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1.
Materials (Basel) ; 17(11)2024 May 29.
Article in English | MEDLINE | ID: mdl-38893892

ABSTRACT

High-temperature tensile tests were developed to explore the flow features of an Al-Zn-Mg-Cu alloy. The fracture characteristics and microstructural evolution mechanisms were thoroughly revealed. The results demonstrated that both intergranular fractures and ductile fractures occurred, which affected the hot tensile fracture mechanism. During high-temperature tensile, the second phase (Al2CuMg) at the grain boundaries (GBs) promoted the formation and accumulation of dimples. With the continual progression of high-temperature tensile, the aggregation/coarsening of dimples along GBs appear, aggravating the intergranular fracture. The coalescence and coarsen of dimples are reinforced at higher tensile temperatures or lower strain rates. Considering the impact of microstructural evolution and dimple formation/coarsening on tensile stresses, a physical mechanism constitutive (PMC) equation is herein proposed. According to the validation and analysis, the predictive results were in preferable accordance with the testing data, showing the outstanding reconfiguration capability of the PMC model for high-temperature tensile features in Al-Zn-Mg-Cu alloys.

2.
Materials (Basel) ; 16(18)2023 Sep 13.
Article in English | MEDLINE | ID: mdl-37763471

ABSTRACT

Isothermal deformation experiments of the Hastelloy C276 alloy were executed using the Gleeble-3500 hot simulator at a temperature range of 1000-1150 °C and a strain rate range of 0.01-10 s-1. Microstructural evolution mechanisms were analyzed via transmission electron microscope (TEM) and electron backscatter diffraction (EBSD). Results reveal that the influences of hot compression parameters on the microstructure variation features and flow behaviors of the Hastelloy C276 alloy were significant. The intense strain hardening (SH) effects caused by the accumulation of substructures were promoted when the strain rates were increased, and true stresses exhibited a notable increasing tendency. However, the apparent DRV effects caused by the annihilation of substructures and the increasingly dynamic recrystallization (DRX) behaviors occurred at high compressed temperature, inducing the reduction in true stresses. In addition, a physical-based (PB) constitutive model and a long short-term memory (LSTM) model optimized using the particle swarm optimization (PSO) algorithm were established to predict the flow behavior of Hastelloy C276 alloy. The smaller average absolute relative error and greater relation coefficient suggest that the LSTM model possesses a higher forecasting accuracy than the PB model.

3.
J Immunol Res ; 2021: 6234560, 2021.
Article in English | MEDLINE | ID: mdl-33575361

ABSTRACT

BACKGROUND: The Traditional Chinese Medicine NiuBeiXiaoHe (NBXH) is a valid antituberculosis (TB) prescription from the experience of clinical practice. However, the mechanism of NBXH extracts' immunotherapy has been poorly understood. Herein, the immunotherapeutic efficacy and the differentially expressed (DE) genes of NBXH extracts were evaluated and identified in BALB/c mice. METHODS: The total RNA was extracted from peripheral blood mononuclear cells, and the DE genes were identified by gene chip. The enrichment and signaling pathway analyses were performed using Gene Ontology (GO) and KEGG database. RESULTS: It was shown that the treatment of NBXH extracts (high dose) significantly reduced mycobacteria loads and histopathological lesions in mice infected by Mycobacterium tuberculosis and resulted in 3,454 DE upregulated genes and 3,594 downregulated DE genes. Furthermore, NBXH extracts killed mycobacteria by inhibiting the supply of necessary ingredients for their growth and proliferation. They restored the disordered immune microenvironments by up- or downregulating immune and inflammation-related pathways. CONCLUSIONS: Taken together, NBXH extracts not only efficiently decreased the mycobacteria loads but also balanced the immune disorders in mice. These new findings provide a fresh perspective for elucidating the immunotherapeutic mechanism of NBXH extracts and pointed out the direction for improving the treatment efficacy of NBXH extracts.


Subject(s)
Antitubercular Agents/pharmacology , Drugs, Chinese Herbal/pharmacology , Immunologic Factors/pharmacology , Mycobacterium tuberculosis/drug effects , Tuberculosis/drug therapy , Tuberculosis/microbiology , Animals , Antitubercular Agents/administration & dosage , Bacterial Load , Biomarkers , Biopsy , Computational Biology , Disease Models, Animal , Disease Susceptibility , Drugs, Chinese Herbal/administration & dosage , Female , Gene Expression Profiling , Gene Ontology , Immunologic Factors/administration & dosage , Medicine, Chinese Traditional , Mice , Mice, Inbred BALB C , Organ Specificity , Signal Transduction
4.
Anal Bioanal Chem ; 413(7): 1955-1966, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33481048

ABSTRACT

The selective detection of salicylaldehyde skeleton is of great significance in phytochemistry and biological research but rarely reported. In this research, a simple and highly selective "turn-on" fluorescence sensor (CDB-Am) for salicylaldehyde skeleton was developed based on switch of photoinduced electron transfer (PET) and aggregation-induced emission (AIE). CDB-Am bearing amino-cyanodistyrene structure responded to salicylaldehyde in the range of 3.1 to 40 µM with a detection limit of 0.94 µM. The sensing process of formation of Schiff-base adduct CDB-SA was confirmed by 1H NMR, MS, and FT-IR spectra, revealing that a recovered AIE property accounted for the turn-on fluorescence response of CDB-Am and the intramolecular hydrogen bonding played a crucial role in the disruption of PET process. This sensing ability was successfully applied for both fluorescence qualitative test of salicylaldehyde skeleton on TLC analysis and quantitative detection of salicylaldehyde skeleton with good accuracy in the root bark of Periploca sepium, suggesting the extensive applications in phytochemistry and traditional Chinese herbal medicine. Furthermore, CDB-Am exhibited the first excellent fluorescence imaging ability in detecting salicylaldehyde skeleton in a living system. This work supplied a new strategy of preparing a novel "turn-on" fluorescence probe for detecting salicylaldehyde skeleton in complex environments and living bodies.


Subject(s)
Aldehydes/analysis , Fluorescent Dyes/analysis , Schiff Bases/analysis , Spectroscopy, Fourier Transform Infrared/methods , Chromatography, Thin Layer , Fluorescence , Humans , Hydrogen Bonding , Hydroxyl Radical , Imines/chemistry , Limit of Detection , MCF-7 Cells , Magnetic Resonance Spectroscopy , Mass Spectrometry , Medicine, Chinese Traditional , Microscopy, Fluorescence , Optical Imaging , Plant Bark , Plant Roots , Spectrophotometry, Ultraviolet , Tetrazolium Salts/analysis , Thiazoles/analysis
5.
Spectrochim Acta A Mol Biomol Spectrosc ; 248: 119191, 2021 Mar 05.
Article in English | MEDLINE | ID: mdl-33239250

ABSTRACT

Previously reported fluorescent sensors for Th4+ experienced emission quenching or generated false positive signal upon aggregate formation in aqueous media. Herein, a simple and novel thorium sensor (CDB-BA) based on cyanodistyrene structure was designed and synthesized, which integrated the highly emitting characteristic of AIE effect and off-on response of PET modulation for the first time to construct the "turn-on" fluorescent probe for Th4+. Besides excellent selectivity, CDB-BA exhibited remarkable fluorescent enhancement which was linearly related to the concentration of Th4+ in the range of 0.25-8 µM. The detection limit was attained 0.074 µM, which was lower than that of most previously reported sensors. The mechanism of tris-chelate complex of CDB-BA with Th4+ was confirmed by mass spectra, IR spectra and DFT calculation. The excellent Th4+ sensing ability of CDB-BA was successfully applied to detecting Th4+ on TLC plates, in real water samples and living-cell imaging. This work suggested that the combination of AIE and PET photophysical mechanism could offer the merits of minimized background and enhanced signal fidelity to develop novel "turn-on" fluorescent probe in complicated aqueous environment and biological research.


Subject(s)
Fluorescent Dyes , Water , Positron-Emission Tomography
6.
Chem Commun (Camb) ; 56(56): 7745-7748, 2020 Jul 18.
Article in English | MEDLINE | ID: mdl-32579619

ABSTRACT

Circularly polarized luminescence controlled by both mechanics and temperature was observed for the first time. The cyano-distyrylbenzene-cholesterol liquid crystals exhibited not only mechanochromism and thermochromism but also mechanically induced and thermally induced circularly polarized.

7.
Spectrochim Acta A Mol Biomol Spectrosc ; 227: 117568, 2020 Feb 15.
Article in English | MEDLINE | ID: mdl-31654844

ABSTRACT

Although all kinds of sensors with unique detecting ability for one guest were reported, the fluorescence sensor with multiple detecting abilities was seldom presented. This work designed and synthesized a novel AIE fluorescence probe bearing double detecting for ATP based on Cu2+ and Zn2+ response of hydrazono-bis-tetraphenylethylene (Bis-TPE). Bis-TPE was prepared in 82% yield with simple procedure. It exhibited strong red AIE fluorescence based on the large conjugated electron effect in aqueous media. It showed outstanding selective sensing abilities for Cu2+ by strong fluorescence quenching and for Zn2+ by red-orange fluorescence change. The sensing mechanism of 1:1 stoichiometric ratios was confirmed by 1H NMR and MS study. The strong red fluorescence of Bis-TPE + Cu2+ system could be recovered by adding ATP. The orange fluorescence of Bis-TPE + Zn2+ system could be quenched by adding Cu2+ and then was recovered by adding ATP. These double detecting abilities for ATP with the "off-on" red fluorescence in Bis-TPE + Cu2+ system and "allochroic-off-on" orange fluorescence in Bis-TPE + Zn2++Cu2+ system were successfully applied to test Cu2+, Zn2+ and ATP in test paper and living cell imaging, displaying the good application prospects for sensing Cu2+, Zn2+ and double detecting ATP in the complicated environment.

8.
Exp Ther Med ; 15(6): 4723-4730, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29849781

ABSTRACT

MicroRNA (miR)-423-5p is a potential target for the diagnosis and therapy of heart failure and cancer. The present study aimed to investigate the expression and role of miR-423-5p in ovarian cancer. miR-423-5p expression in ovarian tissues and plasma collected from ovarian cancer patients and healthy volunteers was analyzed by polymerase chain reaction analysis. In addition, a cell proliferation assay, clonogenic assay and Matrigel-based assay were performed to evaluate the role of miR-423-5p in ovarian cancer cells. The results demonstrated that miR-423-5p was downregulated in ovarian cancer tissues and plasma from ovarian cancer patients, compared with healthy individuals. Of note, miR-423-5p expression in ovarian tissues and plasma was demonstrated to be inversely correlated with ovarian cancer progression. Transfection with miR-423-5p efficiently increased miR-423-5p expression in A2780-s and A2780-cp cells, which had low miR-423-5p expression. Ectopic overexpression of miR-423-5p reduced cell proliferation, colony formation and invasion of ovarian cancer cells. In conclusion, the present study indicated that miR-423-5p may serve as a diagnostic indicator and functions as a tumor suppressor in ovarian cancer.

9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(5): 1415-1419, 2017 Oct.
Article in Chinese | MEDLINE | ID: mdl-29070117

ABSTRACT

OBJECTIVE: To explore the clinical efficacy of GEMOX regimen on patients with refractory non-hodgkin's lymphoma. METHODS: Eighty-two cases of non-Hodgkin's lymphoma were divided into 2 groups: gemcitabine+oxaliplation(Gem+Oxa) group (42 cases) and vinorelbine+oxaliplatin(Vin+Oxa) group (40 cases) according to chemotherapy regimens. The clinical efficacy, side effects, progression-free survival situation in 2 groups were compared. RESULTS: There was no significant difference on the clinical effects of 2 groups (P>0.05); The therapeutic efficacy for B cell lymphoma was higher than that for T cell lymphoma(P<0.05); The therapeutic effects for I-II stages was lower than that for III-IV stages(P<0.05); The incidences of platelet decline, nausea and vomit, peripheral nerve symptoms in Gem+Oxa group were lower than those in Vin+Oxa group(P<0.05); There was no significant difference in the median progression free survival(P>0.05). CONCLUSION: The efficacy of GEMOX regimen for refractory non-Hodgkin's lymphoma has been confirmed to be good, it has distinct clinical curative effect, it can prolong the progression-free survival time in patients with B cell lymphoma, specially for III-IV stages. It can be used as the preferred method for the treatment of patients with refractory NHL.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Humans , Lymphoma, B-Cell , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , Vinorelbine
10.
Cell Biochem Funct ; 35(7): 433-440, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28961318

ABSTRACT

Progress in the understanding of the molecular mechanism for acute myeloid leukaemia is of great significance to generate new potential targets for treatment. Recent studies showed that HOXA9, a homeodomain-containing transcription factor, is commonly deregulated in acute leukaemia. In this study, we elucidated the direct correlation between HoxA9 expression and progression of leukaemia using 2 different types of leukaemia cells HL-60 and MOLT-3. The HoxA9 expression level was decreased in leukaemia cells with the treatment of all-trans retinoic acid or arsenic trioxide (As2 O3 ). Downregulation of HoxA9 could impair the proliferation and promote the leukaemia cell death. HoxA9 silencing also potentiated the differentiation of leukaemia cells, and in vivo studies demonstrated that HoxA9 downregulation could interfere the tumour growth. Interestingly, HoxA9 silencing also led to the alteration in miRNA expression, mediating the promoting effect on the leukaemia cell differentiation. Therefore, this work provided a promising and potentially efficient target to leukaemia treatment, indicating that HoxA9 is likely to be an ideal candidate in the gene therapy against acute myeloid leukaemia. In this study, we elucidated the critical role of HoxA9 in the proliferation and differentiation of leukaemia cells both in vitro and in vivo. The effect of HoxA9 modulation was correlated with the clinical effect of all-trans retinoic acid and As2 O3 . Furthermore, HoxA9 also regulated the miRNA expression, controlling the leukaemia cell differentiation. Therefore, this work provided new insights into molecular mechanism underlying the leukaemia treatment, potentially putting forward a brand new target to the gene therapy against leukaemia.


Subject(s)
Cell Differentiation , Cell Proliferation , Homeodomain Proteins/metabolism , Animals , Apoptosis/drug effects , Arsenic Trioxide , Arsenicals , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , HL-60 Cells , Homeodomain Proteins/antagonists & inhibitors , Homeodomain Proteins/genetics , Humans , Leukemia/metabolism , Leukemia/pathology , Male , Mice , Mice, Nude , MicroRNAs/metabolism , Oxides/toxicity , RNA Interference , RNA, Messenger/metabolism , Transplantation, Heterologous , Tretinoin/toxicity
11.
J Mol Graph Model ; 75: 125-131, 2017 08.
Article in English | MEDLINE | ID: mdl-28551502

ABSTRACT

The TAM receptor tyrosine kinase family member Mer has been recognized as an attractive therapeutic target for pediatric leukemia. Beside Mer the family contains other two kinases, namely, Tyro3 and Axl, which are highly homologues with Mer and thus most existing small-molecule inhibitors show moderate or high promiscuity across the three kinases. Here, the structural basis and energetic property of selective binding of small-molecule inhibitors to the three kinases were investigated at molecular level. It is found that the selectivity is primarily determined by the size, shape and configuration of kinase's ATP-binding site; the Mer and Axl possess a small, closed active pocket as compared to the bulky, open pocket of Tyro3. The location and conformation of active-site residues of Mer and Axl are highly consistent, suggesting that small-molecule inhibitors generally have a low Mer-over-Axl selectivity and a high Mer-over-Tyro3 selectivity. We demonstrated that the difference in ATP binding potency to the three kinases is also responsible for inhibitor selectivity. We also found that the long-range interactions and allosteric effect arising from rest of the kinase's active site can indirectly influence inhibitor binding and selectivity.


Subject(s)
Leukemia/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Small Molecule Libraries/chemistry , Small Molecule Libraries/therapeutic use , Amino Acid Sequence , Child , Crystallography, X-Ray , Enzyme Assays , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Protein Domains , Receptor Protein-Tyrosine Kinases/chemistry , Sequence Alignment
12.
J Ethnopharmacol ; 195: 318-323, 2017 Jan 04.
Article in English | MEDLINE | ID: mdl-27884716

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine Niubeixiaohe (NBXH) is an effective anti-tuberculosis prescription, which is made up of Bulbus Fritillariae Cirrhosae, Rhizoma Bletillae, Radix Platycodonis, Fructus Arctii, Herba Houttuyniae and Glutinous rice. In this study, NBXH powder (I) and three kinds of NBXH extracts (II, III, and IV) were prepared. The water decoction of NBXH had been used to treat TB in clinic sixteen years suggested that it was effective to treat TB. AIM OF THE STUDY: This study evaluated the effects of different processing products of NBXH on mouse TB model in vivo and provide a new Chinese medicine for the clinical treatment of TB. MATERIALS AND METHODS: In this study, 120 female BALB/c mice infected with Mycobacterium tuberculosis H37Rv, were treated with distilled water, M. vaccae vaccine, the low, middle and high doses of NBXH I, the low, middle and high doses of NBXH II, the low, middle and high doses of NBXH III, the low, middle and high doses of NBXH IV for 12 weeks, respectively. RESULTS: The body weights of mice in all NBXH groups were higher than that in the water group. The weight indexes of the spleens in M. vaccae group, the middle dose of NBXH II group, the low dose of NBXH IV group and in the high dose of NBXH IV group were significantly lower than that in the water group(P<0.05). Compared with the water group, the spleen colony counts in the low dose of NBXH I group, the high dose of NBXH II group, the low dose of NBXH III group and the high dose of NBXH IV group reduced by 0.43, 0.46, 0.73, 0.58 logs (P<0.05), respectively. But the lung colony counts had no significant difference between each group. Pulmonary general pathology and histopathology displayed that the lung lesions in treatment groups were improved at certain degree, especially in the low dose of NBXH IIIand IV groups, in which their areas of the lesions were less than 50%, and the half normal lung structure in half of the mice could be observed. CONCLUSION: Powder and three extracts of traditional Chinese medicine NBXH all had anti-tuberculosis therapeutic effects on mouse tuberculosis model, and this study provided a base for the further development of Chinese patent medicine NBXH. Also, this is the first report on comprehensive experimental research of NBXH extracts coming from six kinds of traditional Chinese medicine.


Subject(s)
Antitubercular Agents/pharmacology , Drugs, Chinese Herbal/pharmacology , Lung/drug effects , Mycobacterium tuberculosis/drug effects , Tuberculosis, Pulmonary/drug therapy , Animals , Bacterial Load , Body Weight/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Compounding , Female , Lung/microbiology , Lung/pathology , Mice, Inbred BALB C , Mycobacterium tuberculosis/isolation & purification , Mycobacterium tuberculosis/pathogenicity , Organ Size , Powders , Spleen/drug effects , Spleen/microbiology , Spleen/pathology , Time Factors , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology
13.
Dalton Trans ; 45(42): 17020-17029, 2016 Nov 14.
Article in English | MEDLINE | ID: mdl-27711770

ABSTRACT

An amidinato-phosphino ligand ArN[double bond, length as m-dash]C(R)NH(o-Ph2PC6H4) (Ar = 2,4,6-Me3C6H2, R = Ph (1); Ar = 2,6-iPr2C6H3, R = Ph (2); Ar = 2,6-iPr2C6H3, R = tBu (3)) was prepared. The ligand reacted with CrCl3(THF)3 to yield the N,P-chelation complex [ArNHC(R)[double bond, length as m-dash]N(o-Ph2PC6H4)]CrCl3(THF) (4-6), and the ligand's lithium salt ArN[double bond, length as m-dash]C(R)N(o-Ph2PC6H4)Li reacted with the respective CrCl3(THF)3 and CrCl2(THF)2 to give the N,N,P-chelation complexes [ArN[double bond, length as m-dash]C(R)N(o-Ph2PC6H4)]CrCl2(THF) (7-8) and {[ArN[double bond, length as m-dash]C(R)N(o-Ph2PC6H4)]Cr(µ-Cl)}2 (9-11). Complexes 1-11 were characterized by IR, NMR (for 1-3), EPR (for 4-11) spectroscopy and CHN elemental analysis, of which 3, 5, 8, and 11 were further studied by X-ray crystallography. Upon activation with an organoaluminum cocatalyst, complexes 4-6 were all catalytically active in ethylene tri-/tetramerization along with ethylene polymerization, and complexes 7-11 functioned as well but in ethylene polymerization. The correlation between the structure and the catalytic properties of the catalyst system is discussed.

14.
Brain Res ; 1301: 1-8, 2009 Dec 08.
Article in English | MEDLINE | ID: mdl-19747459

ABSTRACT

BACKGROUND: Dexamethasone treatment of organ of Corti explants challenged with an ototoxic level of an inflammatory cytokine modulates NFkappaB signaling and the expression levels of both pro-and anti-apoptosis-related genes. It is not known if naïve organ of Corti explants will respond in a similar manner to treatment with a corticosteroid. This study examines the response of naïve organ of Corti explants to treatment with dexamethasone. METHODS: Three-day-old rat organ of Corti explants were cultured for 1, 2, or 4 days. Four-day in vitro cultures were fixed, stained with FITC-phalloidin and hair cells were counted. ELISA was performed on 2-day cultures to determine the levels of phosphorylated nuclear factor kappa B protein. One- and 2-day cultures were studied with real-time RT-PCR for expression levels of beta-actin, Bax, Bcl-xl, Bcl-2 and TNFR1 genes with mean fold changes determined with the 2(-)(DeltaDeltaCt) method. All mean fold changes in gene and protein expression were analyzed by the Kruskal-Wallis non-parametric test. RESULTS: There were no significant differences in hair cell counts between naïve explants and explants treated with dexamethasone. Dexamethasone treatment of naïve explants resulted in a significant increase (p<0.01) in the level of phosphorylated-nuclear factor kappa B protein. Bax expression was significantly decreased (p<0.01) in the dexamethasone-treated explants compared to untreated-naïve explants at 1 and 2 days. TNFR1 expression was significantly reduced in dexamethasone-treated explants at 1 (p<0.01) and 2 days (p=0.001). Both Bcl-2 and Bcl-xl expression levels were significantly increased in dexamethasone-treated cultures compared to naïve-cultures at 2 days in vitro (p<0.001). Dexamethasone-treated explants showed a significant decrease in the Bax/Bcl-2 ratio at both 1 (p=0.004) and 2 days (p<0.001) in vitro.


Subject(s)
Apoptosis/drug effects , Dexamethasone/pharmacology , Gene Expression/drug effects , Organ of Corti/drug effects , Analysis of Variance , Animals , Animals, Newborn , Anti-Inflammatory Agents/pharmacology , Apoptosis/genetics , Cell Count , Enzyme-Linked Immunosorbent Assay , NF-kappa B/metabolism , Organ Culture Techniques , Organ of Corti/cytology , Organ of Corti/metabolism , Phosphorylation , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Tumor Necrosis Factor, Type I/genetics , Receptors, Tumor Necrosis Factor, Type I/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Statistics, Nonparametric , Time Factors , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism , bcl-X Protein/genetics , bcl-X Protein/metabolism
15.
Hear Res ; 255(1-2): 22-32, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19442713

ABSTRACT

BACKGROUND: Tumor necrosis factor alpha (TNFalpha) is associated with trauma-induced hearing loss. Local treatment of cochleae of trauma-exposed animals with a glucocorticoid is effective in reducing the level of hearing loss that occurs post-trauma (e.g., electrode insertion trauma-induced hearing loss/dexamethasone treatment). HYPOTHESIS: Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival. MATERIALS AND METHODS: Organ of Corti explants challenged with an ototoxic level of TNFalpha was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNFalpha-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNFalpha ototoxicity was determined by hair cell counts obtained from fixed explants stained with FITC-phalloidin labeling with investigators blinded to specimen identity. RESULTS: The general caspase inhibitor Boc-d-fmk prevented TNFalpha-induced AHC death. There was a significant reduction (p<0.05) in the efficacy of Dex otoprotection against TNFalpha ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NFkappaB (NFkappaB-I). CONCLUSION: Dex treatment protects hair cells against TNFalpha apoptosis in vitro by activation of PI3K/Akt and NFkappaB signaling.


Subject(s)
Apoptosis/drug effects , Dexamethasone/pharmacology , Hair Cells, Auditory/cytology , Hair Cells, Auditory/drug effects , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Animals , Apoptosis/physiology , Benzyl Compounds/pharmacology , Caspase Inhibitors , Dose-Response Relationship, Drug , Hair Cells, Auditory/metabolism , Hydrocarbons, Fluorinated/pharmacology , In Vitro Techniques , NF-kappa B/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/administration & dosage
16.
Otol Neurotol ; 29(7): 1012-9, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18818545

ABSTRACT

HYPOTHESIS: Polymer-eluted dexamethasone (DXM) will retain its ability to protect against tumor necrosis factor alpha (TNFalpha)-induced hair cell (HC) loss. BACKGROUND: TNFalpha has been shown to be associated with trauma-induced hearing loss. DXM has been demonstrated to protect the cochlea against trauma-induced hearing loss. DXM is currently administered either systemically or locally to treat patients with sudden hearing loss of unknown cause. METHODS: P-3 organ of Corti explants challenged with an ototoxic level of TNFalpha was the experimental system, and the base form of DXM (DXMb) incorporated into a biorelease polymer (i.e., SIBS) was the otoprotection molecule tested. The efficacy of otoprotection was determined by counts of fluorescein isothiocyanate-phalloidin-stained HCs and changes in gene expression. RESULTS: HC counts show 1) SIBS alone did not protect HCs from TNFalpha ototoxicity (SIBS versus SIBS + TNFalpha; p < 0.001), and 2) SIBS with DXMb provides a significant level of protection against TNFalpha-induced loss of HCs (TNFalpha + SIBS versus TNFalpha + SIBS/DXMb, 299 mug; p < 0.001). Gene expression results show that polymer-eluted DXMb 1) upregulates antiapoptotic genes (i.e., Bcl-2, Bcl-xl) and downregulates a proapoptotic gene (i.e., Bax) in TNFalpha-challenged explants and 2) downregulates TNFR1 in these explants. CONCLUSION: Polymer-eluted DXMb retains its otoprotection capabilities in our in vitro test system of TNFalpha-challenged organ of Corti explants by altering the pattern of gene expression to favor survival of TNFalpha-exposed HCs. These results, although in vitro, support the application of polymer containing DXMb to electrode arrays for the conservation of hearing during cochlear implantation.


Subject(s)
Cochlear Implants , Delayed-Action Preparations/pharmacology , Dexamethasone/pharmacology , Hair Cells, Auditory/physiology , Hearing Loss/prevention & control , Organ of Corti/drug effects , Prosthesis Design , Tumor Necrosis Factor-alpha/adverse effects , Animals , Animals, Newborn , Biopolymers , Hair Cells, Auditory/drug effects , Hearing Loss/chemically induced , Rats , Rats, Sprague-Dawley
17.
Laryngoscope ; 118(11): 2028-35, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18818553

ABSTRACT

OBJECTIVE/HYPOTHESIS: Local treatment of the cochlea after electrode insertion trauma with dexamethasone base conserves hearing against trauma-induced loss. STUDY DESIGN: Laboratory animal study. METHODS: A guinea pig model of electron insertion trauma (EIT)-induced hearing loss (HL) used 44 guinea pigs sub-divided into four groups: 1) unoperated, controls (Controls, n = 44); 2) EIT, untreated (EIT, n = 15); 3) EIT plus artificial perilymph (EIT + AP, n = 15); and 4) EIT plus dexamethasone base (EIT + DXMb, n = 14). Cochleae that received EIT were randomly selected with contralateral, unoperated cochleae as internal controls. Auditory brainstem responses (ABRs) in response to 0.5 to 16 kHz pure tones were obtained before surgery, immediately after surgery (0 day), and on post-EIT days 3, 7, 14, and 30. Hair cell counts were obtained from stained organ of Corti specimens from all four groups (n = 3/group). Data were analyzed using analysis of variance and a Tukey-Kramer honestly significant difference post hoc test with significance alpha set at <0.05 (hearing) and <0.001 (hair cells). RESULTS: There were significant differences (<0.05) between the ABR thresholds of unoperated (control) and contralateral operated (experimental) ears of EIT and of EIT + AP groups for all tested frequencies. There was no statistical difference (>0.05) in ABR thresholds in the EIT + DXMb versus control groups for 0.5 to 4 kHz tones. DXMb treatment protected hair cells from EIT-induced damage and loss while AP treatment did not. CONCLUSION: The absence of significant differences in hearing thresholds between the EIT + DXMb group and control ears in response to 0.5 to 4 kHz tones demonstrates that DXMb is as effective as the aqueous form of dexamethasone in conserving hearing against EIT-induced loss.


Subject(s)
Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Hearing Loss, Sensorineural/drug therapy , Animals , Auditory Threshold/drug effects , Auditory Threshold/physiology , Cell Count , Disease Models, Animal , Electrodes, Implanted/adverse effects , Evoked Potentials, Auditory, Brain Stem/drug effects , Evoked Potentials, Auditory, Brain Stem/physiology , Follow-Up Studies , Guinea Pigs , Hair Cells, Auditory, Inner/drug effects , Hair Cells, Auditory, Inner/pathology , Hearing Loss, Sensorineural/etiology , Hearing Loss, Sensorineural/physiopathology , Treatment Outcome
18.
Zhonghua Gan Zang Bing Za Zhi ; 14(9): 647-51, 2006 Sep.
Article in Chinese | MEDLINE | ID: mdl-16995975

ABSTRACT

OBJECTIVE: To evaluate the efficacy of artificial liver support system (ALSS) in the treatment of liver failure patients. METHODS: This is a prospective, multi-center, controlled, large sample clinic trial. 518 patients with liver failure from 5 hospitals were studied and followed. All the patients received similar pharmacological manipulation according to one and the same protocol but were divided into an ALSS treatment group and a control group without ALSS treatment. The ALSS treatment procedures included plasma exchange, molecular adsorbent recirculating system (MARS), plasma exchange plus hemofiltration and other combined nonbioartificial methods. The analysis of survival time was computed using the Kaplain-Maier method, and comparison among groups was done using Log-Rank, Breslow and/or the Tarone-Ware test. RESULTS: Survival time of acute liver failure patients was prolonged from 4.0+/-0.2 days to 8.0+/-0.4 days (P=0.004). ALSS was shown to be two times more effective. ALSS increased the survival time of acute on chronic (A on C) liver failure patients from 27.0+/-1.6 days to 39.0+/-4.0 days (P less than 0.01). In addition, it increased the survival time of the patients in the middle and end stage of subacute liver failure and A on C liver failure, but had no significant effects on early stage patients. The survival time of middle stage patients was 38.0+/-17.5 days in the control group vs 66.0+/-18.6 days in the ALSS group (P less than 0.05). The survival time of end stage patients of the control group and the ALSS group was 18.0+/-4.0 days vs 26.0+/-2.5 days (P less than 0.01). CONCLUSIONS: Multi ALSS treatment is more effective than the standard medicinal liver care treatment. Multi-ALSS treatment could increase survival time of patients suffering from acute liver failure or A on C liver failure, especially in their middle and end stages. It is important and necessary to treat these patients with ALSS.


Subject(s)
Liver Failure, Acute/mortality , Liver Failure, Acute/therapy , Liver, Artificial , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Prospective Studies , Survival Analysis , Young Adult
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