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1.
J Nat Prod ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32223193

RESUMO

Seven new daphnane-type diterpenoids, daphgenkins A-G (1-7), and 15 known analogues (8-22) were isolated from the flower buds of Daphne genkwa. Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all daphnane-type diterpenoids (1-22) obtained were evaluated against three human colon cancer cell lines (SW620, RKO, and LoVo). Compounds 1, 12, and 13 exhibited cytotoxic effects against the SW620 and RKO cell lines, with IC50 values in the range of 3.0-9.7 µM. The most active new compound, 1, with an IC50 value of 3.0 µM against SW620 cells, was evaluated further for its underlying molecular mechanism. Compound 1 induced G0/G1 cell cycle arrest, leading to the induction of apoptosis in SW620 cells. Also, it induced cancer cell apoptosis by an increased ratio of Bax/Bcl-2, activated cleaved caspase-3 and caspase-9, and upregulated PARP. Finally, compound 1 significantly inhibited PI3K/Akt/mTOR signaling in SW620 cells. Together, the results suggest that compound 1 may be a suitable lead compound for further biological evaluation.

2.
J Med Chem ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32223235

RESUMO

BRAF is among the most frequently mutated oncogenes in human cancers. Multiple small molecule BRAF kinase inhibitors have been approved for treating melanoma carrying BRAF-V600 mutations. However, the benefits of BRAF kinase inhibitors are generally short lived. Small molecule-mediated targeted protein degradation has recently emerged as a novel pharmaceutical strategy to remove disease proteins through hijacking the cellular ubiquitin proteasome system (UPS). In this study, we developed thalidomide-based heterobifunctional compounds that induced selective degradation of BRAF-V600E, but not the wild type BRAF. Downregulation of BRAF-V600E suppressed the MEK/ERK kinase cascade in melanoma cells and impaired cell growth in culture. Abolishing the interaction between degraders and cereblon or blocking the UPS significantly impaired the activities of these degraders, validating a mechanistic role of UPS in mediating targeted degradation of BRAF-V600E. These findings highlight a new approach to modulate the functions of oncogenic BRAF mutants and provide a framework to treat BRAF-dependent human cancers.

3.
Cancer Res Treat ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138467

RESUMO

Purpose: The purpose of this study was to evaluate the diagnostic value of soluble Axl (sAxl) in hepatocellular carcinoma (HCC) in comparison with serum α-fetoprotein (AFP). Materials and Methods: Eighty HCC patients, 80 liver cirrhosis patients (LC), 80 patients with hepatitis B virus (HBV) infection, and 80 healthy controls (HC) were enrolled. sAxl levels were measured by an enzyme-linked immunosorbent assay (ELISA), serum AFP levels were measured by an electrochemiluminescence immunoassay (ECLIA). Receiver operating characteristic (ROC) curves were used to evaluate diagnostic performances. Results: The results show that levels of sAxl were high expression in patients with HCC (p < 0.05), varied with disease state as follows: HCC > LC > HC > HBV. Logistic regression and ROC curve analysis identified the optimal cut-off for sAxl in differentiating all HCC and non-HCC patients was 1,202 pg/mL (area under the receiver operating characteristic [AUC], 0.888, 95% CI, 0.852 to 0.924) with sensitivity 95.0%, specificity 73.3%. Furthermore, differential diagnosis of early HCC with non-HCC patients for sAxl showed the optimal cut-off was 1,202 pg/mL (AUC, 0.881; 95% CI, 0.831 to 0.931; sensitivity, 94.1%; specificity, 73.3%). Among AFP-negative HCC patients with non-HCC patients, the cut-off was 1,301 pg/mL (AUC, 0.898; 95% CI, 0.854 to 0.942) with a sensitivity of 84.6%, a specificity of 76.3%. The optimal cut-off for sAxl in differentiating all HCC and chronic liver disease (CLD) patients was 1243 pg/mL (AUC, 0.840; 95% CI, 0.791 to 0.888) with sensitivity 93.8%, specificity 61.9%. The combination of AFP and sAxl increased diagnostic value for HCC. Conclusion: sAxl outperforms AFP in detecting HCC, especially in early HCC and in AFP-negative HCC. Combination sAxl with AFP improved the specificity for early HCC diagnosis. In summary, sAxl is a candidate serum marker for diagnosing HCC.

4.
J Dairy Res ; 87(1): 27-31, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32114990

RESUMO

This research communication describes a genome-wide association study for Italian buffalo mammary gland morphology. Three single nucleotide polymorphisms (AX-85117983, AX-8509475 and AX-85117518) were identified to be significantly associated with buffalo anterior teat length, posterior teat length and distance between anterior and posterior teat, respectively. Two significant signals for buffalo mammary gland morphology were observed in two genomic regions on the chromosome 10, and chromosome 20. One of the regions located on the chromosome 10 has the most likely candidate genes ACTC1 and GJD2, both of which have putative roles in the regulation of mammary gland development. This study provides new insights into the genetic variants of buffalo mammary gland morphology and may be beneficial for understanding of the genetic regulation of mammary growth.

5.
Sci Total Environ ; 719: 137416, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32145492

RESUMO

Oxalate-iron is an integral part of the photochemical system in the atmosphere. Here, we combined high-resolution online observations and laboratory simulations to discuss the distribution of oxalate and oxalate-iron photochemical system in Nanjing atmosphere at the molecular level. The results show that the oxidation state of iron in the oxalate-iron photochemical system changes significantly and regularly. Among them, Fe (II)/Fe (III) is 3.82 during the day and 0.76 at night. At the same time, Cl- may accelerate the generation of hydroxyl radicals in the system and promote the photooxidation rate of oxalate. Oxalate can be converted into formate (C1) and acetate (C2) in the photochemical system, but <4% of degraded oxalate is converted, which means that the photochemical system may not be the main source of formate and acetate in the atmosphere. Besides, the ratio of C1/C2 < 1 in the conversion is opposite to the ratio of C1/C2 > 1 in the general secondary conversion, which means that not all ratio of C1/C2 in the photochemical pathway is >1. These results are beneficial for us to understand the effect of the oxalate-iron photochemical system on the distribution of oxalate in the atmosphere, and also help us to analyze the conversion of organics in the atmospheric aqueous phase.

6.
Int Immunopharmacol ; 83: 106365, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32172204

RESUMO

Atherosclerotic cardiovascular disease confers significant morbidity and mortality in patients with systemic lupus erythematosus (SLE). A substantial proportion of patients with SLE display accelerated endothelial dysfunction, which precedes cardiovascular disease. Melatonin and its nuclear receptor retinoid-related orphan receptor alpha (RORα) have been reported to have some protective effects on the development of atherosclerosis. However, the function of melatonin in SLE-induced endothelial dysfunction and the role that RORα plays are still unknown. In this study, we found that RORα protein expression was decreased in aortas of lupus-prone mice and in human umbilical vein endothelial cells (HUVECs) cultured with medium containing sera of patients with SLE. Melatonin-treated HUVECs showed a decrease of pro-inflammatory mRNAs [interleukin-1beta (IL-1ß), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α)] under the stimulation of SLE medium. Melatonin increased nitric oxide and antioxidant mRNAs (SOD1, GPX1, and CAT) and downregulated reactive oxygen species (ROS) level in HUVECs, which may subsequently delay endothelial senescence and promote HUVEC proliferation and repair after injury. Melatonin inhibited SLE medium-induced RAW264.7 macrophage migration. HUVECs pretreated with melatonin expressed less adhesion-related proteins (ICAM-1 and VCAM-1); as a result, these cells adhered to fewer peripheral blood monocytes. In addition, we also showed that the protective effects of melatonin on endothelial cells were largely diminished when RORα was knockdown in HUVECs. In conclusion, by targeting the nuclear receptor RORα, melatonin preserves normal functions of endothelium in SLE by its anti-inflammatory, antioxidant, and anti-senescence effects. RORα may have the potential to become a prophylactic or therapeutic target in preventing endothelial dysfunction and atherosclerotic cardiovascular disease in patients with SLE.

7.
Blood Purif ; : 1-8, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32191939

RESUMO

INTRODUCTION: Double-filtration plasmapheresis (DFPP) is a semi-selective blood purification method based on dual filtration system. Regional citrate anticoagulation (RCA) is an appealing anticoagulation alternative in DFPP. However, there are still few reports on the safety of RCA in DFPP treatment. OBJECTIVE: To investigate the anticoagulation effect and safety of RCA for DFPP in critical patients. METHODS: A total of 34 critical patients treated with DFPP were retrospectively studied. The incidence of coagulation during extracorporeal circulation after single treatment was compared before and after treatment. Heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, blood routine indexes, blood gas analysis, peripheral ionic calcium (iCa), total peripheral calcium (TCa), TCa/iCa, and complications before and after single treatment were compared. The changes of transmembrane pressure, pressure drop were measured, and the indexes of coagulation before and after treatment were compared. RESULTS: The blood coagulation 0.05). Level of TCa was significantly decreased at 5 min after treatment (p < 0.05), but there was no statistically significant difference at 6 and 24 h (p > 0.05). No treatment-related serious complications were observed in any of the patients. CONCLUSIONS: For critical patients who underwent DFPP procedure, RCA is safety and had significant anticoagulation effects, which is worthy of clinical application.

8.
J Autoimmun ; : 102440, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32201226

RESUMO

OBJECTIVES: The objective of this study was to address the biological function of miR-7 in an animal model of systemic lupus erythematosus. METHODS: MRLlpr/lpr lupus mice were administrated antagomiR-7 or a scramble control by tail vein for 5weeks. Three groups of animals' tissues were assessed for lupus manifestations by immunofluorescence and immunohistochemistry, and serum was examined for levels of autoantibodies and inflammatory cytokines. Splenic B cell subsets were assessed for intracellular expression of PI3K signaling by FACS. Finally, the ability of the miR-7 antagomir to regulate the expansion of T follicular helper (Tfh) cells and B cell hyperresponsiveness was further explored. RESULTS: We found that miR-7 was up-regulated in MRLlpr/lpr lupus mice and directly targeted PTEN mRNA in B cells. Up-regulated miR-7 in MRLlpr/lpr lupus B cells was negatively correlated with PTEN expression. Notably, miR-7 antagomir treatment reduced lupus manifestations in MRLlpr/lpr lupus mice. miR-7-mediated down-regulation of PTEN/AKT signaling promoted B cell differentiation into plasmablasts/plasma cells and spontaneous germinal center (GC) formation, whereas miR-7 antagomir normalized splenic B cell subtypes. Besides suppressing the activation of B cells, miR-7 antagomir intervention also down-regulated STAT3 phosphorylation and production of IL-21 and reduced Tfh expansion. CONCLUSION: The above data have demonstrated the critical roles of miR-7 not only in regulating PTEN expression and also B cell and Tfh cell function in lupus-prone MRLlpr/lpr lupus mice. Furthermore, the disease manifestations in MRLlpr/lpr lupus mice are efficiently improved by miR-7 antagomir, indicating miR-7 as a potential treatment strategy in SLE.

9.
Parkinsonism Relat Disord ; 73: 8-13, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32182553

RESUMO

BACKGROUND: Reduced flow into the brain or decreased jugular venous outflow from the brain may serve as a potential biomarker for Parkinson's disease (PD). Our goal was to compare the presence of vascular abnormalities, flow, and increases in midbrain iron content (a hallmark of the disease) in patients with PD. METHODS: A total of 85 PD patients and 85 healthy controls (HCs) were imaged at 3T. We assessed vascular abnormalities using magnetic resonance (MR) venography, average cerebral blood flow using 2D flow quantification, and substantia nigra iron content using susceptibility mapping. RESULTS: Fifty-two percent (52%) of the PD subjects showed venous structural and functional abnormalities in the two most severe categories, while ony 14% of the HC group showed these abnormalities. Total arterial flow (tA) was significantly lower for the PD group (10.9 ± 1.8 ml/s) compared to the HCs (11.6 ± 2.1 ml/s) (t = 2.28, p = 0.02). Of the PD patients (HCs), 42% (14%) had little flow on the left side. PD patients had higher heart rates and lower perfusion and the lower perfusion correlated with increased iron content in the substantia nigra. CONCLUSION: Some PD patients showed abnormal left internal jugular veins, lower tA, higher heart rates, and lower perfusion relative to HCs. These indicators could serve as early biomarkers for PD and create new avenues for future studies regarding the etiology of PD.

10.
Org Lett ; 22(5): 1780-1784, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32073277

RESUMO

A silent ansamycin biosynthetic gene cluster (ovm) was activated in Streptomyces olivaceus SCSIO T05 following mutagenesis and media optimization. A new shunt product, olimycin C (1a) was produced by the ovmO-inactivated mutant strain, along with a minor product, olimycin D (1b). The production of these linear olimycin counterparts suggest that luciferase-like monooxygenase (LLM) OvmO catalyzes an on-PKS Baeyer-Villiger-type oxidation during assembly of the olimycin A (2) linear polyketide backbone.

11.
Medicine (Baltimore) ; 99(5): e18646, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000369

RESUMO

INTRODUCTION: Clear cell adenocarcinoma of the cervix (CCAC), a rare and more severe type of gynecological cancer, is especially rare in pediatric patients. Traditionally, surgery following chemotherapy (CT) and radiation therapy is the preferred treatment for CCAC; however, patients have poor 5-year survival rates than other types of cervical cancers. PATIENT CONCERNS: A 6-year-old girl with a history of vaginal discharge for 18 months was diagnosed with CCAC by histological examination. Her parents refused the traditional treatment of radical hysterectomy and lymph node dissection because of her young age. DIAGNOSIS: The patient's tests revealed negative human papilloma virus and negative methylated paired box 1 gene results. The tumor mass histopathology revealed stage IIA1 CCAC that originated from the cervix. INTERVENTIONS: Tumor mass excision with preservation of the cervix by electrosurgical biopsy under hysteroscopy was performed. Four cycles of docetaxel and oxaliplatin CT were administered every 3 weeks. OUTCOMES: No signs of recurrence were observed in the 28 months after final treatment and diagnosis on magnetic resonance imaging, color ultrasonic imaging, and gynecological examination. Serologic tumor biomarkers were also within normal ranges. CONCLUSIONS: This is the first reported CCAC case in which the primary treatment included electrosurgical biopsy of the polypoid mass under hysteroscopy, followed by CT without traditional treatment: radical surgery with pelvic and/or lymphadenectomy for fertility preservation. This is a new treatment approach for young CCAC patients without the use of surgery.


Assuntos
Adenocarcinoma/cirurgia , Histeroscopia , Tratamentos com Preservação do Órgão , Neoplasias do Colo do Útero/cirurgia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Antineoplásicos/uso terapêutico , Colo do Útero/patologia , Criança , Docetaxel/uso terapêutico , Feminino , Humanos , Oxaliplatina/uso terapêutico , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
12.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G542-G553, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31984787

RESUMO

A lack of sunlight exposure, residence in the northern latitudes, and dietary vitamin D insufficiency are coprevalent with metabolic syndrome (MetS), Type 2 diabetes (T2D), and nonalcoholic fatty liver diseases (NAFLD), implying a potential causality and underlying mechanism. Whether vitamin D supplementation or treatment can improve these disorders is controversial, in part, because of the absence of large-scale trials. Experimental investigations, on the other hand, have uncovered novel biological functions of vitamin D in development, tumor suppression, and immune regulation, far beyond its original role as a vitamin that maintained calcium homeostasis. While the large intestine harbors massive numbers of microbes, the small intestine has a minimal quantity of bacteria, indicating the existence of a gating system located in the distal region of the small intestine that may restrain bacterial translocation to the small intestine. Vitamin D receptor (VDR) was found to be highly expressed at the distal region of small intestine, where the vitamin D signaling promotes innate immunity, including the expression of α-defensins by Paneth cells, and maintains the intestinal tight junctions. Thus, a new hypothesis is emerging, indicating that vitamin D deficiency may impair the intestinal innate immunity, including downregulation of Paneth cell defensins, leading to bacterial translocation, endotoxemia, systemic inflammation, insulin resistance, and hepatic steatosis. Here, we review the studies for vitamin D for innate immunity and metabolic homeostasis, and we outline the clinical trials of vitamin D for mitigating MetS, T2D, and NAFLD.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31991884

RESUMO

Uranium (U) mining activities, which lead to contamination in soils and waters (i.e., leachate from U mill tailings), cause serious environmental problems. However, limited research works have been conducted on U pollution associated with a whole soil-water system. In this study, a total of 110 samples including 96 solid and 14 water samples were collected to investigate the characteristics of U distribution in a natural soil-water system near a U mining tailings pond. Results showed that U concentrations ranged from 0.09 ± 0.02 mg/kg to 2.56 × 104± 23 mg/kg in solid samples, and varied greatly in different locations. For tailings sand samples, the highest U concentration (2.56× 104 ± 23 mg/kg) occurred at the depth of 80 cm underground, whereas, for paddy soil samples, the highest U concentration (5.22 ± 0.04 mg/kg) was found at surface layers. Geo-accumulation index and potential ecological hazard index were calculated to assess the hazard of U in the soils. The calculation results showed that half of the soil sampling sites were moderately polluted. For groundwater samples, U concentrations ranged from 0.55 ± 0.04 mg/L to 3.36 ± 0.02 mg/L with a mean value of 2.36 ± 0.36 mg/L, which was significantly lower than that of percolating waters (ranging from 4.56 ± 0.02 mg/L to 12.05 ± 0.04 mg/L, mean 7.91 ± 0.98 mg/L). The results of this study suggest that the distribution of U concentrations in a soil-water system was closely associated with hydrological cycles and U concentrations decreased with circulation path.

14.
J Cell Physiol ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31943174

RESUMO

Long noncoding RNAs (lncRNAs) have been reported to participate in the development of multiple cancers, including esophageal squamous cell carcinoma (ESCC). A growing number of studies have demonstrated that lncRNA myocardial infarction-associated transcript (MIAT) played an oncogenic role in several human malignancies, but its expression and function in ESCC remain unknown. In this study, we found that MIAT was significantly increased in ESCC tissues, as well as cell lines. Downregulation of MIAT suppressed ESCC cell proliferation, cell cycle, migration, and invasion. Mechanical studies revealed that MIAT promoted ESCC cell proliferation and cell cycle by acting as a competitively endogenous RNA (ceRNA) to upregulate the inner centromere protein (INCENP) expression through sponging miR-1301-3p. Furthermore, we uncovered that MIAT-SOX2 formed a positive feedback loop to facilitate cell proliferation, migration, and invasion of ESCC. Our findings indicated that MIAT promoted ESCC progression via targeting INCENP/miR-1301-3p axis and interacting with SOX2, suggesting novel potential therapeutic targets for ESCC.

15.
Anal Chim Acta ; 1097: 169-175, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-31910957

RESUMO

In this work, a label-free electrochemical immunosensor was developed for the detection of procalcitonin (PCT), using toluidine blue functionalized NiFe Prussian-blue analog nanocubes (NiFe PBA nanocubes@TB) as a signal amplifier. NiFe PBA nanocubes was synthesized by a simple and efficient self-templating method in this work. NiFe PBA nanocubes with open-framework construction not only provides a larger specific area to load a mass of antibodies but produces an excellent signal without adding extra reaction reagent. Besides, the electrochemical performance of NiFe PBA nanocubes can be enhanced after functionalized with TB. The developed immunosensor exhibited favorable performance for PCT detection with a linear range from 0.001 to 25 ng mL-1 and a detection limit of 3 × 10-4 ng mL-1. Moreover, the immunosensor with acceptable reproducibility, selectivity, and stability may provide a new strategy in the clinical detection of PCT.

16.
Life Sci ; 243: 117230, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923422

RESUMO

AIMS: Accumulating evidence has confirmed the involvement of the homeobox (HOX) gene family in carcinogenesis. HOXC11, belongs to the homeobox-C (HOXC) gene cluster, has been reported to play important roles in the development of several cancers. However, its expression and clinical value in pan-cancer remain elusive. MATERIALS AND METHODS: Bioinformatics analysis, CCK-8 assay, Flow cytometry and Western blot were used to analyze gene expression and patient survival, cell proliferation, cell apoptosis and protein level, respectively. KEY FINDINGS: In this study, we comprehensively analyzed the expression profile and prognostic value of HOXC11 in human pan-cancer using online The Cancer Genome Atlas (TCGA) databases. HOXC11 was widely up-regulated in tumor tissues when compared with the normal tissues in pan-cancer across nine cancer types. In addition, high mRNA level of HOXC11 predicted poor overall survival (OS) of patients with adrenocortical carcinoma (ACC), colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), mesothelioma (MESO) and pancreatic adenocarcinoma (PAAD), respectively. By comparative analysis, we found that HOXC11 was up-regulated and closely correlated patient OS in COAD and KIRC. Functionally, down-regulation of HOXC11 inhibited cell proliferation but promoted apoptosis of COAD and KIRC in vitro. Mechanistically, HOXC11 promoted cell proliferation of COAD and KIRC might by inactivating the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. SIGNIFICANCE: Our findings suggest that HOXC11 may act as a tumor driving gene in COAD and KIRC.


Assuntos
Adenocarcinoma/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias do Colo/metabolismo , Proteínas de Homeodomínio/fisiologia , Neoplasias Renais/metabolismo , Oncogenes , Adenocarcinoma/patologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/patologia , Regulação para Baixo/fisiologia , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Renais/patologia , PPAR gama/metabolismo , Análise de Sobrevida
17.
Cell Metab ; 31(1): 148-161.e5, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31761565

RESUMO

Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8+ T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8+ T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CD8+ T cells activates STAT3 to increase FAO, inhibiting CD8+ T effector cell glycolysis and functions. Finally, leptin enriched in mammary adipocytes and fat tissues downregulates CD8+ T cell effector functions through activating STAT3-FAO and inhibiting glycolysis. We identify a critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8+ T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis.

18.
Neurosci Lett ; 716: 134647, 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31765729

RESUMO

BACKGROUND: This study was to investigate the neuroprotective effect of erythropoietin (EPO) on hippocampal neuronal cell injury in developing rats. METHODS: The hippocampal neurons cells were obtained from SD rats aged 10 days and divided into control, propofol, EPO, and propofol + erythropoietin (E + P) groups. Cell proliferation and apoptosis were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Ki-67 immunofluorescence, and flow cytometry, respectively. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-4 and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Cellular immunohistochemistry was utilized to detect the expression of proliferating cell nuclear antigen (PCNA), nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Quantitative real time polymerase chain reaction (qRT-PCR) and western blot were used to detect the expression of Bax, Bcl-2, Caspase-3, toll-like receptor 4 (TLR4) and p65. Furthermore, TLR4 antagonist (TAK-242) and activator (LPS) were used to study the relationship between EPO and TLR4. RESULTS: Propofol treatment caused morphological and structural damage of hippocampal neurons. However, EPO significantly improved this damage, enhanced cell proliferation, decreased apoptosis and pro-inflammatory factor content, up-regulated the expression of Ki-67, PCNA, Bcl-2, NGF, BDNF and NT-3, as well as decreased the expression of Bax, Caspase-3, TLR4 and p65 (p < 0.05). After TAK-242 or LPS treatment, it showed similar results in propofol + TAK-242 (T + P) group and E + P group. CONCLUSION: Erythropoietin could attenuate propofol-induced hippocampal neuronal cell injury in developing rats, which may be related to inhibit TLR4 expression.

19.
Magn Reson Imaging ; 65: 15-26, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31629075

RESUMO

One major thrust in radiology today is image standardization with a focus on rapidly acquired quantitative multi-contrast information. This is critical for multi-center trials, for the collection of big data and for the use of artificial intelligence in evaluating the data. Strategically acquired gradient echo (STAGE) imaging is one such method that can provide 8 qualitative and 7 quantitative pieces of information in 5 min or less at 3 T. STAGE provides qualitative images in the form of proton density weighted images, T1 weighted images, T2* weighted images and simulated double inversion recovery (DIR) images. STAGE also provides quantitative data in the form of proton spin density, T1, T2* and susceptibility maps as well as segmentation of white matter, gray matter and cerebrospinal fluid. STAGE uses vendors' product gradient echo sequences. It can be applied from 0.35 T to 7 T across all manufacturers producing similar results in contrast and quantification of the data. In this paper, we discuss the strengths and weaknesses of STAGE, demonstrate its contrast-to-noise (CNR) behavior relative to a large clinical data set and introduce a few new image contrasts derived from STAGE, including DIR images and a new concept referred to as true susceptibility weighted imaging (tSWI) linked to fluid attenuated inversion recovery (FLAIR) or tSWI-FLAIR for the evaluation of multiple sclerosis lesions. The robustness of STAGE T1 mapping was tested using the NIST/NIH phantom, while the reproducibility was tested by scanning a given individual ten times in one session and the same subject scanned once a week over a 12-week period. Assessment of the CNR for the enhanced T1W image (T1WE) showed a significantly better contrast between gray matter and white matter than conventional T1W images in both patients with Parkinson's disease and healthy controls. We also present some clinical cases using STAGE imaging in patients with stroke, metastasis, multiple sclerosis and a fetus with ventriculomegaly. Overall, STAGE is a comprehensive protocol that provides the clinician with numerous qualitative and quantitative images.

20.
J Autoimmun ; : 102360, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31806420

RESUMO

OBJECTIVE: Gut dysbiosis has been reported implicated in ankylosing spondylitis (AS), a common chronic inflammatory disease mainly affects sacroiliac joints and spine. Utilizing deep sequencing on the feces of untreated AS patients, our study aimed at providing an in-depth understanding of AS gut microbiota. METHODS: We analyzed the fecal metagenome of 85 untreated AS patients and 62 healthy controls by metagenomic shotgun sequencing, and 23 post-treatment feces of those AS patients were collected for comparison. Comparative analyses among different cohorts including AS, rheumatoid arthritis and Behcet's disease were performed to uncover some common signatures related to inflammatory arthritis. Molecular mimicry of a microbial peptide was also demonstrated by ELISpot assay. RESULTS: We identified AS-enriched species including Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri. Pathway analysis revealed increased oxidative phosphorylation, lipopolysaccharide biosynthesis and glycosaminoglycan degradation in AS gut microbiota. Microbial signatures of AS gut selected by random forest model showed high distinguishing accuracy. Some common signatures related to autoimmunity, such as Bacteroides fragilis and type III secretion system (T3SS), were also found. Finally, in vitro experiments demonstrated an increased amount of IFN-γ producing cells triggered by a bacterial peptide of AS-enriched species, mimicking type II collagen. CONCLUSIONS: These findings collectively indicate that gut microbiota was perturbed in untreated AS patients with diagnostic potential, and some AS-enriched species might be triggers of autoimmunity by molecular mimicry. Additionally, different inflammatory arthritis shared some common microbial signatures.

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