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1.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443480

RESUMO

Within this study, new materials were synthesized and characterized based on polysiloxane modified with different ratios of N-acetyl-l-cysteine (NAC) and crosslinked via UV-assisted thiol-ene addition, in order to obtain efficient membranes able to resist bacterial adherence and biofilm formation. These membranes were subjected to in vitro testing for microbial adherence against S. pneumoniae using standardized tests. WISTAR rats were implanted for 4 weeks with crosslinked siloxane samples without and with NAC. A set of physical characterization methods was employed to assess the chemical structure and morphological aspects of the new synthetized materials before and after contact with the microbiological medium.


Assuntos
Antibacterianos/química , Materiais Revestidos Biocompatíveis/química , Implantes Cocleares/microbiologia , Otite/tratamento farmacológico , Polímeros/química , Siloxanas/química , Acetilcisteína/química , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/farmacologia , Materiais Revestidos Biocompatíveis/uso terapêutico , Implantes Cocleares/efeitos adversos , Polímeros/farmacologia , Polímeros/uso terapêutico , Ratos Wistar , Siloxanas/farmacologia , Siloxanas/uso terapêutico , Streptococcus pneumoniae/efeitos dos fármacos , Compostos de Sulfidrila/química , Propriedades de Superfície
2.
Photodiagnosis Photodyn Ther ; 35: 102424, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34214685

RESUMO

A 10-year-old canine with chronic unilateral otitis and a history of unsuccessful systemic and topical antibiotic treatments was referred. A computer tomography scan (CT scan) revealed unilateral chronic otitis with calcification of the ear canal, abscessation and fistula. On bacterial culture a Staphylococcus pseudintermedius sensitive to pradofloxacin was isolated. Systemic treatment with pradofloxacin, 3 mg/kg per os once daily, improved the infection and the dog had total ear canal ablation and bulla osteotomy performed. After one month, despite antibiotic treatment new fistulas developed in the same area. Bacterial culture revealed an drug-resistant S. pseudintermedius sensitive only to rifampicin. Under general anesthesia, the area was cleaned with 0.5% saline solution and 1 mL of indocyanine green (Emundo®, A.R.C.) was injected into the fistulas. A treatment with diode laser (A.R.C. Laser 810 nm, GmbH, Nurnberg, Germany) of four cycles 500 mw for 30 s, with a dosage of 50 J/cm2 in the effected area was performed. No antibiotic was administered and one week later, 50% of the fistulas were closed with a significant improvement of the patient's clinical condition. Cytology and bacterial culture were negative 72 h after the treatment. Total recovery occurred after two weeks. Photodynamic Therapy(PDT) is a promising antibacterial technique in case of localized refractory bacterial infections.


Assuntos
Otite , Preparações Farmacêuticas , Fotoquimioterapia , Abscesso/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cães , Otite/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes , Staphylococcus
3.
J Ethnopharmacol ; 269: 113698, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33338590

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Nymphaea hybrida Peck is used as a traditional medicinal herb for treating pain and inflammatory diseases, and known for its ornamental value and as a hot drink. However, the effects of N. hybrida polar fractions on lipopolysaccharide (LPS)-induced in vitro inflammation model and acute inflammation murine models have yet to be evaluated. AIM OF THE STUDY: The aim of this study was to elucidate the anti-inflammatory effects of N. hybrida ethanol extract (NHE) and its polar fractions: petroleum ether (PE), methylene chloride (MC), ethyl acetate (EA), methanol (ME), and water (WA). The underlying molecular mechanisms of active fraction in LPS-stimulated RAW 264.7 murine macrophages were further investigated. MATERIAL AND METHODS: Fractions with potential anti-inflammatory effects were screened using direct nitric oxide (NO) radical scavenging and cyclooxygenase (COX)-2 inhibition assays in vitro. The anti-inflammatory properties of potential fraction were evaluated in LPS-stimulated RAW264.7 cells, xylene-induced ear edema, carrageenan-induced paw edema and xylene-induced Evans blue exudation of acute inflammation murine models. The regulation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways were investigated using western blotting and immunofluorescence. RESULTS: Compared to other polar fractions, NHE-EA displayed higher phenol and flavonoid content, and exerted greater activity in direct NO radical scavenging and COX-2 inhibition assay in vitro. NHE-EA markedly decreased the levels of inflammatory mediators, NO and prostaglandin E2 (PGE2), by suppressing the over-expression of inducible nitric oxide synthase (iNOS) and COX-2 in LPS-stimulated RAW264.7 cells. The NHE-EA fraction dose-dependently alleviated over-elevation of LPS-associated intracellular calcium and decreased the abnormal secretion of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, and interferon-γ (IFN-γ). The combination with NHE-EA effectively attenuated the activation and nuclear translocation of NF-κB p65, and the phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 kinases of MAPK pathways. NHE-EA could significantly ameliorate the degree of swelling of the mice ear and paw, the skin exudation of Evans blue and the excessive secretion of inflammatory cytokines. CONCLUSION: Our results demonstrated that NHE-EA was the most active polar fraction of N. hybrida extracts. It inhibited the LPS-associated inflammatory response by blocking the activation of NF-κB and MAPKs pathways in RAW264.7 cells. It also effectively alleviated the inflammatory response of acute inflammation. These results indicated the role of NHE-EA as adjuvants and their potential role in alternative strategy for the treatment of inflammatory diseases.


Assuntos
Acetatos/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Nymphaea/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Doença Aguda , Animais , Anti-Inflamatórios/uso terapêutico , Cálcio/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Carragenina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Subunidade p50 de NF-kappa B/efeitos dos fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Otite/induzido quimicamente , Otite/tratamento farmacológico , Otite/patologia , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Células RAW 264.7 , Xilenos/toxicidade
5.
Eur Ann Otorhinolaryngol Head Neck Dis ; 136(4): 289-294, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31420238

RESUMO

OBJECTIVES: To present the guidelines of the French Society of Otolaryngology-Head and Neck Surgery concerning the use of non-steroidal anti-inflammatory drugs (NSAIDs) in pediatric ENT infections. METHODS: Based on a critical analysis of the medical literature up to November 2016, a multidisciplinary workgroup of 11 practitioners wrote clinical practice guidelines. Levels of evidence were classified according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system: GRADE A, B, C or "expert opinion". The first version of the text was reworked by the workgroup following comments by the 22 members of the reading group. RESULTS: The main recommendations are: NSAIDs are indicated at analgesic doses (e.g. 20-30 mg/kg/day for ibuprofen) in combination with paracetamol (acetaminophen) in uncomplicated pediatric ENT infections (acute otitis media, tonsillitis, upper respiratory infections, and maxillary sinusitis) if: o pain is of medium intensity (visual analogue scale (VAS) score 3-5 or "Evaluation Enfant Douleur" (EVENDOL) child pain score 4-7) and insufficiently relieved by first-line paracetamol (residual VAS≥3 or EVENDOL≥4); o pain is moderate to intense (VAS 5-7 or EVENDOL 7-10). When combined, paracetamol and ibuprofen are ideally taken simultaneously every 6h. It is recommended: (1) o not to prescribe NSAIDs in severe or complicated pediatric ENT infections; (2) o to suspend NSAIDs treatment in case of unusual clinical presentation of the infection (duration or symptoms); (3) o not to prescribe NSAIDs for more than 72h.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Pediatria , Acetaminofen/uso terapêutico , Analgésicos não Narcóticos/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Contraindicações de Medicamentos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Empiema Subdural/tratamento farmacológico , França , Humanos , Linfadenite/tratamento farmacológico , Meningite/tratamento farmacológico , Otite/tratamento farmacológico , Medição da Dor , Infecções Respiratórias/tratamento farmacológico , Sociedades Médicas
6.
Int J Mol Sci ; 20(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185643

RESUMO

Maslinic acid is a pentacyclic triterpene with a plethora of biological activities, including anti-inflammatory, antioxidant, antimicrobial, cardioprotective, and antitumor effects. New derivatives with improved properties and broad-spectrum activity can be obtained following structural changes of the compound. The present study was aimed to characterize a benzylamide derivative of maslinic acid-benzyl (2α, 3ß) 2,3-diacetoxy-olean-12-en-28-amide (EM2)-with respect to the anti-angiogenic and anti-inflammatory effects in two in vivo experimental models. Consequently, the compound showed good tolerability and lack of irritation in the chorioallantoic membrane assay with no impairment of the normal angiogenic process during the tested stages of development. In the acute ear inflammation murine model, application of EM2 induced a mild anti-inflammatory effect that was potentiated by the association with zinc chloride (ZnCl2). A decrease in dermal thickness of mice ears was observed when EM2 and ZnCl2 were applied separately or in combination. Moreover, hyalinization of the dermis appeared only when EM2 was associated with ZnCl2, strongly suggesting the role of their combination in wound healing.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Otite/tratamento farmacológico , Triterpenos/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Embrião de Galinha , Cloretos/administração & dosagem , Cloretos/uso terapêutico , Membrana Corioalantoide/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Camundongos , Triterpenos/administração & dosagem , Triterpenos/efeitos adversos , Compostos de Zinco/administração & dosagem , Compostos de Zinco/uso terapêutico
8.
Auris Nasus Larynx ; 44(1): 7-17, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27956101

RESUMO

IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder, characterized by elevated serum IgG4 levels as well as abundant infiltration of IgG4-positive plasmacytes and fibrosis in various organs, including the head and neck region. In particular, the salivary glands, orbit, and thyroid are common sites of disease involvement. IgG4-RD is diagnosed based on various clinical, serological, and histopathological findings, none of which are pathognomonic. Hence, various differential diagnoses, which exhibit elevated serum IgG4 levels and infiltration of IgG4-postive cells into tissues, need to be excluded, especially malignant diseases and mimicking disorders. Systemic corticosteroids are generally effective in inducing IgG4-RD remission; however, recurrent or refractory cases are common. In addition, although the pathogenic mechanisms of IgG4-RD remain unclear, an antigen-driven inflammatory condition is believed to be involved. Recent studies have indicated the important pathogenic role of B cell/T cell collaboration and innate immunity in this disease. Nevertheless, additional research and discussions are needed to resolve many remaining questions. In this review, we provide an overview of the recent insights on the history, clinical features, diagnosis, and treatment of IgG4-RD in the head and neck region. Furthermore, we have also addressed the pathogenesis of this disease.


Assuntos
Doenças Autoimunes/imunologia , Dacriocistite/imunologia , Imunoglobulina G/imunologia , Rinite/imunologia , Sialadenite/imunologia , Sinusite/imunologia , Tireoidite Autoimune/imunologia , Corticosteroides/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Hipofisite Autoimune/tratamento farmacológico , Hipofisite Autoimune/imunologia , Dacriocistite/tratamento farmacológico , Humanos , Linfadenite/tratamento farmacológico , Linfadenite/imunologia , Mastoidite/tratamento farmacológico , Mastoidite/imunologia , Neurite (Inflamação)/tratamento farmacológico , Neurite (Inflamação)/imunologia , Otite/tratamento farmacológico , Otite/imunologia , Rinite/tratamento farmacológico , Sialadenite/tratamento farmacológico , Sinusite/tratamento farmacológico , Tireoidite Autoimune/tratamento farmacológico
9.
Int J Immunopathol Pharmacol ; 29(3): 438-42, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27481884

RESUMO

Hyaluronic acid (HA) treatment has been successfully performed in patients with recurrent upper airway infections or rhinitis. The aim of this study was to assess the efficacy and safety of the topical nasal administration of an HA-based compound by investigating its effects in children with recurrent or chronic middle ear inflammations and chronic adenoiditis. A prospective, single-blind, 1:1 randomised controlled study was performed to compare otoscopy, tympanometry and pure-tone audiometry in children which received the daily topical administration of normal 0.9% sodium chloride saline solution (control group) or 9 mg of sodium hyaluronate in 3 mL of a 0.9% sodium saline solution. The final analysis was based on 116 children (49.1% boys; mean age, 62.9 ± 17.9 months): 58 in the control group and 58 in the study group. At the end of follow-up, the prevalence of patients with impaired otoscopy was significantly lower in the study group (P value = 0.024) compared to baseline but not in the control group. In comparison with baseline, the prevalence of patients with impaired tympanometry at the end of the follow-up period was significantly lower in the study group (P value = 0.047) but not in the control group. The reduction in the prevalence of patients with conductive hearing loss (CHL) (P value = 0.008) and those with moderate CHL (P value = 0.048) was significant in the study group, but not in the control group. The mean auditory threshold had also significantly improved by the end of treatment in the study group (P value = 0.004) but not in the control group. Our findings confirm the safety of intermittent treatment with a topical nasal sodium hyaluronate solution and are the first to document its beneficial effect on clinical and audiological outcomes in children with recurrent or chronic middle ear inflammations associated with chronic adenoiditis.


Assuntos
Doença Crônica/tratamento farmacológico , Ácido Hialurônico/administração & dosagem , Otite/tratamento farmacológico , Administração Intranasal , Administração Tópica , Audiometria de Tons Puros/métodos , Limiar Auditivo/efeitos dos fármacos , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Prospectivos , Método Simples-Cego
10.
J Ethnopharmacol ; 176: 297-304, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26551879

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sempervivum tectorum L. (Crassulaceae), known as houseleek, is used in traditional medicine in the treatment of ear inflammation. It can be spread as a pack on wounds, sores, burns, and abscesses and also on painful areas attacked by gout as a refrigerant and astringent. Drinking tea prepared from leaves of S. tectorum is recommended for ulcer treatment. The present study was designed to investigate ethopharmacological use of S. tectorum in the southern Serbia and to further scientifically justify and confirm effectiveness of the leaf juice used in ethnomedicine for ear inflammation, against otitis linked bacteria. MATERIAL AND METHODS: Ethnopharmacological survey on the use of S. tectorum in southern Serbia was performed using semi structured questionnaires via a face-to-face interview. Chemical composition of the leaf juice regarding phenolic compounds and organic acids was analyzed. Antimicrobial activity was tested on bacteria isolated from ear swabs of the patients suffering from the ear pain (otitis). Anti-quorum-sensing activities of the juice were further investigated on Pseudomonas aeruginosa. RESULTS: Ethnopharmacological survey revealed the use of S. tectorum in southern Serbia for the treatment of ear pain, warts, cancer, stomachache, ulcer and high blood sugar level with the highest fidelity level (FL) for the ear pain. The phenolic composition of the S. tectorum leaf juice consisted of flavonol glycosides, with kaempferol-3-O-rhamnosyl-glucoside-7-O-rhamnoside as the majority compound. Organic acids composition revealed malic acid as the most dominant one. Antimicrobial and anti-quorum-sensing activities of the juice showed to be promising. CONCLUSION: Ethnopharmacological use of S. tectorum juice for treating ear pain is justified, since the juice possessed antimicrobial activity towards clinical isolates of bacteria linked to otitis.


Assuntos
Antibacterianos/farmacologia , Crassulaceae , Extratos Vegetais/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Etnofarmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Otite/tratamento farmacológico , Otite/microbiologia , Fenóis/análise , Fenóis/farmacologia , Fitoterapia , Folhas de Planta , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/fisiologia , Piocianina/metabolismo , Percepção de Quorum/efeitos dos fármacos , Sérvia , Inquéritos e Questionários , Adulto Jovem
11.
Antimicrob Agents Chemother ; 59(12): 7857-61, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26392507

RESUMO

Invasive aspergillosis (IA) is a severe disseminated fungal disease that occurs mostly in immunocompromised patients. However, central nervous system IA, combining meningitis and skull base involvement, does not occur only in groups with classic risk factors for IA; patients with chronic renal failure and diabetes mellitus are also at risk for more chronic forms. In both of our proven IA cases, voriconazole monotherapy was effective without surgery, and cerebrospinal fluid and serum 1,3-ß-d-glucan test results were initially positive, in contrast to galactomannan antigen results.


Assuntos
Antifúngicos/uso terapêutico , Meningite Fúngica/tratamento farmacológico , Neuroaspergilose/tratamento farmacológico , Otite/tratamento farmacológico , Sinusite/tratamento farmacológico , Voriconazol/uso terapêutico , Idoso , Aspergillus flavus/efeitos dos fármacos , Aspergillus flavus/crescimento & desenvolvimento , Aspergillus flavus/patogenicidade , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/crescimento & desenvolvimento , Aspergillus fumigatus/patogenicidade , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Doença Crônica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/microbiologia , Feminino , Humanos , Meningite Fúngica/complicações , Meningite Fúngica/diagnóstico , Meningite Fúngica/microbiologia , Neuroaspergilose/complicações , Neuroaspergilose/diagnóstico , Neuroaspergilose/microbiologia , Otite/complicações , Otite/diagnóstico , Otite/microbiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/microbiologia , Sinusite/complicações , Sinusite/diagnóstico , Sinusite/microbiologia , Resultado do Tratamento , beta-Glucanas/sangue , beta-Glucanas/líquido cefalorraquidiano
12.
BMJ Case Rep ; 20152015 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-25716039

RESUMO

Written information for patients about their medicines has demonstrable benefits for their understanding and adherence. In the UK, no single, complete record of medications for individual patients can be guaranteed. Therefore, patients and carers are often relied on to recall the complete medication list, which can be a challenge given multiple and potentially stressful appointments. Wide-ranging feedback suggests that a medication 'passport' developed by the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care North West London (NIHR CLAHRC NWL) has benefited elderly patients, who often attend many appointments where the current medication list may not be available. We describe the use of this passport (known as 'My Medication Passport'--MMP) in a child with multiple disabilities. The practical advantages are explored, including the potential for a paediatric version to facilitate discussions around the administration of medicines. MMP is an early example of a useful tool to help children and young people, parents and carers to manage medicines more effectively.


Assuntos
Continuidade da Assistência ao Paciente/organização & administração , Crianças com Deficiência , Síndrome de Down/complicações , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Registros de Saúde Pessoal , Conduta do Tratamento Medicamentoso , Polimedicação , Asma/tratamento farmacológico , Criança , Serviços de Saúde da Criança/organização & administração , Prescrições de Medicamentos/normas , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Hipotireoidismo/tratamento farmacológico , Deficiências da Aprendizagem/genética , Masculino , Conduta do Tratamento Medicamentoso/normas , Hipotonia Muscular/genética , Otite/tratamento farmacológico , Reino Unido
13.
PLoS One ; 9(12): e113640, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25502572

RESUMO

BACKGROUND: Intra-lesional injections of corticosteroids, interferon, and chemotherapeutic drugs are currently the most popular treatments of hypertrophic scar formation. However, these drugs can only be used after HS is formed, and not during the inflammatory phase of wound healing, which regulates the HS forming process. OBJECTIVE: To investigate a new, effective, combining therapeutic and safe drug for early intervention and treatment for hypertrophic scars. METHODS: Cell viability assay and flow cytometric analysis were studied in vitro. Animal studies were done to investigate the combining therapeutic effects of 20(S)-ginsenoside Rg3 (Rg3) on the inflammatory phase of wound healing and HS formation. RESULTS: In vitro studies showed that Rg3 can inhibit HS fibroblasts proliferation and induce HSF apoptosis in a concentration-dependent manner. In vivo studies demonstrated that Rg3 can limit the exaggerated inflammation, and do not delay the wound healing process, which indicates that Rg3 could be used as an early intervention to reduce HS formation. Topical injection of 4 mg/mL Rg3 can reduce HS formation by 34%. Histological and molecular studies revealed that Rg3 injection inhibits fibroblasts proliferation thus reduced the accumulation of collagen fibers, and down-regulates VEGF expression in the HS tissue. CONCLUSION: Rg3 can be employed as an early intervention and a combining therapeutic drug to reduce inflammation and HS formation as well.


Assuntos
Cicatriz Hipertrófica/prevenção & controle , Fibroblastos/efeitos dos fármacos , Ginsenosídeos/administração & dosagem , Otite/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cicatriz Hipertrófica/genética , Cicatriz Hipertrófica/patologia , Modelos Animais de Doenças , Regulação para Baixo , Intervenção Médica Precoce/métodos , Feminino , Fibroblastos/citologia , Ginsenosídeos/farmacologia , Humanos , Técnicas In Vitro , Masculino , Coelhos , Fator A de Crescimento do Endotélio Vascular/genética
14.
Redox Biol ; 2: 580-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24688894

RESUMO

N(6)-isopentenyladenosine (i(6)A), a naturally occurring modified nucleoside, inhibits the proliferation of human tumor cell lines in vitro, but its mechanism of action remains unclear. Treatment of MCF7 human breast adenocarcinoma cells with i(6)A or with three synthetic analogs (allyl(6)A, benzyl(6)A, and butyl(6)A) inhibited growth and altered gene expression. About 60% of the genes that were differentially expressed in response to i(6)A treatment were also modulated by the analogs, and pathway enrichment analysis identified the NRF2-mediated oxidative stress response as being significantly modulated by all four compounds. Luciferase reporter gene assays in transfected MCF7 cells confirmed that i(6)A activates the transcription factor NRF2. Assays for cellular production of reactive oxygen species indicated that i(6)A and analogs had antioxidant effects, reducing basal levels and inhibiting the H2O2- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced production in MCF7 or dHL-60 (HL-60 cells induced to differentiate along the neutrophilic lineage) cell lines, respectively. In vivo, topical application of i(6)A or benzyl(6)A to mouse ears prior to TPA stimulation lessened the inflammatory response and significantly reduced the number of infiltrating neutrophils. These results suggest that i(6)A and analogs trigger a cellular response against oxidative stress and open the possibility of i(6)A and benzyl(6)A being used as topical anti-inflammatory drugs.


Assuntos
Antioxidantes/administração & dosagem , Isopenteniladenosina/análogos & derivados , Isopenteniladenosina/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Otite/tratamento farmacológico , Administração Tópica , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Peróxido de Hidrogênio/efeitos adversos , Isopenteniladenosina/farmacologia , Células MCF-7 , Camundongos , Otite/induzido quimicamente , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acetato de Tetradecanoilforbol/efeitos adversos
16.
Am J Otolaryngol ; 33(5): 619-22, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22361345

RESUMO

The temporal bone may be affected by a variety of systemic pathology because the disease nature, location, and extent determine the symptoms. Middle ear and mastoid infections may be the initial clinical manifestation of autoimmune and acquired immunodeficiency disorders. Rituximab, an anti-CD20 chimeric antibody, has become increasingly popular as a therapeutic agent for patients with a wide range of autoimmune disorders refractory to standard treatments. Normal levels of immunoglobulin levels are usually maintained during and after rituximab therapy, and clinical trials to date have shown no statistically significant increase of serious infections among patients with autoimmune diseases being treated with rituximab (Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al, for the REFLEX Trial Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at 24 weeks. Arthritis Rheum. 2006;54:2793-2806. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572-2581). However, there have been several reports of opportunistic infections associated with rituximab (Kelesidis T, Daikos G, et al. Does rituximab increase the incidence of infectious complications? A narrative review. Int J Infect Dis 2011;15:e2-e16. Teichmann LL, Woenckhaus M, Vogel C, et al. Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis. Rheumatology 2008;47:1256-1257), as well as cases of it accelerating the presentation of hypogammaglobulinemia (Diwakar L, Gorrie S, et al. Does rituximab aggravate pre-existing hypogammaglobulinaemia? J Clin Pathol 2010;63:275-277). Humoral immune defects can cause persistent acute and serous otitis media, with the development of chronic suppurative otitis media refractory to medical and surgical therapy (Sasaki CT, Askenase P, Dwyer J, et al. Chronic ear infection in the immunodeficient patient. Arch Otolaryngol 1981;107:82). Here, we describe the first presentation, diagnostic workup, and treatment with intravenous immunoglobulin of chronic bilateral otomastoiditis in the setting of rituximab-induced hypogammaglobulinemia.


Assuntos
Agamaglobulinemia/induzido quimicamente , Anticorpos Monoclonais Murinos/efeitos adversos , Imunoglobulinas Intravenosas/administração & dosagem , Mastoidite/tratamento farmacológico , Otite/tratamento farmacológico , Agamaglobulinemia/tratamento farmacológico , Anticorpos Monoclonais Murinos/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Doença Crônica , Feminino , Seguimentos , Humanos , Fatores Imunológicos/administração & dosagem , Mastoidite/etiologia , Otite/etiologia , Rituximab , Adulto Jovem
17.
Int J Biochem Cell Biol ; 44(3): 525-35, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22185821

RESUMO

Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts oxidative damage protection by selectively activating the transcription factor Nrf2 signalling pathway. Given the existence of a tight interplay of the Nrf2/NF-κB systems and that the pro-inflammatory response is governed by transcription factor NF-κB, here we sought to investigate whether and how cyclo(His-Pro) interferes with the cross-talk between the antioxidant Nrf2/heme oxygenase-1 and the pro-inflammatory NF-κB pathways. By knocking down the Nrf2 gene, we confirmed that cyclo(His-Pro) inhibits NF-κB nuclear accumulation induced by paraquat in rat pheochromocytoma PC12 cells via the Nrf2/heme oxygenase-1 pathway. The protection required functional heme oxygenase-1 activity, since zinc protoporphyrin IX, a heme oxygenase-1 inhibitor, prevented NF-κB inhibition, and the presence of exogenous carbon monoxide and bilirubin afforded cytoprotection against paraquat-induced toxicity by preventing NF-κB activation. Cyclooxygenase-2 and matrix metalloproteinase 3, two gene products governed by NF-κB, were down-regulated by cyclo(His-Pro) and up-regulated in heme oxygenase-1 knock-down cells. We validated the general mechanism underlying the anti-inflammatory effects by treating PC12 and murine microglial BV2 cells with different pro-inflammatory agents. Finally, cyclo(His-Pro) reduced 12-otetradecanoylphorbol-13-acetate-induced oedema in mouse ear inflammation model. Results, by showing that cyclo(His-pro) suppresses the pro-inflammatory NF-κB signalling via the Nrf2-mediated heme oxygenase-1 activation, contribute to the understanding of essential cellular pathways and allow the proposal of cyclo(His-Pro) as an in vivo anti-inflammatory compound.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/administração & dosagem , Edema/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Otite/tratamento farmacológico , Peptídeos Cíclicos/farmacologia , Piperazinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Antioxidantes/efeitos adversos , Monóxido de Carbono/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citoproteção , Edema/etiologia , Edema/fisiopatologia , Edema/prevenção & controle , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , Modelos Animais , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Otite/induzido quimicamente , Otite/complicações , Otite/fisiopatologia , Estresse Oxidativo , Células PC12 , Peptídeos Cíclicos/efeitos adversos , Piperazinas/efeitos adversos , RNA Interferente Pequeno/genética , Ratos , Receptor Cross-Talk/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
18.
Int J Mol Sci ; 12(2): 1115-32, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21541047

RESUMO

Previously, we reported that vitamin K(3) (VK(3)), but not VK(1) or VK(2) (=MK-4), inhibits the activity of human DNA polymerase γ (pol γ). In this study, we chemically synthesized three intermediate compounds between VK(2) and VK(3), namely MK-3, MK-2 and MK-1, and investigated the inhibitory effects of all five compounds on the activity of mammalian pols. Among these compounds, MK-2 was the strongest inhibitor of mammalian pols α, κ and λ, which belong to the B, Y and X families of pols, respectively; whereas VK(3) was the strongest inhibitor of human pol γ, an A-family pol. MK-2 potently inhibited the activity of all animal species of pol tested, and its inhibitory effect on pol λ activity was the strongest with an IC(50) value of 24.6 µM. However, MK-2 did not affect the activity of plant or prokaryotic pols, or that of other DNA metabolic enzymes such as primase of pol α, RNA polymerase, polynucleotide kinase or deoxyribonuclease I. Because we previously found a positive relationship between pol λ inhibition and anti-inflammatory action, we examined whether these compounds could inhibit inflammatory responses. Among the five compounds tested, MK-2 caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear. In addition, in a cell culture system using mouse macrophages, MK-2 displayed the strongest suppression of the production of tumor necrosis factor (TNF)-α induced by lipopolysaccharide (LPS). Moreover, MK-2 was found to inhibit the action of nuclear factor (NF)-κB. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of MK-2 in mice led to suppression of TNF-α production in serum. In conclusion, this study has identified VK(2) and VK(3) intermediates, such as MK-2, that are promising anti-inflammatory candidates.


Assuntos
Anti-Inflamatórios/farmacologia , DNA Polimerase Dirigida por DNA/metabolismo , Macrófagos/efeitos dos fármacos , Vitamina K 2/farmacologia , Vitamina K 3/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Bovinos , Linhagem Celular , DNA Polimerase gama , Humanos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Otite/tratamento farmacológico , Especificidade da Espécie , Fator de Necrose Tumoral alfa/metabolismo , Vitamina K 2/análogos & derivados , Vitamina K 2/uso terapêutico , Vitamina K 3/análogos & derivados , Vitamina K 3/uso terapêutico
20.
Chem Res Toxicol ; 23(5): 955-66, 2010 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-20423157

RESUMO

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, the role of the AHR in normal physiology is still an area of intense investigation. For example, this receptor plays an important role in certain immune responses. We have previously determined that the AHR can mediate repression of acute-phase genes in the liver. For this observation to be therapeutically useful, selective activation of the AHR would likely be necessary. Recently, the selective estrogen receptor ligand WAY-169916 has also been shown to be a selective AHR ligand. WAY-169916 can efficiently repress cytokine-mediated acute-phase gene expression (e.g., SAA1) yet fail to mediate a dioxin response element-driven increase in transcriptional activity. The goals of this study were to structurally modify WAY-169916 to block binding to the estrogen receptor and increase its affinity for the AHR. A number of WAY-169916 derivatives were synthesized and subjected to characterization as AHR ligands. The substitution of a key hydroxy group for a methoxy group ablates binding to the estrogen receptor and increases its affinity for the AHR. The compound 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA 360), in particular, exhibited essentially no AHR agonist activity yet was able to repress cytokine-mediated SAA1 gene expression in Huh7 cells. SGA 360 was tested in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated ear inflammatory edema model using C57BL6/J and Ahr(-/-) mice. Our findings indicate that SGA 360 significantly inhibits TPA-mediated ear swelling and induction of a number of inflammatory genes (e.g., Saa3, Cox2, and Il6) in C57BL6/J mice. In contrast, SGA 360 had no effect on TPA-mediated ear swelling or inflammatory gene expression in Ahr(-/-) mice. Collectively, these results indicate that SGA 360 is a selective Ah receptor modulator (SAhRM) that exhibits anti-inflammatory properties in vivo.


Assuntos
Compostos Alílicos/farmacologia , Anti-Inflamatórios/farmacologia , Indazóis/farmacologia , Pirazóis/química , Receptores de Hidrocarboneto Arílico/metabolismo , Compostos Alílicos/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/metabolismo , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Indazóis/química , Interleucina-6/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Otite/induzido quimicamente , Otite/tratamento farmacológico , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Proteína Amiloide A Sérica/metabolismo , Acetato de Tetradecanoilforbol/toxicidade
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