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1.
Medicine (Baltimore) ; 98(28): e16475, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305482

RESUMO

Afferent loop obstruction is an uncommon complication associated with Billroth-II distal gastrectomy. Inappropriate treatment may result in life-threatening events as perforation and peritonitis. For the benign afferent loop obstruction, Braun or Roux-en-Y reconstruction has been reported as the choice. However, the edematous afferent loop may result in anastomotic fistula. In this study, a less invasive technique was described for treatment of benign afferent loop obstruction. The aim of this study was to investigate the effectiveness and safety of endoscopic nasogastric tube insertion for treatment of benign afferent loop obstruction.We conducted a retrospective review of the data of 2548 gastric cancer patients who underwent distal gastrectomy from January 2002 to January 2018. Patients who developed benign afferent loop obstruction were treated by this procedure. Outcomes were recorded. Follow-up was scheduled at 3, 6, and 12 months after the treatment.Twenty-six patients (1.0%) developed afferent loop obstruction. The median age, consisting of 19 men and 7 women, was 60 years (range 36-69 years). Of these 26 patients, 23 underwent the endoscopic treatment. The obstructive symptoms had a rapid relief in all the 23 patients. No one died due to this procedure. However, 2 patients underwent surgical treatment due to intestinal obstruction because of adhesion at >4 and 7 months after the endoscopic drainage, respectively.Endoscopic nasogastric tube insertion is an effective and safe procedure for treatment of benign afferent loop obstruction. In addition, it could be considered as the first step in treatment, especially in high-surgical-risk patients.


Assuntos
Síndrome da Alça Aferente/terapia , Endoscopia Gastrointestinal , Gastrectomia , Intubação Gastrointestinal , Complicações Pós-Operatórias/terapia , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Descompressão Cirúrgica/métodos , Endoscopia Gastrointestinal/métodos , Seguimentos , Humanos , Intubação Gastrointestinal/métodos , Pessoa de Meia-Idade , Cirurgia Endoscópica por Orifício Natural/métodos , Estudos Retrospectivos , Resultado do Tratamento
2.
J Ethnopharmacol ; 242: 112029, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31216433

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: ShengMai-Yin and Ganmaidazao decoction are classic formulas in traditional Chinese medicine. Individually, Shengmai-Yin is used to treat cardiovascular diseases, and Ganmaidazao decoction for therapy of mental disorders. The combination of Shengmai-Yin and Ganmaidazao decoction (SGD) is normally used as adjuvant therapy for type 2 diabetes mellitus (T2DM). AIM OF THE STUDY: The central aim is to elucidate the pharmacological efficacy of SGD and its mechanism in the treatment of T2DM with non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Active ingredients in SGD and their drug targets were identified using network analysis followed by experimental validation. First, existing databases were mined for information relevant to SGD, including pharmacological actions, chemical components, physicochemical characteristics, potential targets, and implicated diseases. Candidate patterns obtained with the network analysis were then tested in a KKAy mouse model of T2DM with NAFLD. Various doses of SGD were administered, followed by measurements of fasting blood glucose, oral glucose tolerance tests, insulin tolerance tests, markers of lipid metabolism - including free fatty acids (FFA), triglycerides (TG), and total cholesterol (TC) - liver histology, and expression levels of implicated molecules including PI3K/AKT and PPARα. RESULTS: Over 300 potential active compounds with their physicochemical characteristics and 562 candidate targets were collected, and then the network of them was constructed. Follow-up pathway and functional enrichment analyses indicated that SGD influences metabolism-related signaling pathways including PI3K-Akt, AMPK, and PPAR. In validation experiments, treatment of KKAy mice with SGD reduced serum levels of glucose, TC, TG, and FFA, decreased numbers of crown-like structures in visceral adipose tissue, reduced adipocyte size, and lowered liver lipid deposits. Further, SGD improved liver metabolism by increasing the expressions of PPARα, HSL, and PI3K/Akt, and decreasing expressions of SREBP-1 and FASN, inhibiting lipid biosynthesis, and increasing insulin sensitivity. CONCLUSION: Experimental validation of network analysis revealed anti-diabetic effects of the plant product SGD, manifested most notably by improved serum profiles and diminished insulin resistance. These experimental results may have clinical implications.

3.
J Leukoc Biol ; 106(5): 1089-1100, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31211478

RESUMO

Ginsenoside Rh2 (G-Rh2) has well-established potent antitumor activity; yet, the effects of G-Rh2 on immune and metabolism regulation in cancer treatment, especially non-small cell lung cancer (NSCLC) remain unclear. We showed that G-Rh2 had a synergistic antitumor effect with cyclophosphamide (CY) on mice with NSCLC, and improved the immune deficiency caused by CY. Consistently, G-Rh2 exhibited no inhibitory effect on tumor growth of T cells-deficient nude mice. Furthermore, G-Rh2 treatment triggered the oxidative decomposition of fatty acid (FA), suppressed FA synthesis, increased ketone level, and decreased glucocorticoid (CORT) secretion. G-Rh2 significantly down-regulated the expression of fatty acid synthase (FASN). Of note, in liver-specific FASN knockout mice G-Rh2 failed to show the same immune enhancement effects. Further mechanistic exploration revealed that G-Rh2 suppressed the expression and nuclear translocation of sterol regulatory element binding protein 1 (SREBP-1), and disturbed the SREBP-1-FASN interaction in vitro.

4.
Chemosphere ; 228: 586-594, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31059956

RESUMO

BACKGROUND: Benzo[a]pyrene (BaP) is an environmental pollutant known to cause teratogenesis. However, the mechanism underlying this teratogenic effect is not fully understood. Recently, the alteration of DNA methylation of imprinting genes has emerged as a specific epigenetic mechanism linking the impact of environmental pollutants on embryonic development to paternal exposures. The aim of this study was to investigate the transgenerational effects of paternal BaP exposure on the imprinting genes in mouse sperm DNA. METHODS: Male C57BL/6J mice received BaP (1.0 or 2.5 mg/kg) or olive oil twice a week for 12 weeks. The methylation status of 6 imprinting genes (H19, Meg3, Peg1, Peg3, Igf2 and Snrpn) was examined by bisulfite pyrosequencing of the sperm DNA of BaP-exposed F0 generation and their offspring. RESULTS: BaP exposure reduced the methylation levels in the imprinting genes H19 and Meg3 and increased the methylation levels of Peg1 and Peg3; however, no significant differences was observed for the methylation levels of Igf2 or Snrpn in the sperm DNA. Furthermore, BaP-exposed male mice were mated with unexposed female mice to generate F1-2 generations. The methylation levels of the 6 genes in the sperm DNA from F1-2 offspring showed a similar pattern as that of the F0 male. The effects were attenuated in F1-2 generations. CONCLUSIONS: Paternal BaP exposure altered the methylation levels of imprinting genes, implicating that imprinting genes are susceptible to environmental toxicants. Furthermore, a similar alteration was observed in the F1-2 generations although the attenuated in methylation in F2 generation, revealing a potential transgenerational effect.


Assuntos
Benzo(a)pireno/farmacologia , Metilação de DNA/efeitos dos fármacos , Impressão Genômica/genética , Exposição Paterna , Espermatozoides/efeitos dos fármacos , Animais , Poluentes Ambientais/farmacologia , Epigênese Genética/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Reprodução/efeitos dos fármacos
5.
Methods Mol Biol ; 1919: 205-213, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30656632

RESUMO

Lentiviral vectors are increasingly used as efficient gene transfer tools in the experimental and clinical gene therapy treatment of acquired and inherited genetic diseases. Hematopoietic stem cells (HSCs) are characterized by the capacity for self-renewal, as well as multi-lineage differentiation and maintenance of the lymphohematopoietic system throughout life. As such, HSC transplantation (HSCT) has proven to be a powerful therapeutic modality for the treatment of both malignant and nonmalignant disorders. Transduction of lentiviral vectors into HSCs may offer long-term stable expression of a therapeutic gene in both preclinical and clinical settings. The purpose of this chapter is to describe an optimized procedure for lentiviral transduction of mouse HSCs followed by HSCT.


Assuntos
Células da Medula Óssea/metabolismo , Vetores Genéticos/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Lentivirus/genética , Transdução Genética , Animais , Células da Medula Óssea/citologia , Técnicas de Cultura de Células , Células HEK293 , Células-Tronco Hematopoéticas/citologia , Humanos , Camundongos
6.
Mol Oncol ; 13(4): 873-893, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30628173

RESUMO

Forkhead box transcription factor M1 (FOXM1) is a proliferation-associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells (DCs). Although previous work has shown that FOXM1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM1 affects DC maturation in the context of tumor-specific immunity. In this study, we examined the central role of FOXM1 in regulating bone marrow-derived dendritic cell (BMDC) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM1 retarded maturation phenotypes of BMDCs, inhibited promotion of T-cell proliferation, and decreased interleukin-12 (IL-12) p70 in tumor-bearing mice (TBM). Notably, FOXM1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDCs. Increased H3K79me2 enrichment was observed at the FOXM1 promoter in both BMDCs from TBM, and in BMDCs from wild-type mice cultured with tumor-conditioned medium that mimics the tumor microenvironment (TME). Furthermore, inhibition of the H3K79 methyltransferase DOT1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM1 and partially reversed its immunosuppressive effects on BMDCs. Furthermore, we found that FOXM1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDCs in vitro; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDCs through the Wnt5a signaling pathway, and thus provide novel insights into FOXM1-based antitumor immunotherapy.

7.
J Sep Sci ; 42(6): 1133-1143, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30620132

RESUMO

Nonsteroidal anti-inflammatory drugs reportedly reduce the risk of developing cancer. One mechanism by which they reduce carcinogenesis involves the inhibition of the activity of cyclooxygenase-2, an enzyme that is overexpressed in various cancer tissues. Its overexpression increases cell proliferation and inhibits apoptosis. However, selected cyclooxygenase-2 inhibitors can also act through cyclooxygenase-independent mechanisms. In this study, using ultrafiltration, enzyme-immobilized magnetic beads, high-performance liquid chromatography, and electrospray-ionization mass spectrometry, several isoflavonoids in Trifolium pratense L. extracts were screened and identified. Semi-preparative high-performance liquid chromatography and high-speed counter-current chromatography were then applied to separate the active constituents. Using these methods, seven major compounds were identified in Trifolium pratense L. As cyclooxygenase-2 inhibitors: rothindin, ononin, daidzein, trifoside, pseudobaptigenin, formononetin, and biochanin A, which were then isolated with >92% purity. This is the first report of the presence of potent cyclooxygenase-2 inhibitors in Trifolium pratense L. extracts. The results of this study demonstrate that the systematic isolation of bioactive components from Trifolium pratense L., by using ultrafiltration, enzyme-immobilized magnetic beads, semi-preparative high-performance liquid chromatography, and high-speed counter-current chromatography, represents a feasible and efficient technique that could be extended for the identification and isolation of other enzyme inhibitors.


Assuntos
Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Genisteína/isolamento & purificação , Glucosídeos/isolamento & purificação , Isoflavonas/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Distribuição Contracorrente , Inibidores de Ciclo-Oxigenase 2/química , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Genisteína/química , Glucosídeos/química , Isoflavonas/química , Fenômenos Magnéticos , Trifolium/química , Ultrafiltração
8.
Cell Rep ; 25(12): 3405-3421.e7, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30566866

RESUMO

cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1-/- BMDM cells and in Trex1-/- mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases.

9.
PLoS Pathog ; 14(11): e1007435, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30388174

RESUMO

Stimulator of interferon genes (STING) is critical for cytosolic DNA-triggered innate immunity. STING is modified by several types of polyubiquitin chains. Here, we report that the deubiquitinase CYLD sustains STING signaling by stabilizing the STING protein. CYLD deficiency promoted the K48-linked polyubiquitination and degradation of STING, attenuating the induction of IRF3-responsive genes after HSV-1 infection or the transfection of DNA ligands. Additionally, CYLD knockout mice were more susceptible to HSV-1 infection than their wild-type (WT) littermates. Mechanistically, STING translocated from the ER to the Golgi upon HSV-1 stimulation; CYLD partially accumulated with STING and interacted selectively with K48-linked polyubiquitin chains on STING, specifically removing the K48-linked polyubiquitin chains from STING and ultimately boosting the innate antiviral response. Our study reveals that CYLD is a novel checkpoint in the cGAS-STING signaling pathway and sheds new light on the dynamic regulation of STING activity by ubiquitination.

10.
Mov Disord ; 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30440089

RESUMO

BACKGROUND: Parkinson's disease is characterized by the progressive loss of dopamine neurons in the substantia nigra, leading to severe motor deficits. Although the disease likely begins to develop years before observable motor symptoms, the specific morphological and functional alterations involved are poorly understood. OBJECTIVES: MitoPark mice lack the gene coding for mitochondrial transcription factor A specifically in dopamine neurons, which over time produces a progressive decline of neuronal function and related behavior that phenotypically mirrors human parkinsonism. Our previous work identified a progressive decrease in cell capacitance in dopamine neurons from MitoPark mice, possibly suggesting reduced membrane surface area. We therefore sought to identify and quantify somatodendritic parameters in this model across age. METHODS: We used whole-cell patch clamp and fluorescent labeling to quantify somatodendritic morphology of single, neurobiotin-filled dopamine neurons in acutely isolated brain slices from MitoPark mice. RESULTS: We found that MitoPark mice exhibit an adult-onset, age-dependent reduction of neuritic branching and soma size in dopamine neurons. This decline proceeds similarly in MitoPark mice of both sexes, but does not begin until after the age that early decrements in ion channel physiology and behavior have previously been observed. CONCLUSIONS: A progressive and severe decline in somatodendritic morphology occurs prior to cell death, but is not responsible for the subtle decrements observable in the earliest stages of neurodegeneration. This work could help identify the ideal time window for specific treatments to halt disease progression and avert debilitating motor deficits in Parkinson's patients. © 2018 International Parkinson and Movement Disorder Society.

12.
Sci Rep ; 8(1): 5460, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615705

RESUMO

Glial cell line-derived neurotrophic factor (GDNF) is the most potent neuroprotective agent tested in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF is restricted by the blood-brain barrier (BBB). Using total body irradiation as transplant preconditioning, we previously reported that hematopoietic stem cell (HSC) transplantation (HSCT)-based macrophage-mediated gene therapy could deliver GDNF to the brain to prevent degeneration of nigrostriatal dopamine (DA) neurons in an acute murine neurotoxicity model. Here, we validate this therapeutic approach in a chronic progressive PD model - the MitoPark mouse, with head shielding to avoid inducing neuroinflammation and compromising BBB integrity. Bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into MitoPark mice exhibiting well developed PD-like impairments. Transgene-expressing macrophages infiltrated the midbrains of MitoPark mice, but not normal littermates, and delivered GDNF locally. Macrophage GDNF delivery markedly improved both motor and non-motor symptoms, and dramatically mitigated the loss of both DA neurons in the substantia nigra and tyrosine hydroxylase-positive axonal terminals in the striatum. Our data support further development of this HSCT-based macrophage-mediated GDNF delivery approach in order to address the unmet need for a disease-modifying therapy for PD.

13.
Stem Cells Dev ; 27(14): 995-1005, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29562865

RESUMO

Glial cell line-derived neurotrophic factor (GDNF) exhibits potent neuroprotective properties in preclinical models of Parkinson's disease (PD), but challenges in GDNF delivery have been reported from clinical trials. To address this barrier, we developed a hematopoietic stem cell transplantation-based macrophage-mediated GDNF therapy platform. Here, we introduced a regulatable lentiviral vector (LV-MSP-Tet-Off-hGDNF) to allow the expression of human GDNF (hGDNF) to be adjusted or stopped by oral administration of doxycycline (Dox). C57BL/6J mice were lethally irradiated with head protection and then transplanted with syngeneic bone marrow cells transduced with either the hGDNF-expressing vector or a corresponding GFP-expressing vector, LV-MSP-Tet-Off-GFP. Suppression of vector gene expression was achieved through administration of Dox in drinking water. To create a toxin-induced Parkinsonian model, mice were injected in two cycles with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to yield nigral cell/striatal dopamine loss and behavioral deficits. During the presence of Dox in the drinking water, plasma GDNF was at a basal level, whereas during the absence of Dox, plasma GDNF was significantly elevated, indicating reliable regulation of therapeutic gene expression. Midbrain GDNF levels were altered in parallel, although these did not return completely to basal levels during the periods of Dox withdrawal. Motor activities of the MPTP-Tet-off-hGDNF group were comparable to those of the Tet-off-GFP (subject to no MPTP treatment) group, but substantially better than those of the MPTP-Tet-off-GFP group. Interestingly, the improvement in motor activities was sustained during the Dox-withdrawn periods in MPTP-Tet-off-hGDNF animals. Neuroprotection by therapeutic GDNF expression was further evidenced by significant amelioration of nigral tyrosine hydroxylase loss after both the first and second MPTP treatment cycles. These data suggest that neurotrophic factor expression can be upregulated to achieve efficacy or downregulated in case of off-target effects or adverse events, a feature that may eventually increase the acceptance of this potentially neuroprotective/disease-modifying PD therapy.

14.
Front Pharmacol ; 9: 187, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29556199

RESUMO

Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB). Pathway and functional enrichment analysis of these putative targets indicated that DGLHD obviously influenced NF-κB and PPAR signaling pathway. Consistently, DGLHD downregulated levels of ALT (alanine transaminase) and AST (aspartate transaminase), reduced production of proinflammatory cytokines-TNF (tumor necrosis factor) -α and IL (Interleukin) -1ß in serum and liver from mice with hepatic fibrosis, and inhibited hepatic stellate cell (HSC)-T6 cells proliferation. DGLHD decreased TGF (transforming growth factor) -ß1 and α-SMA (smooth muscle actin) expression as well, maintained MMP (matrix metalloprotein) 13-TIMP (tissue inhibitor of metalloproteinases) 1 balance, leading to mitigated ECM (extracellular matrix) deposition in vivo and in vitro. Moreover, our experimental data confirmed that the alleviated inflammation and ECM accumulation were pertinent to NF-κB inhibition and PPAR-γ activation. Overall, our results suggest that DGLHD aims at multiply targets and impedes the progression of hepatic fibrosis by ameliorating abnormal inflammation and ECM deposition, thereby serving as a novel regimen for treating hepatic fibrosis in clinic.

16.
Am J Cancer Res ; 7(9): 1971-1977, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979818

RESUMO

BACKGROUND: We conducted a phase II study by combining FOLFOX4 plus bevacizumab (BV) with erlotinib (ER) as second-line chemotherapy for patients with metastatic colorectal cancer (mCRC). METHODS: Patients were divided into two groups in randomized double-blind manner. One group was given FOLFOX4 plus 5 mg/kg BV on day 1 of 2-week cycle. The other group was given 2-week-cycle of BV + FOLFOX4, and 100 mg ER every day. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), clinical response rates and adverse events (AEs). RESULTS: 66 patients received 2nd-line treatment of ER + BV+ FOLFOX4, and 65 received BV + FOLFOX4. Median PFS was 9.6 months of ER + BV + FOLFOX4 group, significantly better than 6.9 months of BV + FOLFOX4 group (P = 0.021, HR = 1.15, 95% CI = 0.88-1.39). Medium OS for ER + BV + FOLFOX4 group was 12.5 months, not statistically different than 12.1 months for BV + FOLFOX4 group (P = 00.146, HR = 0.63, 95% CI = 0.34-1.02). Combined partial response and stable disease rate was 48.5% for ER + BV + FOLFOX4 group, significantly higher than 32.2% for BV + FOLFOX4 group (P = 0.015). Patients in ER + BV + FOLFOX4 group had higher incidence rates of AEs. CONCLUSION: In second-line chemotherapy for patients with mCRC, combining erlotinib with FOLFOX4 plus bevacizumab may improve PFS, clinical response rates, but not OS. AEs, though with high incidence rates, were generally tolerable among patients receiving multiple reagents.

17.
Environ Pollut ; 230: 882-890, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28735245

RESUMO

To elucidate the environmental fate of polycyclic aromatic hydrocarbons (PAHs) once released into soil, sixteen humic acids (HAs) and one humin (HM) fractions were sequentially extracted from a peat soil, and sixteen priority PAHs in these humic substances (HSs) were analyzed. It was found that the total concentration of 16 PAHs (∑16PAHs) increased evidently from HA1 to HA16, and then dramatically reached the highest value in HM. The trend of ∑16PAHs in HAs relates to surface carbon and C-H/C-C contents, the bulk aliphatic carbon content and aliphaticity, as well as the condensation enhancement of carbon domains, which were derived from elemental composition, XPS, 13C NMR, as well as thermal analyses. HM was identified to be the dominant sink of 16 PAHs retention in soil, due to its aliphatic carbon-rich chemical composition and the highly condensed physical makeup of its carbon domains. This study highlights the joint roles of the physical and chemical properties of HSs in retention of PAHs in soil and the associated mechanisms; the results are of significance for PAH-polluted soil risk assessment and remediation.


Assuntos
Substâncias Húmicas/análise , Modelos Químicos , Hidrocarbonetos Policíclicos Aromáticos/análise , Poluentes do Solo/análise , Solo/química , Carbono , Poluição Ambiental/análise
18.
Chem Biol Interact ; 272: 182-187, 2017 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-28535922

RESUMO

Perfluoroalkylated substances (PFASs), including perfluorooctyl sulphonate (PFOS) and perfluorooctane acid (PFOA), have been classified as persistent organic pollutants and are known to cause endocrine-disrupting effects in humans. The objective of the present study was to compare the potencies of four different PFASs, PFOS, PFOA, perfluorohexyl sulfonate (PFHxS), and perfluorobutyl sulfonate (PFBS), to inhibit neurosteroidogenic 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C9), and retinol dehydrogenase 2 (RoDH2) in rats. The potencies of PFASs to inhibit SRD5A1 are PFOS > PFOA > PFHxS = PFBS, with IC50 values of PFOS and PFOA of 1.92 ± 0.07 and 14.24 ± 0.07 µM and no effects for PFHxS and PFBS at 100 µM, respectively. The potencies of PFASs to inhibit AKR1C9 and RoDH2 are PFOS > PFOA > PFHxS = PFBS, with IC50 values of PFOS and PFOA on these two enzymes about 100 µM and no effects for PFHxS and PFBS at 100 µM, respectively. PFOS and PFOA competitively inhibited rat SRD5A1. In conclusion, PFOS and PFOA are potent inhibitors of rat SRD5A1, thereby controlling the biosynthesis of neurosteroids.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Ácidos Alcanossulfônicos/metabolismo , Fluorcarbonetos/metabolismo , Proteínas de Membrana/metabolismo , Oxirredutases/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Ácidos Alcanossulfônicos/química , Animais , Células COS , Caprilatos/química , Caprilatos/metabolismo , Cercopithecus aethiops , Fluorcarbonetos/química , Cinética , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Oxirredutases/antagonistas & inibidores , Oxirredutases/genética , Ratos , Relação Estrutura-Atividade
19.
J Sep Sci ; 40(12): 2565-2574, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28444982

RESUMO

The separation of a compound of interest from its structurally similar homologues to produce high-purity natural products is a challenging problem. This work proposes a novel method for the separation of iristectorigenin A from its structurally similar homologues by ionic-liquid-based ultrasound-assisted extraction and the subsequent screening and isolation of potential α-glucosidase inhibitors via ultrafiltration and semipreparative high-performance liquid chromatography. Ionic-liquid-based ultrasound-assisted extraction was successfully applied to the extraction of tectorigenin, iristectorigenin A, irigenin, and irisflorentin from Belamcanda chinensis. The optimum conditions for the efficient extraction of isoflavones were determined as 1.0 M 1-ethyl-3-methylimidazolium tetrafluoroborate with extraction time of 30 min and a solvent to solid ratio of 30 mL/g. Ultrafiltration with liquid chromatography and mass spectrometry was applied to screen and identify α-glucosidase inhibitors from B. chinensis, followed by the application of semipreparative high-performance liquid chromatography to separate and isolate the active constituents. Four major compounds including tectorigenin, iristectorigenin A, irigenin, and irisflorentin were screened and identified as α-glucosidase inhibitors, and then the four active compounds abovementioned were subsequently isolated by semipreparative high-performance liquid chromatography (99.89, 88.97, 99.79, and 99.97% purity, respectively). The results demonstrate that ionic liquid extraction can be successfully applied to the extraction of isoflavones from B. chinensis.


Assuntos
Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Iridaceae/química , Isoflavonas/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Ultrafiltração
20.
PLoS Pathog ; 13(3): e1006264, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28273161

RESUMO

The cyclic GMP-AMP synthase (cGAS), upon cytosolic DNA stimulation, catalyzes the formation of the second messenger 2'3'-cGAMP, which then binds to stimulator of interferon genes (STING) and activates downstream signaling. It remains to be elucidated how the cGAS enzymatic activity is modulated dynamically. Here, we reported that the ER ubiquitin ligase RNF185 interacted with cGAS during HSV-1 infection. Ectopic-expression or knockdown of RNF185 respectively enhanced or impaired the IRF3-responsive gene expression. Mechanistically, RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS, which promoted its enzymatic activity. Additionally, Systemic Lupus Erythematosus (SLE) patients displayed elevated expression of RNF185 mRNA. Collectively, this study uncovers RNF185 as the first E3 ubiquitin ligase of cGAS, shedding light on the regulation of cGAS activity in innate immune responses.


Assuntos
Imunidade Inata/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Mitocondriais/imunologia , Nucleotidiltransferases/imunologia , Ubiquitina-Proteína Ligases/imunologia , Adolescente , Adulto , Células Cultivadas , Feminino , Herpes Simples/imunologia , Herpesvirus Humano 1 , Humanos , Immunoblotting , Imunoprecipitação , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Transfecção , Adulto Jovem
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