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1.
Dalton Trans ; 50(46): 17372-17377, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34792060

RESUMO

Treatment of CoCl2·6H2O and tris(pyrazolyl-1-yl)borate tricyanoiron(III) anions at an elevated temperature (55 °C) afforded two less-common pearl-chain-like compounds, {[(TpR)Fe(CN)3CoCl2]2Co(DMF)4}·nDMF (1, TpR = Tp4-Me = hydridotris(4-methylpyrazol-1-yl)borate, n = 1 and 2, TpR = Tp*Me = hydridotris(3,4,5-trimethylpyrazol-1-yl)borate, n = 4.5), in which the 4-coordinate Co(II) ions and [(TpR)FeIII(CN)3]- units are alternately bridged by cyanide groups into squares, which are further linked with the 6-coordinate Co(II) ions into an infinite chain. Interestingly, the magnetic study revealed that 1 exhibits a typical single-chain magnet behaviour with an effective energy barrier of 28.0 K, while surprisingly no Glauber dynamics was observed for 2 despite their very similar structures. The variations of the local coordination environments of the cobalt ions and the cyanide linkages were evidenced, and they may account for the significant difference in their magnetic properties related to the global magnetic anisotropy and magnetic exchange of the chain.

2.
Brain Res Bull ; 177: 73-80, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34555432

RESUMO

Our previous study showed that neuronal apoptosis was significantly increased upon treatment of conditioned medium (CM) from necroptotic astrocytes (NAS), leaving the underlying mechanism unclear. Considering the nutritive and supportive roles of astrocytes, we first examined the neurotrophic phenotype of necroptotic astrocytes with focus on glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), two important neurotrophic factors, and it was unexpectedly found that the expression of GDNF and BDNF were up-regulated in necroptotic astrocytes in vitro. A question was raised as to whether the functional secreted forms of neurotrophic factors were increased. Considering that extracellular vesicles (EVs) were carriers of secreted substances and their roles in cellular interaction, we isolated EVs from astrocytes and found EVs from normal and necroptotic astrocytes (EVs-NAS) had characteristics of exosomes. We then examined GDNF and BDNF in EVs-NAS, and BDNF was interestingly found as an immature form of pro-BDNF. The expression of pro-BDNF was found to be increased in EVs-NAS, and EVs-NAS had a negative effect on neuronal survival. To verify that whether pro-BDNF was involved in the detrimental effect of EVs-NAS, anti-pro-BDNF antibody was applied, and we found that neuronal apoptosis-induced by EVs-NAS could be significantly attenuated by blocking pro-BDNF, which suggested that necroptotic astrocytes induced neuronal apoptosis partially through EVs-derived pro-BDNF. The data expand our understanding in neurotrophic phenotype of necroptotic astrocytes, and may provide us new strategies targeting on EVs-NAS in treatment of neurological diseases.

3.
Thorac Cancer ; 12(18): 2439-2448, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34337871

RESUMO

PURPOSE: The objective of our study was to investigate the epidemiologic characteristics and prognostic factors in patients with pulmonary acinar cell carcinoma (PACC). METHODS: PACC patients diagnosed between 1975 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The trend in PACC incidence was assessed using joinpoint regression software. Overall survival (OS) and disease-specific survival (DSS) were evaluated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analysis was performed to identify the independent prognostic factors for OS and DSS. Nomograms to predict survival possibilities were constructed based on the identified independent prognostic factors. RESULTS: A total of 2918 patients were identified with PACC. The mean age was 65.2 ± 8.95 years with a female to male of 1.6:1. The incidence of PACC steadily increased by an annual percentage change (APC) of 3.2% (95% CI 2.1-4.4, p < 0.05). Multivariate Cox regression analysis revealed that age, gender, race, stage, grade, tumor size, number of positive lymph nodes, surgery, and chemotherapy were independent prognostic factors for survival. Nomograms specifically for PACC were constructed to predict 1- and 5-year OS and DSS possibility, respectively. The concordance index (C-index) and calibration plots showed the established nomograms had robust and accurate performance. CONCLUSION: PACC was rare but the incidence has been steadily increasing over the past four decades. Survival has improved in recent years. Surgery or chemotherapy could provide better OS and DSS. The established nomograms specifically for PACC were robust and accurate in predicting 1- and 5-year OS and DSS.

4.
Zhongguo Zhong Yao Za Zhi ; 46(13): 3270-3287, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34396746

RESUMO

The multi-component pharmacokinetic study of Chinese herbal extracts elaborates the in vivo processes,including absorption,distribution,metabolism,and excretion,of multiple bioactive components,which is of significance in revealing pharmacodynamic material basis of Chinese herbal medicine. In recent years,with the innovation in ideas,and development of techniques and methods on traditional Chinese medicine( TCM) research,the pharmacokinetic studies of Chinese herbal extracts were extensively performed,and notable progress has been made. This paper reviewed the advancement of multi-component pharmacokinetics of Chinese herbal extracts in recent five years from analysis technology of biological sample,the pharmacokinetic characteristics of Chinese herbal medicine with complex system,and the impacts of processing and pathological state on pharmacokinetics of Chinese herbal extracts,aiming to provide a reference for quality control,product development and rational medication of Chinese herbal extracts.


Assuntos
Medicamentos de Ervas Chinesas , China , Humanos , Medicina Tradicional Chinesa , Controle de Qualidade
5.
Biomed Res Int ; 2021: 6641701, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34212036

RESUMO

Introduction: Animal models are valid for in vivo research on the pathophysiological process and drug screening of gout arthritis. Intra-articular injection of monosodium urate (MSU) is the most common method, while stable MSU deposition enveloped by inflammatory cells was rarely reported. Objective: To develop a modified gouty arthritis rat model characterized by intra-articular MSU deposition and continuous joint pain with a minimally invasive method. Method: A total of twenty-four rats were randomly allocated into six groups. Three intervention groups of rats received intra-articular MSU embedment. Sham groups received pseudosurgeries with equal normal saline (NS). Gross parameters and pathological features of synovium harvested from anterior capsule were estimated. Mechanical pain threshold tests were conducted over a 96-hour period postoperatively. Moreover, quantitative immunofluorescence was conducted to assess tissue inflammation. Result: After MSU embedding, rats got more persistent arthritic symptoms as well as tissue MSU deposition. More significant synovial swelling was detected in the MSU group compared to sham groups (P < 0.025). Behavioral tests showed that the embedding of MSU resulted in prolonged mechanical hyperalgesia during 2 hours to 96 hours postoperatively (P < 0.05). MSU depositions enveloped by inflammatory cells that express IL-1ß and TNF-α were detected in embedding groups. Quantitative immunofluorescence suggested that the frequencies of MSU interventions upregulated expression of proinflammatory factors including IL-1ß and TNF-α (P < 0.05). Conclusion: A minimally invasive method was developed to establish modified rat model of intra-articular MSU deposition. This model was proved to be a simple reproducible method to mimic the pathological characteristics of persistent gouty arthritis.


Assuntos
Artrite Gotosa/induzido quimicamente , Artrite Gotosa/patologia , Ácido Úrico/farmacologia , Animais , Artrite Gotosa/metabolismo , Modelos Animais de Doenças , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Inflamação/metabolismo , Inflamação/patologia , Injeções Intra-Articulares/métodos , Interleucina-1beta/metabolismo , Masculino , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
6.
BMC Endocr Disord ; 21(1): 39, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663458

RESUMO

BACKGROUND: Recently, the relationship between thyroid hormones (THs) across the euthyroid ranges and metabolic syndrome (MetS) has been widely discussed. This study aimed to present specific cutoff values of THs to assess the association between THs and MetS in a euthyroid cohort. METHODS: Data of 2694 subjects, aged 18-80 years, who attended health examination in Xi'an Electric Power Central Hospital from April 2011 to December 2015 were collected and analyzed. The first cohort enrolled 929 participants (followed up by 2221 person-years totally) to assess correlations between serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4) levels and MetS. The second cohort included 698 participants (followed up by 1709 person-years totally) to evaluate relationships between serum free triiodothyronine (FT3), free thyroxine (FT4) levels and MetS. MetS was defined according to the criteria of the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) scientific statements of 2009. Euthyroidism was defined as serum TSH, FT3 and FT4 levels within the reference ranges without taking any thyroid medication. RESULTS: The cutoff values for TSH, T3, T4, FT3 and FT4 were 2.0mIU/L, 1.9 nmol/L, 117 nmol/L, 4.3 pmol/L and 16 pmol/L, respectively. Participants were categorized into two groups according to cutoff values: the lower-THs group and the higher-THs group. There was no significant difference in the risk of MetS between two groups in TSH, T3, T4 and FT3. The incidence of MetS was significantly higher in lower-FT4 group than higher-FT4 group (1.00 vs 0.622 (0.458, 0.846), P = 0.002). The lower-FT4/higher-TSH group had the highest hazard ratios of MetS. (2.131vs 1.0 (1.380,3.291), P = 0.006). CONCLUSIONS: Lower normal FT4 (FT4 ≤ 16.0 pmol/L) is an independent risk factor for MetS, and lower normal thyroid function (TSH > 2.0 mIU/L and FT4 ≤ 16.0 pmol/L) is associated with a higher risk of developing MetS.


Assuntos
Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Vigilância da População , Tiroxina/sangue , Adulto , Idoso , China/epidemiologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Síndrome Metabólica/diagnóstico , Pessoa de Meia-Idade , Vigilância da População/métodos , Estudos Retrospectivos , Fatores de Risco , Hormônios Tireóideos/sangue
7.
Thyroid ; 31(4): 638-648, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33076782

RESUMO

Background: Graves' orbitopathy (GO) is the most common and serious manifestation of Graves' disease (GD). It is characterized by orbital inflammation and tissue remodeling. Although several GO models have been reported, most lack a full assessment or mechanistic evaluation. Here, we established a promising mouse model mimicking many aspects of human GO with a frequency of 70% and characterized the key role of T cells in the progression of GO. Methods: An adenovirus expressing the human thyrotropin (TSH) receptor A subunit (Ad-TSHRA) was injected in the muscles of female BALB/C mice nine times to induce GO. At predetermined time points, histological examinations of retrobulbar tissues and thyroid glands were performed to dynamically monitor changes; serum autoantibodies and total thyroxine levels were examined to evaluate thyroid function. Flow cytometry of CD4+ T cell subgroups and RNA sequencing (RNA-Seq) of splenocytes were also performed to explore the underlying mechanism. Results: After nine injections, 7 of 10 mice challenged with Ad-TSHRA developed the orbital changes associated with GO. Seven mice manifested retrobulbar fibrosis, and four mice showed adipogenesis. Exophthalmia, conjunctival redness, and orbital lymphocyte infiltration were also observed in a subset of mice. The orbitopathy was first detected after seven injections and followed the hyperplastic change observed in thyroids after four injections. Flow cytometry revealed increased proportions of Th1 cells and decreased proportions of Th2 cells and regulatory T (Treg) cells in the splenocytes of GO mice. This change in CD4+ T cell subgroups was confirmed by orbital immunohistochemical staining. Genes involved in T cell receptor signaling, proliferation, adhesion, inflammation, and cytotoxicity were upregulated in GO mice according to the RNA-Seq; a trend of upregulation of these GO-specific genes was observed in mice with hyperthyroidism without orbitopathy after four injections. Conclusions: A GO mouse model was successfully established by administering nine injections of Ad-TSHRA. The model was achieved with a frequency of 70% and revealed the importance of T cell immunity. A potential time window from Graves' hyperthyroidism to GO was presented for the first time. Therefore, this model could be used to study the pathogenesis and novel treatments for GO.

8.
Chronic Dis Transl Med ; 6(3): 198-207, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32885155

RESUMO

Background: To date, there is only scare evidence characterizing the temporal features and progression of metabolic dysfunction in high-fat diet (HFD)-fed obese mice. Hence, its specific pathogenesis remains unclear. Methods: Sixty 6-week-old male C57BL/6J mice were randomly divided into HFD and control diet (CD) groups and sacrificed at 1, 5, 9, 13, 17, and 21 weeks, respectively. At weekly intervals, intraperitoneal glucose tolerance testing (IPGTT) and intraperitoneal insulin tolerance testing (IPITT) were performed in both groups. A detailed time course in HFD-fed mice was investigated by evaluating the initiation of glucose homeostasis impairment, dyslipidemia, systemic insulin sensitivity, monocyte chemoattractant protein-1 (MCP-1) levels, epididymal white adipose tissue (eWAT) expansion, macrophage content changes, pro-inflammatory (M1)/anti-inflammatory (M2) macrophage imbalance, lipid accumulation in the liver, and ß-cell morphometry in the pancreas. Results: In the HFD group, progressive weight gain and impairments in glucose metabolism (elevated fasting blood glucose and area under the curve (AUC) of IPGTT) were observed from the 3rd week, and a significantly elevated AUC of IPITT was first detected after week 7 of HFD feeding. As for dyslipidemia, after 9 weeks of feeding, the low-density lipoprotein cholesterol level and total cholesterol level in HFD group were significantly higher than those in the CD group (all P < 0.05), whereas no significant differences were shown in triglyceride level. Adipocyte size increased significantly in the HFD group in the 1st week, a phenotypic switch in eWAT from anti-inflammatory (M2) to pro-inflammatory (M1) macrophages was observed in the 5th week, and the metabolic inflammation was distinct in eWAT in the 9th week. Additionally, liver steatosis was considerably obvious at the 17th week and pancreatic ß-cell morphometry did not change during 21 weeks of HFD feeding. Conclusion: The eWAT expansion was detected early in HFD-induced obese mice, which occurred prior to obvious insulin resistance.

9.
Inorg Chem ; 59(12): 8025-8033, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32464054

RESUMO

Treatment of CoCl2·6H2O and tris(pyrazolyl-1-yl)borate tricyanoiron(III) anions at 55 °C afforded a series of new Fe-Co polynuclear clusters: {Co2Cl2(DMF)4[(Tp4-Me)Fe(CN)3]2} (1; Tp4-Me = hydridotris(4-methylpyrazol-1-yl)borate), (H3O+)@{Co4Cl4[(Tp4-Me)Fe(CN)3]4} (2), (MePh3P)4{Co6Cl6[(Tp4-Me)Fe(CN)3]6}·15CH3CN·3CH3OH·2H2O (3), and (BnEt3N)4{Co5Cl8[(Tp*)Fe(CN)3]4}·4CH3CN·2H2O (4; Tp*= hydridotris(3,5-dimethylpyrazol-1-yl)borate). They feature an asymmetric [Fe2Co2(CN)4] square, a pseudocubic [Fe4Co4(CN)12] cluster, a distorted-hexagonal-prism-shaped [Fe6Co6(CN)18] cage, and a bis(trigonal-bipyramidal) cluster of [Fe4Co5(CN)12] fused at one cobalt center, respectively. The Co(II) ions adopt a four-coordinate tetrahedral geometry except for half of 1 in an octahedral geometry. It should be mentioned that 3 and 4 provide two novel molecular skeletons in the cyanometalate family. Interestingly, 1 behaved as a single-molecule magnet with an effective energy barrier for spin reverse of 30.7 K at zero dc field. Our result demonstrated a possible self-assembly route toward high-nuclearity cyanide-bridged clusters by introducing four-coordinate cobalt(II) ions.

10.
Epilepsia Open ; 5(1): 50-60, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32140643

RESUMO

Objective: To investigate the effect of water extract of Gastrodiae Rhizoma (GR) on the development of acquired temporal lobe epilepsy (TLE) and on regulating the expression of the mammalian target of rapamycin (mTOR) and semaphorin 3F (SEMA3F). Methods: A pilocarpine-induced status epilepticus (SE) model was adopted to precipitate injury in the limbic systems. GR and carbamazepine (CBZ) treatments were given to mice for 14 days prior to SE induction to demonstrate the antiepileptic effects and continued for 5 more days to illustrate the effects on histologic studies. Results: Our results consolidated that GR treatment (92.1 minutes) could delay the SE onset in comparison with the control group (61.5 minutes, P = .041). Fewer mice had reached SE with GR treatment (41.7%) when compared with the control group (83.3%, P = .044). GR treatment (2.1 hours/mouse) could suppress the number of acute seizures in post-SE survival mice when compared with the control group (4.5 hours/mouse, P < .001). The effects of GR treatment were elucidated with the mechanism of actions. GR treatment reduced the overexpression of mTOR (0.27 vs 0.67 AU/mg protein, P = .047). GR treatment increased the underexpression of SEMA3F (0.51 vs 0.16 µg/mg protein, P = .034). In the histochemical study of microtubule-associated protein 2 (MAP2) staining, our results showed that GR prevented neuronal loss in the GR treatment group (64.8% positively stained pixel area) as compared with the control group (59%, P = .014) in the hippocampus. In glial fibrillary acidic protein (GFAP) staining, the severity of astrogliosis was mitigated by the GR treatment (4.1% positively stained pixel area) when compared to the control group (5.6%, P = .047) in the hippocampus. Significance: These results provide preclinical evidence to support the use of GR, which could suppress acute seizures and relieve pathological changes in pilocarpine-induced TLE mice. We demonstrated that the antiepileptic effects of GR could be accompanied by mTOR reduction and astrogliosis attenuation.

11.
Chem Asian J ; 12(20): 2763-2769, 2017 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-28914496

RESUMO

A series of seven new complexes including silver-thiolate molecular clusters and their covalent supramolecular frameworks have been assembled from the silver carbide precursor Ag2 C2 using a C22- pre-templated approach. Herein, two prototype clusters Ag14 (SR)6 and CO3 @Agm (SR)10 (R=isopropyl, cyclohexyl or tert-butyl; m=18 or 20) are employed to construct cluster-based metal-organic frameworks of different dimensions. In particular, both new ellipsoidal tetradecanuclear molecular cluster compounds, namely, Ag14 (S-iPr)6 (CO2 CF3 )8 ⋅(DMSO)6 (two polymorphic forms 1, 2) and [Ag14 (S-Cy)6 (CO2 CF3 )8 (DMSO)4 ]⋅(DMSO)3 (3), and a cluster-based metal-organic framework {Ag3 [Ag14 (S-iPr)6 (CO2 CF3 )11 (H2 O)3 CH3 OH]⋅(H2 O)2.5 }n (4) have been isolated and structurally characterized. Furthermore, increased acidity of the reaction mixture afforded three carboxylate-templated cluster based frameworks: a chain-like compound {[HN(CH3 )2 CO]⋅[CO3 @Ag18 (S-tBu)10 (NO3 )7 (DMF)4 ]⋅DMF}n (5), as well as two layer-type compounds, namely, {Ag[CO3 @Ag20 (S-iPr)10 (CO2 CF3 )9 (CO2 HCF3 )(CH3 OH)2 ]}n (6) and {Ag2 [CO3 @Ag20 (S-Cy)10 (CO2 CF3 )10 (CO2 HCF3 )2 (H2 O)2 ]⋅(H2 O)3 ⋅(CH3 OH)3 }n (7) exhibiting sql-net characteristics. It is demonstrated that the C≡C2- pre-template, which draws several Ag+ ions together to form the C2 @Agn entity, plays an indispensable role in the syntheses of these compounds. Furthermore, covalent linkage of these nano-sized silver thiolate clusters from one- to three-dimensions revealed enormous potential for the future development of silver cluster-based frameworks.

12.
Nanoscale ; 9(26): 8930-8937, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28650033

RESUMO

Using a chloride-assisted supramolecular building-block approach, we have employed the molecular Cl@Agm(C[triple bond, length as m-dash]CPh)n entity in the construction of a gigantic cluster namely [Ag216S56Cl7(C[triple bond, length as m-dash]CPh)98(H2O)12][Ag3(imidazole)(H2O)4](SbF6)2 (1), which contains the largest discrete organometallic cluster investigated by X-ray crystallography. Based on an icosahedral Cl@Ag12 kernel, this spheroidal cluster features an unprecedented five-shell structure Cl@Ag12@S12@Ag32@S44Cl6@Ag172 with idealized Th symmetry. The MALDI-MS, 1D, 2D 1H NMR, electronic absorption, emission spectra and HR-TEM of 1 were measured. Compound 1 shows intense red luminescence in solution at room temperature (QY = 4.7% in CH2Cl2), in addition to its 3.4 nm diameter, which makes it a unique example that fills the gap between small luminescent silver clusters and large luminescent silver nanoparticles.

13.
Chem Commun (Camb) ; 52(36): 6119-22, 2016 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-27071972

RESUMO

Inexpensive 1,1'-thiocarbonyldiimidazole and di(2-pyridyl) thionocarbonate have been used as respective sulfide precursors to assemble unprecedented high-nuclearity ethynide-stabilized silver(i) sulfido molecular clusters [Ag9S6@Ag36(C[triple bond, length as m-dash]C(t)Bu)32(H2O)2] [Ag(imidazole)(CH3OH)(H2O)](BF4)2·8H2O·2CH3OH (1) and [Ag120S24(PhC[triple bond, length as m-dash]C)52Cl4(2-pyridone)10(H2O)8](H3O)4(SiF6)8(BF4)4·CH3OH·22H2O (2), the latter being the largest isolated silver(i) ethynide cluster reported to date.

14.
Inflamm Res ; 64(10): 789-97, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26249853

RESUMO

BACKGROUND AND AIM: Studies have verified the protective effect of Hydrogen Sulfide (H2S) on gastric ulcer and ulcerative colitis, but the mechanisms are not fully illustrated. In this study, the possible protective effect of H2S on TNF-α/IFN-γ induced barrier dysfunction was investigated in Caco-2 cell monolayers. METHOD: The barrier function of Caco-2 monolayers was evaluated by measuring trans-epithelial electrical resistance (TEER) and FITC-Dextran 4 kDa (FD-4) trans-membrane flux. ZO-1 and Occludin were chosen as markers of the localization of tight junction (TJ) proteins for immunofluorescence. The expression of MLCK and phosphorylation level of myosin light chain (MLC) were measured by immunoblotting. The activation of NF-kB p65 was analyzed by EMSA and immunofluorescence. RESULTS: NaHS at 500 uM significantly attenuated TNF-α/IFN-γ-indueced Caco-2 monolayer barrier injury. The increased expression of MLCK and increased phosphorylation level of MLC induced by TNF-α/IFN-γ was also inhibited significantly by NaHS. Additionally, NaHS inhibited TNF-α/IFN-γ induced activation and nuclear translocation of NF-kB p65. CONCLUSION: The present study reveals the protective effect of H2S on TNF-α and IFN-γ-induced injury of intestinal epithelial barrier function in Caco-2 monolayers and suggests that the suppression of MLCK-P-MLC signaling mediated by NF-kB P65 might be one of the mechanisms underlying the protective effect of H2S.


Assuntos
Epitélio/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Interferon gama/antagonistas & inibidores , Interferon gama/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/toxicidade , Biomarcadores/metabolismo , Células CACO-2 , Humanos , Mucosa Intestinal/citologia , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Ocludina/metabolismo , Fosforilação , Úlcera Gástrica/patologia , Úlcera Gástrica/prevenção & controle , Proteínas de Junções Íntimas/metabolismo , Fator de Transcrição RelA/metabolismo
15.
Toxicol Lett ; 237(2): 79-88, 2015 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-26068064

RESUMO

Studies have suggested the role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in protecting intestinal barrier function from injuries induced by multiple reagents. Vitamin D deficiency was reported to be associated with poor prognosis in patients with alcoholic liver disease (ALD). This study is designed to investigate the effect of 1,25(OH)2D3 on ethanol-induced intestinal barrier dysfunction and the underlying mechanisms utilizing Caco-2 cell monolayers and a mouse model with acute ethanol injury. In Caco-2 monolayers, ethanol significantly increased monolayer permeability, disrupted TJ distribution, increased phosphorylation level of MLC, and induced generation of ROS compared with controls. However, pre-treatment with 1,25(OH)2D3 greatly ameliorated the ethanol-induced barrier dysfunction, TJ disruption, phosphorylation level of MLC, and generation of ROS compared with ethanol-exposed monolayers. Mice fed with vitamin d-sufficient diet had a higher plasma level of 25(OH)D3 and were more resistant to ethanol-induced acute intestinal barrier injury compared with the vitamin d-deficient group. These results suggest that the suppression of generation of ROS and increased phosphorylation level of MLC might be one of the mechanisms underlying the protective effect of 1,25(OH)2D3 on ethanol-induced intestinal barrier injury and provide evidence for the application of vitamin D as therapeutic factors against ethanol-induced gut leakiness.


Assuntos
Calcitriol/farmacologia , Etanol/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Impedância Elétrica , Feminino , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Cadeias Leves de Miosina/metabolismo , Permeabilidade , Fosforilação , Substâncias Protetoras/farmacologia , Proteína da Zônula de Oclusão-1/análise
16.
PLoS One ; 10(5): e0124835, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25946026

RESUMO

Exogenous intestinal alkaline phosphatase (IAP), an enzyme produced endogenously at the brush edge of the intestinal mucosa, may mitigate the increase in aberrant intestinal permeability increased during sepsis. The aim of this study was to test the efficacy of the inhibitory effect of IAP on acute intestinal inflammation and to study the molecular mechanisms underlying IAP in ameliorating intestinal permeability. We used an in vivo imaging method to evaluate disease status and the curative effect of IAP. Two Escherichia coli (E.coli) B21 strains, carrying EGFP labeled enhanced green fluorescent protein (EGFP) and RFP labeled red fluorescent protein (RFP), were constructed as tracer bacteria and were administered orally to C57/B6N mice to generate an injection peritonitis (IP) model. The IP model was established by injecting inflammatory lavage fluid. C57/B6N mice bearing the tracer bacteria were subsequently treated with (IP+IAP group), or without IAP (IP group). IAP was administered to the mice via tail vein injections. The amount of tracer bacteria in the blood, liver, and lungs at 24 h post-injection was analyzed via flow cytometry (FCM), in vivo imaging, and Western blotting. Intestinal barrier function was measured using a flux assay with the macro-molecule fluorescein isothiocyanate dextran, molecular weight 40kD, (FD40). To elucidate the molecular mechanism underlying the effects of IAP, we examined the levels of ERK phosphorylation, and the expression levels of proteins in the ERK-SP1-VEGF and ERK-Cdx-2-Claudin-2 pathways. We observed that IAP inhibited the expression of Claudin-2, a type of cation channel-forming protein, and VEGF, a cytokine that may increase intestinal permeability by reducing the levels of dephosphorylated ERK. In conclusion, exogenous IAP shows a therapeutic effect in an injection peritonitis model. This including inhibition of bacterial translocation. Moreover, we have established an imaging methodology for live-animals can effectively evaluate intestinal permeability and aberrant bacterial translocation in IP models.


Assuntos
Fosfatase Alcalina/administração & dosagem , Escherichia coli/química , Escherichia coli/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Peritonite/microbiologia , Animais , Sangue/microbiologia , Células CACO-2 , Modelos Animais de Doenças , Escherichia coli/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/microbiologia , Substâncias Luminescentes/metabolismo , Pulmão/microbiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Peritonite/etiologia , Peritonite/metabolismo , Permeabilidade , Fosforilação
17.
Inflammation ; 38(1): 375-83, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25344656

RESUMO

Lipopolysaccharide was found to be elevated in the plasma of necrotizing enterocolitis (NEC) and inflammatory bowel disease (IBD) patients and may play an important role in the pathogenesis and propagation of these intestinal diseases. To illustrate the destructive effect of lipopolysaccharide (LPS) and to test the protective effect of 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) on LPS-induced barrier injury, an in vitro intestinal epithelia barrier model was established with Caco-2 monolayers and treated with clinically relevant concentrations (1-10 ng/ml) of LPS with or without 1,25(OH)2D3. Transepithelial electrical resistance (TEER) and FITC-Dextran 40kda (FD-40) flux were measured to reflect monolayer permeability. We found that LPS at clinically relevant concentrations increased intestinal permeability by downregulating and redistributing tight junction (TJ) proteins. 1,25(OH)2D3 added at baseline or at day 4 abrogated the destructive effect of LPS on monolayer permeability by restoring the expression and localization of TJ proteins. LPS, at clinically relevant concentrations, also downregulated the expression of vitamin D receptor (VDR); 1,25 (OH)2D3, however, could restore the expression of VDR. Our findings illustrate the mechanism underlying the destructive effect of clinically relevant concentrations of LPS on intestinal TJ barrier and provide evidence for the clinical application of vitamin D in LPS-related intestinal barrier dysfunction.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/toxicidade , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Vitamina D/análogos & derivados , Células CACO-2 , Humanos , Substâncias Protetoras/farmacologia , Vitamina D/farmacologia
18.
Sci Rep ; 4: 7035, 2014 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-25516351

RESUMO

Secreted protein acidic and rich in cysteine (SPARC) gene has been shown to be epigenetically silenced in several cancers. We investigated the loss of expression and promoter methylation of this tumor suppressor gene in gastric cancers and correlated the data with clinicopathological features. We observed the loss of SPARC mRNA and SPARC protein expression in 7 of 10 (70%) gastric cancer cell lines. Upon treatment of expression-negative cell lines with a demethylating agent, expression of mRNA and protein was restored in all cells. Methylation rate of SPARC gene was 80% in ten gastric cancer cell lines and 74% (163 of 220) in primary tumors, while it was 5% in normal gastric mucosa (n = 40). In intestinal gastric cancer, SPARC methylation correlated with a negative prognosis (P < 0.001; relative risk 2.754, 95% confidence interval 1.780-4.261). Immunostaining revealed that SPARC protein was overexpressed in stromal fibroblasts adjacent to neoplastic epithelium but rarely expressed in the primary gastric cancer cells. These results implicate SPARC promoter methylation as an important factor in the tumorigenesis of gastric carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and the potential clinical importance in human gastric cancers.


Assuntos
Metilação de DNA/genética , Osteonectina/genética , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Carcinogênese/genética , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular , Linhagem Celular Tumoral , Epitélio/patologia , Fibroblastos/patologia , Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Prognóstico , RNA Mensageiro/genética , Neoplasias Gástricas/patologia
19.
Seizure ; 21(9): 729-33, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22944116

RESUMO

PURPOSE: The incidence of polycystic ovary syndrome (PCOS) increases in women with epilepsy (WWE), which appears to vary with ethnicity. This study was conducted to determine the incidence and risk factors of PCOS in Chinese WWE. METHODS: The study was carried out in 102 of 139 Chinese WWE at reproductive ages, with 32 receiving valproic acid (VPA), 40 receiving other antiepileptic drugs (AEDs), and 30 without AEDs therapy. PCOS was defined as having 2 or more of the following components: polycystic ovaries, hyperandrogenism, and amenorrhoea or oligomenorrhoea (a/oligomenorrhoea). RESULTS: One or more isolated components of PCOS were found in 56 (54.9%) patients, with 29 (28.4%) having polycystic ovaries, 20 (19.6%) with a/oligomenorrhea, 7 (6.9%) with hyperandrogenism, and 13 (12.7%) with defined PCOS. Their average age at the start of seizure was 13.8±6.5 years, younger than that of patients without these disorders (16.9±8.6 years, p<0.05). VPA therapy increased the incidence of PCOS (11/32, 34.4%), in addition to increased blood levels of testosterone and luteinizing hormone (LH) as well as LH to FSH (follicle-stimulating hormone) ratio. No significant relationship was found between the incidence of PCOS and the type, duration, or frequency of seizures in these WWE. CONCLUSION: There is an increased incidence of PCOS in Chinese WWE at reproductive ages, by more than 2 times of that in the general population. Risk factors include seizures starting at a young age and VPA therapy.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Epilepsia/etnologia , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/etnologia , Ácido Valproico/efeitos adversos , Adolescente , Adulto , Biomarcadores/sangue , Criança , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/sangue , Fatores de Risco , Testosterona/sangue , Adulto Jovem
20.
Immunopharmacol Immunotoxicol ; 34(2): 196-204, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21721923

RESUMO

Many attempts have been made to develop in vitro sensitization tests that employ dendritic cells (DCs), DC-like cell lines or keratinocytes. The aim of the present investigation was to establish a co-culture of THP-1 cells and keratinocytes for evaluation of skin sensitization potential of chemicals. Co-cultures were constructed by THP-1 cells cultured in lower compartments and keratinocytes cultured in upper compartments of cell culture inserts. After 24 h exposure to sensitizers (2, 4-dinitrochlorobenzene, p-phenylenediamine, formaldehyde, nickel sulfate, isoeugenol and eugenol) and non-sensitizers (sodium lauryl sulfate, benzalkonium chloride and lactic acid), the expression of CD86 and CD54 on THP-1 cells were evaluated by flow cytometry, and cell viabilities were determined. The sensitizers induced the augmentation of CD86 and CD54 expression, but the non-sensitizers had no significant effect. Compared with mono-cultures of THP-1 cells, the augmentation of CD86 and CD54 could be detected even at a non-toxic concentration of sensitizers in THP-1 cell/keratinocyte co-cultures. Moreover, isoeugenol was distinguished as a sensitizer in co-cultures, but failed to be identified in mono-cultures. These results revealed that the co-cultures of THP-1 cells and keratinocytes were successfully established and suitable for identifying sensitizers using CD86 and CD54 expression as identification markers.


Assuntos
Alternativas aos Testes com Animais/métodos , Dermatite Alérgica de Contato/imunologia , Haptenos/imunologia , Queratinócitos/imunologia , Monócitos/imunologia , Antígeno B7-2/metabolismo , Compostos de Benzalcônio/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Dinitroclorobenzeno/imunologia , Dinitroclorobenzeno/farmacologia , Eugenol/análogos & derivados , Eugenol/imunologia , Eugenol/farmacologia , Formaldeído/imunologia , Formaldeído/farmacologia , Haptenos/farmacologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Queratinócitos/citologia , Ácido Láctico/imunologia , Ácido Láctico/farmacologia , Monócitos/citologia , Monócitos/metabolismo , Níquel/imunologia , Níquel/farmacologia , Fenilenodiaminas/imunologia , Fenilenodiaminas/farmacologia , Sensibilidade e Especificidade , Testes Cutâneos/métodos , Dodecilsulfato de Sódio/farmacologia
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