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1.
Anal Methods ; 16(22): 3530-3538, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38779841

RESUMO

Biomolecules play vital roles in many biological processes and diseases, making their identification crucial. Herein, we present a colorimetric sensing method for detecting biomolecules like cysteine (Cys), homocysteine (Hcy), and glutathione (GSH). This approach is based on a reaction system whereby colorless 3,3',5,5'-tetramethylbenzidine (TMB) undergoes catalytic oxidation to form blue-colored oxidized TMB (ox-TMB) in the presence of hydrogen peroxide (H2O2), utilizing the peroxidase and catalase-mimicking activities of metal-phenolic coordination frameworks (MPNs) of Cu-TA, Co-TA, and Fe-TA nanospheres. The Fe-TA nanospheres demonstrated superior activity, more active sites and enhanced electron transport. Under optimal conditions, the Fe-TA nanospheres were used for the detection of biomolecules. When present, biomolecules inhibit the reaction between TMB and H2O2, causing various colorimetric responses at low detection limits of 0.382, 0.776 and 0.750 µM for Cys, Hcy and GSH. Furthermore, it was successfully applied to real water samples with good recovery results. The developed sensor not only offers a rapid, portable, and user-friendly technique for multi-target analysis of biomolecules at low concentrations but also expands the potential uses of MPNs for other targets in the environmental field.


Assuntos
Benzidinas , Colorimetria , Cisteína , Glutationa , Peróxido de Hidrogênio , Colorimetria/métodos , Peróxido de Hidrogênio/química , Glutationa/química , Glutationa/análise , Cisteína/química , Cisteína/análise , Benzidinas/química , Homocisteína/análise , Homocisteína/química , Estruturas Metalorgânicas/química , Limite de Detecção , Fenóis/química , Fenóis/análise , Oxirredução , Catálise , Peroxidase/química , Catalase/química
2.
Talanta ; 270: 125542, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38109810

RESUMO

The rational development of efficient nanozymes for the colorimetric detection of targets is still challenging. Herein, Prussian blue analogues of Ni-Co-MoS2 nano boxes were fabricated for colorimetric detection of glyphosate and copper ions owing to its peroxidase like activity. At the sensing system, the Ni-Co-MoS2 nano boxes display high peroxidase activity, which could catalytically oxidize the colourless TMB to blue colour oxTMB. In presence of glyphosate in this sensing system the blue colour is diminished, ascribed to the inhibit the catalytic activity of Ni-Co-MoS2 nano boxes. Concurrently, the addition of copper ion, which result in blue colour was reappear due to the generation of glyphosate-copper complex formation. The Ni-Co-MoS2 nano boxes based colorimetric sensing platform was developed to sensitive detection of glyphosate and copper ions with low detection limit of 3 nM for glyphosate and 3.8 nM for copper. This method also displays satisfactory outcomes from real samples analysis and its good accuracy. Therefore, this work provides a great potential for rapid detection of the targets from the environments.


Assuntos
Glifosato , Peroxidase , Peroxidase/metabolismo , Cobre , Molibdênio , Oxirredução , Peroxidases , Ferrocianetos , Corantes , Colorimetria/métodos , Peróxido de Hidrogênio/análise
3.
Indian J Otolaryngol Head Neck Surg ; 74(Suppl 1): 692-698, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36032926

RESUMO

To compare the outcome and efficacy of mastoid obliteration following canal wall down mastoidectomy, using two different materials such as bone pâté and bioactive glass granules. This is a prospective, randomized, single blind comparative study conducted for a period of 2 years in a tertiary care center. The patients were divided into two groups A and B. In group A, the mastoid was obliterated with bone pâté and inferiorly based musculoperiosteal flap and in group B, bioactive glass with inferiorly based musculoperiosteal flap. They were assessed post operatively at 4th, 12th and 24th week for cavity healing (merchant et.al., score), subjective satisfaction and at the 24th week the effectiveness of obliteration was assessed visually by oto endoscopy and HRCT was done additionally to assess the volume of external auditory canal. A total of 40 patients with chronic otitis media (Squamosal type) were included and divided into 2 groups. At the end of 4 weeks, bioactive glass had better healing, which was statistically significant. At the end of 24 weeks both groups had similar rate of healing. There was no difference in subjective satisfaction at end of 24 weeks. The patients in bioactive glass group had statistically better obliteration than Group A and the volume of the EAC was less in this group signifying better obliteration. The cavity healing were similar for both bone pâté and Bioactive glass at end of 24 weeks. Bioactive glass had better outcomes for effectiveness of obliteration compared to bone pâté.

5.
RSC Adv ; 11(59): 37162-37170, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-35496385

RESUMO

Prussian blue nanocubes were synthesized via a hydrothermal method. Significantly, the redox couple Ni3+/Ni2+ provided rich oxidation and reduction reactions, which enhance catalytic activity. Furthermore, PBNCs mimic peroxidase activity which could oxidise colourless tetramethyl benzidine (TMB) to a blue colour (TMB+) in the presence of H2O2. Thus, it can be used as a colorimetric sensing platform for detecting cysteine and Cu2+. The addition of cysteine to a TMB + PBNCs sensing system decreases the intensity of the blue colour in the solution with a decrease in the absorption peak at 652 nm in the UV visible spectrum. Subsequently, the addition of Cu2+ into the TMB + PBNCs + Cys sensing system increases the intensity of the blue colour due to complex formation of Cu and cysteine. Therefore, the change in intensity of the blue colour of TMB is directly proportional to the concentration of Cys and Cu2+. As a result, this sensing system is highly sensitive and selective with an effective low detection limit of 0.002 mM for cysteine and 0.0181 mM for Cu2+. Furthermore, this method was applied to the detection of cysteine and copper in spiked real samples and gave satisfactory results.

7.
Mol Med ; 26(1): 98, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126860

RESUMO

BACKGROUND: Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. METHOD: GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O2) and subsequently challenged with PA. RESULTS: The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA. CONCLUSIONS: Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.


Assuntos
Compostos de Benzilideno/farmacologia , Hiperóxia/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Infecções por Pseudomonas/tratamento farmacológico , Piridinas/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Proteína HMGB1/metabolismo , Hiperóxia/dietoterapia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Pseudomonas aeruginosa , Células RAW 264.7
8.
Mol Med ; 26(1): 63, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600307

RESUMO

BACKGROUND: Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury. METHODS: Mice were exposed to hyperoxia (≥99% O2) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline. RESULTS: The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology. CONCLUSIONS: Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Compostos de Benzilideno/farmacologia , Proteína HMGB1/metabolismo , Hiperóxia/complicações , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Biomarcadores , Suscetibilidade a Doenças , Proteína HMGB1/sangue , Proteína HMGB1/genética , Imuno-Histoquímica , Masculino , Camundongos , Modelos Biológicos
9.
Mol Med ; 26(1): 16, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013888

RESUMO

The Editors-in-Chief would like to alert readers that this article (Sitapara et al. 2014) is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1.

10.
RSC Adv ; 9(8): 4268-4276, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-35520178

RESUMO

A novel colorimetric sensing platform using the peroxidase mimicking activity of ternary MoS2-loaded ZnO-g-C3N4 nanocomposites (ZnO-g-C3N4/MoS2) has been developed for the determination of Hg(ii) ions over co-existing metal ions. The nanocomposite was prepared using an exfoliation process, and the product was further characterized using SEM, TEM, XRD and FTIR analysis. The ZnO-g-C3N4/MoS2 possesses excellent intrinsic catalytic activity to induce the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in aqueous solution in the presence of H2O2 to generate deep blue coloured cation radicals (TMB+) which can be viewed with the naked eye and produce absorbance at a wavelength of 652 nm. The addition of a well known bioradical scavenger, glutathione (GSH), to the solution hinders the generation of cation radicals and turns the solution colourless. The introduction of Hg(ii) to this solution brings the blue colour back into it, due to the strong affinity of the thiol in the GSH. Based on this mechanism, we have developed a simple and rapid colorimetric sensor for the highly sensitive and selective detection of Hg(ii) ions in aqueous solution with a low detection limit of 1.9 nM. Furthermore, the prepared colorimetric sensor was effectively applied for the quantification analysis of real water samples.

11.
Org Biomol Chem ; 15(36): 7696-7704, 2017 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-28872171

RESUMO

A novel I2 promoted, highly efficient metal-free and peroxide-free greener domino protocol for the C3-dicarbonylation of benzo[d]imidazo[2,1-b]thiazoles (IBTs) with styrenes has been developed via oxidative cleavage of the C(sp2)-H bond, followed by C3-nucleophilic attack of IBT and oxidation. Interestingly, under these conditions 2-(benzo[d]imidazo[2,1-b]thiazol-2-yl)aniline gave the benzo[4',5']thiazolo[2',3':2,3]imidazo[4,5-c]quinoline derivative via oxidative cleavage of the C(sp2)-H bond, followed by Pictet-Spengler cyclization and aromatization. This method offers the advantages of broad substrate scope, ecofriendly feature and high atom economy apart from higher yields.

12.
J Fluoresc ; 27(6): 2101-2109, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28819702

RESUMO

A label -free DNAzyme amplified biosensor is found to be highly selective and sensitive towards fluorescent detection of Pb2+ ions in aqueous media. The DNAzyme complex has designed by the hybridization of the enzyme and substrate strand. In the presence of Pb2+, the DNAzyme activated and cleaved the substrate strand of RNA site (rA) into two oligonucleotide fragments. Further, the free fragment was hybridized with a complementary strand on the surface of MBs. After magnetic separation, SYBER Green I was added and readily intercalate with the dsDNA to gives a bright fluorescence signal with intensity directly proportional to the concentration of Pb2+ions. A detection limit of 5 nM in Pb2+ the detection range 0 to 500 nM was obtained. This label- free fluorescent biosensor has been successfully applied to the determination of environmental water samples. Then results open up the possibility for real-time quantitative detection of Pb2+ with convenient potential applications in the biological and environmental field. Graphical Abstract.


Assuntos
Técnicas Biossensoriais/métodos , DNA Catalítico/química , Fluorescência , Chumbo/análise , Água/química , Limite de Detecção
13.
Apoptosis ; 22(1): 118-134, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27770267

RESUMO

Apoptosis is a representative form of programmed cell death, which has been assumed to be critical for cancer prevention. Thus, any agent that can induce apoptosis may be useful for cancer treatment and apoptosis induction is arguably the most potent defense against cancer promotion. In our previous studies, 2-aryl benzimidazole conjugates were synthesized and evaluated for their antiproliferative activity and one of the new molecule (2f) was considered as a potential lead. This lead molecule showed significant antiproliferative activity against human breast cancer cell line, MCF-7. The results of the present study revealed that this compound arrested the cell cycle at G2/M phase. Topoisomerase II inhibition assay and Western blot analysis suggested that this compound effectively inhibits topoisomerase II activity which leads to apoptotic cell death. Apoptosis induction in MCF-7 cells was further confirmed by loss of mitochondrial membrane potential (∆Ψm), release of cytochrome c from mitochondria, an increase in the level of apoptosis inducing factor (AIF), generation of reactive oxygen species (ROS), up regulation of proapoptotic protein Bax and down regulation of anti apoptotic protein Bcl-2. Apoptosis assay using Annexin V-FITC assay also suggested that this compound induced cell death by apoptosis. However, compound 2f induced apoptosis could not be reversed by Z-VAD-FMK (a pan-caspase inhibitor) demonstrated that the 2f induced apoptosis was caspase independent. Further, 2f treatment did not activate caspase-7 and caspase-9 activity, suggesting that this compound induced apoptosis in breast cancer cells via a caspase independent pathway. Most importantly, this compound was less toxic towards non-tumorigenic breast epithelial cells, MCF-10A. Furthermore, docking studies also support the potentiality of this molecule to bind to the DNA topoisomerase II.


Assuntos
Apoptose/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , DNA Topoisomerases Tipo II/química , Fator de Indução de Apoptose/genética , Benzimidazóis/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Inibidores de Caspase/administração & dosagem , Inibidores de Caspase/química , Caspases/genética , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/genética , Feminino , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
14.
ChemMedChem ; 11(18): 2050-62, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27465681

RESUMO

Several 2-anilino-3-aroylquinolines were designed, synthesized, and screened for their cytotoxic activity against five human cancer cell lines: HeLa, DU-145, A549, MDA-MB-231, and MCF-7. Their IC50 values ranged from 0.77 to 23.6 µm. Among the series, compounds 7 f [(4-fluorophenyl)(2-((4-fluorophenyl)amino)quinolin-3-yl)methanone] and 7 g [(4-chlorophenyl)(2-((4-fluorophenyl)amino)quinolin-3-yl)methanone] showed remarkable antiproliferative activity against human lung cancer and prostate cancer cell lines. The IC50 values for inhibiting tubulin polymerization were 2.24 and 2.10 µm for compounds 7 f and 7 g, respectively, and were much lower than that of the reference compound E7010 [N-(2-(4-hydroxyphenylamino)pyridin-3-yl)-4-methoxybenzenesulfonamide]. Furthermore, flow cytometric analysis revealed that these compounds arrest the cell cycle at the G2 /M phase, leading to apoptosis. Apoptosis was also confirmed by mitochondrial membrane potential, Annexin V-FITC assay, and intracellular ROS generation. Immunohistochemistry, western blot, and tubulin polymerization assays showed that these compounds disrupt tubulin polymerization. Molecular docking studies revealed that these compounds bind efficiently to ß-tubulin at the colchicine binding site.


Assuntos
Compostos de Anilina/farmacologia , Polimerização/efeitos dos fármacos , Quinolinas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Compostos de Anilina/síntese química , Compostos de Anilina/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Moduladores de Tubulina/química
15.
Eur J Med Chem ; 122: 164-177, 2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-27344493

RESUMO

A series of new (N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives (8-35) were designed, synthesized and evaluated as CDK1/Cdc2 inhibitors. Biological evaluation assays indicated that compounds 16 and 27 showed the most potent growth inhibitory activity against human cancer cell lines (MIAPaCa-2, MCF-7 and HeLa) with GI50 values ranging from 0.13 to 0.7 µM, compared with the positive control nocodazole (0.81-0.95 µM). Flow cytometric analysis revealed that these compounds induce cell cycle arrest in the G2/M phase and Western blot analysis suggested that compound treatment resulted in reduction of CDK1 expression levels in MCF-7 cell line. Moreover, the apoptosis inducing effect of the compounds was studied using Hoechst staining, Rhodamine 123 staining (MMP), carboxy-DCFDA staining (ROS), Annexin V-FITC assay. Based on these studies, two compounds 16 and 27 have been identified as promising new molecules that have the potential to be developed as leads.


Assuntos
Proteína Quinase CDC2/antagonistas & inibidores , Desenho de Fármacos , Pirazóis/síntese química , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2/química , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Fase G2/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirazóis/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
16.
Bioorg Med Chem ; 24(8): 1729-40, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26970659

RESUMO

A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049 to 38.90 µM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC50 values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23 µM and 1.01 µM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin.


Assuntos
Antimitóticos/síntese química , Antimitóticos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofenonas/farmacologia , Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Estilbenos/farmacologia , Antimitóticos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Benzofenonas/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Organofosfatos , Oxindóis , Estilbenos/química , Relação Estrutura-Atividade
17.
Indian J Otolaryngol Head Neck Surg ; 67(3): 210-22, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26405653

RESUMO

Indications for cochlear implantation have expanded today to include very young children and those with syndromes/multiple handicaps. Programming the implant based on behavioral responses may be tedious for audiologists in such cases, wherein matching an effective MAP and appropriate MAP becomes the key issue in the habilitation program. In 'Difficult to MAP' scenarios, objective measures become paramount to predict optimal current levels to be set in the MAP. We aimed, (a) to study the trends in multi-modal electrophysiological tests and behavioral responses sequentially over the first year of implant use, (b) to generate normative data from the above, (c) to correlate the multi-modal electrophysiological thresholds levels with behavioral comfort levels, and (d) to create predictive formulae for deriving optimal comfort levels (if unknown), using linear and multiple regression analysis. This prospective study included ten profoundly hearing impaired children aged between 2 and 7 years with normal inner ear anatomy and no additional handicaps. They received the Advanced Bionics HiRes 90K Implant with Harmony Speech processor and used HiRes-P with Fidelity 120 strategy. They underwent, Impedance Telemetry, Neural Response Imaging, Electrically Evoked Stapedial Response Telemetry and Electrically Evoked Auditory Brainstem Response tests at 1, 4, 8 and 12 months of implant use, in conjunction with behavioral Mapping. Trends in electrophysiological and behavioral responses were analyzed using paired t test. By Karl Pearson's correlation method, electrode-wise correlations were derived for NRI thresholds versus Most Comfortable Levels (M-Levels) and offset based (apical, mid-array and basal array) correlations for EABR and ESRT thresholds versus M-Levels were calculated over time. These were used to derive predictive formulae by linear and multiple regression analysis. Such statistically predicted M-Levels were compared with the behaviorally recorded M-Levels among the cohort, using Cronbach's Alpha Reliability test method for confirming the efficacy of this method. NRI, ESRT and EABR thresholds showed statistically significant positive correlations with behavioral M-Levels, which improved with implant use over time. These correlations were used to derive predicted M-Levels using regression analysis. Such predicted M-Levels were found to be in proximity to the actual behavioral M-Levels recorded among this cohort and proved to be statistically reliable. When clinically applied, this method was found to be successful among subjects of our study group. Although there existed disparities of a few clinical units, between the actual and predicted comfort levels among the subjects, this statistical method was able to provide a working MAP, close to the behavioral MAP used by these children. The results help to infer that behavioral measurements are mandatory to program cochlear implantees, but in cases where they are difficult to obtain, this study method may be used as reference for obtaining additional inputs, in order to set an optimal MAP. The study explores the trends and correlations between electrophysiological tests and behavioral responses, recorded over time among a cohort of cochlear implantees and provides a statistical method which may be used as a guideline to predict optimal behavioral levels in difficult situations among future implantees. In 'Difficult to MAP' scenarios, following a protocol of sequential behavioral programming, in conjunction with electrophysiological correlates will provide the best outcomes.

18.
Bioorg Med Chem Lett ; 25(18): 3867-72, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26253635

RESUMO

Natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) and its analogues are found to exhibit potent anti-tubercular activity against MDR-TB. A novel class of indolo[2,1-b]quinazolinones have been synthesized to evaluate their anti-mycobacterial activity. Enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis is one of the key enzymes and has been validated as an effective anti-microbial target. In silico molecular docking study demonstrates that the synthesized compounds exhibit high affinity for the M. tuberculosis drug target InhA. Phaitanthrin is a natural product, which belongs to a family of tryptanthrin and exhibits structural similarity except at position 6. Phaitanthrin derivatives are prepared by modifying the keto functionality of tryptanthrin. These phaitanthrin congeners are found to display promising anti-tubercular activity.


Assuntos
Antituberculosos/farmacologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Quinazolinonas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
19.
Am J Respir Cell Mol Biol ; 52(2): 171-82, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24992505

RESUMO

The prolonged exposure to hyperoxia can compromise macrophage functions and contribute to the development of ventilator-associated pneumonia. High levels of extracellular high-mobility group box-1 (HMGB1) in the airways of mice exposed to hyperoxia can directly cause macrophage dysfunction. Hence, inhibition of the release of nuclear HMGB1 into the extracellular milieu may help to maintain macrophage functions under hyperoxic conditions. The present study investigates whether ethacrynic acid (EA) affects hyperoxia-induced HMGB1 release from macrophages and improves their functions. Macrophage-like RAW 264.7 cells and bone marrow-derived macrophages were exposed to different concentrations of EA for 24 hours in the presence of 95% O2. EA significantly decreased the accumulation of extracellular HMGB1 in cultured media. Importantly, the phagocytic activity and migration capability of macrophages were significantly enhanced in EA-treated cells. Interestingly, hyperoxia-induced NF-κB activation was also inhibited in these cells. To determine whether NF-κB plays a role in hyperoxia-induced HMGB1 release, BAY 11-7082, an inhibitor of NF-κB activation, was used. Similar to EA, BAY 11-7082 significantly inhibited the accumulation of extracellular HMGB1 and improved hyperoxia-compromised macrophage migration and phagocytic activity. Furthermore, 24-hour hyperoxic exposure of macrophages caused hyperacetylation of HMGB1 and its subsequent cytoplasmic translocation and release, which were inhibited by EA and BAY 11-7082. Together, these results suggest that EA enhances hyperoxia-compromised macrophage functions by inhibiting HMGB1 hyperacetylation and its release from macrophages, possibly through attenuation of the NF-κB activation. Therefore, the activation of NF-κB could be one of the underlying mechanisms that mediate hyperoxia-compromised macrophage functions.


Assuntos
Ácido Etacrínico/farmacologia , Proteína HMGB1/metabolismo , Hiperóxia/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Células Cultivadas , Lipopolissacarídeos/farmacologia , Camundongos , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia
20.
J Clin Diagn Res ; 8(8): FD04-6, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25302202

RESUMO

Primary malignant melanoma of the external auditory canal is rarely reported. Malignant melanoma of the ear is estimated to occur in 1-4% of all skin melanomas and about 7-20% of melanomas of the head and neck region. The pathophysiology of these tumours is different from other skin lesions because of their anatomical and functional characteristics. The case presented is of a 11 year old female child with malignant melanoma of the external auditory canal confined to the right side, who initially presented with right ear pain, bleeding, post auricular swelling and also a mass in the external auditory canal which was thought to be an aural polyp in the right ear. Excision of the tumour was accomplished by a radical mastoidectomy. It was confirmed to be malignant melanoma after histopathological examination and Immunohistochemistry. Despite all efforts, the patient succumbed to the disease after receiving three cycles of chemotherapy. Even though this malignancy is rarely found in the external auditory canal, it should be expanded into the differential diagnosis of an aural polyp and a post aural abscess. The incidence, symptoms, investigations, treatment and prognosis of malignant melanoma of the external auditory canal is discussed in this article.

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