIP), resulting in DNA damage and apoptosis. In addition, S-phase-retained ASS1-low PDAC cells (due to Arg deprivation) were also sensitized to DNA damage, thus yielding effective cell death. Compared to single agents, the combination of PAN and ADI-PEG20 showed better efficacy in suppressing ASS1-low PDAC tumor growth in mouse xenograft models. Conclusion: The combination of PAN and ADI-PEG20 is a rational translational therapeutic strategy for treating ASS1-low PDAC tumors through synergistic induction of DNA damage.

2.
Diabetes ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915155

RESUMO

Diabetic retinopathy is the most common microvascular complication of diabetes, characterized by the formation of fibrovascular membranes that consist of a variety of cells including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular (HRECs) high glucose induced expression of p110δ, which was also expressed in ECs of fibrovascular membranes from diabetic patients. This catalytic subunit of a receptor regulated PI3K isoform δ is known to be highly-enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110δ inactivation was found to attenuate pathological retinal angiogenesis. p110δ inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110δ constitutes a previously-unappreciated therapeutic opportunity for diabetic retinopathy.

3.
Vet Res ; 50(1): 106, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31806006

RESUMO

The binding and activation of host plasminogen (PLG) by worm surface enolases has been verified to participate in parasite invasion, but the role of this processes during Trichinella spiralis infection has not been clarified. Therefore, the expression and immunolocalization of a T. spiralis enolase (TsENO) and its binding activity with PLG were evaluated in this study. Based on the three-dimensional (3D) molecular model of TsENO, the protein interaction between TsENO and human PLG was analysed by the ZDOCK server. The interacting residues were identified after analysis of the protein-protein interface by bioinformatics techniques. The key interacting residues were confirmed by a series of experiments. The qPCR analysis results demonstrated that Ts-eno was transcribed throughout the whole life cycle of T. spiralis. The immunofluorescence assay (IFA) results confirmed that TsENO was distributed on the T. spiralis surface. The binding assays showed that recombinant TsENO (rTsENO) and native TsENO were able to bind PLG. Four lysine residues (90, 289, 291 and 300) of TsENO were considered to be active residues for PLG interaction. The quadruple mutant (Lys90Ala + Lys289Ala + Lys291Ala + Lys300Ala) TsENO, in which the key lysine residues were substituted with alanine (Ala) residues, exhibited a reduction in PLG binding of nearly 50% (45.37%). These results revealed that TsENO has strong binding activity with human PLG. The four lysine residues (90, 289, 291 and 300) of TsENO play an important role in PLG binding and could accelerate PLG activation and invasion of the host's intestinal wall by T. spiralis.

4.
Neuropsychiatr Dis Treat ; 15: 3351-3357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819460

RESUMO

Introduction: The study was designed to explore the possible adverse effects of prenatal polycyclic aromatic hydrocarbons (PAHs) on the neurodevelopment of the infants at the age of 12 months in a birth cohort in Qingdao of China. Benzo[a]pyrene (BaP)-DNA adduct level in umbilical cord blood was measured by enzyme immunoassay. Methods: Child neurodevelopment was assessed at both 6 months and 12 months of age using the Gesell Development Inventory (GDI). Results: This study results reveal that multivariate linear analysis, cord BaP-DNA adduct level was inversely associated with developmental quotient score in the adaptive domain [ß = -0.08; 95% CI: (-0.16, -0.003); p = 0.04], gross motor domain [ß = -0.10; 95% CI: (-0.20, -0.01); p = 0.02], fine motor domain [ß = -0.15; 95% CI: (-0.25, -0.05); p = 0.01], language domain [ß = -0.12; 95% CI: (-0.21, -0.03); p = 0.02], and personal-social domain [ß = -0.13; 95% CI: (-0.22, -0.04); p<0.01]. Further, multivariate logistic regression analysis showed increased cord BaP-DNA adduct levels associated with increased odds of delayed in language domain. Conclusion: In conclusion, the study suggested that prenatal PAH exposure monitored by umbilical cord blood BaP-DNA adducts may adversely affect the neurodevelopment of the infants at 12 months of age.

5.
Parasit Vectors ; 12(1): 581, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829230

RESUMO

BACKGROUND: Trichinella spiralis is a major zoonotic tissue-dwelling nematode, which is a public health concern and a serious hazard to animal food safety. It is necessary to exploit an anti-Trichinella vaccine to interrupt the transmission of Trichinella infection among animals and from animals to humans. The purpose of the present study was to characterize the novel T. spiralis cathepsin B (TsCB) and to evaluate the immune protection elicited by immunization with recombinant TsCB (rTsCB). METHODS: The complete cDNA sequences of the TsCB gene were cloned, expressed and purified. The antigenicity of rTsCB was investigated by western blot analysis and ELISA. Transcription and expression of TsCB at various T. spiralis life-cycle stages were analyzed by RT-PCR and indirect immunofluorescent assay (IIFA). The mice were subcutaneously immunized with rTsCB, and serum level of TsCB-specific IgG (IgG1 and IgG2a) and IgE antibodies were assayed by ELISA. Immune protection elicited by vaccination with rTsCB was investigated. RESULTS: The TsCB was transcribed and expressed in four T. spiralis life-cycle stages (adult worm, AW; newborn larvae, NBL; muscle larvae, ML; and intestinal infective L1 larvae), it was primarily located in the cuticle and stichosome of the parasitic nematode. Vaccination of mice with rTsCB produced a prominent antibody response (high level of specific IgG and IgE) and immune protection, as demonstrated by a 52.81% AW burden reduction of intestines at six days post-infection (dpi) and a 50.90% ML burden reduction of muscles at 35 dpi after oral larva challenge. The TsCB-specific antibody response elicited by immunization with rTsCB also impeded intestinal worm growth and decreased the female fecundity. CONCLUSIONS: TsCB might be considered as a novel potential molecular target to develop vaccines against T. spiralis infection.

6.
Exp Eye Res ; 190: 107884, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31786159

RESUMO

Proliferative vitreoretinopathy (PVR) is a blinding fibrotic eye disease that develops in 8-10% of patients who undergo primary retinal detachment-reparative surgery and in 40-60% of patients with open-globe injury. At present, there is no pharmacological treatment for this devastating disease. Vitreal growth factors activate their respective receptors of cells in the vitreous, trigger their downstream signaling transduction (e.g. phosphoinositide 3 kinases (PI3Ks)/Akt), and drive cellular responses intrinsic to the pathogenesis of PVR. PI3Ks play a central role in experimental PVR. However, which isoform(s) are involved in PVR pathogenesis remain unknown. Herein, we show that p110δ, a catalytic subunit of receptor-regulated PI3K isoform δ, is highly expressed in epiretinal membranes from patients with PVR, and that idelalisib, a specific inhibitor of PI3Kδ, effectively inhibits vitreous-induced Akt activation, proliferation, migration and contraction of retinal pigment epithelial cells derived from an epiretinal membrane of a PVR patient. Small molecules of kinase inhibitors have shown great promise as a class of therapeutics for a variety of human diseases. The data herein suggest that idelalisib is a promising PVR prophylactic.

7.
JAMA Ophthalmol ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31876943

RESUMO

Importance: Patients with the EPAS1 gain-of-function mutation syndrome (or Pacak-Zhuang syndrome) present with multiple paragangliomas or pheochromocytomas, duodenal somatostatinoma, polycythemia, headaches, and sometimes diminished visual acuity at an early age. The characteristic phenotype and known genetic cause of the syndrome provide an opportunity to study the role of hypoxia-inducible factor 2α (HIF-2α) in oxygen sensing, development in regions of physiologic hypoxia, and other pathological processes. Objectives: To describe the ocular lesions in EPAS1 gain-of-function mutation syndrome and to establish whether early-onset diminished visual acuity is developmental or associated with long-term physiologic sequelae of the syndrome. Design, Setting, and Participants: This clinical case series with a transgenic murine model study was conducted from July 2013 to June 2019. Participants were 3 patients referred by their primary care physicians to the National Institutes of Health for evaluation of recurrent and metastatic paragangliomas or pheochromocytomas accompanied by polycythemia. The syndrome and somatic mosaicism in patients were confirmed by the identification of gain-of-function mutations in the EPAS1 gene in resected tumors and other tissues. Main Outcomes and Measures: Ocular findings in patients with EPAS1 gain-of-function mutation syndrome. Results: A total of 3 patients (mean [SD] age, 29 [6.2] years) with confirmed ocular abnormalities were included in the study. Increased contrast accumulation at the posterior aspect of the globe was seen bilaterally on magnetic resonance imaging scans in all patients. Ophthalmoscopy images demonstrated fibrosis overlying the optic disc, tortuous and dilated retinal vessels, and retinal pigment epithelium changes. Optic disc edema and retinal exudates were also seen. Fluorescein angiography images showed leakage of dye from postcapillary venules surrounding the optic disc and highlighted aberrant retinal vascular patterns. Enhanced-depth imaging optical coherence tomography images showed substantial thickening of the choroid and dilation of choroidal vessels. The ocular features of the syndrome were confirmed with a transgenic model of mice with gain-of-function Epas1A529V mutation. Conclusions and Relevance: In this case series, HIF-2α and hypoxia signaling was found to have a role in vessel development within the choroid and retina, indicating that the marked permanent choroidal thickening and tortuous and dilated veins seen in the choroid and retina in patients with EPAS1 gain-of-function mutation syndrome were suggestive of the persistence of venous elements within the developing mesenchyme. These findings may explain other eye and vascular abnormalities whose pathogenesis remains unclear.

8.
Zhongguo Gu Shang ; 32(12): 1156-1159, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31870078

RESUMO

OBJECTIVE: To investigate the long-term effect of posterior lumbar pedicle screw fixation combined with isthmus bone grafting and fusion in young patients with spondylolysis. METHODS: A retrospective study was carried out, consisting of 16 young patients with lumbar spondylolysis without spondylolisthesis treated by lumbar posterior pedicle screw fixation combined with isthmic bone grafting fusion from January 2006 to July 2014. There were 11 males and 5 females, aged from 18 to 21 years old, with an average age of 19.3 years old, and the course of disease ranged from 12 to 26 months, with an average of 22 months. All the patients suffered from lumbar pain and difficulty in getting out of bed. Preoperative CT confirmed 12 cases of L5 isthmus fissure and 4 cases of L4 isthmus fissure. Bone graft fusion was confirmed and internal fixation was removed after operation. Lumbar spondylolysis was evaluated by lumbago visual analogue scoring method at preoperative and postoperative time points. Lumbar isthmic fusion was evaluated by lumbar CT, and degeneration of fixed and adjacent segments of lumbar intervertebral disc was evaluated by lumbar MRI. RESULTS: Of the 16 patients, 13 patients (26 sides) were followed up, with a mean duration of 96 months. The operation time ranged from 80 to 105 minutes, with an average of 95 minutes. The intraoperative bleeding volume ranged from 150 to 300 ml, with an average of 225 ml. All the patients were successfully operated without any complications related to the operation. VAS scores at each time point after operation were improved compared with those before operation(P<0.01). Postoperative CT scans of lumbar spine showed osseous fusion at 6 to 14 months, with an average of 12 months. There were no changes of adjacent segment degeneration, fixed segment disc degeneration and protrusion on lumbar spine MRI, and no symptomatic recurrence or recurrent spondylolysis in the long term. CONCLUSIONS: The posterior lumbar pedicle screw fixation combined with isthmic bone grafting and fusion is safe and effective in the treatment of young spondylolysis. The fusion rate is high and the interference of normal physiological range is reduced. The long-term effect is satisfactory.


Assuntos
Parafusos Pediculares , Fusão Vertebral , Espondilólise , Adolescente , Transplante Ósseo , Feminino , Humanos , Vértebras Lombares , Masculino , Estudos Retrospectivos , Espondilólise/cirurgia , Resultado do Tratamento , Adulto Jovem
9.
Zhen Ci Yan Jiu ; 44(12): 926-31, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31867915

RESUMO

OBJECTIVE: To collect literatures on the application of neural tracing technique in experimental acupuncture research, and summarize its application status in acupoints, meridians and Zang-fu organs. METHODS: We collected papers published from databases of CNKI (1979-2017), Wan-Fang (1990-2017), VIP (1989-2017) and PubMed(1997-2017)by using keywords of "neural tracing technique" "neuroanatomic tracing" "neural tracers" and "acupuncture" "electroacupuncture" "auricular acupuncture" "eye acupuncture" "meridians" "acupuncture points" "acupoint injection", and made a summary about the current state of application of neural tracing technique in the fields of acupoint, meridian and Zang-fu organs (viscera). RESULTS: A total of 94 articles were collected, the most commonly used neural tracers were horseradish peroxidase and cholera toxin subunit B. The experimental animals used were rat, rabbit, cat, monkey, etc., and injection site was acupoint. After the injection of neural tracers, the survival time of animals was range from 1 day to 12 weeks, and the labelled tissues included neurons and nerve fibers of the sensory, motor, and autonomic systems. The outcomes of neural labeling mainly revealed the segmental pattern, neuroanatomical connection (neural pathways/circuits) and chemical features (shown by immunohistochemical staining) of neurons and nerve fibers innervating both the acupoints and visceral organs, suggesting their involvement in the effect of acupuncture and moxibustion treatment. CONCLUSION: This application of neural tracing technology help us understand the under-lying mechanisms of acupuncture and moxibustion interventions from different perspectives of neural pathways/circuits and related chemical properties, which also lays a greater role for this technology in future experimental acupuncture research.


Assuntos
Terapia por Acupuntura , Meridianos , Animais , Humanos
10.
Res Vet Sci ; 128: 1-8, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31706217

RESUMO

The aim of this work was to identify the molecular characteristics of a chymotrypsin-like enzyme from Trichinella spiralis (Tschy) and its facilitation of larval penetration into enteral epithelial cells (EECs). The complete Tschy cDNA sequence was cloned and expressed in Escherichia coli BL21. RT-PCR, IIFA and western blotting showed that Tschy was expressed at the T. spiralis muscle larvae (ML), intestinal infective L1 larvae (IL1), adult worms (AW) and embryo stages and was primarily located in the stichosome of this parasite. The results of ELISA, IIFA and Far-western assays showed that there was a specific binding between rTschy and EECs, and the binding was dependent on the dose of both rTschy and EEC proteins. Confocal microscopy demonstrated that the binding was located in the EEC cytoplasm. rTschy facilitated T. spiralis larval penetration of EECs, and anti-rTschy antibodies impeded the larval intrusion of EECs. These results demonstrate that Tschy facilitated the larval intrusion of the host's enteral epithelium and could be a candidate molecular target for vaccine against the enteral invasive phase of T. spiralis.

11.
Cell Oncol (Dordr) ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31713003

RESUMO

PURPOSE: Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance. METHODS: GEM-sensitive BxPC-3-derived BxS and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived BxR cells (BxR-CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in BxS and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo. RESULTS: BxR-CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEM-induced apoptosis, and promoted tube formation and cell migration in BxS and PANC-1 cells. Elevated miR-210 expression levels were detected in BxR-CSCs and BxR-CSC-derived exosomes compared to those in BxS-CSCs and BxS-CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in BxS and PANC-1 cells cultured with BxR-CSC-derived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in BxS cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by BxR-CSC-derived exosomes. CONCLUSIONS: Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.

12.
Magn Reson Med ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31691367

RESUMO

PURPOSE: Chemical exchange saturation transfer (CEST) signals at 3 ppm acquired with high irradiation powers, termed GluCEST, have been suggested as an indicator of glutamate in neural systems. However, amines in proteins may also contribute to the GluCEST signal, but they have been ignored in previous studies. This study aims to investigate the molecular origins and specificity of GluCEST signal in rat brain. METHODS: Dialysis was used to selectively remove small molecules, such as glutamate and other metabolites, from tissue homogenates prepared from rat brain. This approach allowed the specific influence of proteins on GluCEST to be measured. Clean CEST effects were also quantified by a 2-step analysis, which first used a fitting approach to quantify the asymmetric magnetization transfer effect and an inverse subtraction to remove it, and then combined an apparent exchange-dependent relaxation method with asymmetric analysis to remove the direct water saturation and T1 weighting. RESULTS: The removal of glutamate and other small metabolites by dialysis decreases the GluCEST signal by approximately 24%, indicating that a major contributor to GluCEST in the brain is amines in proteins under our experimental conditions. CONCLUSION: Data from in vivo GluCEST measurements should be interpreted with caution, especially in disorders in which changes in the content or conformation of proteins are expected.

13.
Arthritis Res Ther ; 21(1): 246, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753003

RESUMO

BACKGROUND: Anti-citrullinated protein antibodies (ACPA) are central to rheumatoid arthritis (RA) pathogenesis and may develop at inflamed mucosa. We investigated whether asthma, a disease of airway mucosal inflammation, was associated with elevated ACPA before RA diagnosis. METHODS: We performed a nested case-control study among women in two prospective cohorts, the Nurses' Health Study (NHS; 1976-2014) and NHSII (1989-2015). Blood was obtained on a subset (NHS: 1989-1990; NHSII: 1996-1999). Cases met 1987 ACR or 2010 ACR/EULAR RA criteria by medical record review and were classified as seropositive (ACPA+ or rheumatoid factor positivity) or seronegative by clinical laboratory testing at diagnosis. We identified RA cases with blood drawn before the date of RA diagnosis (index date), matching each to three controls by age, cohort, year, time from blood draw to index date, and menopause. Pre-RA ACPA elevation for cases was defined as >99th percentile of the control distribution on a research assay composed of autoantibodies targeting citrullinated protein epitopes or positivity on the second-generation commercial assay for cyclic citrullinated peptide. Asthma status and covariates were obtained through biennial questionnaires before blood draw. Conditional logistic regression estimated ORs and 95%CIs for RA by pre-RA ACPA and clinical serostatus, adjusted for matching factors, smoking pack-years, passive smoking, and body mass index (BMI). RESULTS: We identified 284 incident RA cases and 849 matched controls; mean age at the index date was 61.2 years (SD 10.1). Blood was drawn 9.7 years (mean; SD 5.8) before the index date. We identified 96 (33.8%) RA cases with elevated pre-RA ACPA. At blood draw, 17.7% of pre-RA ACPA+ cases and 6.3% of matched controls (p = 0.0008) reported clinician-diagnosed asthma. After adjusting for matching factors, smoking pack-years, passive smoking, and BMI, asthma was significantly associated with pre-RA ACPA+ RA (OR 3.57, 95%CI 1.58,8.04). Asthma was not associated with overall RA (OR 1.45, 95%CI 0.91,2.31), but was significantly associated with seropositive RA (OR 1.79, 95%CI 1.01,3.18). CONCLUSIONS: Asthma was strongly associated with ACPA elevation in blood drawn prior to RA diagnosis, independent of smoking. Chronic mucosal airway inflammation may contribute to ACPA development and RA pathogenesis.

14.
Front Genet ; 10: 1093, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737057

RESUMO

In China, the nematode Trichinella spiralis is the main aetiological agent of human trichinellosis. We performed multi-locus microsatellite typing of T. spiralis isolates to improve the current knowledge of the evolution and population diversity. First, seven polymorphic microsatellite loci were used to infer the genetic diversity of T. spiralis collected in 10 endemic regions. Then, a Bayesian model-based STRUCTURE analysis, a clustering based on the neighbor-joining method, and a principal coordinate analysis (PCA) were performed to identify the genetic structure. Finally, the phylogenetic position of Chinese isolates was explored based on six mitochondrial and nuclear genetic markers (cox1, cytb, 5S ISR, ESV, ITS1, and 18S rDNA) using the maximum likelihood and Bayesian methods. In addition, the divergence time was estimated with multiple genes using an uncorrelated log-normal relaxed molecular-clock model. A total of 16 alleles were detected in 2,310 individuals (1,650 muscle larvae and 660 adult worms) using seven loci. The STRUCTURE analysis indicated that the T. spiralis isolates could be organized and derived from the admixture of two ancestral clusters, which was also substantiated through the clustering analysis based on the allelic data. PCA separated most samples from Tiandong, Guangxi (GX-td), and Linzhi, Tibet (Tibet-lz), from the remaining isolates. However, both maximum likelihood and Bayesian inference supported the close relationship between Xiangfan, Hubei (HB-xf), and GX-td. The molecular dating analysis suggested that the Chinese isolates started to diverge during the Late Pleistocene (0.69 Mya). Generally, T. spiralis was observed to harbor low genetic variation, and further investigation with deeper sampling is needed to elucidate the population structure.

15.
J Am Chem Soc ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31743020

RESUMO

We report a new class of porous liquids (PLs) using internally functionalized metal-organic framework (MOF) particles as pore carriers and poly(dimethylsiloxane) as bulky solvents. Using a generalizable noncovalent surface-initiated controlled radical polymerization technique, a series of isoreticular UiO-66 particles were dispersed in a liquid PDMS matrix with excellent homogeneity and colloidal stability. Benefiting from the inherent properties of PDMS, the PLs exhibit low vapor pressure, high thermal stability, and fluidity down to -35 °C. Attributed to the bulkiness of PDMS and its inherent high permeability, the sorption properties of the MOF fillers can be largely retained in their respective PLs as confirmed by low-pressure CO2, N2, Xe, and H2O sorption isotherms. The permanent porosity of the PLs can also be largely preserved even after 15 months of storage. Finally, we demonstrate that by tuning the molecular weight and polymer chain architecture of PDMS, it is possible to preserve the permanent porosity of a mesoporous MOF, MIL-101(Cr), within a PL.

16.
Med Sci Monit ; 25: 7202-7208, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31587013

RESUMO

BACKGROUND Hypoxia promotes cancer progression. Hypoxia-inducible factor-1alpha (HIF-1alpha) has been reported to enhance tumor invasion and metastasis via activating downstream genes, such as matrix metalloproteinases (MMPs). The purpose of this study was to explore the probable roles of HIF-1alpha and MMP13 in the invasion and metastasis of ovarian cancer under hypoxic conditions. MATERIAL AND METHODS The expression of HIF-1alpha and MMP13 protein were detected with immunohistochemistry staining in ovarian cancer tissues, metastatic lesions, and normal fallopian tissues. Ovarian cancer A2780 cells were cultured under normoxic condition and hypoxic condition. mRNA and protein expression of HIF-1alpha and MMP13 were detected by RT-PCR and Western blot analysis. The effects of siRNA against HIF-1alpha on MMP13 expression were examined by RT-PCR and Western blot analysis. Transwell invasion assays were performed to test the invasive ability of A2780 cells. RESULTS Immunohistochemistry staining showed significantly higher expression of HIF-1alpha and MMP13 protein in ovarian cancer tissues and metastatic lesions than in normal fallopian tissues. HIF-1alpha and MMP13 expression were closely related. After exposure to hypoxia, mRNA and protein levels of HIF-1alpha and MMP13 were upregulated. siRNA effectively inhibited HIF-1alpha expression and MMP13 expression. The number of invading A2780 cells decreased after HIF-1alpha was silenced. CONCLUSIONS This study suggests that HIF-1alpha promotes ovarian cancer cell invasion through a MMP13 mechanism. It might be an effective strategy targeting HIF-1alpha - MMP13 to inhibit invasion and metastasis of ovarian cancer.

17.
Eur J Pharmacol ; 865: 172737, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31622594

RESUMO

Strong evidence has shown that long non-coding RNAs (lncRNAs) play important roles in genetic modulations in human CNS. In this study, we utilized an in vitro model of human induced pluripotent stem cells (hiPSCs)-derived neurons, and hypothesized that lncRNA of bladder cancer associated transcript 1 (BLACAT1) had a functional role in anesthesia-induced cytotoxicity in human lineage neural cells. To test that, HiPSCs were induced toward neural cells and then treated with ketamine in vitro. We demonstrated that, ketamine induced neuronal apoptosis, neurite degeneration, and upregulated BLACAT1 gene expression. Inversely, lentiviral-induced BLACAT1 downregulation rescued ketamine-induced neural cytotoxicity in hiPSCs-derived neurons. In addition, BLACAT1 downregulation was demonstrated to prevent ketamine-induced mitochondrial dysregulations by suppressing ROS and caspase 3/7 activities in hiPSCs-derived neurons. Thus, we discovered a new mechanism that inhibition of LncRNA BLACAT1 could rescue anesthesia-induced neural cytotoxicity in human induced pluripotent stem cells derived neurons.

18.
Eur J Med Chem ; 184: 111779, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629165

RESUMO

The burst of reactive oxygen species (ROS) contributes to and exacerbates cardiac injury. Exogenous supplementation of antioxidants or upregulation of endogenous antioxidant defense genes should be the potential therapies for cardiovascular disease. Sixteen coumarin-derived imino sulfonates compounds were synthesized with the ability of attenuating oxidative stress directly by reducing intracellular ROS level via promoting Nrf2 pathway. The cell-based assays showed that most of the compounds had significant protective activity against H2O2-induced oxidative injury in H9c2 cells. Compound 5h with the highest activity and low cytotoxicity was demonstrated to remarkably remove the intracellular ROS accumulation by activating expressions of Nrf2 and its downstream antioxidant proteins (ie. HO-1 and NQO1), indicating a novel promising antioxidant and Nrf2 activator. Overall, these findings demonstrated that compound 5h could serve as a potential cardioprotective agent. Moreover, our study features developing new antioxidants and Nrf2 activators by introducing a sulfonyl group and nitrogen atom to the α,ß-unsaturated carbonyl entity in coumarin, rather than adding new functional groups or active fragments to coumarin itself.

19.
mSystems ; 4(5)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594827

RESUMO

Gut microbiota play important roles in host metabolism, especially in diabetes. However, why different diets lead to similar diabetic states despite being associated with different microbiota is not clear. Mice were fed two high-energy diets (HED) with the same energy density but different fat-to-sugar ratios to determine the associations between the microbiota and early-stage metabolic syndrome. The two diets resulted in different microbiota but similar diabetic states. Interestingly, the microbial gene profiles were not significantly different, and many common metabolites were identified, including l-aspartic acid, cholestan-3-ol (5ß, 3α), and campesterol, which have been associated with lipogenesis and inflammation. Our study suggests that different metabolic-syndrome-inducing diets may result in different microbiota but similar microbiomes and metabolomes. This suggests that the metagenome and metabolome are crucial for the prognosis and pathogenesis of obesity and metabolic syndrome.IMPORTANCE Various types of diet can lead to type 2 diabetes. The gut microbiota in type 2 diabetic patients are also different. So, two questions arise: whether there are any commonalities between gut microbiota induced by different pro-obese diets and whether these commonalities lead to disease. Here we found that high-energy diets with two different fat-to-sugar ratios can both cause obesity and prediabetes but enrich different gut microbiota. Still, these different gut microbiota have similar genetic and metabolite compositions. The microbial metabolites in common between the diets modulate lipid accumulation and macrophage inflammation in vivo and in vitro This work suggests that studies that only use 16S rRNA amplicon sequencing to determine how the microbes respond to diet and associate with diabetic state are missing vital information.

20.
Chem Commun (Camb) ; 55(85): 12829-12832, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31595892

RESUMO

Surface modification based on a photo-induced electron transfer (PET) reaction in a pyridinium-decorated MOF material was found to be effective in regulating adsorption capacity. The current system enables the adsorption behavior to be manipulated based on variable affinity toward guest molecules through the redistribution of charge population with the preservation of the original pore structure, which is different from the prevalent approaches depending on photoinduced changes in molecular configurations of the pore backbone.

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